1. 作用机制与药理学特性对比
1.1 特立帕肽的作用机制
特立帕肽（Teriparatide）是一种重组人甲状旁腺激素（PTH）1-34片段，是目前唯一获批的骨形成促进剂，用于治疗骨质疏松症 12。其药理学特性主要体现在对骨代谢的双向调节作用上。
在分子层面，特立帕肽通过与成骨细胞表面的甲状旁腺激素1型受体（PTH1R）结合发挥作用 3。间歇性给予特立帕肽（每日皮下注射）能够模拟内源性PTH的脉冲式分泌，从而优先刺激成骨细胞的活性，促进骨形成 24。研究表明，特立帕肽能够增加成骨前体细胞的数量，并驱动其分化为成熟成骨细胞，同时抑制这些前体细胞向脂肪细胞分化 356。这种作用机制与传统抗骨吸收药物（如双膦酸盐和地诺单抗）有本质区别，后者主要通过抑制破骨细胞活性来减少骨量流失。
具体而言，特立帕肽能够促进骨小梁和皮质骨的骨形成，从而增加骨量和改善骨微结构。在体外研究中，特立帕肽被证明能通过激活cAMP/PKA/CREB信号通路，促进MC3T3-E1成骨细胞在高糖微环境下的分化 7。此外，有研究指出，特立帕肽还能诱导Gprc5a基因的表达，该基因编码一种孤儿G蛋白偶联受体，可能在PTH信号传导中发挥负向调节作用，但其在骨形成中的具体机制仍在探索中 4。
特立帕肽的药代动力学特征也对其作用机制至关重要。每日皮下注射后，特立帕肽被迅速吸收（约30分钟内达到峰值浓度），并迅速清除（半衰期约为1小时），导致肽段的暴露总持续时间约为4小时 28。这种短暂的、脉冲式的暴露是其促骨形成作用的关键。在一项针对绝经后骨质疏松女性的药代动力学研究中，特立帕肽可短暂升高血清钙水平（中位数增加0.4 mg/dl），并在约4.25小时后达到最大效应，随后血钙水平在16-24小时内恢复至给药前水平，未观察到持续性高钙血症 8。这种“短暂而脉冲”的给药模式避免了内源性PTH持续高水平所导致的骨吸收增加效应，从而实现了骨形成的净增加。目前，有研究正在探索基于脂质的温敏递送平台，以期实现特立帕肽的控释，提高患者依从性和临床疗效 9。
1.2 主要竞品的作用机制
与特立帕肽的促骨形成机制不同，市场上其他主要竞品通过不同的途径调控骨代谢，主要集中在抑制骨吸收或同时兼顾骨形成与骨吸收。
地诺单抗 (Denosumab) 是一种人源化单克隆抗体，靶向受体激活剂核因子-κB配体 (RANKL)。RANKL在破骨细胞的形成、功能和存活中起关键作用。地诺单抗通过与RANKL结合，阻止其与破骨细胞前体细胞和成熟破骨细胞表面的RANK受体结合，从而抑制破骨细胞的活性和数量，减少骨吸收10。这种作用机制使其成为一种强效的抗骨吸收药物，尤其适用于肾功能受损且不能使用双膦酸盐的患者。
罗莫佐单抗 (Romosozumab) 是一种新型的、具有双重作用机制的药物，它是一种靶向硬骨素（sclerostin）的人源化单克隆抗体1112。硬骨素主要由骨细胞产生，是Wnt信号通路的一种天然抑制剂，通过结合低密度脂蛋白受体相关蛋白5/6（LRP5/6）来抑制成骨细胞的分化和功能13。罗莫佐单抗通过抑制硬骨素，解除对Wnt信号通路的抑制，从而激活成骨细胞活性，促进骨形成1114。与此同时，罗莫佐单抗还通过其他机制（可能是间接作用）抑制骨吸收12。这种独特的双重作用使其能够在短期内显著增加骨密度并降低骨折风险14。
雷洛昔芬 (Raloxifene) 是一种选择性雌激素受体调节剂（SERM），在不同组织中表现出不同的雌激素样或抗雌激素样作用1516。在骨骼方面，雷洛昔芬表现出雌激素激动剂活性，能抑制骨吸收，减少骨质流失1517。它通过与骨细胞上的雌激素受体结合，调节骨代谢，降低绝经后女性的椎体骨折风险18。然而，雷洛昔芬对乳腺和子宫组织表现出抗雌激素活性，避免了传统雌激素替代疗法可能带来的乳腺癌和子宫内膜癌风险1719。
双膦酸盐类 (Bisphosphonates) 是目前最常用的抗骨质疏松药物。它们通过化学键与骨基质中的羟磷灰石晶体结合，并被活跃的破骨细胞吸收2021。双膦酸盐的作用机制取决于其化学结构。非含氮双膦酸盐（如氯膦酸盐）被代谢为细胞毒性ATP类似物，诱导破骨细胞凋亡2122。而更强效的含氮双膦酸盐（N-BP，如阿仑膦酸盐、利塞膦酸盐、唑来膦酸等）则通过抑制甲羟戊酸途径中的法尼基焦磷酸合酶（FPP合酶），阻止异戊二烯化脂质（如法尼基焦磷酸和香叶基香叶基焦磷酸）的生物合成2324。这些脂质对于小GTP酶信号蛋白的翻译后修饰至关重要，而这些小GTP酶在破骨细胞的正常功能和存活中发挥着关键作用。FPP合酶的抑制导致这些小GTP酶失活，从而抑制破骨细胞的骨吸收活性并诱导其凋亡2225。双膦酸盐主要通过抑制破骨细胞活性来减少骨吸收，达到增加骨密度的效果26。
下表总结了这些药物在作用机制和骨代谢调控上的主要差异：
| 药物类型 | 作用机制 | 主要靶点 | 骨代谢调控方式 |
|---|---|---|---|
| 特立帕肽 | 间歇性激活PTH1R，促进成骨细胞活性 | 成骨细胞PTH1R | 促进骨形成 |
| 地诺单抗 | 抑制RANKL与RANK结合，减少破骨细胞活性 | RANKL | 抑制骨吸收 |
| 罗莫佐单抗 | 抑制硬骨素，激活Wnt信号通路 | 硬骨素 | 促进骨形成与抑制骨吸收 |
| 雷洛昔芬 | 选择性雌激素受体调节剂 | 雌激素受体 | 抑制骨吸收 |
| 双膦酸盐类 | 抑制FPP合酶或其他酶，诱导破骨细胞凋亡 | 破骨细胞（FPP合酶） | 抑制骨吸收 |
2. 疗效对比：基于骨折风险与骨密度的临床研究证据
2.1 骨折风险降低效果
骨折风险的降低是评估骨质疏松治疗药物疗效的核心指标。特立帕肽及其竞品在不同骨折类型和不同患者群体中的表现存在差异。
椎体骨折：
特立帕肽在降低椎体骨折风险方面显示出显著优势。一项对绝经后骨质疏松女性进行的随机对照试验（FPT）随访研究显示，即使在停药18个月后，特立帕肽（20或40微克）仍能使椎体骨折风险分别降低41%（P=0.004）和45%（P=0.001），相对于安慰剂组 27。从FPT基线到18个月随访结束，两剂量的绝对风险降低均为13% 27。即使在随访期间有47%的女性使用了骨质疏松药物，且前安慰剂组使用率更高（P=0.04），特立帕肽的骨折保护作用依然持续存在 27。
网络Meta分析进一步证实，在预防椎体骨折方面，骨形成促进剂（包括特立帕肽）比双膦酸盐更有效 28。特别是对于糖皮质激素诱导的骨质疏松症（GIOP）患者，一项针对18种抗骨质疏松药物的系统评价和网络Meta分析（NMA）指出，特立帕肽在降低椎体骨折发生率方面表现最佳，其累积排序曲线下面积（SUCRA）评分为95.9% 29。这意味着特立帕肽在GIOP患者中预防椎体骨折的概率最高。
罗莫佐单抗也展现出优异的椎体骨折风险降低效果。在关键的III期临床试验（FRAME和ARCH）中，罗莫佐单抗治疗12个月后，与安慰剂或阿仑膦酸钠相比，椎体和临床骨折风险显著降低 30。
地诺单抗同样能显著降低椎体骨折风险。一项涵盖51项随机对照试验的NMA发现，地诺单抗在预防椎体骨折方面具有最高的SUCRA评分（0.806），提示其在这一指标上表现出最佳的疗效 31。另一项大型研究FREEDOM（Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months）显示，在患有骨质疏松症的绝经后女性中，地诺单抗显著降低了椎体骨折风险 3233。
非椎体与髋部骨折：
在非椎体骨折方面，特立帕肽同样表现出良好的保护作用。一项NMA结果表明，特立帕肽在预防非椎体骨折方面具有最高的SUCRA评分（0.927）31。这对于GIOP患者尤为重要，因为糖皮质激素会增加非椎体骨折的风险。
地诺单抗在降低髋部骨折风险方面的表现突出。在FREEDOM试验及其7年开放标签扩展研究中，地诺单抗显著降低了绝经后骨质疏松女性的椎体、非椎体和髋部骨折风险，且这些益处在长达10年的治疗中得以维持 34。对高风险患者的亚组分析显示，地诺单抗能显著降低75岁及以上患者（安慰剂组2.3% vs 地诺单抗组0.9%；P<0.01）或股骨颈骨密度T值≤-2.5的患者（安慰剂组2.8% vs 地诺单抗组1.4%；P=0.02）的髋部骨折风险，这表明其在髋部骨折高风险人群中具有一致的抗骨折效力 32。
罗莫佐单抗在12个月的治疗期内，显著降低了主要骨质疏松性骨折（major osteoporotic fractures）的风险（RR=0.37；95% CI 0.25-0.54），其中包括一部分非椎体骨折 35。
药物间比较：
一项针对绝经后女性骨质疏松症治疗药物的NMA指出，与甲状旁腺激素受体激动剂（如特立帕肽）相比，双膦酸盐在降低临床骨折方面效果较差（OR 1.49，95% CI 1.12至2.00）28。而与甲状旁腺激素受体激动剂和罗莫佐单抗相比，地诺单抗在降低临床骨折方面效果也较差（地诺单抗vs甲状旁腺激素受体激动剂：OR 1.85，1.18至2.92；地诺单抗vs罗莫佐单抗：OR 1.56，1.02至2.39）28。这提示骨形成促进剂在临床骨折的整体预防方面可能优于传统的抗骨吸收药物。
| 药物类型 | 椎体骨折风险降低 | 非椎体骨折风险降低 | 髋部骨折风险降低 | 备注 |
|---|---|---|---|---|
| 特立帕肽 | 显著降低（FPT随访18个月后仍有效，GIOP中SUCRA 95.9%）2729 | 显著降低（SUCRA 0.927）31 | 较少直接证据，但通常与非椎体骨折风险降低相关 | 骨形成促进剂，对GIOP椎体骨折优势明显 |
| 地诺单抗 | 显著降低（SUCRA 0.806）31 | 显著降低 34 | 显著降低（高风险人群中效果一致）3234 | 强效抗骨吸收，对髋部骨折保护作用突出 |
| 罗莫佐单抗 | 显著降低 30 | 显著降低主要骨质疏松性骨折风险（RR=0.37）35 | 显著降低主要骨质疏松性骨折风险 35 | 双重作用机制，短期内快速降低骨折风险 |
| 双膦酸盐 | 降低 28 | 降低 28 | 降低 28 | 传统抗骨吸收药物，整体效果不如骨形成促进剂 |
| 雷洛昔芬 | 降低（主要针对椎体骨折） | 证据较少 | 证据较少 | 主要针对椎体骨折，对非椎体/髋部骨折效果有限 |
2.2 骨密度提升效果
骨密度（BMD）的提升是评估骨质疏松治疗药物疗效的另一个重要指标，特别是腰椎、股骨颈和全髋部的BMD变化率。不同的药物在这些部位的BMD提升效果存在显著差异，并且可能受治疗周期及患者特定状况（如慢性肾脏病CKD阶段）的影响。
特立帕肽的BMD提升效果：
特立帕肽作为骨形成促进剂，在腰椎BMD提升方面表现尤为突出。在对绝经后骨质疏松女性进行的临床研究中，特立帕肽（每日20 µg）治疗1年可使腰椎BMD平均增加7.1%，股骨颈BMD增加2.6%，但对全髋BMD影响较小，甚至可能略微下降（-0.8%） 36。这可能与特立帕肽对皮质骨和松质骨的不同作用有关。另一项对比特立帕肽生物类似药（RGB-10）与原研特立帕肽的研究显示，两者在腰椎BMD、股骨颈BMD和全髋BMD的提升效果上无显著差异，均能显著改善绝经后高骨折风险女性的腰椎BMD和骨健康参数 37。对糖皮质激素诱导的骨质疏松症（GIOP）患者，特立帕肽在不同基线糖皮质激素剂量下均能显著提升腰椎BMD，且在低剂量糖皮质激素组中，腰椎BMD增幅更大（8.1% vs 4.6%），均显著优于阿仑膦酸钠 38。
罗莫佐单抗的BMD提升效果：
罗莫佐单抗以其独特的双重作用机制（促进骨形成和抑制骨吸收），在短期内实现显著的BMD提升。在FRAME研究中，罗莫佐单抗治疗12个月后，可使腰椎BMD提升13%，全髋BMD提升7% 39。一项针对绝经后骨质疏松女性的研究对比了罗莫佐单抗与地诺单抗，结果显示罗莫佐单抗在12个月时腰椎BMD平均增加12.5%，显著高于地诺单抗组的7.2% 40。在全髋和股骨颈BMD的百分比变化方面，罗莫佐单抗组同样显著高于地诺单抗组 40。在日本绝经后女性的亚组分析中，罗莫佐单抗治疗12个月后，腰椎BMD可增加12.7%，全髋BMD增加4.2%，股骨颈BMD增加4.1% 41。
值得注意的是，既往抗骨吸收治疗史可能会影响罗莫佐单抗的BMD提升效果。一项前瞻性多中心队列研究发现，既往接受过抗骨吸收治疗的患者，罗莫佐单抗对BMD的应答会减弱，且既往治疗持续时间与腰椎和全髋BMD变化呈负相关 42。这提示对于初治患者，罗莫佐单抗可能表现出更强的BMD提升潜力。
地诺单抗的BMD提升效果：
地诺单抗作为强效抗骨吸收药物，在BMD提升方面也表现良好。在针对绝经后骨质疏松女性的FREEDOM研究中，地诺单抗可显著增加腰椎、全髋和股骨颈的BMD 43。在与罗莫佐单抗的比较中，地诺单抗在12个月时腰椎BMD提升7.2% 40。对于从阿仑膦酸钠转换为地诺单抗的患者，地诺单抗在12个月时使全髋BMD增加了1.90%，腰椎、股骨颈和1/3桡骨的BMD也有显著增加 43。
双膦酸盐的BMD提升效果：
双膦酸盐作为抑制骨吸收的药物，同样能够有效增加BMD。Meta分析显示，对于接受雄激素剥夺治疗的男性，双膦酸盐可显著提高腰椎、全髋和股骨颈的BMD百分比变化 44。具体而言，唑来膦酸和阿仑膦酸钠均能显著改善BMD 44。
特殊人群（慢性肾脏病患者）的BMD提升：
骨质疏松与慢性肾脏病（CKD）并存的患者面临更高的骨折风险。对于CKD患者，抗骨质疏松药物的疗效和安全性需特别关注。
- 罗莫佐单抗： 对两项III期临床试验（FRAME和ARCH）的亚组分析发现，罗莫佐单抗在伴有轻中度CKD（eGFR 30-89 mL/min）的绝经后骨质疏松女性中，腰椎、全髋和股骨颈的BMD增幅显著优于对照组（安慰剂或阿仑膦酸钠），且在不同肾功能类别中的安全性相似 45。一项Meta分析也指出，罗莫佐单抗在所有肾功能类别中均表现出显著更大的BMD变化 46。
- 特立帕肽和地诺单抗： 一项Meta分析表明，抗骨质疏松药物（包括特立帕肽、地诺单抗、罗莫佐单抗和雷洛昔芬）可显著降低CKD 1-3期患者的椎体骨折风险，但在CKD 4-5期患者中未观察到显著降低 46。这可能提示在重度CKD患者中，这些药物的BMD提升效果及骨折预防作用可能受限，需要更谨慎的评估。然而，在CKD 1-3期患者中，特立帕肽和地诺单抗对BMD的提升效果与普通人群相似 47。对于CKD 5期血液透析患者，骨活检引导下的特立帕肽治疗显示出骨代谢的改善和BMD的增加 48。
BMD增幅的临床意义：
BMD的增加通常与骨折风险的降低相关联。快速且大幅度的BMD提升，尤其是在高危骨折部位（如腰椎和髋部），对临床决策具有重要指导意义。例如，罗莫佐单抗在12个月内腰椎BMD增幅达到12.5-13%，远高于地诺单抗的7.2%，表明其在短期内具有更强的骨骼重建能力 3940。这种快速的BMD改善，特别是早期骨形成指标（如PINP）较高的患者，可能预示着更好的髋部BMD应答，进一步强化了罗莫佐单抗在需要快速骨骼重建患者中的应用价值 49。
表1：主要药物在不同部位BMD的平均提升效果（12-24个月）
| 药物类型 | 腰椎BMD提升 (%) | 全髋BMD提升 (%) | 股骨颈BMD提升 (%) | 备注 |
|---|---|---|---|---|
| 特立帕肽 | 7.1-8.4 3650 | -0.8-1.8 3650 | 2.6-2.8 36 | 对腰椎BMD提升显著，对全髋影响较小。 |
| 地诺单抗 | 7.2-7.9 4043 | 1.9-3.2 4043 | 2.0-2.2 4043 | 对各部位BMD均有良好提升，且长期效果稳定。 |
| 罗莫佐单抗 | 12.5-17.5 394049 | 4.9-7.0 394049 | 4.1-4.3 4041 | 短期内BMD提升最显著，尤其是腰椎。 |
| 双膦酸盐 | 3.6-6.3 44 | 2.2-4.8 44 | 1.9-3.6 44 | 稳定提升BMD，但通常低于骨形成促进剂。 |
| 雷洛昔芬 | 约2.5-3.5 | 约1-1.5 | 约1-1.5 | BMD提升幅度相对较小。 |
注：表格数据为约数，具体数值可能因研究设计、人群特征和测量方法而异。
3. 安全性评价：不良反应与特殊人群适用性
3.1 常见与严重不良反应
骨质疏松症治疗药物在有效降低骨折风险和提升骨密度的同时，也伴随着不同程度的不良反应。全面评估这些不良反应，特别是严重不良事件（SAE），对于临床选择具有重要意义。
特立帕肽（Teriparatide）：
特立帕肽的常见不良反应通常为轻中度，包括恶心、头痛、眩晕和肢体疼痛等 515253。在药物警戒研究中，与特立帕肽相关的最常见不良事件涉及肌肉骨骼、结缔组织和给药部位疾病，如关节痛、肢体疼痛、背痛、肌肉痉挛、骨痛和肌肉无力等 54。在心血管事件方面，一项国际药物警戒研究发现，特立帕肽的使用与心房颤动、心律失常和心绞痛相关，并且与阿仑膦酸钠或唑来膦酸相比，特立帕肽与动脉粥样硬化冠状动脉（ACA）和冠状动脉疾病（CAD）事件的关联较低 55。
颌骨坏死（Medication-Related Osteonecrosis of the Jaw, MRONJ）是多种骨质疏松药物的罕见但严重不良事件。对于特立帕肽，由于其促骨形成的作用机制，一些病例报告指出特立帕肽可能有助于MRONJ的愈合 565758。然而，这并非意味着特立帕肽完全没有MRONJ风险，目前关于特立帕肽自身引发MRONJ的证据较少，更多是将其应用于MRONJ的治疗。
竞品不良反应：
地诺单抗（Denosumab）：
地诺单抗的主要不良反应包括低钙血症，尤其是在肾功能受损的患者中。一项针对接受透析的65岁及以上女性患者的研究发现，地诺单抗与口服双膦酸盐相比，严重低钙血症（血清白蛋白校正钙<7.5 mg/dL）的发生率显著升高，12周累积发生率地诺单抗组为41.1%，而口服双膦酸盐组为2.0%（风险比为20.7） 59。极重度低钙血症（血钙<6.5 mg/dL）的发生率地诺单抗组也高达10.9% 59。此外，地诺单抗还可能引起皮肤反应和MRONJ，尽管在骨质疏松患者中MRONJ的发生率很低（0.001%至0.01%），但在肿瘤患者中由于剂量较高，发生率可达1%至15% 5660。罗莫佐单抗（Romosozumab）：
罗莫佐单抗的安全性问题主要集中在心血管事件。尽管在与安慰剂比较的研究中，心血管事件的发生率相似，但在与阿仑膦酸钠比较的FRAME和ARCH临床试验中，罗莫佐单抗组报告的严重心血管事件（如心肌梗死、中风和心血管死亡）发生率较高 6162。因此，对有心血管疾病史或高风险的患者，罗莫佐单抗的使用需谨慎。硬骨素在血管平滑肌细胞中表达，但这与心血管风险增加的机制尚不明确，临床前和遗传学研究未显示硬骨素抑制剂会增加心血管风险 616263。双膦酸盐类（Bisphosphonates）：
口服双膦酸盐的常见不良反应是上消化道症状，如食管炎、胃刺激和反流，这与药物的给药方式和患者依从性密切相关 516465。静脉注射双膦酸盐（如唑来膦酸）可能引起急性期反应，表现为流感样症状，通常在首次给药后发生 53。肾毒性是静脉注射双膦酸盐的另一个关注点 64。MRONJ是双膦酸盐的罕见并发症，尤其是在接受高剂量静脉双膦酸盐治疗的肿瘤患者中，其发生率高于口服双膦酸盐治疗的骨质疏松患者 56646667。此外，双膦酸盐还与非典型股骨骨折的风险增加相关，尽管这种风险非常罕见 526668。
严重不良事件（SAE）发生率对比：
一项网络Meta分析对绝经后骨质疏松女性患者的药物安全进行了比较。结果显示，特立帕肽在预防不良事件（SUCRA=0.908）和严重不良事件（SUCRA=0.813）方面具有最大的优势，提示其整体安全性可能优于其他药物。具体而言，特立帕肽在不良事件风险方面优于唑来膦酸（RR = 0.958；95% CI (0.919, 0.988)） 31。这表明在整体的安全性评估中，特立帕肽可能是一个相对更安全的治疗选择。
| 药物类型 | 常见不良反应 | 严重不良事件 | MRONJ风险 | 心血管事件风险 | 低钙血症风险 | 肾毒性风险 |
|---|---|---|---|---|---|---|
| 特立帕肽 | 恶心、头痛、眩晕、肢体痛 515354 | 整体SAE发生率较低（SUCRA 0.813） 31 | 低，有病例报告指出有助于MRONJ愈合 565758 | 关联较低（ACA、CAD） 55 | 低 | 低 |
| 地诺单抗 | 皮肤反应、感染 60 | 低钙血症、MRONJ | 骨质疏松患者中低（0.001%-0.01%），肿瘤患者中高（1%-15%） 56 | 心血管安全性数据仍需更多研究 60 | 高（尤其CKD患者） 59 | 低 |
| 罗莫佐单抗 | 关节痛、肌肉骨骼疼痛 | 心肌梗死、中风、心血管死亡（与阿仑膦酸钠比较） 61 | 低 61 | 较高（有黑框警告） 6162 | 低 | 低 |
| 双膦酸盐类 | 上消化道症状（口服）、流感样症状（静脉） 51536465 | MRONJ、非典型股骨骨折、肾毒性（静脉） 52646668 | 骨质疏松患者中低，肿瘤患者中高 5667 | 部分研究提示与心房颤动有关，但证据不一 5568 | 低 | 静脉注射双膦酸盐较高 64 |
| 雷洛昔芬 | 潮热、腿部痉挛 5152 | 静脉血栓栓塞、中风 5152 | 低 | 增加静脉血栓栓塞和中风风险 5152 | 低 | 低 |
需要强调的是，药物不良反应的发生率往往与患者的个体特征、基础疾病、用药剂量、用药时长以及是否联合其他药物等多种因素相关。因此，在临床实践中，应根据患者的具体情况权衡利弊，选择最合适的治疗方案，并密切监测可能出现的不良反应。
3.2 特殊人群的安全性考量
在特定人群中评估骨质疏松治疗药物的安全性至关重要，这些人群可能对药物的代谢、排泄或不良反应表现出不同的敏感性。主要特殊人群包括慢性肾脏病（CKD）患者、有心血管疾病史的患者和老年人。
慢性肾脏病（CKD）患者：
CKD患者由于骨代谢异常和药物清除途径受损，其骨质疏松的治疗选择受到限制。
特立帕肽： 特立帕肽在CKD患者中的应用具有一定优势。一项对日本CKD 4-5期患者（包括30名4期和3名5期患者）进行的上市后观察性研究（事后分析）显示，每日20 µg皮下注射特立帕肽治疗长达24个月，未观察到新的安全问题，且多数患者的骨形成指标（P1NP）和骨密度（BMD）有所增加 69。在该研究中，仅有1例CKD 5期患者出现新发骨折，CKD 4期患者均未发生骨折 69。这提示特立帕肽在严重CKD患者中可能仍具有一定的应用潜力，尤其是在缺乏其他有效选择的情况下。然而，目前大型RCTs关于特立帕肽在CKD 4-5期患者中的疗效和安全性数据仍然有限，需要进一步的大规模研究来证实其长期效益和风险 70。由于特立帕肽经肾脏代谢，对于严重肾功能不全的患者，其清除可能减慢，潜在蓄积风险需要关注。
地诺单抗： 地诺单抗主要通过肾脏清除，但其本身不直接对肾脏造成损害 71。在CKD患者中，地诺单抗的使用需要特别警惕低钙血症的风险，尤其是在CKD 4-5期和透析患者中，低钙血症的发生率显著升高 72。一项对接受透析的患者进行的观察性研究显示，与口服双膦酸盐相比，地诺单抗可使主要不良心血管事件（MACE）的风险增加36%，但同时骨折风险降低45% 72。这提示在地诺单抗用于透析患者时，需权衡心血管风险与骨折预防的效益。
罗莫佐单抗： 罗莫佐单抗在不同肾功能类别的绝经后骨质疏松女性中，其安全性相似 73。然而，对于CKD 4-5期患者，罗莫佐单抗的安全性数据相对较少。
双膦酸盐类： 双膦酸盐主要通过肾脏排泄，因此在CKD患者中应用受到严格限制。大多数双膦酸盐在eGFR低于30或35 mL/min时被禁用或需谨慎使用，因为存在药物蓄积和肾毒性的风险 7475。一项对CKD 3b-5期患者的回顾性队列研究发现，使用口服双膦酸盐与CKD进展风险适度增加（约15%）相关，但未发现急性肾损伤、胃肠道出血/溃疡或严重低钙血症的风险增加 76。虽然某些双膦酸盐（如伊班膦酸盐）在肾功能受损患者中表现出较好的肾脏安全性 77，但总体而言，双膦酸盐在重度CKD患者中的应用需极为谨慎。
心血管疾病史患者：
骨质疏松和心血管疾病常并存，因此评估药物对心血管系统的影响至关重要。
罗莫佐单抗： 罗莫佐单抗是心血管安全性方面争议较多的药物。尽管一些研究表明罗莫佐单抗与安慰剂或某些对照药物相比，其心血管事件风险无显著差异 7879，但在ARCH研究中，罗莫佐单抗组报告了更高的严重心血管事件（如心肌梗死、中风和心血管死亡）发生率 7380。基于此，罗莫佐单抗带有黑框警告，不建议在过去一年内发生过心肌梗死或中风的患者中使用 73。对于有心血管高风险的患者，应权衡罗莫佐单抗带来的骨折预防益处与潜在的心血管风险。
特立帕肽： 如前所述，特立帕肽与动脉粥样硬化冠状动脉疾病（ACA）和冠状动脉疾病（CAD）事件的关联较低，表明其对心血管系统的安全性可能相对较好。
地诺单抗： 多项研究和Meta分析表明，地诺单抗与心血管事件风险的增加无显著关联，但需注意其可能导致的低钙血症，这本身可能间接影响心血管健康 79。
雷洛昔芬： 雷洛昔芬作为选择性雌激素受体调节剂，虽然能降低骨折风险，但会增加静脉血栓栓塞和中风的风险 81。因此，对于有血栓栓塞史或高风险的患者应避免使用。
老年人群：
老年患者通常存在多重共病、多重用药，且药物代谢清除能力下降，对药物不良反应更敏感。
特立帕肽： 特立帕肽在老年患者中的安全性与年轻患者相似，常见不良反应多为轻中度。其每日皮下注射的给药方式对视力或手部灵活性受损的老年患者可能构成挑战，但可通过家庭成员协助或预填充注射笔来解决。
地诺单抗： 地诺单抗在老年患者中通常耐受良好，且在75岁及以上患者中显示出显著的髋部骨折风险降低作用 82。然而，仍需关注低钙血症的风险，尤其是在营养不良或维生素D缺乏的老年患者中。
罗莫佐单抗： 在老年患者中，罗莫佐单抗的骨密度提升效果显著，但心血管风险的顾虑在老年患者中可能更为突出，需要更严格的心血管风险评估。
双膦酸盐类： 口服双膦酸盐在上消化道不良反应方面，老年患者的依从性问题可能更为突出。静脉注射双膦酸盐则需警惕肾功能不全的风险。
总而言之，特殊人群的骨质疏松治疗需要个体化决策。对于CKD患者，特立帕肽在4-5期CKD中的初步研究显示出潜力，但需更多数据。地诺单抗在CKD患者中需严密监测低钙血症。双膦酸盐在重度CKD患者中应避免使用。对于心血管高风险患者，罗莫佐单抗应慎用，而特立帕肽可能是一个相对更安全的选项。老年患者在选择药物时，应综合考虑共病、用药情况、依从性以及潜在的不良反应风险。
4.1 高骨折风险患者的优选方案
针对高骨折风险患者，尤其是在绝经后骨质疏松症中，选择合适的治疗方案至关重要。临床决策往往需要综合考虑患者的骨折风险水平、骨密度（BMD）、既往骨折史、合并症以及药物的疗效与安全性特征。在此背景下，骨折风险评估工具如FRAX（Fracture Risk Assessment Tool）扮演着关键角色，能够帮助医生识别高危患者，从而指导个体化治疗 83。
特立帕肽（Teriparatide）：
特立帕肽作为唯一的促骨形成药物，在极高骨折风险患者中具有独特的临床定位。对于那些既往有严重骨质疏松性骨折史（尤其是椎体骨折）、骨密度极低（T值≤-3.0）、或对传统抗骨吸收药物治疗失败的患者，特立帕肽是优先推荐的治疗选择 8485。其促骨形成的作用机制能够快速增加骨量，改善骨微结构，从而在短期内显著降低骨折风险 8687。
- 适用场景：
地诺单抗（Denosumab）：
地诺单抗作为一种强效的抗骨吸收药物，适用于需要长期抗骨吸收治疗且骨折风险较高的患者。其给药途径（每六个月一次皮下注射）方便了患者依从性。
- 适用场景：
罗莫佐单抗（Romosozumab）：
罗莫佐单抗是一种具有促骨形成和抑制骨吸收双重作用机制的新型药物，能够在短期内显著提升骨密度和降低骨折风险，尤其适用于极高骨折风险的患者。
- 适用场景：
- 极高骨折风险患者： 例如近期发生骨折（特别是椎体骨折）的绝经后女性，骨密度T值≤-2.5，或有多种骨折高风险因素的患者 889293。罗莫佐单抗在12个月内显著降低了新发椎体骨折（降低73%）和临床骨折（降低36%）的风险 92。
- 需要快速实现骨骼重建的患者： 罗莫佐单抗在治疗早期显示出强大的促骨形成作用，骨密度提升幅度显著，对于需要迅速改善骨骼状况以减少骨折风险的患者非常有利。
- 双膦酸盐治疗失败或不耐受的患者： 对于无法从双膦酸盐治疗中获得足够益处，或无法耐受其副作用的患者，罗莫佐单抗提供了一个强效的替代方案。
- 不适合使用特立帕肽的患者： 如果特立帕肽存在禁忌症或不适用，罗莫佐单抗可作为促骨形成的替代选择。
总结与权衡：
对于高骨折风险患者，特别是近期发生过骨折或骨密度极低的患者，骨形成促进剂（如特立帕肽和罗莫佐单抗）通常作为起始治疗，以快速重建骨骼并降低骨折风险 88。特立帕肽在GIOP患者和椎体骨折风险方面表现突出；罗莫佐单抗则以其独特的双重作用机制，在短期内提供更强的BMD提升和骨折风险降低效果。地诺单抗则适合需要长期稳定抗骨吸收治疗的患者，尤其是在肾功能不全或髋部骨折高风险人群中具有优势。
在选择药物时，医生需要结合FRAX或其他风险评估工具的结果，全面评估患者的骨折风险。对于极高危患者，例如在过去12个月内发生过髋部或椎体骨折、多发性骨折、或接受治疗期间再次骨折的患者，起始使用骨形成促进剂（特立帕肽或罗莫佐单抗）是更优的选择，随后通常需要序贯抗骨吸收药物以维持疗效。
| 药物类型 | 临床定位 | 适用人群特征 | 优势 | 考虑因素 |
|---|---|---|---|---|
| 特立帕肽 | 骨形成促进剂，适用于极高危患者起始治疗 | 严重骨质疏松、既往椎体骨折、GIOP、对传统药物失败或不耐受 | 快速促进骨形成，改善骨微结构，显著降低椎体骨折和非椎体骨折风险（尤其GIOP） | 每日注射，价格较高，治疗周期有限（24个月） |
| 地诺单抗 | 强效抗骨吸收，适用于需长期治疗或肾功能不全患者 | 长期抗骨吸收需求、肾功能受损、髋部骨折高风险、无法口服双膦酸盐 | 显著降低椎体、非椎体、髋部骨折风险，依从性好（6月1次），肾功能不全患者可用 | 停药后骨吸收反弹风险高，需序贯治疗，有低钙血症风险 |
| 罗莫佐单抗 | 双重作用机制，适用于极高危患者起始治疗 | 近期骨折（特别是椎体）、极低BMD、需快速重建骨骼 | 短期内BMD提升最显著，强效降低椎体和临床骨折风险 | 心血管事件风险（有黑框警告），治疗周期有限（12个月），价格高 |
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参考文献
1An overview of the management of osteoporosis in the aging female population.PubMed
Usman Amin, Aoife McPartland, Miriam O'Sullivan, et al.
Womens Health (Lond). 2023 Jan-Dec;19:17455057231176655. doi: 10.1177/17455057231176655.
Osteoporosis is a systemic skeletal disease that is a cause of morbidity and mortality. It can affect all ages but most frequently postmenopausal women. It is a silent condition, however, osteoporotic fractures can lead to significant pain and disability. In this review article, we aim to review the clinical approach to the management of postmenopausal osteoporosis. We include risk assessment, investigations, and the various pharmacological and non-pharmacological options used in the treatment of osteoporosis. We have discussed the pharmacological options individually including their mechanism of action, safety profile, effects on bone mineral density and fracture risks, and duration of use. Potential new treatments are also discussed. The importance of sequence in the use of osteoporotic medicine is also highlighted in the article. An understanding of the different treatment options will hopefully help in the management of this very common and debilitating condition.
2Teriparatide for severe osteoporosis.PubMed
Kimberly A Cappuzzo, Jeffrey C Delafuente
Ann Pharmacother. 2004 Feb;38(2):294-302. doi: 10.1345/aph.1D353. Epub 2003 Dec 30.
OBJECTIVE: To review the pharmacology, toxicology, pharmacokinetics, pharmacodynamics, efficacy, safety, therapeutic controversies, administration, patient counseling, and formulary recommendations for teriparatide (rDNA origin). DATA SOURCES: A MEDLINE search (1966-May 2003) of articles using the key words parathyroid hormone and osteoporosis, parathyroid hormone and fracture, and teriparatide was conducted to identify relevant literature in the English language. Additional references were obtained from bibliographies of those articles. Some clinical trial data not yet published were obtained from the manufacturer. STUDY SELECTION AND DATA EXTRACTION: All articles obtained from the data sources were reviewed; all data deemed relevant were included. DATA SYNTHESIS: Teriparatide, recombinant human parathyroid hormone (1-34) [rhPTH (1-34)], is the first anabolic agent to treat postmenopausal women with osteoporosis and men with idiopathic or hypogonadal osteoporosis who are at high risk for osteoporotic fracture. Daily subcutaneous injections of teriparatide significantly increase both spine and hip bone-mineral density (BMD) while decreasing the incidence of fractures in both women and men. Common adverse effects noted with teriparatide use were nausea, headache, dizziness, and arthralgias. An increased incidence of osteosarcoma in rats during preclinical trials with teriparatide led to a black box warning for the drug. CONCLUSIONS: Teriparatide substantially increases spine and hip BMD and may offer additional benefits to patients with severe osteoporosis. Clinical trials comparing teriparatide with other available agents to treat osteoporosis are needed to more clearly define its place in therapy. Long-term safety and efficacy are not known.
3Gli1 progenitors mediate bone anabolic function of teriparatide via Hh and Igf signaling.PubMed
Yu Shi, Xueyang Liao, James Y Long, et al.
Cell Rep. 2021 Aug 17;36(7):109542. doi: 10.1016/j.celrep.2021.109542.
Teriparatide is the most widely prescribed bone anabolic drug in the world, but its cellular targets remain incompletely defined. The Gli1 metaphyseal mesenchymal progenitors (MMPs) are a main source for osteoblasts in postnatal growing mice, but their potential response to teriparatide is unknown. Here, by lineage tracing, we show that teriparatide stimulates both proliferation and osteoblast differentiation of MMPs. Single-cell RNA sequencing reveals heterogeneity among MMPs, including an unexpected chondrocyte-like osteoprogenitor (COP). COP expresses the highest level of Hedgehog (Hh) target genes and the insulin-like growth factor 1 receptor (Igf1r) among all cell clusters. COP also expresses Pth1r and further upregulates Igf1r upon teriparatide treatment. Inhibition of Hh signaling or deletion of Igf1r from MMPs diminishes the proliferative and osteogenic effects of teriparatide. The study therefore identifies COP as a teriparatide target wherein Hh and insulin-like growth factor (Igf) signaling are critical for the osteoanabolic response in growing mice.
4Gprc5a is a novel parathyroid hormone-inducible gene and negatively regulates osteoblast proliferation and differentiation.PubMed
Chisato Sampei, Kosuke Kato, Yasuhiro Arasaki, et al.
J Cell Physiol. 2024 Aug;239(8):e31297. doi: 10.1002/jcp.31297. Epub 2024 May 20.
Teriparatide is a peptide derived from a parathyroid hormone (PTH) and an osteoporosis therapeutic drug with potent bone formation-promoting activity. To identify novel druggable genes that act downstream of PTH signaling and are potentially involved in bone formation, we screened PTH target genes in mouse osteoblast-like MC3T3-E1 cells. Here we show that Gprc5a, encoding an orphan G protein-coupled receptor, is a novel PTH-inducible gene and negatively regulates osteoblast proliferation and differentiation. PTH treatment induced Gprc5a expression in MC3T3-E1 cells, rat osteosarcoma ROS17/2.8 cells, and mouse femurs. Induction of Gprc5a expression by PTH occurred in the absence of protein synthesis and was mediated primarily via the cAMP pathway, suggesting that Gprc5a is a direct target of PTH signaling. Interestingly, Gprc5a expression was induced additively by co-treatment with PTH and 1α, 25-dihydroxyvitamin D3 (calcitriol), or retinoic acid in MC3T3-E1 cells. Reporter analysis of a 1 kb fragment of human GPRC5A promoter revealed that the promoter fragment showed responsiveness to PTH via the cAMP response element, suggesting that GPRC5A is also a PTH-inducible gene in humans. Gprc5a knockdown promoted cell viability and proliferation, as demonstrated by MTT and BrdU assays. Gprc5a knockdown also promoted osteoblast differentiation, as indicated by gene expression analysis and mineralization assay. Mechanistic studies showed that Gprc5a interacted with BMPR1A and suppressed BMP signaling induced by BMP-2 and constitutively active BMP receptors, ALK2 (ACVR1) Q207D and ALK3 (BMPR1A) Q233D. Thus, our results suggest that Gprc5a is a novel gene induced by PTH that acts in an inhibitory manner on both cell proliferation and osteoblast differentiation and is a candidate for drug targets for osteoporosis.
5Gli1 Progenitors Mediate Glucocorticoid-Induced Osteoporosis In Vivo.PubMed
Puying Yang, Fangyuan Shen, Chengjia You, et al.
Int J Mol Sci. 2024 Apr 16;25(8):4371. doi: 10.3390/ijms25084371.
For a wide range of chronic autoimmune and inflammatory diseases in both adults and children, synthetic glucocorticoids (GCs) are one of the most effective treatments. However, besides other adverse effects, GCs inhibit bone mass at multiple levels, and at different ages, especially in puberty. Although extensive studies have investigated the mechanism of GC-induced osteoporosis, their target cell populations still be obscure. Here, our data show that the osteoblast subpopulation among Gli1 metaphyseal mesenchymal progenitors (MMPs) is responsive to GCs as indicated by lineage tracing and single-cell RNA sequencing experiments. Furthermore, the proliferation and differentiation of Gli1 MMPs are both decreased, which may be because GCs impair the oxidative phosphorylation(OXPHOS) and aerobic glycolysis of Gli1 MMPs. Teriparatide, as one of the potential treatments for GCs in bone mass, is sought to increase bone volume by increasing the proliferation and differentiation of Gli1 MMPs in vivo. Notably, our data demonstrate teriparatide ameliorates GC-caused bone defects by targeting Gli1 MMPs. Thus, Gli1 MMPs will be the potential mesenchymal progenitors in response to diverse pharmaceutical administrations in regulating bone formation.
6Parathyroid hormone regulates fates of murine osteoblast precursors in vivo.PubMed
Deepak H Balani, Noriaki Ono, Henry M Kronenberg
J Clin Invest. 2017 Sep 1;127(9):3327-3338. doi: 10.1172/JCI91699. Epub 2017 Jul 31.
Teriparatide, a recombinant form of parathyroid hormone (PTH), is the only approved treatment for osteoporosis that increases the rate of bone formation. Teriparatide increases osteoblast numbers by suppressing osteoblast apoptosis and activating bone-lining cells. No direct evidence for teriparatide's actions on early cells of the osteoblast lineage has been demonstrated. Here, we have employed a lineage-tracing strategy that uses a tamoxifen-dependent, promoter-driven cre to mark early cells of the osteoblast lineage in adult mice. We show that teriparatide increases the numbers of osteoblast precursors and drives their differentiation into mature osteoblasts. Unexpectedly, following withdrawal of teriparatide therapy, bone marrow adipocytes increased dramatically in number. Some of these adipocytes derived from cells marked by Sox9-cre expression weeks earlier. Continued therapy with teriparatide prevented the appearance of adipocytes. Selective, inducible deletion of the PTH receptor in Sox9-cre cells demonstrated that PTH receptor expression is required for teriparatide-mediated increases in early osteoblast precursors. The increase in early precursors after teriparatide administration was associated with robust suppression of precursor apoptosis without affecting their rate of proliferation. Thus, teriparatide increases the numbers of early cells of the osteoblast lineage, hastens their differentiation into osteoblasts, and suppresses their differentiation into adipocytes in vivo.
7[Teriparatide regulates osteoblast differentiation in high-glucose microenvironment through the cAMP/PKA/CREB signaling pathway].PubMed
T Hou, Y Qin, Y Zhang, et al.
Nan Fang Yi Ke Da Xue Xue Bao. 2023 Jan 20;43(1):39-45. doi: 10.12122/j.issn.1673-4254.2023.01.05.
OBJECTIVE: To investigate the effect of teriparatide on the differentiation of MC3T3-E1 cells in high-glucose microenvironment and explore the possible mechanism. METHODS: MC3T3-E1 cells cultured in normal glucose or high-glucose (25 mmol/L) medium were treated with 10 nmol/L teriparatide with or without co-treatment with H-89 (a PKA inhibitor). CCK-8 assay was used to detect the changes in cell proliferation, and cAMP content in the cells was determined with ELISA. Alkaline phosphatase (ALP) activity and mineralized nodules in the cells were detected using ALP kit and Alizarin red staining, respectively. The changes in cell morphology were detected by cytoskeleton staining. Real-time PCR was used to detect the mRNA expressions of PKA, CREB, RUNX2 and Osx in the treated cells. RESULTS: The treatments did not result in significant changes in proliferation of MC3T3-E1 cells ( > 0.05). Compared with the cells in routine culture, the cells treated with teriparatide showed significantly increased cAMP levels ( < 0.05) with enhanced ALP activity and increased area of mineralized nodules ( < 0.05). Teriparatide treatment also resulted in more distinct visualization of the cytoskeleton in the cells and obviously up-regulated the mRNA expressions of PKA, CREB, RUNX2 and Osx ( < 0.05). The opposite changes were observed in cells cultured in high glucose. In cells exposed to high glucose, treatment with teriparatide significantly increased cAMP levels ( < 0.05), ALP activity and the area of mineralized nodules ( < 0.05) and enhanced the clarity of the cytoskeleton and mRNA expressions of PKA, CREB, RUNX2 and Osx; the effects of teriparatide was strongly antagonized by co-treatment with H-89 ( < 0.05). CONCLUSION: Teriparatide can promote osteoblast differentiation of MC3T3-E1 cells in high-glucose microenvironment possibly by activating the cAMP/PKA/CREB signaling pathway.
8Pharmacokinetics of teriparatide (rhPTH[1-34]) and calcium pharmacodynamics in postmenopausal women with osteoporosis.PubMed
Julie Satterwhite, Michael Heathman, Paul D Miller, et al.
Calcif Tissue Int. 2010 Dec;87(6):485-92. doi: 10.1007/s00223-010-9424-6. Epub 2010 Oct 16.
Teriparatide (rhPTH[1-34]) affects calcium metabolism in a pattern consistent with the known actions of endogenous parathyroid hormone (PTH). This report describes the pharmacokinetics and resulting serum calcium response to teriparatide in postmenopausal women with osteoporosis. Pharmacokinetic samples for this analysis were obtained from 360 women who participated in the Fracture Prevention Trial. Postmenopausal women with osteoporosis received daily subcutaneous injections of either teriparatide 20 μg (4.86 μmol) or placebo, median 21 months' treatment. Serum teriparatide and calcium concentrations were measured throughout the study. An indirect-response model was developed to describe the pharmacokinetic-pharmacodynamic relationship between teriparatide concentrations and serum calcium response. The pharmacokinetics of teriparatide were characterized by rapid absorption (maximum concentration achieved within 30 min) and rapid elimination (half-life of 1 h), resulting in a total duration of exposure to the peptide of approximately 4 h. Teriparatide transiently increased serum calcium, with the maximum effect observed at approximately 4.25 h (median increase 0.4 mg/dl [0.1 mmol/l]). Calcium concentrations returned to predose levels by 16-24 h after each dose. Persistent hypercalcemia was not observed; one teriparatide 20 μg-treated patient had a predose serum calcium value above the normal range but <11.0 mg/dl (2.75 mmol/l). Following once-daily subcutaneous administration, teriparatide produces a modest but transient increase in serum calcium, consistent with the known effects of endogenous PTH on mineral metabolism. The excursion in serum calcium is brief, due to the short length of time that teriparatide concentrations are elevated.
9A lipid-based delivery platform for thermo-responsive delivery of teriparatide.PubMed
Corinna S Schlosser, Wojciech Rozek, Ryan D Mellor, et al.
Int J Pharm. 2024 Dec 25;667(Pt A):124853. doi: 10.1016/j.ijpharm.2024.124853. Epub 2024 Oct 20.
Teriparatide (and analogue peptides) are the only FDA approved anabolic treatments for osteoporosis. Current therapies are administered as a daily subcutaneous injection, which limits patient adherence and clinical efficacy. To achieve the desired anabolic effect, a controlled delivery system must ensure a pulsatile release profile over a prolonged period. Thermo-responsive formulations (e.g. liposomes) can undergo a temperature-related phase-transition which can allow active control of drug release. Herein, thermo-responsive liposomes were developed to permit control over teriparatide release rate through modulation of temperature. Entrapment of hydrophilic molecules, including peptides, within liposomes remains challenging due to the large volume of hydration. In this work, hydrophobic ion pairing was employed for the first time to enhance peptide entrapment within liposomes. The method resulted in a hydrophobic complex that achieved high teriparatide entrapment (>75 %) in sub-200 nm monodispersed liposomes. Hydrophobic ion pairing outperformed other entrapment approaches. Several liposomal formulations with transition temperatures between 38 and 50 °C were obtained by modulation of the phospholipid composition. In vitro assays demonstrated temperature-dependent release kinetics with faster rates of release observed at/above the transition temperature. The maintenance of biological activity of released teriparatide was demonstrated in a cell-based assay utilising the PTH1 receptor. Overall, this provides the first proof-of-concept of the suitability of thermo-responsive systems for pulsatile delivery of teriparatide and similar peptides.
10Bone-Targeted Therapies in Cancer-Induced Bone Disease.PubMed
Sofia Sousa, Philippe Clézardin
Calcif Tissue Int. 2018 Feb;102(2):227-250. doi: 10.1007/s00223-017-0353-5. Epub 2017 Oct 27.
Cancer-induced bone disease is a major source of morbidity and mortality in cancer patients. Thus, effective bone-targeted therapies are essential to improve disease-free, overall survival and quality of life of cancer patients with bone metastases. Depending of the cancer-type, bone metastases mainly involve the modulation of osteoclast and/or osteoblast activity by tumour cells. To inhibit metastatic bone disease effectively, it is imperative to understand its underlying mechanisms and identify the target cells for therapy. If the aim is to prevent bone metastasis, it is essential to target not only bone metastatic features in the tumour cells, but also tumour-nurturing bone microenvironment properties. The currently available bone-targeted agents mainly affect osteoclasts, inhibiting bone resorption (e.g. bisphosphonates, denosumab). Some agents targeting osteoblasts begin to emerge which target osteoblasts (e.g. romosozumab), activating bone formation. Moreover, certain drugs initially thought to target only osteoclasts are now known to have a dual action (activating osteoblasts and inhibiting osteoclasts, e.g. proteasome inhibitors). This review will focus on the evolution of bone-targeted therapies for the treatment of cancer-induced bone disease, summarizing preclinical and clinical findings obtained with anti-resorptive and bone anabolic therapies.
11Romosozumab for the treatment of osteoporosis.PubMed
Leonardo Bandeira, E Michael Lewiecki, John P Bilezikian
Expert Opin Biol Ther. 2017 Feb;17(2):255-263. doi: 10.1080/14712598.2017.1280455.
Sclerostin, a glycoprotein produced primarily by osteocytes, blocks the canonical Wnt signaling bone formation pathway. Romosozumab is a humanized monoclonal antibody to sclerostin that binds to sclerostin, permitting the engagement of Wnt ligands with their co-receptors, resulting in an increase in bone formation and bone mineral density (BMD). Clinical studies with romosozumab have shown dramatic improvements in BMD at the spine and hip. Romosozumab is associated with improvement in bone strength through mechanisms that include increases in bone formation and, different from classical osteoanabolic agents, suppression of bone resorption. Areas covered: Herein, the authors highlight the available data on romosozumab for the treatment of osteoporosis. This includes the latest data on the efficacy, pharmacokinetics and pharmacodynamics as well as safety and tolerability data. Expert opinion: Monthly subcutaneous dosing of romosozumab reduces the risk of vertebral and clinical fractures in women with postmenopausal osteoporosis, with a favorable balance of benefits and risks. Romosozumab is a promising emerging anabolic agent with a novel mechanism of action that may expand the options for treating osteoporotic patients at high risk of fracture.
12Profile of romosozumab and its potential in the management of osteoporosis.PubMed
Sian Yik Lim, Marcy B Bolster
Drug Des Devel Ther. 2017 Apr 13;11:1221-1231. doi: 10.2147/DDDT.S127568. eCollection 2017.
Increased understanding of bone biology has led to the discovery of several unique signaling pathways that regulate bone formation and resorption. The Wnt signaling pathway plays a significant role in skeletal development, adult skeletal homeostasis, and bone remodeling. Sclerostin is an inhibitor of the Wnt signaling pathway. Romosozumab, a humanized monoclonal antibody that binds to sclerostin, prevents sclerostin from exerting this inhibitory effect. Therefore, in the presence of romosozumab, the Wnt signaling pathway is activated leading to bone formation and bone mineral density gain. Clinical studies of romosozumab have shown that this agent is one of the most potent bone anabolic agents in development to date. Romosozumab does not act solely as an anabolic agent, but rather, it has effects on increasing bone formation as well as reducing bone resorption. In the clinical studies, patients tolerated romosozumab well with no major safety signals reported. In a Phase III study, romosozumab as compared to placebo has been shown to reduce vertebral fractures by 73% after 1 year of treatment. Sequential therapy with romosozumab for 1 year followed by denosumab in the second year reduced vertebral fractures by 75% as compared to the group that received placebo for 1 year and denosumab in the second year. Romosozumab holds significant potential, by a novel mechanism of action, to expand our ability to treat osteoporosis. More studies are needed to determine the ideal setting in which romosozumab may be used to optimize osteoporosis treatment.
13Sclerostin: from bench to bedside.PubMed
Sakae Tanaka, Toshio Matsumoto
J Bone Miner Metab. 2021 May;39(3):332-340. doi: 10.1007/s00774-020-01176-0. Epub 2020 Nov 18.
Skeletal integrity is maintained by a meticulous balance between bone resorption and bone formation, and recent studies have revealed the essential role of canonical Wnt signaling pathways in maintaining skeletal homeostasis. The SOST gene, which encodes sclerostin, a member of Dan family glycoproteins, was originally identified as the gene responsible for two sclerosing bone dysplasias, sclerosteosis and van Buchem disease. Sclerostin is highly expressed by osteocytes, negatively regulates canonical Wnt signaling pathways by binding to low-density lipoprotein receptor-related protein (LRP) 5/6, and suppresses osteoblast differentiation and/or function. Romosozumab, a specific anti-sclerostin antibody, inhibits sclerostin-LRP5/6 interactions and indirectly activates canonical Wnt signaling pathways and bone formation. This review focuses on the mechanism of action of sclerostin and summarizes clinical studies that demonstrated the efficacy of romosozumab to increase bone mineral density and reduce osteoporotic fractures, as well as its cardiovascular safety.
14Clinical Utility of Romosozumab in the Management of Osteoporosis: Focus on Patient Selection and Perspectives.PubMed
Sian Yik Lim, Marcy B Bolster
Int J Womens Health. 2022 Dec 15;14:1733-1747. doi: 10.2147/IJWH.S315184. eCollection 2022.
As one of the most potent osteoanabolic agents with a unique mechanism of action, romosozumab has high efficacy for osteoporosis treatment. It is a monoclonal antibody against sclerostin, a natural inhibitor of the Wnt signaling pathway, and by inhibiting sclerostin, activation of Wnt signaling occurs with a cascade of changes ultimately leading to bone mineral density (BMD) gains. Romosozumab stimulates bone modeling and has a dual effect of activating bone formation while inhibiting bone resorption. With this unique mechanism of action, treatment with romosozumab leads to a rapid and significant gain in BMD; these gains are higher than seen with bisphosphonates, denosumab, or parathyroid hormone (PTH) analogs. The FRAME and ARCH studies represent two pivotal trials demonstrating the efficacy of romosozumab in treating osteoporosis. Treatment with romosozumab should be followed by an antiresorptive agent, as this approach has demonstrated maintenance of or greater increases in BMD and reduced fracture risk even after finishing romosozumab treatment. As an osteoanabolic agent, romosozumab has shown superiority to alendronate in reducing fracture risk, increasing bone density, and potentially more rapid fracture risk reduction. Recent data have suggested that romosozumab prior to antiresorptive therapy may be the ideal treatment sequence, especially in high-risk patients and patients at imminent risk of fracture. Carrying a black box warning, romosozumab should be avoided in patients who have had myocardial infarction or stroke in the past year. Further studies are needed to clarify the increased cardiovascular risk attributed to this drug. Romosozumab has expanded our osteoporosis armamentarium and has enabled novel approaches, including "treat to target." Future studies are needed to evaluate the optimal use sequence and to assess its safety, especially in patients with cardiovascular risk factors.
15Raloxifene hydrochloride.PubMed
K R Snyder, N Sparano, J M Malinowski
Am J Health Syst Pharm. 2000 Sep 15;57(18):1669-75; quiz 1676-8.
The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and therapeutic role of raloxifene hydrochloride are reviewed. Raloxifene is a selective estrogen-receptor modulator (SERM) that has been approved for use in the prevention and treatment of osteoporosis in postmenopausal women. A SERM interacts with estrogen receptors, functioning as an agonist in some tissues and an antagonist in other tissues. Because of their unique pharmacologic properties, these agents can achieve the desired effects of estrogen without the possible stimulatory effects on the breasts or uterus. Raloxifene is rapidly absorbed from the gastrointestinal tract and undergoes extensive first-pass glucuronidation. Approximately 60% of a dose is absorbed; however, absolute bioavailability is only 2%. The volume of distribution is 2348 L/kg for a single oral dose of 30-150 mg, and the elimination half-life averages 32.5 hours. In clinical trials in postmenopausal women, raloxifene had an estrogen-like effect on bone turnover and increased bone mineral density. It reduced the risk of fractures in women with osteoporosis. Raloxifene also seemed to reduce the risk of breast cancer and positively influenced blood lipid markers of cardiovascular disease. Raloxifene is generally well tolerated; the most common adverse effects are hot flashes and leg cramps. A serious adverse effect is venous thromboembolism. The recommended dosage is 60 mg/day orally without regard to meals. Ultimately, it will be information on cardiovascular or breast cancer benefits that will determine the future role of raloxifene. Raloxifene is an alternative to traditional hormone replacement therapy for the prevention and treatment of osteoporosis in selected postmenopausal women. More study is needed to verify possible benefits related to heart disease and breast cancer.
16Selective estrogen receptor modulators and bone health.PubMed
S R Goldstein
Climacteric. 2022 Feb;25(1):56-59. doi: 10.1080/13697137.2021.1936485. Epub 2021 Jun 25.
Selective estrogen receptor modulators (SERMs) are synthetic molecules that bind to the estrogen receptor and can have agonistic activity in some tissues while being estrogen antagonistic in others. While not all SERMs are clinically available in all parts of the world, this article will review preclinical and clinical effects of various SERMs on bone. These include tamoxifen, used as adjuvant therapy in breast cancer patients as well as for breast cancer prevention; raloxifene, approved for osteoporosis prevention and treatment as well as breast cancer prevention; bazedoxifene, approved for prevention of osteoporosis and also in combination with conjugated equine estrogen for treatment of vasomotor symptoms and prevention of bone loss in postmenopausal patients; and ospemifene, approved for treatment of dyspareunia due to vulvovaginal atrophy/genitourinary syndrome of menopause. Thus, these SERMs are a diverse group of estrogen agonist/antagonists that seem to have class effects in the bone and breast, although the amount of clinical trial data is quite variable. However, there does not seem to be the same unidirectional class activity in tissues like the uterus or vagina. Health-care providers should be cognizant of all available information in helping patients make the best possible shared decision-making choices.
17Selective estrogen receptor modulators.PubMed
Sally G Haskell
South Med J. 2003 May;96(5):469-76. doi: 10.1097/01.SMJ.0000051146.93190.4A.
Because of recent concerns about the long-term risks of estrogen replacement therapy in postmenopausal women, there is growing interest in a group of compounds known as selective estrogen receptor modulators (SERMs). The SERMs bind to estrogen receptors and have tissue-specific effects that allow them to function as estrogen agonists in some tissues and estrogen antagonists in other tissues. There are four SERMs currently marketed in the United States. These include the triphenylethylenes--clomiphene citrate (Clomid), tamoxifen, and toremifene--and the benzothiophene, raloxifene. Clomid is used primarily in the treatment of infertility. Tamoxifen is indicated for the treatment and prevention of breast cancer. It has an estrogen antagonist effect on breast tissue, but an estrogen-like effect on lipids, bone, and the endometrium. Toremifene has an antagonist/agonist profile similar to that of tamoxifen. Raloxifene is approved for the prevention of osteoporosis in postmenopausal women. It is thought to be an estrogen antagonist on the uterus and breast tissues and an estrogen agonist with respect to bone and serum lipids.
18Raloxifene.PubMed
E Seeman
J Bone Miner Metab. 2001;19(2):65-75. doi: 10.1007/s007740170043.
Raloxifene is a selective estrogen receptor modulator, a compound that has estrogen agonist activity at some sites and antagonist activity at others. In investigations in animals and in rigorously conducted trials in humans, raloxifene treatment is associated with a 30%-40% reduction in risk of one or more spine fractures using the 60 mg dose. This reduction in risk is found in women with or without baseline fractures, in women with bone mineral density (BMD) in the lower, middle, or upper third of the low range (all had BMD reduced by more than 2.5 SD) and in women aged less than 65 years, between 65-70 years, and greater than 70 years. A reduction in ankle fractures, but not hip or wrist fractures, was found. Raloxifene treatment also is associated with a 60%-70% reduction in risk for breast cancer and is associated with reduced total and LDL cholesterol, lower fibrinogen, and no rise in triglyceride. Reduced aortic wall cholesterol content is reported in animal studies. These are surrogate endpoints of cardioprotection. There is no evidence that raloxifene reduces the incidence of myocardial or cerebrovascular events. Raloxifene does not induce breast tenderness, endometrial hyperplasia, menstrual bleeding, or endometrial cancer, but may be associated with an increased risk of thromboembolic disease (1/1000 cases per year), leg cramps in 2%-4% of cases and hot flushes in 4%-6% of cases, usually in first 6 months.
19Raloxifene.PubMed
J A Kellen
Curr Drug Targets. 2001 Dec;2(4):423-5. doi: 10.2174/1389450013348263.
Efforts to interfere with the initiation and promotion of breast and other cancers by endocrine manipulation are not new. It is of obvious benefit to cancer patients to administer substances that combine minimal general toxicity with maximal oestrogen inhibition. Raloxifene is a relatively recent addition to a group of compounds loosely designated as antioestrogens, which implies their ability to antagonize oestrogen effects via competitive binding to the various receptors. This is a reductionist simplification, since their effect varies and ranges from interaction with lipid transduction cascades, covalent binding to proteins and DNA, regulation of growth factors, erbB2, mdr1 and probably p53 expression, complexing with E-cadherin/catenin to active induction of apoptosis and many other effects on the genome. Also, the action of most antioestrogens is not solely antagonistic and different compounds do exert some agonistic effects in various tissues. Apart from some "pure" antioestrogens, the benzothiophene derivative Raloxifene has been found to combine a high degree of selective oestrogen suppression with several other desirable characteristics, such as reduction of bone demineralisation and antiatherogenic effects without endometrial stimulation. It is well tolerated, has been successfully tested as a chemopreventive agent for breast cancer in certain groups of the population and does not prevent ovulation in women with normal menstrual cycles. Certainly, Raloxifene is only another forerunner of upcoming "designer" oestrogen modulators, but it represents a welcome addition to the therapeutic choices available for the control of some menopausal problems as well as for the prevention and treatment of breast cancer, as outlined in the following brief review.
20Bisphosphonates and cancer.PubMed
Rowan J Milner, James Farese, Carolyn J Henry, et al.
J Vet Intern Med. 2004 Sep-Oct;18(5):597-604. doi: 10.1892/0891-6640(2004)18<597:bac>2.0.co;2.
Bisphosphonates form a family of drugs characterized pharmacologically by their ability to inhibit bone resorption and pharmacokinetically by similar intestinal absorption, skeletal distribution, and renal elimination. Two groups of bisphosphonates exist chemically, non-amino-bisphosphates and amino-bisphosphonates. The amino-bisphosphonates have greater antiresorptive capabilities and represent a newer generation of bisphosphonates. The primary mechanism of action of bisphosphonates is inhibition of osteoclastic activity. Non-amino-bisphosphonates are incorporated into the energy pathways of the osteoclast, resulting in disrupted cellular energy metabolism leading to apoptosis. Amino-bisphosphonates exert their effect on osteoclasts via their inhibition of the mevalonate pathways, resulting in disruption of intracellular signaling and induction of apoptosis. Bisphosphonates also inhibit cancer cell proliferation, induce apoptosis in in vitro cultures, inhibit angiogenesis, inhibit matrix metalloproteinase, have effects on cytokine and growth factors, and are immunomodulatory. Clinical applications in oncology could include therapy for hypercalcemia of malignancy, inhibition of bone metastasis, and therapy for bone pain. Although bisphosphonates are regarded as metabolically inert in the body, adverse effects do occur and include esophagitis, gastritis, suppression of bone repair, and allergic reactions. Little is published on the effects of bisphosphonates in dogs with cancer. Further research into the role of bisphosphonates in veterinary oncology is needed to identify clinical efficacy and safety of these potentially beneficial drugs.
21New insights into the molecular mechanisms of action of bisphosphonates.PubMed
Michael J Rogers
Curr Pharm Des. 2003;9(32):2643-58. doi: 10.2174/1381612033453640.
Bisphosphonates are currently the most important and effective class of anti-resorptive drugs available, but the exact molecular mechanisms by which they inhibit osteoclast-mediated bone resorption have only recently been identified. Due to the targeting of bisphosphonates to bone mineral and the ability of osteoclasts to release bone-bound bisphosphonate, a direct effect on mature osteoclasts appears to be the most important route of action. As a result of recent discoveries concerning their molecular mechanism of action, bisphosphonates can be grouped into two classes. The simple bisphosphonates that closely resemble PPi (such as clodronate, etidronate and tiludronate) can be metabolically incorporated into non-hydrolysable analogues of ATP that accumulate intracellularly in osteoclasts, resulting in induction of osteoclast apoptosis. By contrast, the more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. Loss of bone-resorptive activity and osteoclast apoptosis is due primarily to loss of geranylgeranylated small GTPases. Identification of FPP synthase as the target of nitrogen-containing bisphosphonates has also helped explain the molecular basis for the adverse effects of these agents in the GI tract and on the immune system.
22Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages.PubMed
A J Roelofs, K Thompson, F H Ebetino, et al.
Curr Pharm Des. 2010;16(27):2950-60. doi: 10.2174/138161210793563635.
Bisphosphonates are widely used in the treatment of diseases involving excessive bone resorption, such as osteoporosis, cancer-associated bone disease, and Paget's disease of bone. They target to the skeleton due to their calcium-chelating properties, where they primarily act by inhibiting osteoclast-mediated bone resorption. The simple bisphosphonates, clodronate, etidronate and tiludronate, are intracellularly metabolised to cytotoxic ATP analogues, while the more potent, nitrogen-containing bisphosphonates act by inhibiting the enzyme FPP synthase, thereby preventing the prenylation of small GTPases that are necessary for the normal function and survival of osteoclasts. In recent years, these concepts have been refined, with an increased understanding of the exact mode of inhibition of FPP synthase and the consequences of inhibiting this enzyme. Recent studies further suggest that the R2 side chain, as well as determining the potency for inhibiting the target enzyme FPP synthase, also influences bone mineral binding, which may influence distribution within bone and duration of action. While bisphosphonates primarily affect the function of resorbing osteoclasts, it is becoming increasingly clear that bisphosphonates may also target the osteocyte network and prevent osteocyte apoptosis, which could contribute to their anti-fracture effects. Furthermore, increasing evidence implicates monocytes and macrophages as direct targets of bisphosphonate action, which may explain the acute phase response and the anti-tumour activity in certain animal models. Bone mineral affinity is likely to influence the extent of any such effects of these agents on non-osteoclast cells. While alternative anti-resorptive therapeutics are becoming available for clinical use, bisphosphonates currently remain the principle drugs used to treat excessive bone resorption.
23Nitrogen-containing bisphosphonate mechanism of action.PubMed
Alfred A Reszka, Gideon A Rodan
Mini Rev Med Chem. 2004 Sep;4(7):711-9.
The current paradigm for drug discovery requires the identification of a target involved in the disease process (e.g. enzyme or receptor) and the development of an appropriate ligand (activator, inhibitor or selective modulator). Selection of ligands for clinical development is based on the therapeutic window between efficacy vs. safety and ADME (absorption, distribution, metabolism and elimination) considerations. For bisphosphonates (BPs) the process has not followed that paradigm. BPs have very low absorption and are retained in bone, their target tissue. A few have been used on a limited basis for over 20 years in diseases of rapid bone destruction (e.g. post-menopausal osteoporosis, Paget's disease, bone metastases, etc.), without understanding their molecular mechanism of action. The nitrogen-containing BPs (N-BPs) are the latest and most potent addition to this family of compounds and have the widest use. They have high potency, are specifically targeted to the osteoclast on bone and are used at very low doses (5-10 mg clinically). Over the last four years, there was significant progress in elucidating the mechanism of action of BPs, both lacking and containing nitrogen. This review will focus on the mechanism of action of the N-BPs, specifically alendronate (ALN) and risedronate (RIS), the two agents most widely used. For these and all other N-BPs, the molecular target is the isoprenoid biosynthetic enzyme, farnesyl diphosphate synthase, in the cholesterol biosynthesis pathway. Although inhibition of this enzyme by N-BPs results in the suppression of sterol biosynthesis, it is actually disruption of a branch pathway, isoprenylation, that is responsible for N-BP pharmacological activity. Isoprenylation involves covalent linkage of the 15 or 20 carbon isoprene moiety farnesyl diphosphate or geranylgeranyl diphosphate, respectively, to the carboxy-terminus of regulatory proteins, including the small GTPases Ras, Rac, Rho and Cdc42. The latter three, as well as numerous others, are geranylgeranylated and play a rate-limiting role in the activity of the bone-resorbing osteoclast. This targeted osteoclast inhibition accounts for the potency of the N-BPs and for their ability to elicit the desired therapeutic response of suppressing bone turnover. The occasional gastrointestinal irritation caused by N-BPs appears to be mechanism-based and is also briefly reviewed.
24Antitumor effects of bisphosphonates.PubMed
Jonathan R Green
Cancer. 2003 Feb 1;97(3 Suppl):840-7. doi: 10.1002/cncr.11128.
BACKGROUND: Bisphosphonates are widely used to treat skeletal complications of malignancy. These drugs accumulate in bone where they inhibit osteoclastic bone resorption and reduce the local release of factors that stimulate tumor growth. The mechanism of action of bisphosphonates is dependent on chemical structure: Nonnitrogen-containing compounds (e.g., etidronate, clodronate) are metabolized into cytotoxic analogues of ATP, whereas the more potent nitrogen-containing compounds (N-BPs; e.g., pamidronate, ibandronate, zoledronic acid) inhibit protein prenylation, thus affecting cell function and survival. Because protein prenylation is required by all cells, not just osteoclasts, the possibility arises that N-BPs could also affect the viability of tumor cells. METHODS: Several groups have investigated the in vitro effects of bisphosphonates, either alone or in combination with other antineoplastic agents, on the viability and metastatic properties of many tumor cell types. Similarly, the effect of bisphosphonate treatment on osteolysis and tumor burden has been studied in a variety of animal tumor models. RESULTS: In vitro, submicromolar concentrations of N-BPs inhibited tumor cell adhesion and reduced invasion through extracellular matrix. At higher concentrations, antiproliferative and proapoptotic effects have been reported. In animal models of bone metastases, bisphosphonate treatment markedly reduced osteolytic lesions. There is also evidence of a reduction in tumor burden in bone and occasionally in other organs. Survival may be prolonged, but bisphosphonates do not appear to inhibit the growth of primary soft tissue tumors or orthotopic xenografts. CONCLUSIONS: The cell culture data clearly demonstrated that N-BPs exert antitumor properties and interact synergistically with other antineoplastic agents. As bisphosphonates accumulate in bone, they can also exert cytostatic effects on tumor cells in bone metastases, either directly or indirectly via osteoclast inhibition and alterations in the bone microenvironment. Further in vivo research is now required to optimize the dosing regimen of N-BPs to exploit fully their antitumor potential.
25Bisphosphonate mechanism of action.PubMed
Alfred A Reszka, Gideon A Rodan
Curr Rheumatol Rep. 2003 Feb;5(1):65-74. doi: 10.1007/s11926-003-0085-6.
The nitrogen-containing bisphosphonates (N-BPs), alendronate and risedronate, are the only pharmacologic agents shown to prevent spine and nonvertebral fractures associated with postmenopausal and glucocorticoid-induced osteoporosis. At the tissue level, this is achieved through osteoclast inhibition, which leads to reduced bone turnover, increased bone mass, and improved mineralization. The molecular targets of bisphosphonates (BPs) have recently been identified. This review will discuss the mechanism of action of BPs, focusing on alendronate and risedronate, which are the two agents most widely studied. They act on the cholesterol biosynthesis pathway enzyme, farnesyl diphosphate synthase. By inhibiting this enzyme in the osteoclast, they interfere with geranylgeranylation (attachment of the lipid to regulatory proteins), which causes osteoclast inactivation. This mechanism is responsible for N-BP suppression of osteoclastic bone resorption and reduction of bone turnover, which leads to fracture prevention.
26Pharmacological management of osteoporosis in postmenopausal women: The current state of the art.PubMed
Davide Gatti, Angelo Fassio
J Popul Ther Clin Pharmacol. 2019 Nov 20;26(4):e1-e17. doi: 10.15586/jptcp.v26.i4.646.
Osteoporosis is a common disease that increases fracture risk. Fragility fractures bring heavy consequences in terms of mortality and disability, with burdensome health and social costs. In subjects with clinical bone fragility, the first goal is to identify the secondary forms of osteoporosis, especially in young subjects, in males and in patients who recently experienced a fragility fracture. In addition, before considering any sort of treatment, it is fundamental to check for adequate calcium and vitamin D intake, since their deficiency is the most common reason for drug failure.In the last decade of the 20th century, several molecules have been developed and proved to be effective in achieving the true goal of any antiosteoporotic drug: fracture prevention.In this article, we considered the most commonly prescribed antiresorptive drugs (hormonal therapy, bisphosphonates, and denosumab), the anabolic agents (teriparatide), the dual-action drugs (romosozumab), and the drugs characterized by an unclear mechanism of action (strontium ranelate) to provide physicians with useful insights for their clinical practice. We discussed the main criteria for the appropriate choice selection and management of each treatment. Finally, we addressed the current controversies related to treatment discontinuation, sequential, and combination therapy.
27Sustained vertebral fracture risk reduction after withdrawal of teriparatide in postmenopausal women with osteoporosis.PubMed
Robert Lindsay, Wim H Scheele, Robert Neer, et al.
Arch Intern Med. 2004 Oct 11;164(18):2024-30. doi: 10.1001/archinte.164.18.2024.
BACKGROUND: Teriparatide (recombinant human parathyroid hormone [1-34]) reduces fracture risk in postmenopausal women with osteoporosis. We assessed the safety and incidence of new vertebral fractures after withdrawal of teriparatide. METHODS: This study is a follow-up to the Fracture Prevention Trial (FPT), a randomized, placebo-controlled study of postmenopausal women with osteoporosis treated with teriparatide (20 or 40 microg) once daily for a mean of 18 months. More than 90% of the women remaining at the end of the FPT continued into the follow-up study (n = 1262). Patients and investigators were unblinded to original treatment group assignment. Women were treated according to standard clinical practice, including elective use of osteoporosis drugs. New vertebral fractures were determined by semiquantitative scoring of lateral thoracic lumbar spine radiographs 18 months after the end of the FPT. RESULTS: During the follow-up study, the reduction in fracture risk associated with previous treatment with teriparatide, 20 and 40 microg, was 41% (P = .004) and 45% (P = .001), respectively, vs placebo. The absolute reduction from the FPT baseline to the 18-month follow-up visit was 13% for both doses. Osteoporosis drugs were used by 47% of women during follow-up, with greater use in the former placebo group (P = .04); nevertheless, persistent fracture protection of previous teriparatide therapy was evident. Post hoc analysis also suggests that teriparatide treatment substantially reduced the increased risk of subsequent fracture in women who sustained a fracture during the FPT (P = .05). CONCLUSION: Vertebral fracture risk reduction by teriparatide administration persists for at least 18 months after discontinuation of therapy.
28Fracture risk reduction and safety by osteoporosis treatment compared with placebo or active comparator in postmenopausal women: systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials.PubMed
Mina Nicole Händel, Isabel Cardoso, Cecilie von Bülow, et al.
BMJ. 2023 May 2;381:e068033. doi: 10.1136/bmj-2021-068033.
OBJECTIVE: To review the comparative effectiveness of osteoporosis treatments, including the bone anabolic agents, abaloparatide and romosozumab, on reducing the risk of fractures in postmenopausal women, and to characterise the effect of antiosteoporosis drug treatments on the risk of fractures according to baseline risk factors. DESIGN: Systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials. DATA SOURCES: Medline, Embase, and Cochrane Library to identify randomised controlled trials published between 1 January 1996 and 24 November 2021 that examined the effect of bisphosphonates, denosumab, selective oestrogen receptor modulators, parathyroid hormone receptor agonists, and romosozumab compared with placebo or active comparator. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials that included non-Asian postmenopausal women with no restriction on age, when interventions looked at bone quality in a broad perspective. The primary outcome was clinical fractures. Secondary outcomes were vertebral, non-vertebral, hip, and major osteoporotic fractures, all cause mortality, adverse events, and serious cardiovascular adverse events. RESULTS: The results were based on 69 trials (>80 000 patients). For clinical fractures, synthesis of the results showed a protective effect of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab compared with placebo. Compared with parathyroid hormone receptor agonists, bisphosphonates were less effective in reducing clinical fractures (odds ratio 1.49, 95% confidence interval 1.12 to 2.00). Compared with parathyroid hormone receptor agonists and romosozumab, denosumab was less effective in reducing clinical fractures (odds ratio 1.85, 1.18 to 2.92 for denosumab parathyroid hormone receptor agonists and 1.56, 1.02 to 2.39 for denosumab romosozumab). An effect of all treatments on vertebral fractures compared with placebo was found. In the active treatment comparisons, denosumab, parathyroid hormone receptor agonists, and romosozumab were more effective than oral bisphosphonates in preventing vertebral fractures. The effect of all treatments was unaffected by baseline risk indicators, except for antiresorptive treatments that showed a greater reduction of clinical fractures compared with placebo with increasing mean age (number of studies=17; β=0.98, 95% confidence interval 0.96 to 0.99). No harm outcomes were seen. The certainty in the effect estimates was moderate to low for all individual outcomes, mainly because of limitations in reporting, nominally indicating a serious risk of bias and imprecision. CONCLUSIONS: The evidence indicated a benefit of a range of treatments for osteoporosis in postmenopausal women for clinical and vertebral fractures. Bone anabolic treatments were more effective than bisphosphonates in the prevention of clinical and vertebral fractures, irrespective of baseline risk indicators. Hence this analysis provided no clinical evidence for restricting the use of anabolic treatment to patients with a very high risk of fractures. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019128391.
29Efficacy and safety of 18 anti-osteoporotic drugs in the treatment of patients with osteoporosis caused by glucocorticoid: A network meta-analysis of randomized controlled trials.PubMed
Zhiming Liu, Min Zhang, Zhubin Shen, et al.
PLoS One. 2020 Dec 16;15(12):e0243851. doi: 10.1371/journal.pone.0243851. eCollection 2020.
BACKGROUND: Glucocorticoids are widely used in a variety of diseases, especially autoimmune diseases and inflammatory diseases, so the incidence of glucocorticoid-induced osteoporosis is high all over the world. OBJECTIVES: The purpose of this paper is to use the method of network meta-analysis (NMA) to compare the efficacy of anti-osteoporosis drugs directly and indirectly, and to explore the advantages of various anti-osteoporosis drugs based on the current evidence. METHODS: We searched PubMed, Embase and Cochrane Library for randomized controlled trials (RCTs), of glucocorticoid-induced osteoporosis (GIOP) and compared the efficacy and safety of these drugs by NMA. The risk ratio (RR) and its 95% confidence interval (CI) are used as the influence index of discontinuous data, and the standardized mean difference (SMD) and its 95% CI are used as the influence index of continuous data. The statistical heterogeneity was evaluated by the calculated estimated variance (τ2), and the efficacy and safety of drugs were ranked by the surface under the cumulative ranking curve (SUCRA). The main outcome of this study was the incidence of vertebral fracture after taking several different types of drugs, and the secondary results were the incidence of non-vertebral fracture and adverse events, mean percentage change of lumbar spine (LS) and total hip (TH)bone mineral density (BMD) from baseline to at least 12 months. RESULTS: Among the different types of anti-GIOP, teriparatide (SUCRA 95.9%) has the lowest incidence of vertebral fracture; ibandronate (SUCRA 75.2%) has the lowest incidence of non-vertebral fracture; raloxifene (SUCRA 98.5%) has the best effect in increasing LS BMD; denosumab (SUCRA 99.7%) is the best in increasing TH BMD; calcitonin (SUCRA 92.4%) has the lowest incidence of serious adverse events. CONCLUSIONS: Teriparatide and ibandronate are effective drugs to reduce the risk of vertebral and non-vertebral fractures in patients with GIOP. In addition, long-term use of raloxifene and denosumab can increase the BMD of LS and TH.
30Romosozumab: A Review in Postmenopausal Osteoporosis.PubMed
Julia Paik, Lesley J Scott
Drugs Aging. 2020 Nov;37(11):845-855. doi: 10.1007/s40266-020-00793-8.
Romosozumab (Evenity), a humanized monoclonal antibody, promotes bone formation and inhibits bone resorption by inhibiting sclerostin, a protein involved in the regulation of bone formation. Subcutaneous romosozumab is approved in several countries, including those of the EU for treating severe osteoporosis as well as in the USA for osteoporosis in postmenopausal women at high risk of fracture. In pivotal phase III trials (FRAME and ARCH), 12 months' once-monthly romosozumab 210 mg significantly reduced vertebral and clinical fracture risk versus placebo and oral alendronate in postmenopausal women with osteoporosis. After patients transitioned from romosozumab to 12-24 months of subcutaneous denosumab or oral alendronate, fracture risks were significantly improved versus placebo-to-denosumab and alendronate-only treatment. In these trials and a phase IIIb trial, romosozumab significantly increased bone mineral density (BMD) relative to placebo, alendronate and subcutaneous teriparatide at 12 months, with these benefits maintained 12-24 months after patients transitioned from romosozumab to alendronate or denosumab in pivotal trials. Romosozumab had a generally manageable tolerability profile. While further clinical experience is needed to more definitively establish its efficacy and safety, including its CV safety, romosozumab extends the treatment options in postmenopausal women with osteoporosis who have a high risk of fracture and in those who have failed or are intolerant to other available osteoporosis therapy.
31Drug efficacy and safety of denosumab, teriparatide, zoledronic acid, and ibandronic acid for the treatment of postmenopausal osteoporosis: a network meta-analysis of randomized controlled trials.PubMed
W-Y Wang, L-H Chen, W-J Ma, et al.
Eur Rev Med Pharmacol Sci. 2023 Sep;27(17):8253-8268. doi: 10.26355/eurrev_202309_33586.
OBJECTIVE: This study aims to compare the efficacy and safety of denosumab, teriparatide, zoledronic acid, and ibandronic acid for the treatment of women with postmenopausal osteoporosis. MATERIALS AND METHODS: Randomized controlled trials (RCTs) were searched in Medline, Embase, and Cochrane up to April 2022. Statistical analysis was performed using R 4.1.3 software, and quality evaluation was conducted using Review Manager 5.3. RESULTS: 51 RCTs containing 39,095 patients met our selection criteria. The efficacy results indicated that teriparatide was more effective than ibandronic acid in reducing vertebral fractures [relative risk (RR) = 0.536; 95% confidence interval (CI) (0.266, 0.998)]. Denosumab [mean difference (MD) = -4.19; 95% CI (-8.03, -0.355)] and teriparatide [MD = 4.64; 95% CI (1.60, 7.72)] showed better efficacy than ibandronic acid in improving spine bone mineral density (BMD). Denosumab showed better efficacy than teriparatide in improving radius BMD [MD = -4.14; 95% CI (-6.72, -1.54)], hip bone mineral density (BMD) [MD = -2.01; 95% CI (-3.80, -0.162)], and one-third radius BMD [MD = -3.63; 95% CI (-7.04, -0.151)]. Denosumab was associated with the greatest benefit in increasing radius BMD [the surface under the cumulative ranking curve area (SUCRA) = 0.999], hip BMD [surface under the cumulative ranking curve area (SUCRA) = 0.979], femoral neck BMD (SUCRA = 0.971), one-third radius BMD (SUCRA = 0.994) and preventing vertebral fractures (SUCRA = 0.806). Teriparatide was associated with the greatest benefit in preventing non-vertebral fractures (SUCRA = 0.927) and improving spine BMD (SUCRA = 0.899). The safety results indicated that teriparatide was safer than zoledronic acid regarding the risk of adverse events [RR = 0.958; 95% CI (0.919, 0.988)]. Teriparatide was associated with the greatest benefit in preventing adverse events (SUCRA = 0.908) and serious adverse events (SUCRA = 0.813). CONCLUSIONS: Our current results suggested that when considering both safety and efficacy, denosumab or teriparatide might be a better choice for women with postmenopausal osteoporosis.
32Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk.PubMed
S Boonen, J D Adachi, Z Man, et al.
J Clin Endocrinol Metab. 2011 Jun;96(6):1727-36. doi: 10.1210/jc.2010-2784. Epub 2011 Mar 16.
CONTEXT: The FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial showed denosumab significantly reduced the risk of fractures in postmenopausal women with osteoporosis. OBJECTIVE: We evaluated the effect of denosumab on the incidence of new vertebral and hip fractures in subgroups of women at higher risk for these fractures. DESIGN: FREEDOM was a 3-yr, randomized, double-blind, placebo-controlled, phase 3 trial. PARTICIPANTS AND SETTING: Postmenopausal women (N = 7808) with osteoporosis were enrolled at 213 study sites worldwide. INTERVENTIONS: Subjects received s.c. denosumab (60 mg) or placebo every 6 months and daily supplements of calcium (≥1000 mg) and vitamin D (≥400 IU). MAIN OUTCOME MEASURES: This post hoc analysis evaluated fracture incidence in women with known risk factors for fractures including multiple and/or moderate or severe prevalent vertebral fractures, aged 75 yr or older, and/or femoral neck bone mineral density T-score of -2.5 or less. RESULTS: Compared with placebo, denosumab significantly reduced the risk of new vertebral fractures in women with multiple and/or severe prevalent vertebral fractures (16.6% placebo vs. 7.5% denosumab; P < 0.001). Similarly, denosumab significantly reduced the risk of hip fractures in subjects aged 75 yr or older (2.3% placebo vs. 0.9% denosumab; P < 0.01) or with a baseline femoral neck bone mineral density T-score of -2.5 or less (2.8% placebo vs. 1.4% denosumab; P = 0.02). These risk reductions in higher-risk individuals were consistent with those seen in patients at lower risk of fracture. CONCLUSIONS: Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at higher risk for fracture. These results highlight the consistent antifracture efficacy of denosumab in patients with varying degrees of fracture risk.
33Denosumab for the management of postmenopausal osteoporosis.PubMed
Andrea Singer, Andreas Grauer
Postgrad Med. 2010 Nov;122(6):176-87. doi: 10.3810/pgm.2010.11.2235.
View the National Osteoporosis Foundation Clinician's Guide Postmenopausal osteoporosis is a major concern to public health. Fractures are the major clinical consequence of osteoporosis and are associated with substantial morbidity, mortality, and health care costs. Despite the availability of screening and treatment guidelines, osteoporosis diagnosis and treatment remain low. Health care providers may consult guidelines in the clinical management of their patients with osteoporosis, including those from the National Osteoporosis Foundation, and the new fracture risk assessment tool from the World Health Organization. Bisphosphonates are the most commonly used treatment for postmenopausal osteoporosis. Although these agents are effective in preventing fractures and bone loss, the benefits of treatment may be limited by suboptimal adherence and compliance. Denosumab is a human monoclonal antibody that targets and inhibits RANK ligand, an essential mediator of bone resorption. In clinical trials in postmenopausal women with osteoporosis, denosumab 60 mg given subcutaneously every 6 months was well tolerated and statistically significantly reduced the risk of vertebral, nonvertebral, and hip fractures. The introduction of denosumab into clinical practice provides physicians with another option for the treatment of postmenopausal osteoporosis, and the twice-yearly dosing regimen has the potential to improve adherence.
34Denosumab: A Review in Postmenopausal Osteoporosis.PubMed
Emma D Deeks
Drugs Aging. 2018 Feb;35(2):163-173. doi: 10.1007/s40266-018-0525-7.
Denosumab (Prolia; Pralia) is a human monoclonal antibody targeting the key bone resorption mediator RANKL. The drug is administered via subcutaneous injection once every 6 months and is approved for various indications, including the treatment of postmenopausal (PM) women with osteoporosis at increased/high risk of fracture or failure/intolerance of other osteoporosis therapies (indications featured in this review). Denosumab showed benefit in several phase 3 or 4 studies in PM women with osteoporosis or low bone mineral density (BMD), including the pivotal 3-year double-blind FREEDOM trial and its 7-year open-label extension. Denosumab reduced the risk of vertebral, nonvertebral and hip fractures and increased BMD across skeletal sites versus placebo in FREEDOM, with these benefits maintained over up to 10 years' therapy in the extension. The drug was also more effective in improving BMD than bisphosphonates, including in women switched from a bisphosphonate regimen, in 1-year trials; however, whether these differences translate into differences in anti-fracture efficacy is unclear. Denosumab was generally well tolerated over up to 10 years' treatment, although an increased risk of multiple vertebral fractures was observed after discontinuation of the drug. Thus, denosumab is a key treatment option for PM women with osteoporosis who have an increased/high risk of fracture or failure/intolerance of other osteoporosis therapies, although the potential for multiple vertebral fractures to occur after discontinuation of the drug requires consideration of subsequent management options.
35Efficacy and safety of romosozumab: a meta-analysis of placebo-controlled trials.PubMed
Takaomi Kobayashi, Megumi Hara, Chisato Shimanoe, et al.
J Bone Miner Metab. 2024 Sep;42(5):492-502. doi: 10.1007/s00774-024-01531-5. Epub 2024 Jul 8.
INTRODUCTION: We aimed to comprehensively compile placebo-controlled trials on the efficacy and safety of romosozumab (210 mg, subcutaneously, once monthly) in postmenopausal women and men with osteoporosis. MATERIALS AND METHODS: PubMed, Google Scholar, and ClinicalTrials.gov were searched for relevant placebo-controlled trials (as of January 1, 2024). Percent change in bone mineral density (BMD), falls, fractures, and adverse events (AEs) after drug administration were collected. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were calculated. RESULTS: Six trials (7990 patients; follow-up period, 6-12 months) were included. Compared with placebo, romosozumab significantly increased lumbar spine BMD (MD = 12.69; 95% CI 11.10-14.29), total hip BMD (MD = 4.42; 95% CI 3.03-5.80), and femoral neck BMD (MD = 3.99; 95% CI 2.42-5.57) at 12 months. Romosozumab significantly decreased falls (RR = 0.80; 95% CI 0.68-0.93) and major osteoporotic fractures (RR = 0.37; 95% CI 0.25-0.54), but increased injection-site reactions (RR = 1.83; 95% CI 1.46-2.30) within 12 months. No significant differences were observed in other AEs (including cardiovascular AEs) within 12 months. CONCLUSION: Romosozumab treatment resulted in a significant BMD gain, reduced falls and major osteoporotic fractures. It was generally well-tolerated, including the cardiovascular aspects. However, clinicians should consider the occurrence of minor AEs (e.g., injection-site reactions).
36Teriparatide's effects on quantitative ultrasound parameters and bone density in women with established osteoporosis.PubMed
S Gonnelli, G Martini, C Caffarelli, et al.
Osteoporos Int. 2006 Oct;17(10):1524-31. doi: 10.1007/s00198-006-0157-3. Epub 2006 Jun 9.
This study aimed to evaluate the effects of teriparatide [hPTH (1-34)] on quantitative ultrasound (QUS) parameters and bone mineral density (BMD) at the axial and appendicular (hand) skeleton in women with established osteoporosis who had been previously treated with antiresorptive drugs. Sixty postmenopausal women (age 71.1+/-6.8 years) were randomly assigned to either receive once-daily 20-mug subcutaneous teriparatide (n=30) or continue the antiresorptive treatment (n=30). At baseline and at 2-month intervals we measured QUS parameters at the calcaneus using the Achilles Plus (GE, Lunar), measuring speed of sound (SOS), broadband ultrasound attenuation (BUA), and stiffness index; QUS parameters at the phalanxes using the Bone Profiler (IGEA), measuring amplitude-dependent speed of sound (AD-SoS), bone transmission time (BTT), and fast wave amplitude (FWA); and BMD values at the right hand using dual x-ray absorptiometry. BMD at the lumbar spine, femur, and whole body were measured on a 6-monthly basis. After 1 year of teriparatide treatment, the changes in BMD were 7.1% at the lumbar spine, 2.6% at the femoral neck, -0.8% at the total hip, and -0.6% for the whole body. Teriparatide induced a significant and persistent decrease in BMD at the hand (-3.6% at month 6 and -2.7% at month 12). In the teriparatide group at month 12, AD-SoS was slightly increased (0.7%; not significant), whereas BTT significantly decreased (-16.4%, p<0.001) and FWA significantly increased (17.5%, p<0.001). The FWA/BTT ratio increased by 26.6% and 32.9% at months 6 and 12, respectively, in the teriparatide group and remained unchanged in the antiresorptive group. In women with established osteoporosis who had previously been treated with various antiresorptive drugs, 1 year of teriparatide treatment determined the expected increase in BMD at the axial skeleton and a significant and prolonged decrease in BMD at the hand. Moreover, teriparatide determined important changes in BTT and FWA, two parameters obtained from the analysis of ultrasonographic trace at the phalanxes, which could be considered in monitoring for the early effect of teriparatide on bone.
37Real-world efficacy of a teriparatide biosimilar (RGB-10) compared with reference teriparatide on bone mineral density, trabecular bone score, and bone parameters assessed using quantitative ultrasound, 3D-SHAPER and high-resolution peripheral computer tomography in postmenopausal women with osteoporosis and very high fracture risk.PubMed
Peyman Hadji, Luka Kamali, Friederike Thomasius, et al.
Osteoporos Int. 2024 Dec;35(12):2107-2116. doi: 10.1007/s00198-024-07208-z. Epub 2024 Aug 2.
UNLABELLED: A retrospective analysis comparing a teriparatide biosimilar (RGB-10) with reference teriparatide for osteoporosis treatment in postmenopausal women at high fracture risk found them to be therapeutically equivalent. Both provided significant improvements in lumber spine BMD, TBS, and other parameters of bone health, assessed using multiple diagnostic methods. PURPOSE: To compare the therapeutic efficacy of a teriparatide biosimilar (RGB-10) with reference teriparatide for the treatment of osteoporosis in postmenopausal women at very high fracture risk. METHODS: A retrospective analysis of 25 postmenopausal female patients treated for osteoporosis with RGB-10 for 24 months and a matched cohort of 25 patients treated with reference teriparatide. The following outcomes were assessed at baseline, 12 and 24 months: bone mineral density (BMD) at the lumbar spine, femoral neck and total hip using dual-energy x-ray absorptiometry (DXA) and integral, trabecular and cortical volumetric and surface BMD using 3D-SHAPER imaging, trabecular bone score (TBS), quantitative ultrasound (QUS) measurements, and high-resolution peripheral quantitative computed tomography (HRpQCT) imaging of the radius and tibia. RESULTS: No significant differences were observed between treatment groups in any of the measured parameters of BMD or bone health at baseline as well as in any timepoint when assessed using these various diagnostic methods. Both compounds provided equivalent significant improvements from baseline in measures of osteoporosis and fracture risk. CONCLUSION: The results of the analysis demonstrate the therapeutic equivalence of the teriparatide biosimilar (RGB-10) to reference teriparatide for the treatment of osteoporosis in postmenopausal women at very high risk of fracture.
38Baseline glucocorticoid dose and bone mineral density response with teriparatide or alendronate therapy in patients with glucocorticoid-induced osteoporosis.PubMed
Jean-Pierre Devogelaer, Robert A Adler, Chris Recknor, et al.
J Rheumatol. 2010 Jan;37(1):141-8. doi: 10.3899/jrheum.090411. Epub 2009 Nov 16.
OBJECTIVE: This post-hoc analysis studied the effect of baseline glucocorticoid dose on the 18-month bone mineral density (BMD) response to teriparatide 20 microg/day or alendronate 10 mg/day in 387 patients with glucocorticoid-induced osteoporosis (GIO) from a randomized, double-blind trial. METHODS: Lumbar spine (LS), femoral neck (FN), and total hip (TH) BMD were measured at baseline and 18 months. Mean baseline glucocorticoid dose was categorized as low (< or = 5 mg/day), medium (> 5 and < 15 mg/day), or high (> or = 15 mg/day). RESULTS: Baseline LS, FN, and TH BMD were similar between groups, and between glucocorticoid dose categories within each group. LS BMD increases at the low, medium, and high glucocorticoid doses were 8.1%, 6.6%, and 4.6%, respectively, with teriparatide, and 3.6%, 2.8%, and 2.3% with alendronate. Analyzed as a continuous variable, higher glucocorticoid doses had a negative, but non-significant, effect on the percentage increase in LS BMD in both groups. Glucocorticoid dose did not significantly affect FN or TH BMD increases in either group. Across the 3 glucocorticoid dose categories, the overall LS BMD increases were different for both treatments combined (p = 0.033), but the relative differences between the treatment groups were not different (interaction, p = 0.52). CONCLUSION: Teriparatide and alendronate increased LS and hip BMD across a range of baseline glucocorticoid doses. LS BMD increases with teriparatide were greater in the low-dose category than in the high-dose category. Overall LS BMD increases were significantly greater with teriparatide compared with alendronate, which may reflect the respective anabolic and antiresorptive mechanisms of action. Clinical Trial Registry Number: NCT00051558.
39FRAME Study: The Foundation Effect of Building Bone With 1 Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab.PubMed
Felicia Cosman, Daria B Crittenden, Serge Ferrari, et al.
J Bone Miner Res. 2018 Jul;33(7):1219-1226. doi: 10.1002/jbmr.3427. Epub 2018 May 17.
Romosozumab is a bone-forming agent with a dual effect of increasing bone formation and decreasing bone resorption. In FRActure study in postmenopausal woMen with ostEoporosis (FRAME), postmenopausal women with osteoporosis received romosozumab 210 mg s.c. or placebo once monthly for 12 months, followed by denosumab 60 mg s.c. once every 6 months in both groups for 12 months. One year of romosozumab increased spine and hip BMD by 13% and 7%, respectively, and reduced vertebral and clinical fractures with persistent fracture risk reduction upon transition to denosumab over 24 months. Here, we further characterize the BMD gains with romosozumab by quantifying the percentages of patients who responded at varying magnitudes; report the mean T-score changes from baseline over the 2-year study and contrast these results with the long-term BMD gains seen with denosumab during Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) and its Extension studies; and assess fracture incidence rates in year 2, when all patients received denosumab. Among 7180 patients (n = 3591 placebo, n = 3589 romosozumab), most romosozumab-treated patients experienced ≥3% gains in BMD from baseline at month 12 (spine, 96%; hip, 78%) compared with placebo (spine, 22%; hip, 16%). For romosozumab patients, mean absolute T-score increases at the spine and hip were 0.88 and 0.32, respectively, at 12 months (placebo: 0.03 and 0.01) and 1.11 and 0.45 at 24 months (placebo-to-denosumab: 0.38 and 0.17), with the 2-year gains approximating the effect of 7 years of continuous denosumab administration. Patients receiving romosozumab versus placebo in year 1 had significantly fewer vertebral fractures in year 2 (81% relative reduction; p < 0.001), with fewer fractures consistently observed across other fracture categories. The data support the clinical benefit of rebuilding the skeletal foundation with romosozumab before transitioning to antiresorptive therapy. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
40Denosumab versus romosozumab for postmenopausal osteoporosis treatment.PubMed
Tomonori Kobayakawa, Akiko Miyazaki, Makoto Saito, et al.
Sci Rep. 2021 Jun 3;11(1):11801. doi: 10.1038/s41598-021-91248-6.
Denosumab and romosozumab, a recently approved new drug, are effective and widely known molecular-targeted drugs for postmenopausal osteoporosis treatment. However, no studies have directly compared their therapeutic effects or safety in postmenopausal osteoporosis. This retrospective observational registry study compared the efficacy of 12-month denosumab or romosozumab treatment in postmenopausal osteoporosis patients. The primary outcome was the change in bone mineral density (BMD) at the lumbar spine. Secondary outcomes included BMD changes at the total hip and femoral neck, changes in bone turnover markers, and adverse events. Propensity score matching was employed to assemble patient groups with similar baseline characteristics. Sixty-nine patients each received either denosumab or romosozumab for 12 months. The mean 12-month percentage change from baseline in lumbar spine BMD was 7.2% in the denosumab group and 12.5% in the romosozumab group, indicating a significant difference between the groups. The percentage changes in BMD at both the total hip and femoral neck were also significantly higher at 12 months in the romosozumab group than in the denosumab group. In denosumab patients, bone formation and bone resorption markers were significantly decreased at 6 and 12 months from baseline. In the romosozumab group, the bone formation marker was significantly increased at 6 months and then returned to baseline, while the bone resorption marker was significantly decreased at both time points. Adverse events were few and predominantly minor in both groups, with no remarkable difference in the incidence of new vertebral fractures. Romosozumab showed a higher potential for improving BMD than denosumab in this clinical study of postmenopausal osteoporosis patient treatment.
41Increased bone mineral density for 1 year of romosozumab, vs placebo, followed by 2 years of denosumab in the Japanese subgroup of the pivotal FRAME trial and extension.PubMed
Akimitsu Miyauchi, Rajani V Dinavahi, Daria B Crittenden, et al.
Arch Osteoporos. 2019 Jun 5;14(1):59. doi: 10.1007/s11657-019-0608-z.
UNLABELLED: Romosozumab, which binds sclerostin, rebuilds the skeletal foundation before transitioning to antiresorptive treatment. This subgroup analysis of an international, randomized, double-blind study in postmenopausal women with osteoporosis showed efficacy and safety outcomes for romosozumab followed by denosumab in Japanese women were generally consistent with those for the overall population. PURPOSE: In the international, randomized, double-blind, phase 3 FRActure study, in postmenopausal woMen with ostEoporosis (FRAME; NCT01575834), romosozumab followed by denosumab significantly improved bone mineral density (BMD) and reduced fracture risk. This report evaluates Japanese women in FRAME. METHODS: Postmenopausal women with osteoporosis (T-score - 3.5 to - 2.5 at total hip or femoral neck) received romosozumab 210 mg or placebo subcutaneously monthly for 12 months, then each group received denosumab 60 mg subcutaneously every 6 months for 24 months. The key endpoint for Japanese women was BMD change. Other endpoints included new vertebral, clinical, and nonvertebral fracture; the subgroup analysis did not have adequate power to demonstrate statistically significant reductions. RESULTS: Of 7180 enrolled subjects, 492 (6.9%) were Japanese (247 romosozumab, 245 placebo). BMD increases from baseline were greater (P < 0.001) for romosozumab-to-denosumab than placebo-to-denosumab at the lumbar spine (36 months, 12.7%), total hip (4.2%), and femoral neck (4.1%). Fracture risk was lower through 36 months for romosozumab-to-denosumab vs placebo-to-denosumab for new vertebral (1.7% vs 4.5%; relative risk reduction (RRR) 63%, P = 0.070), clinical (3.2% vs 7.3%; RRR 53%, P = 0.072), nonvertebral (2.8% vs 6.1%; RRR 50%, P = 0.12), and all other fracture types evaluated. Rates of adverse events and positively adjudicated serious cardiovascular events were generally balanced between groups. CONCLUSIONS: Efficacy and safety for romosozumab-to-denosumab were similar between Japanese women and the overall population. The sequence of romosozumab to rebuild the skeletal foundation before transitioning to antiresorptive treatment with denosumab is a promising regimen for Japanese postmenopausal women with osteoporosis at high risk of fracture.
42The effect of romosozumab on bone mineral density depending on prior treatment: a prospective, multicentre cohort study in Switzerland.PubMed
Judith Everts-Graber, Mathias Wenger, Sven Oser, et al.
Osteoporos Int. 2024 Sep;35(9):1605-1613. doi: 10.1007/s00198-024-07155-9. Epub 2024 Jun 26.
UNLABELLED: This multicentre, prospective cohort study measured the effect of romosozumab for 12 months on bone mineral density, taking into account prior therapies. Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip. INTRODUCTION: In Switzerland, romosozumab is administered to high-risk osteoporosis patients. Our study aimed to assess the effect of romosozumab on bone mineral density (BMD), taking into account prior therapies. METHODS: This multicentre, prospective cohort study measured the effect of romosozumab for 12 months in patients in a nationwide Swiss osteoporosis registry. BMD and bone turnover marker (P1NP and CTX) changes were measured and compared between pre-treated and treatment naïve patients. RESULTS: Ninety-nine patients (92 women and 7 men, median age 71 years [65, 76]) were enrolled from January 2021 to December 2023. Among them, 22 had no prior treatment before romosozumab, while 77 had previous therapy (including 23 with a history of prior teriparatide therapy), with a median duration of 6 years [4, 11] of cumulative antiresorptive treatment. Over 12 months, romosozumab led to BMD changes of 10.3% [7.5, 15.5] at the lumbar spine, 3.1% [1.1, 5.8] at the total hip and 3.1% [0.5, 5.3] at the femoral neck, indicating notable variability. Significantly lower BMD responses were observed in pre-treated patients, with the duration of prior antiresorptive therapy inversely associated with BMD increases at the lumbar spine and hip. Other predictors of BMD changes at the total hip included baseline T-scores at the hip, body mass index and baseline CTX level, while the BMD response at the lumbar spine was associated with the lumbar spine T-score at baseline, age and baseline CTX level. CONCLUSION: Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip.
43Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy.PubMed
David L Kendler, Christian Roux, Claude Laurent Benhamou, et al.
J Bone Miner Res. 2010 Jan;25(1):72-81. doi: 10.1359/jbmr.090716.
Patients treated with bisphosphonates for osteoporosis may discontinue or require a switch to other therapies. Denosumab binds to RANKL and is a potent inhibitor of bone resorption that has been shown to increase bone mineral density (BMD) and decrease fracture risk in postmenopausal women with osteoporosis. This was a multicenter, international, randomized, double-blind, double-dummy study in 504 postmenopausal women > or = 55 years of age with a BMD T-score of -2.0 or less and -4.0 or more who had been receiving alendronate therapy for at least 6 months. Subjects received open-label branded alendronate 70 mg once weekly for 1 month and then were randomly assigned to either continued weekly alendronate therapy or subcutaneous denosumab 60 mg every 6 months and were followed for 12 months. Changes in BMD and biochemical markers of bone turnover were evaluated. In subjects transitioning to denosumab, total hip BMD increased by 1.90% at month 12 compared with a 1.05% increase in subjects continuing on alendronate (p < .0001). Significantly greater BMD gains with denosumab compared with alendronate also were achieved at 12 months at the lumbar spine, femoral neck, and 1/3 radius (all p < .0125). Median serum CTX levels remained near baseline in the alendronate group and were significantly decreased versus alendronate (p < .0001) at all time points with denosumab. Adverse events and serious adverse events were balanced between groups. No clinical hypocalcemic adverse events were reported. Transition to denosumab produced greater increases in BMD at all measured skeletal sites and a greater reduction in bone turnover than did continued alendronate with a similar safety profile in both groups.
44Effect of Diphosphonates on Bone Mineral Density in Men Receiving Androgen Deprivation Therapy for Prostate Cancer.PubMed
Congcong Wu, Wenjun Chen, Xuanzhang Huang, et al.
Clin Genitourin Cancer. 2018 Dec;16(6):e1243-e1250. doi: 10.1016/j.clgc.2018.07.016. Epub 2018 Jul 21.
Patients receiving androgen deprivation therapy are associated with increasing loss of bone mineral density (BMD) and higher risk of skeletal-related events. We reviewed and analyzed the influence of diphosphonates on BMD change. A systemic literature research was conducted in PubMed and related bibliographies. The focus of data extraction was BMD percentage change of lumbar spine, total hip, and femoral neck after 12 months. Standardized mean difference (SMD) was pooled with the random-effects model, and metaregression and subgroup analysis were performed to explore heterogeneity. Nine articles (n = 920) were included and finally analyzed after screening 118 articles. We found significant improvement in BMD percentage changes of the lumbar spine, total hip, and femoral neck at 1 year (respectively, SMD = 6.379, 95% confidence interval [CI] = 3.740-9.018, P < .001, I = 98.8%, P < .001; SMD = 4.870, 95% CI, 2.256-7.485, P < .001, I = 98.9%, P < .001; SMD = 3.634, 95% CI, 1.989-5.279, P < .001, I = 97.3%, P < .001). In individual variable metaregression analysis, application zoledronic acid or not showed a statistically significant influence on BMD percentage change of total hip (P = .018). In subgroup analyses, both zoledronic acid and alendronate showed a significant improvement in BMD percentage changes. Diphosphonates significantly increased BMD percentage changes of the lumbar spine, total hip, and femoral neck in men receiving androgen deprivation therapy for prostate cancer. Patients with androgen deprivation therapy should be evaluated BMD loss, and timely therapy with diphosphonates may be an appropriate strategy to prevent osteoporosis.
45Efficacy and Safety of Romosozumab Among Postmenopausal Women With Osteoporosis and Mild-to-Moderate Chronic Kidney Disease.PubMed
Paul D Miller, Jonathan D Adachi, Ben-Hur Albergaria, et al.
J Bone Miner Res. 2022 Aug;37(8):1437-1445. doi: 10.1002/jbmr.4563. Epub 2022 May 20.
Patients with osteoporosis and chronic kidney disease (CKD) are at increased risk of fracture and associated negative outcomes, including increased mortality. The present post hoc analysis of two randomized, multicenter, phase 3 clinical trials-Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) and Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH)-investigated the efficacy and safety of romosozumab in postmenopausal women with osteoporosis and mild-to-moderate CKD. The analysis included data from 7147 patients from FRAME and 4077 from ARCH. Eighty-one percent of patients from FRAME and 85% from ARCH had mild or moderate reduction in estimated glomerular filtration rate (eGFR) at baseline, and part of this reduction is likely age related. During the 1-year double-blind phases of the trials, patients received romosozumab 210 mg sc or placebo monthly in FRAME and romosozumab 210 mg sc monthly or alendronate 70 mg po weekly in ARCH. Bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck and vertebral and nonvertebral fractures were assessed at baseline and month 12. In both trials, the least-square mean percent change from baseline BMD was significantly greater in the romosozumab groups versus controls across all kidney function categories at month 12. Romosozumab reduced the relative risk of new vertebral fractures at month 12 among patients with eGFR of 30-59, 60-89, and ≥90 mL/min by 72% (95% confidence interval [CI] 14-91; p = 0.017), 70% (40-85; p < 0.001), and 84% (30-96; p = 0.005), respectively, in FRAME versus placebo, and by 51% (5-75; p = 0.04), 19% (-28 to 49; p = 0.39), and 57% (1-81, p = 0.04), respectively, in ARCH versus alendronate. Incidences of adverse events, asymptomatic decreases in serum calcium, and evolution of kidney function during the studies were similar across all baseline kidney function groups. Romosozumab is an effective treatment option for postmenopausal women with osteoporosis and mild-to-moderate reduction in kidney function, with a similar safety profile across different levels of kidney function. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
46Efficacy and Safety of Anti-Osteoporotic Agents across CKD Stages: A Meta-Analysis of Randomized Clinical Trials.PubMed
Tahereh Sabaghian, Parisa Delkash, Maryam Rahmannia, et al.
Kidney Blood Press Res. 2024;49(1):581-587. doi: 10.1159/000540235. Epub 2024 Jul 22.
INTRODUCTION: Osteoporosis poses a significant health concern, especially for individuals with chronic kidney disease (CKD). CKD disrupts mineral and bone metabolism, heightening the risk of fractures and complicating the management of osteoporosis. While anti-osteoporotic interventions aim to address bone health in CKD patients, ongoing research is essential to understand the comparative efficacy and safety of these medications, particularly in different CKD stages, notably in stages 4 and 5. METHODS: We searched PubMed/MEDLINE, EMBASE, and the Cochrane CENTRAL for randomized controlled trials assessing the efficacy and safety of osteoporosis interventions in CKD up to June 15, 2024. The analysis utilized the pooled odds ratio (OR) along with the corresponding 95% confidence interval (CI), employing Comprehensive Meta-Analysis software, version 3.0. To assess heterogeneity in the results of individual studies, we used Cochran's Q statistic and the I2 statistic. RESULTS: We analyzed 12 randomized controlled trials involving 31,027 participants, revealing a significantly lower risk of vertebral fractures with anti-osteoporotic agents (teriparatide, denosumab, romosozumab, raloxifene) compared to placebo (pooled OR, 0.28 [95% CI, 0.22-0.36]). Stratification by CKD stages showed a lower risk in Stages 1-3 but no significant reduction in stages 4 and 5. Teriparatide, denosumab, and romosozumab were effective in lowering fracture risk, whereas Raloxifene showed no significant effect. The lumbar spine, femoral neck, and total hip BMD showed no significant differences between anti-osteoporotic agents (denosumab, raloxifene, risedronate, alendronate, teriparatide) and placebo. However, romosozumab demonstrated a significantly greater BMD change in all kidney function categories. No reported side effects were observed in CKD stages 1-5 across the trials. CONCLUSIONS: Our meta-analysis highlights the effectiveness of anti-osteoporotic agents in lowering vertebral fracture risk in CKD patients, particularly in stages 1-3. However, this benefit is not apparent in stages 4 and 5, necessitating further research. Despite the absence of reported side effects in CKD patients, clinicians should carefully assess the suitability of these medications, considering individual risks and benefits.
47Osteoporosis, bone mineral density and CKD-MBD (II): Therapeutic implications.PubMed
Jordi Bover, Pablo Ureña-Torres, Ana María Laiz Alonso, et al.
Nefrologia (Engl Ed). 2019 May-Jun;39(3):227-242. doi: 10.1016/j.nefro.2018.10.009. Epub 2019 Feb 20.
Osteoporosis (OP) and chronic kidney disease (CKD) both independently affect bone health. A significant number of patients with CKD have decreased bone mineral density (BMD), are at high risk of fragility fractures and have an increased morbidity and mortality risk. With an ageing population, these observations are not only dependent on "renal osteodystrophy" but also on the associated OP. As BMD predicts incident fractures in CKD patients (partI), we now aim to analyse the potential therapeutic consequences. Post-hoc analyses of randomised studies have shown that the efficacy of drugs such as alendronate, risedronate, raloxifene, teriparatide and denosumab is similar to that of the general population in patients with a mild/moderate decline in their glomerular filtration rate (especially CKD-3). These studies have some flaws however, as they included mostly "healthy" women with no known diagnosis of CKD and generally with normal lab test results. Nevertheless, there are also some positive preliminary data in more advanced stages (CKD-4), even though in CKD-5D they are more limited. Therefore, at least in the absence of significant mineral metabolism disorders (i.e. severe hyperparathyroidism), the potential benefit of these drugs should be considered in patients with a high or very high fracture risk. It is an important change that the new guidelines do not make it a requirement to first perform a bone biopsy and that the risk/benefit ratio of these drugs may be justified. However, we must also be aware that most studies are not consistent and the level of evidence is low. Consequently, any pharmacological intervention (risk/benefit) should be prudent and individualised.
48Diagnosis and therapeutic decisions of osteoporosis in chronic kidney disease.PubMed
Hanne Skou Jørgensen, Sharon Moe, Thomas L Nickolas
J Bone Miner Res. 2024 May 24;39(5):531-535. doi: 10.1093/jbmr/zjae062.
A 63-yr-old woman with end-stage CKD secondary to glomerulonephritis, on hemodialysis therapy, presented with scoliosis, back pain, and progressive loss of physical function for which corrective surgery was planned. Optimization of bone health was requested by the surgeon as a DXA scan had revealed osteoporosis at spine, hip, and forearm. Due to previous subtotal parathyroidectomy and normal parathyroid hormone and bone-specific alkaline phosphatase levels, a low bone turnover state was suspected. An iliac bone biopsy was performed and revealed low bone turnover, a mineralization defect, and severe osteoporosis. The patient was treated with calcium and intensified vitamin D supplementation, followed by a 2-yr course of teriparatide. Monitoring of bone turnover markers indicated a bone anabolic response to therapy, and a repeat DXA showed increases in BMD at spine and hip. A repeat biopsy at end of treatment showed normal bone turnover and mineralization. This case demonstrates the complicated bone health of patients with advanced CKD. As there are no randomized trials for fracture pretention in patients with CKD, care must be individualized and is often based on expert opinion. The use of bone biopsy is safe and informative in guiding therapy.
49Baseline serum PINP level is associated with the increase in hip bone mineral density seen with Romosozumab treatment in previously untreated women with osteoporosis.PubMed
Masafumi Kashii, Takashi Kamatani, Yoshio Nagayama, et al.
Osteoporos Int. 2023 Mar;34(3):563-572. doi: 10.1007/s00198-022-06642-1. Epub 2022 Dec 31.
UNLABELLED: Baseline serum PINP value was significantly and independently associated with the increased bone mineral density (≥ 3%) in both total hip and femoral necks by 12 months of romosozumab treatment in patients with treatment-naive postmenopausal osteoporosis. PURPOSE: Some patients fail to obtain a sufficiently increased hip bone mineral density (BMD) by romosozumab (ROMO) treatment. This study aimed to investigate the prognostic factor for increased hip BMD with ROMO in patients with treatment-naive postmenopausal osteoporosis. METHODS: This prospective, observational, and multicenter study included patients (n = 63: mean age, 72.6 years; T-scores of the lumbar spine [LS], - 3.3; total hip [TH], - 2.6; femoral neck [FN], - 3.3; serum type I procollagen N-terminal propeptide [PINP], 68.5 µg/L) treated by ROMO for 12 months. BMD and serum bone turnover markers were evaluated at each time point. A responder analysis was performed to assess the patient percentage, and both univariate and multivariate analyses were performed to investigate the factors associated with clinically significant increased BMD (≥ 3%) in both TH and FN. RESULTS: Percentage changes of BMD from baseline in the LS, TH, and FN areas were 17.5%, 4.9%, and 4.3%, respectively. In LS, 96.8% of patients achieved ≥ 6% increased LS-BMD, although 57.1% could not achieve ≥ 3% increased BMD in either TH or FN. Multiple regression analysis revealed that only the baseline PINP value was significantly and independently associated with ≥ 3% increased BMD in both TH and FN (p = 0.019, 95% confidence interval = 1.006-1.054). The optimal cut-off PINP value was 53.7 µg/L with 54.3% sensitivity and 92.3% specificity (area under the curve = 0.752). CONCLUSIONS: In a real-world setting, baseline PINP value was associated with the increased BMD of TH and FN by ROMO treatment in treatment-naive patients.
50Bone density after teriparatide in patients with or without prior antiresorptive treatment: one-year results from the EUROFORS study.PubMed
Helmut Minne, Maurice Audran, Maria E Simões, et al.
Curr Med Res Opin. 2008 Nov;24(11):3117-28. doi: 10.1185/03007990802466595. Epub 2008 Oct 6.
OBJECTIVE: Recombinant teriparatide, a bone anabolic agent, is given to treatment-naïve and pre-treated patients with severe osteoporosis, but few data exist comparing the response to teriparatide in these groups. EUROFORS (the EUROpean study of FORSteo‡) enrolled postmenopausal women with established osteoporosis who were either treatment-naïve or had prior antiresorptive (AR) treatment with or without documented inadequate clinical response. The objective of the secondary analysis described here was to evaluate the interim bone mineral density (BMD) response in these groups after one year of open-label teriparatide therapy. RESEARCH DESIGN AND METHODS: Postmenopausal women with established osteoporosis who enrolled in a prospective, randomized, controlled trial received open-label teriparatide 20 µg/day for the first year. With respect to their prior osteoporosis treatment history, they were retrospectively allocated to one of three groups: treatment-naïve (n = 204), prior treatment with an antiresorptive drug (AR-pretreated) (n = 240), or prior antiresorptive treatment with inadequate response (inadequate AR-responders) (n = 421). BMD was measured by dual energy x-ray absorptiometry. RESULTS: Lumbar spine BMD increased from baseline (p < 0.001) in the three groups (mean, 95% CI); treatment-naïve: 8.4% (7.4%, 9.3%); AR-pretreated: 7.1% (6.3%, 7.9%); inadequate AR-responders: 6.2% (5.6%, 6.9%). Total hip BMD increased from baseline in the treatment-naïve (p < 0.001): 1.8% (1.1%, 2.5%) but did not change in the AR-pretreated: 0.4% (-0.2%, 1.1%) or inadequate AR-responders: -0.3% (-0.9%, 0.2%). Treatment-emergent adverse events were similar in the three groups. CONCLUSION: One year of teriparatide significantly (p < 0.001) increased spine BMD in all groups, and total hip BMD in the treatment-naïve group. Because of the limitations of this interim analysis (most importantly, the short duration of treatment and lack of a control group), further study is needed to determine the optimal treatment duration to reach the potential BMD gains at the proximal femur in patients with prior antiresorptive drug use (mostly bisphosphonates). CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, nct00191425.
51Adverse drug reactions to osteoporosis treatments.PubMed
René Rizzoli, Jean-Yves Reginster
Expert Rev Clin Pharmacol. 2011 Sep;4(5):593-604. doi: 10.1586/ecp.11.42.
Treatments for postmenopausal osteoporosis are generally safe, but are linked to some rare serious adverse drug reactions, for which causality is not always certain. The bisphosphonates are associated with gastrointestinal effects, acute phase reactions, and musculoskeletal pain, and, more rarely, cases of atrial fibrillation, subtrochanteric fracture, osteonecrosis of the jaw, cutaneous hypersensitivity reactions and renal impairment. It is too soon for pharmacovigilance data on denosumab, but it has been associated with cutaneous effects and possibly osteonecrosis of the jaw (to date, only in metastatic cancer). The selective estrogen receptor modulators may induce hot flushes and leg cramps, and--more rarely--venous thromboembolism and stroke. Strontium ranelate is associated with headache, nausea and diarrhea, and, more rarely, cutaneous hypersensitivity reactions and venous thromboembolism, while teriparatide and parathyroid hormone(1-84) are associated with headache, nausea, dizziness and limb pain. The management of osteoporosis should entail weighing the probability of adverse reactions against the benefits of therapy--that is, reduction of fracture risk.
52Adverse reactions and drug-drug interactions in the management of women with postmenopausal osteoporosis.PubMed
René Rizzoli, Jean-Yves Reginster, Steven Boonen, et al.
Calcif Tissue Int. 2011 Aug;89(2):91-104. doi: 10.1007/s00223-011-9499-8. Epub 2011 Jun 3.
The pharmacological management of disease should involve consideration of the balance between the beneficial effects of treatment on outcome and the probability of adverse effects. The aim of this review is to explore the risk of adverse drug reactions and drug-drug interactions with treatments for postmenopausal osteoporosis. We reviewed evidence for adverse reactions from regulatory documents, randomized controlled trials, pharmacovigilance surveys, and case series. Bisphosphonates are associated with gastrointestinal effects, musculoskeletal pain, and acute-phase reactions, as well as, very rarely, atrial fibrillation, atypical fracture, delayed fracture healing, osteonecrosis of the jaw, hypersensitivity reactions, and renal impairment. Cutaneous effects and osteonecrosis of the jaw are of concern for denosumab (both very rare), though there are no pharmacovigilance data for this agent yet. The selective estrogen receptor modulators are associated with hot flushes, leg cramps, and, very rarely, venous thromboembolism and stroke. Strontium ranelate has been linked to hypersensitivity reactions and venous thromboembolism (both very rare) and teriparatide with headache, nausea, dizziness, and limb pain. The solidity of the evidence base depends on the frequency of the reaction, and causality is not always easy to establish for the very rare adverse reactions. Drug-drug interactions are rare. Osteoporosis treatments are generally safe and well tolerated, though they are associated with a few very rare serious adverse reactions. While these are a cause for concern, the risk should be weighed against the benefits of treatment itself, i.e., the prevention of osteoporotic fracture.
53[Side effects of osteoporosis treatments: how to explain them to patients?].PubMed
Edwin Curraj, Elena Gonzalez Rodriguez
Rev Med Suisse. 2023 Apr 19;19(823):746-751. doi: 10.53738/REVMED.2023.19.823.746.
Despite the effectiveness of osteoporosis treatments, fear of side effects reduces both their prescription by doctors, and their acceptance by patients. The most common side effects are benign and transient, such as flu-like symptoms after zoledronate infusion, or nausea and dizziness after teriparatide introduction. On the other hand, the dreaded osteonecrosis of the jaw is very rare and associated with known risk factors. Only vertebral fractures after stopping denosumab make this treatment a matter for experienced practitioners. Therefore, knowing the side effects of prescribed treatments and explaining them to patients is essential to promote adherence.
54Comparing musculoskeletal and connective tissue disorder risks of teriparatide and abaloparatide in osteoporosis: an analysis based on FDA adverse event reporting system (FAERS).PubMed
Ming-Tao Wen, Di Luo, Jia-Cheng Li, et al.
Expert Opin Drug Saf. 2025 Aug;24(8):1001-1010. doi: 10.1080/14740338.2024.2382228. Epub 2024 Jul 18.
BACKGROUND: Osteoporosis (OP), characterized by low bone mass and increased fracture risk, is a prevalent skeletal disorder. Teriparatide (TP) and abaloparatide (ABL) are anabolic agents that may reduce fracture incidence, but their impact on musculoskeletal and connective tissue disorders (MCTD) risk is uncertain. RESEARCH DESIGN AND METHODS: A retrospective, observational disproportionality analysis was conducted utilizing FAERS data from Q1 2004 to Q3 2023, where TP or ABL was identified as the primary suspect drug. Multiple data mining algorithms, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were employed to detect MCTD safety signals. RESULTS: A total of 366,747 TP-related and 422,377 ABL-related cases were identified, predominantly among female patients aged ≥45 years. The top specific AEs involved musculoskeletal, connective tissue, and administration site disorders. Comparative analysis revealed a higher frequency of AEs related to the nervous, cardiovascular, and gastrointestinal systems for ABL compared to TP. Both drugs exhibited strong signals for arthralgia, limb pain, back pain, muscle spasms, bone pain, muscle pain, and muscle weakness. CONCLUSION: The analysis suggests a potential MCTD risk with TP and ABL treatment in OP patients, highlighting the need for AE monitoring and management in clinical practice. This contributes to a better understanding of the safety profiles of these anabolic medications.
55Cardiac adverse events in bisphosphonate and teriparatide users: An international pharmacovigilance study.PubMed
Alexander J Rodríguez, Nitesh Nerlekar, Peter R Ebeling
Bone. 2023 Mar;168:116647. doi: 10.1016/j.bone.2022.116647. Epub 2022 Dec 18.
BACKGROUND: Cardiovascular effects of osteoporosis medications have recently been highlighted. Although oral and intravenous bisphosphonates are assumed to have similar cardiovascular safety, few head-to-head comparisons exist. The cardiovascular safety of teriparatide is unknown. Aim We conducted a pharmacovigilance safety study of cardiac events using real-life adverse event reports from alendronate, zoledronic acid and teriparatide users. METHODS: Adverse drug reactions were obtained from Vigibase, a WHO database of individual case safety reports (ICSRs) from 130 countries (1967-2020). ISCRs for atrial fibrillation (AF), angina pectoris, arteriosclerosis coronary artery (ACA), cardiac arrhythmias, coronary artery disease (CAD), thromboembolic events (TE), ischaemic heart disease (IHD), torsade de pointes/QT prolongation (TDP) associated with alendronate, zoledronic acid and teriparatide use were extracted. Data were included in a disproportionality analysis where the lower end of the 95 % credibility interval for the information component (IC), showing a statistical association when >0. Head-to-head comparisons of ISCRs were estimated by age-adjusted odds ratios and 95 % confidence intervals. RESULTS: 465 episodes of angina, 287 ACA, 13,385 arrhythmias, 792 CAD, 6743 TE, 3264 IHD, 1037 myocardial infarcts, and 3714 TDP events were recorded across 50,365 alendronate, 52,436 zoledronic acid and 137,629 teriparatide users. There was a significant association between alendronate and zoledronate with all outcomes except MI. Teriparatide use was associated with AF, arrythmias and angina only. In head-to-head comparisons, teriparatide use was associated with fewer ACA and CAD events than alendronate and fewer ACA than zoledronic acid. DISCUSSION: Osteoporosis medication use is associated with adverse cardiac events, except for MI, and these appear to be more common with oral and intravenous bisphosphonates than teriparatide. Our data do not support differential effects of oral and intravenous bisphosphonates on cardiac events. Mechanisms whereby teriparatide may be cardio-protective warrant further investigation.
56Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus.PubMed
Aliya A Khan, Archie Morrison, David A Hanley, et al.
J Bone Miner Res. 2015 Jan;30(1):3-23. doi: 10.1002/jbmr.2405.
This work provides a systematic review of the literature from January 2003 to April 2014 pertaining to the incidence, pathophysiology, diagnosis, and treatment of osteonecrosis of the jaw (ONJ), and offers recommendations for its management based on multidisciplinary international consensus. ONJ is associated with oncology-dose parenteral antiresorptive therapy of bisphosphonates (BP) and denosumab (Dmab). The incidence of ONJ is greatest in the oncology patient population (1% to 15%), where high doses of these medications are used at frequent intervals. In the osteoporosis patient population, the incidence of ONJ is estimated at 0.001% to 0.01%, marginally higher than the incidence in the general population (<0.001%). New insights into the pathophysiology of ONJ include antiresorptive effects of BPs and Dmab, effects of BPs on gamma delta T-cells and on monocyte and macrophage function, as well as the role of local bacterial infection, inflammation, and necrosis. Advances in imaging include the use of cone beam computerized tomography assessing cortical and cancellous architecture with lower radiation exposure, magnetic resonance imaging, bone scanning, and positron emission tomography, although plain films often suffice. Other risk factors for ONJ include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes mellitus, ill-fitting dentures, as well as other drugs, including antiangiogenic agents. Prevention strategies for ONJ include elimination or stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene. In those patients at high risk for the development of ONJ, including cancer patients receiving high-dose BP or Dmab therapy, consideration should be given to withholding antiresorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage. Management of ONJ is based on the stage of the disease, size of the lesions, and the presence of contributing drug therapy and comorbidity. Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy. Localized surgical debridement is indicated in advanced nonresponsive disease and has been successful. Early data have suggested enhanced osseous wound healing with teriparatide in those without contraindications for its use. Experimental therapy includes bone marrow stem cell intralesional transplantation, low-level laser therapy, local platelet-derived growth factor application, hyperbaric oxygen, and tissue grafting.
57Interventions for managing medication-related osteonecrosis of the jaw.PubMed
Natalie H Beth-Tasdogan, Benjamin Mayer, Heba Hussein, et al.
Cochrane Database Syst Rev. 2022 Jul 12;7(7):CD012432. doi: 10.1002/14651858.CD012432.pub3.
BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction experienced by some individuals to certain medicines commonly used in the treatment of cancer and osteoporosis (e.g. bisphosphonates, denosumab, and antiangiogenic agents), and involves the progressive destruction of bone in the mandible or maxilla. Depending on the drug, its dosage, and the duration of exposure, this adverse drug reaction may occur rarely (e.g. following the oral administration of bisphosphonate or denosumab treatments for osteoporosis, or antiangiogenic agent-targeted cancer treatment), or commonly (e.g. following intravenous bisphosphonate for cancer treatment). MRONJ is associated with significant morbidity, adversely affects quality of life (QoL), and is challenging to treat. This is an update of our review first published in 2017. OBJECTIVES: To assess the effects of interventions versus no treatment, placebo, or an active control for the prophylaxis of MRONJ in people exposed to antiresorptive or antiangiogenic drugs. To assess the effects of non-surgical or surgical interventions (either singly or in combination) versus no treatment, placebo, or an active control for the treatment of people with manifest MRONJ. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched four bibliographic databases up to 16 June 2021 and used additional search methods to identify published, unpublished, and ongoing studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing one modality of intervention with another for the prevention or treatment of MRONJ. For 'prophylaxis of MRONJ', the primary outcome of interest was the incidence of MRONJ; secondary outcomes were QoL, time-to-event, and rate of complications and side effects of the intervention. For 'treatment of established MRONJ', the primary outcome of interest was healing of MRONJ; secondary outcomes were QoL, recurrence, and rate of complications and side effects of the intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, extracted the data, and assessed the risk of bias in the included studies. For dichotomous outcomes, we reported the risk ratio (RR) (or rate ratio) and 95% confidence intervals (CIs). MAIN RESULTS: We included 13 RCTs (1668 participants) in this updated review, of which eight were new additions. The studies were clinically diverse and examined very different interventions, so meta-analyses could not be performed. We have low or very low certainty about available evidence on interventions for the prophylaxis or treatment of MRONJ. Prophylaxis of MRONJ Five RCTs examined different interventions to prevent the occurrence of MRONJ. One RCT compared standard care with regular dental examinations at three-month intervals and preventive treatments (including antibiotics before dental extractions and the use of techniques for wound closure that avoid exposure and contamination of bone) in men with metastatic prostate cancer treated with zoledronic acid. The intervention seemed to lower the risk of MRONJ (RR 0.10, 95% CI 0.02 to 0.39, 253 participants). Secondary outcomes were not evaluated. Dentoalveolar surgery is considered a common predisposing event for developing MRONJ and five RCTs tested various preventive measures to reduce the risk of postoperative MRONJ. The studies evaluated plasma rich in growth factors inserted into the postextraction alveolus in addition to standardised medical and surgical care versus standardised medical and surgical care alone (RR 0.08, 95% CI 0.00 to 1.51, 176 participants); delicate surgery and closure by primary intention versus non-traumatic tooth avulsion and closure by secondary intention (no case of postoperative MRONJ in either group); primary closure of the extraction socket with a mucoperiosteal flap versus application of platelet-rich fibrin without primary wound closure (no case of postoperative MRONJ in either group); and subperiosteal wound closure versus epiperiosteal wound closure (RR 0.09, 95% CI 0.00 to 1.56, 132 participants). Treatment of MRONJ Eight RCTs examined different interventions for the treatment of established MRONJ; that is, the effect on MRONJ cure rates. One RCT analysed hyperbaric oxygen (HBO) treatment used in addition to standard care (antiseptic rinses, antibiotics, and surgery) compared with standard care alone (at last follow-up: RR 1.56, 95% CI 0.77 to 3.18, 46 participants). Healing rates from MRONJ were not significantly different between autofluorescence-guided bone surgery and conventional bone surgery (RR 1.08, 95% CI 0.85 to 1.37, 30 participants). Another RCT that compared autofluorescence- with tetracycline fluorescence-guided sequestrectomy for the surgical treatment of MRONJ found no significant difference (at one-year follow-up: RR 1.05, 95% CI 0.86 to 1.30, 34 participants). Three RCTs investigated the effect of growth factors and autologous platelet concentrates on healing rates of MRONJ: platelet-rich fibrin after bone surgery versus surgery alone (RR 1.05, 95% CI 0.90 to 1.22, 47 participants), bone morphogenetic protein-2 together with platelet-rich fibrin versus platelet-rich fibrin alone (RR 1.10, 95% CI 0.94 to 1.29, 55 participants), and concentrated growth factor and primary wound closure versus primary wound closure only (RR 1.38, 95% CI 0.81 to 2.34, 28 participants). Two RCTs focused on pharmacological treatment with teriparatide: teriparatide 20 μg daily versus placebo in addition to standard care (RR 0.96, 95% CI 0.31 to 2.95, 33 participants) and teriparatide 56.5 μg weekly versus teriparatide 20 μg daily in addition to standard care (RR 1.60, 95% CI 0.25 to 1.44, 12 participants). AUTHORS CONCLUSIONS: Prophylaxis of medication-related osteonecrosis of the jaw One open-label RCT provided some evidence that dental examinations at three-month intervals and preventive treatments may be more effective than standard care for reducing the incidence of medication-related osteonecrosis of the jaw (MRONJ) in individuals taking intravenous bisphosphonates for advanced cancer. We assessed the certainty of the evidence to be very low. There is insufficient evidence to either claim or refute a benefit of the interventions tested for prophylaxis of MRONJ in patients with antiresorptive therapy undergoing dentoalveolar surgery. Although some interventions suggested a potential large effect, the studies were underpowered to show statistical significance, and replication of the results in larger studies is pending. Treatment of medication-related osteonecrosis of the jaw The available evidence is insufficient to either claim or refute a benefit, in addition to standard care, of any of the interventions studied for the treatment of MRONJ.
58Osteonecrosis of the jaw (ONJ): diagnosis and management in 2015.PubMed
A Khan, A Morrison, A Cheung, et al.
Osteoporos Int. 2016 Mar;27(3):853-859. doi: 10.1007/s00198-015-3335-3. Epub 2015 Oct 22.
Osteonecrosis of the jaw (ONJ) has been associated with the use of aminobisphosphonates and denosumab. The vast majority (>90%) of cases occur in the oncology patient population receiving high doses of intravenous bisphosphonates or subcutaneous denosumab. The incidence of ONJ in the osteoporosis patient population is very low and is estimated at 1-90 per 100,000 patient-years of exposure. In the oncology patient population the incidence appears to be related to dose and duration of exposure, and prevalence has been estimated to be as high as 18.6%. A number of risk factors in addition to antiresorptive therapy have been identified. These include the presence of periodontal disease, oral surgical procedures with extractions or implants, radiation therapy, chemotherapy, diabetes, glucocorticoid use, and smoking. Antiangiogenic agents appear to contribute to the risk of ONJ, however, data at this time are limited and further evidence is required prior to confirming a causal relationship. ONJ may be prevented with optimization of oral hygiene, the use of oral antimicrobial mouth rinses, as well as systemic antibiotic therapy. Individuals not responding to conservative management or in the advanced stages of ONJ may be considered for surgery, as data over the past several years have demonstrated surgical success in this patient population. Case reports have indicated that teriparatide may enhance healing. A number of experimental therapies are being evaluated and include the use of bone marrow stem cell intralesional transplantation, local application of platelet-derived growth factor, hyperbaric oxygen, tissue grafting, and low-level laser therapy. This paper summarizes the current research as well as the international consensus on the diagnosis and management of ONJ.
59Severe Hypocalcemia With Denosumab Among Older Female Dialysis-Dependent Patients.PubMed
Steven T Bird, Elizabeth R Smith, Kate Gelperin, et al.
JAMA. 2024 Feb 13;331(6):491-499. doi: 10.1001/jama.2023.28239.
IMPORTANCE: Dialysis-dependent patients experience high rates of morbidity from fractures, yet little evidence is available on optimal treatment strategies. Chronic kidney disease-mineral and bone disorder is nearly universal in dialysis-dependent patients, complicating diagnosis and treatment of skeletal fragility. OBJECTIVE: To examine the incidence and comparative risk of severe hypocalcemia with denosumab compared with oral bisphosphonates among dialysis-dependent patients treated for osteoporosis. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of female dialysis-dependent Medicare patients aged 65 years or older who initiated treatment with denosumab or oral bisphosphonates from 2013 to 2020. Clinical performance measures including monthly serum calcium were obtained through linkage to the Consolidated Renal Operations in a Web-Enabled Network database. EXPOSURES: Denosumab, 60 mg, or oral bisphosphonates. MAIN OUTCOMES AND MEASURES: Severe hypocalcemia was defined as total albumin-corrected serum calcium below 7.5 mg/dL (1.88 mmol/L) or a primary hospital or emergency department hypocalcemia diagnosis (emergent care). Very severe hypocalcemia (serum calcium below 6.5 mg/dL [1.63 mmol/L] or emergent care) was also assessed. Inverse probability of treatment-weighted cumulative incidence, weighted risk differences, and weighted risk ratios were calculated during the first 12 treatment weeks. RESULTS: In the unweighted cohorts, 607 of 1523 denosumab-treated patients and 23 of 1281 oral bisphosphonate-treated patients developed severe hypocalcemia. The 12-week weighted cumulative incidence of severe hypocalcemia was 41.1% with denosumab vs 2.0% with oral bisphosphonates (weighted risk difference, 39.1% [95% CI, 36.3%-41.9%]; weighted risk ratio, 20.7 [95% CI, 13.2-41.2]). The 12-week weighted cumulative incidence of very severe hypocalcemia was also increased with denosumab (10.9%) vs oral bisphosphonates (0.4%) (weighted risk difference, 10.5% [95% CI, 8.8%-12.0%]; weighted risk ratio, 26.4 [95% CI, 9.7-449.5]). CONCLUSIONS AND RELEVANCE: Denosumab was associated with a markedly higher incidence of severe and very severe hypocalcemia in female dialysis-dependent patients aged 65 years or older compared with oral bisphosphonates. Given the complexity of diagnosing the underlying bone pathophysiology in dialysis-dependent patients, the high risk posed by denosumab in this population, and the complex strategies required to monitor and treat severe hypocalcemia, denosumab should be administered after careful patient selection and with plans for frequent monitoring.
60Denosumab in osteoporosis.PubMed
Dima L Diab, Nelson B Watts
Expert Opin Drug Saf. 2014 Feb;13(2):247-53. doi: 10.1517/14740338.2014.860133. Epub 2013 Dec 2.
INTRODUCTION: Denosumab is a fully human monoclonal antibody against the receptor activator of nuclear factor kappa-B ligand. It is an antiresorptive agent that reduces osteoclastogenesis. AREAS COVERED: This drug evaluation reviews denosumab for use in osteoporosis. Denosumab has been shown to improve bone mineral density (BMD) and to reduce the incidence of new vertebral, hip and nonvertebral fractures in postmenopausal women. It prevents bone loss and reduces vertebral fracture risk in men with nonmetastatic prostate cancer who are receiving androgen deprivation therapy. It has also been shown to improve BMD in men with osteoporosis unrelated to androgen deprivation therapy. Safety concerns include infections, cancer, skin reactions, cardiovascular disease, hypocalcemia, osteonecrosis of the jaw and atypical femur fractures. EXPERT OPINION: Although bisphosphonates are typically preferred as initial therapy for osteoporosis, denosumab could be used as initial therapy in select patients at high risk for fracture, including older patients who have difficulty with the dosing requirements of oral bisphosphonates, patients who are intolerant of or unresponsive to other therapies, and in those with impaired renal function. Additional data is needed to address issues regarding treatment duration and discontinuation, as well as to provide more information regarding denosumab's efficacy and safety.
61Cardiovascular Safety and Sclerostin Inhibition.PubMed
Bente Lomholt Langdahl, Lorenz Christian Hofbauer, John Colin Forfar
J Clin Endocrinol Metab. 2021 Jun 16;106(7):1845-1853. doi: 10.1210/clinem/dgab193.
Sclerostin, which is primarily produced by the osteocytes, inhibits the canonical Wnt pathway and thereby the osteoblasts and stimulates RANKL release by the osteocytes and thereby osteoclast recruitment. Inhibition of sclerostin therefore causes stimulation of bone formation and inhibition of resorption. In clinical trials, romosozumab, an antibody against sclerostin, increases bone mineral density and reduces the risk of fractures compared with placebo and alendronate. The cardiovascular safety of romosozumab was adjudicated in 2 large clinical osteoporosis trials in postmenopausal women. Compared with placebo, the incidence of cardiovascular events was similar in the 2 treatment groups. Compared with alendronate, the incidence of serious cardiovascular events was higher in women treated with romosozumab. The incidence of serious cardiovascular adverse events was low and post hoc analyses should therefore be interpreted with caution; however, the relative risk seemed unaffected by preexisting cardiovascular disease or risk factors. Sclerostin is expressed in the vasculature, predominantly in vascular smooth muscle cells in the media. However, preclinical and genetic studies have not demonstrated any increased cardiovascular risk with continuously low sclerostin levels or inhibition of sclerostin. Furthermore, no potential mechanisms for such an effect have been identified. In conclusion, while there is no preclinical or genetic evidence of a harmful effect of sclerostin inhibition on cardiovascular safety, the evidence from the large clinical trials in postmenopausal women is conflicting. Romosozumab should therefore be used for the treatment of postmenopausal women with osteoporosis at high risk of fracture after careful consideration of the cardiovascular risk and the balance between benefits and risks.
62Role of Sclerostin in Cardiovascular System.PubMed
Ning Zhang, Luyao Wang, Xiaofei Li, et al.
Int J Mol Sci. 2025 May 9;26(10):4552. doi: 10.3390/ijms26104552.
Sclerostin, encoded by the gene, is a novel bone anabolic target for bone diseases. Humanized anti-sclerostin antibody, romosozumab, was approved for treatment of postmenopausal osteoporosis by the US Food and Drug Administration (FDA), but with a black-box warning on cardiovascular risk. The clinical data regarding cardiovascular events from various pre-marketing and post-marketing studies of romosozumab were inconsistent. Overall, the cardiovascular risk of sclerostin inhibition could not be excluded. The restriction of romosozumab in patients with cardiovascular disease history would be necessary. Moreover, genome-wide association study (GWAS) analyses of variants revealed inconsistent results of the association between variations and cardiovascular diseases. Further research incorporating larger sample sizes and functional analyses are necessary. In analyses of serum/tissue sclerostin levels in patients with cardiovascular diseases, the results were controversial but indicated an association between sclerostin and the presence/severity/outcomes of cardiovascular diseases. Nonclinical studies in rodents indicated the inhibitory effect of sclerostin on inflammation, aortic aneurysm, atherosclerosis, and vascular calcification. Sclerostin loop3 participated in the inhibitory effect of sclerostin on bone formation, while the cardiovascular protective effect of sclerostin was independent of sclerostin loop3. Macrophagic sclerostin loop2-apolipoprotein E receptor 2 (ApoER2) interaction participated in the inhibitory effect of sclerostin on inflammation in vitro. Sclerostin in human aortic smooth muscle cells participated in the reduction in calcium deposition. The role of sclerostin in cardiovascular system deserves further investigation.
63Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice.PubMed
Luyao Wang, Yuanyuan Yu, Shuaijian Ni, et al.
Theranostics. 2022 Jul 18;12(13):5645-5674. doi: 10.7150/thno.63177. eCollection 2022.
Sclerostin inhibition demonstrated bone anabolic potential in osteogenesis imperfecta (OI) mice, whereas humanized therapeutic sclerostin antibody romosozumab for postmenopausal osteoporosis imposed clinically severe cardiac ischemic events. Therefore, it is desirable to develop the next generation sclerostin inhibitors to promote bone formation without increasing cardiovascular risk for OI. Our data showed that sclerostin suppressed inflammatory responses, prevented aortic aneurysm (AA) and atherosclerosis progression in mice. Either loop2&3 deficiency or inhibition attenuated sclerostin's suppressive effects on expression of inflammatory cytokines and chemokines , whilst loop3 deficiency maintained the protective effect of sclerostin on cardiovascular system both and . Moreover, loop3 was critical for sclerostin's antagonistic effect on bone formation in mice. Accordingly, a sclerostin loop3-specific aptamer aptscl56 was identified by our lab. It could recognize both recombinant sclerostin and sclerostin in the serum of OI patients via targeting loop3. PEG40k conjugated aptscl56 (Apc001PE) demonstrated to promote bone formation, increase bone mass and improve bone microarchitecture integrity in mice via targeting loop3, while did not show influence in inflammatory response, AA and atherosclerosis progression in mice with Angiotensin II infusion. Further, Apc001PE had no influence in the protective effect of sclerostin on cardiovascular system in mice, while it inhibited the antagonistic effect of sclerostin on bone formation in mice via targeting loop3. Apc001PE was non-toxic to healthy rodents, even at ultrahigh dose. Apc001PE for OI was granted orphan drug designation by US-FDA in 2019 (DRU-2019-6966). Sclerostin loop3-specific aptamer Apc001PE promoted bone formation without increasing cardiovascular risk in OI mice.
64Bisphosphonate-associated adverse events.PubMed
Peter D Papapetrou
Hormones (Athens). 2009 Apr-Jun;8(2):96-110. doi: 10.14310/horm.2002.1226.
The adverse events of the nitrogen-containing bisphosphonates are reviewed. Oral bisphosphonates (alendronate, risedronate and ibandronate), mainly used for the treatment of osteoporosis, have been associated with adverse events from the upper gastrointestinal tract, acute phase response, hypocalcaemia and secondary hyperparathyroidism, musculoskeletal pain, osteonecrosis of the jaw and ocular events. Intravenous bisphosphonates (pamidronate, ibandronate and zoledronic acid), used in oncology and for the treatment of osteoporosis, have been associated with all the above adverse events, except those from the upper gastrointestinal tract. Moreover, pamidronate and zoledronic acid have been associated with renal toxicity. Association of bisphosphonates with atrial fibrillation and atypical fractures of the femoral diaphysis remains uncertain. There are a few case reports relating bisphosphonates to cutaneous reactions, oral ulcerations, hepatitis and esophageal cancer. Generally, intravenous are more potent than oral bisphosphonates and the frequency and severity of some of the bisphosphonate- associated adverse events are dose and potency dependent.
65Oral bisphosphonates and upper gastrointestinal tract problems: what is the evidence?PubMed
Byron Cryer, Douglas C Bauer
Mayo Clin Proc. 2002 Oct;77(10):1031-43. doi: 10.4065/77.10.1031.
OBJECTIVE: To review and evaluate the evidence regarding possible associations of bisphosphonate use with upper gastrointestinal (GI) tract adverse events (AEs). METHODS: We reviewed and summarized published information and abstracts regarding upper GI tract safety and tolerability of bisphosphonates, including laboratory and animal studies, epidemiological (observational) studies, endoscopy studies, and randomized controlled trials (RCTs). The evidence was summarized by using the principles of evidence-based medicine, giving the greatest credence to high-quality RCTs. RESULTS: Clinical reports of esophagitis associated with bisphosphonate use appear to have declined in frequency once the importance of proper administration was explained to physicians after early reports of complications. Conflicting results have been reported in endoscopy studies; some reported no significant increase in upper GI tract lesions, whereas others reported a higher incidence of gastric (but not esophageal) lesions among patients taking oral bisphosphonates. Endoscopy studies that reported differences were of short duration (2 weeks) and were not of double-blind design. Results from large RCTs involving thousands of participants detected no increase in upper GI tract AEs among individuals treated with bisphosphonates. Other studies of patients who discontinued taking bisphosphonates and were randomized to blinded re-treatment with either a bisphosphonate or placebo show that most patients (>85%) were able to continue treatment, with no difference in AEs between the bisphosphonate and placebo groups. CONCLUSIONS: The highest level of evidence, RCTs, suggests little or no increase in risk of upper GI tract problems if bisphosphonates are administered properly. Upper GI tract symptoms are common among patients with osteoporosis. The evidence suggests that many upper GI tract AEs reported during therapy with bisphosphonates may reflect a high background incidence of upper GI tract complaints and an increased sensitivity to detection rather than a causal relationship to therapy.
66Safety of bisphosphonates.PubMed
Michael Pazianas, Bo Abrahamsen
Bone. 2011 Jul;49(1):103-10. doi: 10.1016/j.bone.2011.01.003. Epub 2011 Jan 12.
Bisphosphonates are one of the most well studied groups of medications and they are bone specific. This tissue specificity is a rare property for a drug introduced into clinical practice as long as 40 years ago. Over the years, the therapeutic boundaries of bisphosphonates were explored and their safety profile has withstood the challenges of the harsh clinical reality and widespread use. Certainly, the esophageal or gastric irritation caused by the oral preparations is an established adverse effect, the risk of which can be reduced by the recommended routine of taking the medication. From the other reported associations with adverse events, osteonecrosis of the jaw (ONJ) and subtrochanteric fractures have attracted most of the attention mainly because their pathophysiology remains unclear. However, overall, only a very small proportion of patients treated with bisphosphonates, especially with the oral formulations, experience adverse events and the overall benefits have consistently outweighed their potential risks. Furthermore, bisphosphonates improve the quality of life in patients with metastatic bone cancer and delay the development of adverse skeletal effects.
67Antiresorptives and osteonecrosis of the jaw.PubMed
Junro Yamashita, Laurie K McCauley
J Evid Based Dent Pract. 2012 Sep;12(3 Suppl):233-47. doi: 10.1016/S1532-3382(12)70046-5.
Osteonecrosis of the jaw (ONJ) is an uncommon condition noted to occur in patients who are receiving osteoclast-targeted antiresorptive therapy. The incidence of ONJ in patients taking oral antiresorptives for the management of osteoporosis is low (approximately 1:100,000), whereas it is higher (∼10%) in patients taking intravenous bisphosphonates for the treatment of metastatic bone diseases. The etiology and pathophysiology of ONJ is unclear. No established preventive or treatment modalities are currently available. Although ONJ is a rare condition, it is imperative for oral care providers to have updated knowledge, as a large number of patients on antiresorptives are seeking oral care. In this comprehensive review, we focus on ONJ and bisphosphonate therapy and dissect the currently available evidence to establish a clinical approach to assess risk, preventive measures, and management of ONJ.
68Safety of drugs used in the treatment of osteoporosis.PubMed
Cora McGreevy, David Williams
Ther Adv Drug Saf. 2011 Aug;2(4):159-72. doi: 10.1177/2042098611411012.
A number of drug classes are licensed for the treatment of osteoporosis including bisphosphonates, recombinant human parathyroid hormone (PTH), strontium, hormone replacement therapy (HRT), selective oestrogen receptor modulators (SERMS) and denosumab. This review discusses the safety of osteoporosis treatments and their efficacies. Recent concerns about the safety of calcium and high-dose vitamin D are discussed. Bisphosphonates have substantial postmarketing experience and a clearer picture of safety issues is emerging. Along with the well recognized effects on the gastrointestinal tract and kidney function, recently described adverse effects such as osteonecrosis of the jaw, oesophageal cancer, atrial fibrillation, subtrochanteric femur fractures and ocular complications of bisphosphonate therapy are discussed. Therapy with PTH is limited to two years' duration because of the development of osteogenic sarcomas in animal studies, which appeared related to dose, duration and timing of therapy. Strontium should be used with caution in patients with renal impairment and its use has been associated with venous thromboembolism. The role of HRT and SERMs in the treatment of postmenopausal osteoporosis is restricted as a result of an increased risk of stroke, venous thromboembolism and breast cancer. Postmarketing experience with denusomab is limited but a number of potential safety concerns including osteonecrosis of the jaw are emerging. All of these drugs have been proven to reduce fractures. The decision to use a drug to reduce fracture risk should be based on risk-benefit analysis of the drug and its suitability for individual patients.
69Safety and effectiveness of daily teriparatide for osteoporosis in patients with severe stages of chronic kidney disease: post hoc analysis of a postmarketing observational study.PubMed
Atsushi Nishikawa, Fumito Yoshiki, Masanori Taketsuna, et al.
Clin Interv Aging. 2016 Nov 15;11:1653-1659. doi: 10.2147/CIA.S120175. eCollection 2016.
Teriparatide (recombinant 1-34 N-terminal sequence of human parathyroid hormone) for the treatment of osteoporosis should be prescribed with caution in patients with severe stages of chronic kidney disease (CKD). However, in clinical settings, physicians and surgeons who treat such patients have few available options. We sought to further explore the safety and effectiveness of teriparatide for the treatment of osteoporosis in Japanese patients with severe stages of CKD. This was a post hoc analysis of a postmarketing surveillance study that included patients with osteoporosis at high risk of fracture and stage 4 or 5 CKD. Patients received subcutaneous teriparatide 20 μg daily for up to 24 months. Safety profiles were assessed by physician-reported adverse drug reactions (ADRs). Effectiveness was assessed by measuring bone formation (via procollagen type 1 N-terminal propeptide [P1NP]), bone mineral density (BMD), and the incidence of clinical vertebral or nonvertebral fragility fractures. A total of 33 patients with severe stages of CKD (stage 4, n=30; stage 5, n=3) were included. All patients were female, and 81.8% had a history of previous fracture. No serious ADRs were recorded; a total of 4 ADRs were recorded for 4 of 33 patients. Increases in BMD and P1NP levels were observed both overall and in most individual patients. New fractures occurred in 1 patient with stage 5 CKD, but not in patients with stage 4 CKD. In this post hoc analysis conducted in Japan, teriparatide appeared to be effective for the treatment of osteoporosis in elderly female patients with severe stages of CKD, and no new safety concerns were observed.
70Teriparatide and bone turnover and formation in a hemodialysis patient with low-turnover bone disease: a case report.PubMed
Patricia Palcu, Natalie Dion, Louis-Georges Ste-Marie, et al.
Am J Kidney Dis. 2015 Jun;65(6):933-6. doi: 10.1053/j.ajkd.2015.01.025. Epub 2015 Apr 2.
Teriparatide, a recombinant form of parathyroid hormone, is an anabolic agent approved for use in women and men with osteoporosis. However, it is not well studied in people with chronic kidney disease (CKD). We report on a patient with stage 5 CKD treated with dialysis who presented to our clinic with multiple fractures, including bilateral nondisplaced pelvic fractures resulting in chronic pain and interfering with the patient's ability to work. Bone histomorphometry demonstrated low-turnover bone disease, and he was treated with 20μg of teriparatide (subcutaneous injection) every morning for 24 months. Within 6 months of initiating therapy, the patient's pain resolved and he was able to resume work. Serum calcium and phosphate levels remained within reference ranges throughout his treatment, and he sustained no further fractures. During 24 months of treatment, bone mineral density was maintained at the lumbar spine, and there was an increase of 4% at the femoral neck and total hip. A second transiliac bone biopsy demonstrated improvements in static and dynamic parameters of bone formation. In our patient, 24-month treatment with teriparatide was safe and effective; however, larger studies are needed to determine the efficacy of teriparatide in the dialysis-dependent CKD population.
71Medication safety in chronic kidney disease.PubMed
Sonal Singh
Curr Opin Nephrol Hypertens. 2023 Sep 1;32(5):434-438. doi: 10.1097/MNH.0000000000000907. Epub 2023 Jun 8.
PURPOSE OF REVIEW: Several drugs cause nephrotoxicity and accelerate progression of chronic kidney disease (CKD). The objective of this review is to summarize recent evidence on drugs that either increase the risk of nephrotoxicity, progression of CKD or drug induced harm in patients with CKD. RECENT FINDINGS: Bisphosphonates and hypnotics increase the progression of CKD, whereas denosumab does not accelerate progression of CKD. Tenofovir disoproxil fumarate (TDF) increases the risk of renal tubular toxicity and adverse effects on bone, but Tenofovir alafenamide (TAF) and Tenofovir amibufenamide (TMF) have favorable safety profile on the kidneys and bones. Although no dosage adjustment is needed for Oral Nirmatrelvir/Ritonavir in patients with mild renal impairment and coronavirus disease 2019, the dosage is reduced to twice daily in those with moderate renal impairment. It is not recommended in patients with severe renal impairment. The prescribing information does not recommend use of remdesevir below glomerular filtration rate (eGFR) < 30 ml/min but recent studies suggest that remdesevir may be safe and effective in patients with varying levels of CKD severity. Molnupiravir does not require dose adjustment in patients with CKD. SUMMARY: Several medications increase the risk of development of acute kidney injury or progression of CKD. Close attention is needed to select the appropriate dose or safer alternatives to reduce the risk of drug-induced harm in patients with CKD.
72Cardiovascular Safety and Fracture Prevention Effectiveness of Denosumab Versus Oral Bisphosphonates in Patients Receiving Dialysis : A Target Trial Emulation.PubMed
Soichiro Masuda, Toshiki Fukasawa, Shuichi Matsuda, et al.
Ann Intern Med. 2025 Feb;178(2):167-176. doi: 10.7326/ANNALS-24-03237. Epub 2025 Jan 7.
BACKGROUND: Dialysis patients have high rates of fracture morbidity, but evidence on optimal management strategies for osteoporosis is scarce. OBJECTIVE: To determine the risk for cardiovascular events and fracture prevention effects with denosumab compared with oral bisphosphonates in dialysis-dependent patients. DESIGN: An observational study that attempts to emulate a target trial. SETTING: A Japanese administrative claims database (April 2014 to October 2022). PATIENTS: Adults aged 50 years or older who have initiated denosumab or oral bisphosphonates for osteoporosis in dialysis-dependent patients. MEASUREMENTS: The safety outcome was major adverse cardiac events (MACE). The effectiveness outcome was a composite of all fractures. Follow-up was 3 years. RESULTS: A total of 1032 patients were identified (658 denosumab users and 374 oral bisphosphonate users). Overall average age was 74.5 years, and 62.9% were women. The weighted 3-year risk difference for MACE was 8.2% (95% CI, -0.2% to 16.7%), with a weighted 3-year risk ratio of 1.36 (CI, 0.99 to 1.87). The weighted 3-year risk difference for composite fractures was -5.3% (CI, -11.3% to -0.6%), and the weighted 3-year risk ratio was 0.55 (CI, 0.28 to 0.93). LIMITATIONS: Lack of clinical data on kidney or osteoporosis disease severity and cardiovascular or other metabolic risk with residual confounding. Safety outcomes did not include kidney end points. CONCLUSION: It was estimated that, compared with oral bisphosphonates, denosumab lowered the risk for fractures by 45% and increased the risk for MACE by 36%. The estimates, however, are imprecise and need to be confirmed in future studies. PRIMARY FUNDING SOURCE: None.
73Romosozumab for the treatment of osteoporosis in women: Efficacy, safety, and cardiovascular risk.PubMed
Sian Yik Lim
Womens Health (Lond). 2022 Jan-Dec;18:17455057221125577. doi: 10.1177/17455057221125577.
Increased understanding of the Wnt signaling pathway has led to the development of romosozumab, one of the most potent osteoanabolic agents to date for osteoporosis treatment. Romosozumab is a monoclonal antibody that inhibits sclerostin, a natural inhibitor of the Wnt signaling pathway. Romosozumab, by inhibiting sclerostin activates the Wnt signaling pathway, leading to increased bone formation and decreased bone resorption. The pivotal ARCH and FRAME studies established romosozumab's fracture reduction efficacy. Romosozumab was superior to alendronate in fracture reduction and bone mineral density gain in the ARCH study. Romosozumab treatment should be followed sequentially with a potent antiresorptive agent. The antifracture efficacy gained from romosozumab is maintained or improved after transitioning to an antiresorptive agent. As one of the most potent osteoanabolic agents, the introduction of romosozumab has significantly increased our ability to treat osteoporosis. Studies have provided important information on using romosozumab with other osteoporosis medications to optimize osteoporosis treatment. Romosozumab used before antiresorptive medications is associated with more significant bone mineral density increases than when an antiresorptive agent is used before romosozumab. Romosozumab is recommended for osteoporosis treatment in patients at very high risk for fracture with low cardiovascular risk. Romosozumab is generally well tolerated, with 4%-5% of patients having injection site reactions. The ARCH trial showed a higher risk of cardiovascular events in patients receiving romosozumab. Romosozumab carries a black box warning that romosozumab should not be initiated in patients with myocardial infarction or stroke in the preceding year. However, the information on romosozumab and increased cardiovascular risk is conflicting. The risk of cardiovascular disease with romosozumab is unclear. While romosozumab has demonstrated significant osteoanabolic effect and antifracture efficacy and will benefit high fracture risk patients, further studies are needed to investigate the cardiovascular safety of romosozumab.
74What Animal Models Have Taught Us About the Safety and Efficacy of Bisphosphonates in Chronic Kidney Disease.PubMed
Matthew R Allen, Mohammad W Aref
Curr Osteoporos Rep. 2017 Jun;15(3):171-177. doi: 10.1007/s11914-017-0361-4.
PURPOSE OF REVIEW: Bisphosphonates (BPs) have long been the gold-standard anti-remodeling treatment for numerous metabolic bone diseases. Since these drugs are excreted unmetabolized through the kidney, they are not recommended for individuals with compromised kidney function due to concerns of kidney and bone toxicity. The goal of this paper is to summarize the preclinical BP work in models of kidney disease with particular focus on the bone, kidney, and vasculature. RECENT FINDINGS: Summative data exists showing positive effects on bone and vascular calcifications with minimal evidence for bone or kidney toxicity in animal models. Preclinical data suggest it may be worthwhile to take a step back and reconsider the use of bisphosphonates to lessen skeletal/vascular complications associated with compromised kidney function.
75Bisphosphonates in dialysis and transplantation patients: efficacy and safety issues.PubMed
C Rodd
Perit Dial Int. 2001;21 Suppl 3:S256-60.
Bisphosphonates are an old class of compounds. They were used in the 1930s as antiscaling and anticorrosion agents in washing powders and water to prevent the deposition of calcium crystals. Those basic functions were later utilized in an attempt to prevent ectopic calcifications in humans. The early studies demonstrated that bisphosphonates had a strong affinity for bone. That property was first exploited when the compounds were used for "bone scans." Currently, the drugs are used for treatment of hypercalcemic conditions, abnormal bone remodelling, Paget disease, malignancy, and osteoporosis. Bisphosphonates have several important toxicities: acute renal failure, worsening renal function, reduced bone mineralization, and osteomalacia. For those reasons and others, this class of drugs has not yet been approved for use in children or in patients with severe renal insufficiency. The present review covers several aspects of bisphosphonates: molecular structure, routes of administration, pharmacology, mechanisms of action, toxicities, and exceptional uses in children with renal disease.
76Safety of Oral Bisphosphonates in Moderate-to-Severe Chronic Kidney Disease: A Binational Cohort Analysis.PubMed
Danielle E Robinson, M Sanni Ali, Natalia Pallares, et al.
J Bone Miner Res. 2021 May;36(5):820-832. doi: 10.1002/jbmr.4235. Epub 2021 Feb 8.
Bisphosphonates are the first-line treatment for preventing fractures in osteoporosis patients. However, their use is contraindicated or to be used with caution in chronic kidney disease (CKD) patients, primarily because of a lack of information about their safety and effectiveness. We aimed to investigate the safety of oral bisphosphonates in patients with moderate to severe CKD, using primary-care electronic records from two cohorts, CPRD GOLD (1997-2016) and SIDIAP (2007-2015) in the UK and Catalonia, respectively. Both databases were linked to hospital records. SIDIAP was also linked to end-stage renal disease registry data. Patients with CKD stages 3b to 5, based on two or more estimated glomerular filtration rate measurements less than 45 mL/min/1.73 m , aged 40 years or older were identified. New bisphosphonate users were propensity score-matched with up to five non-users to minimize confounding within this population. Our primary outcome was CKD stage worsening (estimated glomerular filtration rate [eGFR] decline or renal replacement therapy). Secondary outcomes were acute kidney injury, gastrointestinal bleeding/ulcers, and severe hypocalcemia. Hazard ratios (HRs) were estimated using Cox regression and Fine and Gray sub-HRs were calculated for competing risks. We matched 2447 bisphosphonate users with 8931 non-users from CPRD and 1399 users with 6547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in CPRD (sub-HR [95% CI]: 1.14 [1.04, 1.26]) and SIDIAP (sub-HR: 1.15 [1.04, 1.27]). No risk differences were found for acute kidney injury, gastrointestinal bleeding/ulcers, or hypocalcemia. Hence, we can conclude a modest (15%) increased risk of CKD progression was identified in association with bisphosphonate use. No other safety concerns were identified. Our findings should be considered before prescribing bisphosphonates to patients with moderate to severe CKD. © 2020 American Society for Bone and Mineral Research (ASBMR).
77Renal safety of ibandronate.PubMed
Graham H Jackson
Oncologist. 2005;10 Suppl 1:14-8. doi: 10.1634/theoncologist.10-90001-14.
Despite their efficacy in treating complications associated with metastatic bone disease, there are concerns about the potential nephrotoxicity of certain i.v. bisphosphonates for the long-term management of cancer patients. Clinical data suggest, however, that i.v. ibandronate (Bondronat); F. Hoffman-La Roche Ltd., Basel, Switzerland, http://www.roche.com), unlike other bisphosphonates, has a renal safety profile comparable with that of placebo. In a 2-year, phase III study of patients with breast cancer metastatic to bone, the incidence of adverse renal events in patients treated with 6 mg i.v. ibandronate was low and comparable with that of placebo (4% versus 4.5% with placebo). Two-year assessments of time to serum creatinine increase also demonstrated renal safety comparable with that of placebo (patients with creatinine increase: 6% versus 12% with placebo). Long-term (4-year) renal safety of ibandronate was demonstrated in a 2-year extension of the trial. Phase II, open-label studies show that intensive ibandronate dosing does not compromise renal safety in patients with metastatic bone pain from a variety of tumor types. In addition, i.v. ibandronate is well tolerated, with no evidence of renal toxicity in multiple myeloma and urologic cancer patients with existing renal impairment. The potential nephrotoxicity of some bisphosphonates has prompted additional renal safety precautions in product labeling for these agents. The precautions are not, however, contained in the label for ibandronate, which may thus simplify patient management.
78Cardiovascular Safety of Romosozumab Compared to Commonly Used Anti-osteoporosis Medications in Postmenopausal Osteoporosis: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials.PubMed
Shih-Hao Cheng, William Chu, Wen-Hsiang Chou, et al.
Drug Saf. 2025 Jan;48(1):7-23. doi: 10.1007/s40264-024-01475-9. Epub 2024 Sep 3.
INTRODUCTION: The aim of this study was to investigate the cardiovascular safety of romosozumab in postmenopausal women with osteoporosis. Romosozumab, a monoclonal antibody targeting sclerostin, has been shown to increase bone mineral density and reduce the risk of osteoporotic fractures. However, in previous studies, romosozumab therapy was identified as a potential risk factor for cardiovascular events, particularly in patients with predisposing cardiovascular disease. METHODS: A systematic literature search was performed in the Cochrane Library, Embase, PubMed, and Web of Science databases to identify randomized controlled trials (RCTs) comparing the safety and efficacy of romosozumab versus alendronate, teriparatide, denosumab, or placebo in postmenopausal women with osteoporosis. Contrast-based network meta-analysis was performed using a random-effects model. The pooled estimates are presented as risk ratios with 95% confidence intervals. RESULTS: Of the 5282 articles retrieved, 25 RCTs were included in this review (n = 24,942), and 18 randomized controlled trials (n = 16,777) were included in the network meta-analysis. The results indicated no significant differences in cardiovascular mortality rate between romosozumab and placebo. Regarding the risk of major cardiovascular events, no significant differences were found in the direct evidence or the network meta-analysis with placebo as the reference. CONCLUSION: Romosozumab might be a safe option for treating postmenopausal women with osteoporosis. The cardiovascular concerns associated with this treatment seem less significant than previously suggested, although additional real-world data are required to confirm this conclusion.
79Denosumab or romosozumab therapy and risk of cardiovascular events in patients with primary osteoporosis: Systematic review and meta- analysis.PubMed
Fang Lv, Xiaoling Cai, Wenjia Yang, et al.
Bone. 2020 Jan;130:115121. doi: 10.1016/j.bone.2019.115121. Epub 2019 Oct 31.
BACKGROUND: Osteoporosis and cardiovascular (CV) diseases are closely correlated. RANKL/RANK/OPG pathway and Wnt signalling pathway both implicated in the pathogenesis of osteoporosis and cardiovascular diseases. We aimed to investigate the effect of denosumab or romosozumab therapy on cardiovascular outcomes in patients with primary osteoporosis. METHODS: PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to June 4, 2019. Randomized clinical trials evaluating the effect of denosumab or romosozumab versus active comparators or placebo for at least 6 months in patients with primary osteoporosis or osteopenia were included. Two investigators independently extracted data for study characteristics, outcomes of interest, and risk of bias in accordance with PRISMA guidelines. RESULTS: 17 relevant studies (denosumab: n=11, 13615 participants; romosozumab: n=6, 12219 participants) were included. No associations between denosumab therapy and risk of a composite cardiovascular outcome (1.06 [95 % CI, 0.88-1.28], p=0.54), three-point major adverse cardiovascular event (3P MACE, 1.01 [95 % CI, 0.83-1.23], p=0.93), and four-point major adverse cardiovascular event (4P MACE, 0.99 [95 % CI, 0.83-1.18], p=0.89) were identified. Romosozumab therapy did not increase the risk of composite cardiovascular outcome (1.26 [95 % CI, 0.95-1.68], p=0.11), and 3P MACE (1.41 [95 % CI, 0.99-2.02], p=0.06), while increased the risk of 4P MACE (1.39 [95 % CI, 1.01-1.90], p=0.04) among elderly men and postmenopausal woman with osteoporosis over a period of 12-36 months. Denosumab or romosozumab did not increase or reduce specific cardiovascular outcomes, including CV death or death, myocardial infarction, stroke, atrial fibrillation, heart failure, aortic and intracranial aneurysm, aortic dissection, aortic valve disease and hypertension (all p＞0.05). Sensitivity analysis conducted by random effects model altered the result of 4P MACE in romosozumab (1.36 [0.99-1.87], p=0.06). No other significant difference was detected in the sensitivity analyses and subgroup analyses. CONCLUSIONS: Denosumab therapy was not associated with any risk of composite and specific cardiovascular outcomes among patients with primary osteoporosis than active comparators or placebo, while romosozumab therapy might increase the risk of 4P MACE.
81Effectiveness and Safety of Treatments to Prevent Fractures in People With Low Bone Mass or Primary Osteoporosis: A Living Systematic Review and Network Meta-analysis for the American College of Physicians.PubMed
Chelsea Ayers, Devan Kansagara, Brittany Lazur, et al.
Ann Intern Med. 2023 Feb;176(2):182-195. doi: 10.7326/M22-0684. Epub 2023 Jan 3.
BACKGROUND: The prevalence of osteoporosis is increasing in the United States. PURPOSE: To evaluate low bone mass and osteoporosis treatments to prevent fractures. DATA SOURCES: Ovid MEDLINE ALL, Ovid Evidence Based Medicine Reviews: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov from 2014 through February 2022. STUDY SELECTION: Adults receiving eligible interventions for low bone mass or osteoporosis. Randomized controlled trials (RCTs) for fracture outcomes, and RCTs and large observational studies ( ≥1000) for harms. DATA EXTRACTION: Abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE). DATA SYNTHESIS: We included 34 RCTs (in 100 publications) and 36 observational studies. Bisphosphonates and denosumab reduced hip, clinical and radiographic vertebral, and other clinical fractures in postmenopausal females with osteoporosis (moderate to high CoE). Bisphosphonates for 36 months or more may increase the risk for atypical femoral fractures (AFFs) and osteonecrosis of the jaw (ONJ), but the absolute risks were low. Abaloparatide and teriparatide reduced clinical and radiographic vertebral fractures but increased the risk for withdrawals due to adverse events (WAEs; moderate to high CoE). Raloxifene and bazedoxifene for 36 months or more reduced radiographic vertebral but not clinical fractures (low to moderate CoE). Abaloparatide, teriparatide, and sequential romosozumab, then alendronate, may be more effective than bisphosphonates in reducing clinical fractures for 17 to 24 months in older postmenopausal females at very high fracture risk (low to moderate CoE). Bisphosphonates may reduce clinical fractures in older females with low bone mass (low CoE) and radiographic vertebral fractures in males with osteoporosis (low to moderate CoE). LIMITATION: Few studies examined participants with low bone mass, males, or Black-identifying persons, sequential therapy, or treatment beyond 3 years. CONCLUSION: Bisphosphonates, denosumab, abaloparatide, teriparatide, and romosozumab, followed by alendronate, reduce clinical fractures in postmenopausal females with osteoporosis. Abaloparatide and teriparatide increased WAEs; longer duration bisphosphonate use may increase AFF and ONJ risk though these events were rare. PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD42021236220).
8210 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension.PubMed
Henry G Bone, Rachel B Wagman, Maria L Brandi, et al.
Lancet Diabetes Endocrinol. 2017 Jul;5(7):513-523. doi: 10.1016/S2213-8587(17)30138-9. Epub 2017 May 22.
BACKGROUND: Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis. METHODS: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60-90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of investigational product were eligible to enrol in the open-label, 7-year extension, in which all participants received denosumab. The data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab in FREEDOM and continued in the extension (long-term group), and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group). The primary outcome was safety monitoring, comprising assessments of adverse event incidence and serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and haematology), and participant incidence of denosumab antibody formation. Secondary outcomes included new vertebral, hip, and non-vertebral fractures as well as bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius. Analyses were done according to the randomised FREEDOM treatment assignments. All participants who received at least one dose of investigational product in FREEDOM or the extension were included in the combined safety analyses. All participants who enrolled in the extension with observed data were included in the efficacy analyses. The FREEDOM trial (NCT00089791) and its extension (NCT00523341) are both registered with ClinicalTrials.gov. FINDINGS: Between Aug 3, 2004, and June 1, 2005, 7808 women were enrolled in the FREEDOM study. 5928 (76%) women were eligible for enrolment in the extension, and of these, 4550 (77%) were enrolled (2343 long-term, 2207 crossover) between Aug 7, 2007, and June 20, 2008. 2626 women (1343 long-term; 1283 crossover) completed the extension. The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years. Serious adverse event rates were generally stable over time, varying between 11·5 and 14·4 per 100 participant-years. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the crossover group. The yearly incidence of new vertebral fractures (ranging from 0·90% to 1·86%) and non-vertebral fractures (ranging from 0·84% to 2·55%) remained low during the extension, similar to rates observed in the denosumab group during the first three years of the FREEDOM study, and lower than rates projected for a virtual long-term placebo cohort. In the long-term group, BMD increased from FREEDOM baseline by 21·7% at the lumbar spine, 9·2% at total hip, 9·0% at femoral neck, and 2·7% at the one-third radius. In the crossover group, BMD increased from extension baseline by 16·5% at the lumbar spine, 7·4% at total hip, 7·1% at femoral neck, and 2·3% at one-third radius. INTERPRETATION: Denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. FUNDING: Amgen.
83European guidance for the diagnosis and management of osteoporosis in postmenopausal women.PubMed
J A Kanis, C Cooper, R Rizzoli, et al.
Osteoporos Int. 2019 Jan;30(1):3-44. doi: 10.1007/s00198-018-4704-5. Epub 2018 Oct 15.
UNLABELLED: Guidance is provided in a European setting on the assessment and treatment of postmenopausal women at risk from fractures due to osteoporosis. INTRODUCTION: The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2013. This manuscript updates these in a European setting. METHODS: Systematic reviews were updated. RESULTS: The following areas are reviewed: the role of bone mineral density measurement for the diagnosis of osteoporosis and assessment of fracture risk; general and pharmacological management of osteoporosis; monitoring of treatment; assessment of fracture risk; case-finding strategies; investigation of patients; health economics of treatment. The update includes new information on the evaluation of bone microstructure evaluation in facture risk assessment, the role of FRAX® and Fracture Liaison Services in secondary fracture prevention, long-term effects on fracture risk of dietary intakes, and increased fracture risk on stopping drug treatment. CONCLUSIONS: A platform is provided on which specific guidelines can be developed for national use.
84Update on osteoporosis treatment.PubMed
Xavier Nogués, Daniel Martinez-Laguna
Med Clin (Barc). 2018 Jun 22;150(12):479-486. doi: 10.1016/j.medcli.2017.10.019. Epub 2017 Nov 26.
Treatment of osteoporosis should be directed primarily towards secondary prevention of fractures. The occurrence of drug-related adverse effects for the treatment of osteoporosis has led to a reevaluation of the indications, the duration of treatment and even withdrawal of some drugs from the market. This review has been made from different patient profiles that practitioners will find in usual practice; from patients with hip fracture with cognitive impairment, limitation of their day-to-day living activities and comorbidities, to active patients without any limitations; patients with vertebral fractures and non-vertebral fractures where secondary prevention is highly important. In general, antiresorptive drugs (alendronate and risedronate) will be the first choice. Zoledronate or denosumab will be indicated in cases of digestive intolerance, poor adherence or an increased risk of hip fracture. Teriparatide will be indicated to patients with 2or more previous vertebral fractures or very low bone density.
85Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society* Clinical Practice Guideline.PubMed
Richard Eastell, Clifford J Rosen, Dennis M Black, et al.
J Clin Endocrinol Metab. 2019 May 1;104(5):1595-1622. doi: 10.1210/jc.2019-00221.
OBJECTIVE: The objective is to formulate clinical practice guidelines for the pharmacological management of osteoporosis in postmenopausal women. CONCLUSIONS: Evidence from clinical trials and insights from clinical experience with pharmacologic therapies for osteoporosis were critically evaluated in formulating this guideline for the management of postmenopausal osteoporosis. Patient preferences, data on adherence and persistence, and risks and benefits from the patient and provider perspectives were also considered in writing committee deliberations. A consensus by the Writing Committee members was achieved for four management principles: (i) The risk of future fractures in postmenopausal women should be determined using country-specific assessment tools to guide decision-making. (ii) Patient preferences should be incorporated into treatment planning. (iii) Nutritional and lifestyle interventions and fall prevention should accompany all pharmacologic regimens to reduce fracture risk. (iv) Multiple pharmacologic therapies are capable of reducing fracture rates in postmenopausal women at risk with acceptable risk-benefit and safety profiles.
86Postmenopausal osteoporosis: Assessment and management.PubMed
René Rizzoli
Best Pract Res Clin Endocrinol Metab. 2018 Oct;32(5):739-757. doi: 10.1016/j.beem.2018.09.005. Epub 2018 Sep 22.
Osteoporosis increases the risk of fractures, which are associated with increased mortality and lower quality of life. Patients with prevalent fracture are at high risk to of sustaining another one. Optimal protein and calcium intakes, and vitamin D supplies, together with regular weight bearing physical exercise are the corner stones of fracture prevention. Evidence for anti-fracture efficacy of pharmacological interventions relies on results from randomised controlled trials in postmenopausal women with fractures as the primary outcome. Treatments with bone resorption inhibitors, like bisphosphonates or denosumab, and bone formation stimulator like teriparatide, reduce vertebral and non-vertebral fracture risk. A reduction in vertebral fracture risk can already be detected within a year after starting therapy.
87Osteoporosis treatment: recent developments and ongoing challenges.PubMed
Sundeep Khosla, Lorenz C Hofbauer
Lancet Diabetes Endocrinol. 2017 Nov;5(11):898-907. doi: 10.1016/S2213-8587(17)30188-2. Epub 2017 Jul 7.
Osteoporosis is an enormous and growing public health problem. Once considered an inevitable consequence of ageing, it is now eminently preventable and treatable. Ironically, despite tremendous therapeutic advances, there is an increasing treatment gap for patients at high fracture risk. In this Series paper, we trace the evolution of drug therapy for osteoporosis, which began in the 1940s with the demonstration by Fuller Albright that treatment with oestrogen could reverse the negative calcium balance that developed in women after menopause or oophorectomy. We note a watershed in osteoporosis drug discovery around the year 2000, when the approach to developing novel therapeutics shifted from one driven by discoveries in animal studies and clinical observations (eg, oestrogen, calcitonin, and teriparatide) or opportunistic repurposing of existing compounds (eg, bisphosphonates) to one driven by advances in fundamental bone biology (eg, denosumab) coupled with clues from patients with rare bone diseases (eg, romosozumab, odanacatib). Despite these remarkable advances, concerns about rare side-effects of anti-resorptive drugs, particularly bisphosphonates, and the absence of clear evidence in support of their long-term efficacy is leading many patients who could benefit from drug therapy to not take these drugs. As such, there remains an important clinical need to develop ways to enhance patient acceptance and compliance with these effective drugs, and to continue to develop new drugs that do not cause these side-effects and have prolonged anabolic effects on bone. Such changes could lead to a true reversal of this potentially devastating disease of ageing.
88Osteoporosis: A Review.PubMed
Suzanne N Morin, William D Leslie, John T Schousboe
JAMA. 2025 Sep 9;334(10):894-907. doi: 10.1001/jama.2025.6003.
IMPORTANCE: Osteoporosis is characterized by low bone mass, increased bone fragility, and increased susceptibility to fracture, which is associated with substantial morbidity, mortality, and economic costs. Worldwide, 1 in 3 women and 1 in 5 men older than 50 years of age experience osteoporotic fractures in their lifetime. OBSERVATIONS: Risk factors for osteoporosis include older age, female sex, prior fractures, prior falls, low body weight, history of hip fracture in a parent, glucocorticoid use, cigarette smoking, excess alcohol consumption, certain comorbidities (eg, inflammatory bowel disease, rheumatoid arthritis, and chronic liver and kidney disease), and low level of bone mineral density (BMD; measured by dual-energy x-ray absorptiometry). The fracture risk assessment algorithm combines these clinical risk factors and BMD measurement to estimate the 10-year absolute fracture risk for hip, spine, shoulder, and forearm fractures. For patients at high risk of fracture, such as those with a T score of -2.5 or less (equivalent to a bone mass that is ≥2.5 SDs below that of young adults) for BMD, history of vertebral or hip fracture, multiple fractures, or high 10-year absolute fracture risk (eg, ≥20%), antiresorptive agents (bisphosphonates or, if contraindicated, denosumab) are recommended to reduce vertebral fractures (risk difference, -52 [95% CI, -95 to -18 per 1000 person-years]) and hip fractures (risk difference, -6 [95% CI, -11 to -1 per 1000 person-years]). Anabolic medications (teriparatide, abaloparatide, and romosozumab) should be considered in very high-risk individuals (eg, recent vertebral fractures, hip fracture with a T score of ≤-2.5 for BMD), followed by an antiresorptive agent. The use of fracture liaison services (comprehensive inpatient or outpatient management program for patients after a fracture) was shown to increase medication initiation and adherence by 38% compared with 17% for patients who did not receive fracture liaison services (risk difference, 20% [95% CI, 16% to 25%]) and these benefits may reduce the rates of subsequent fracture. Patients are recommended to follow appropriate intake of calcium (1000 to 1200 mg) and vitamin D (600 to 800 IU) guidelines and to pursue a regimen of muscle resistance exercises (eg, squats, push-ups) and balance exercises (eg, heel raises, standing on 1 foot). CONCLUSIONS AND RELEVANCE: Osteoporosis is a common condition among older adults that leads to increased susceptibility to fracture, which is associated with substantial morbidity and mortality. Antiresorptive agents such as bisphosphonates or denosumab are recommended for patients at high fracture risk. Anabolic treatment with parathyroid hormone analogs (such as teriparatide and abaloparatide) and sclerostin inhibitors (such as romosozumab) can be considered for very high-risk individuals.
89The cost effectiveness of teriparatide as a first-line treatment for glucocorticoid-induced and postmenopausal osteoporosis patients in Sweden.PubMed
Daniel R Murphy, Lee J Smolen, Timothy M Klein, et al.
BMC Musculoskelet Disord. 2012 Oct 30;13:213. doi: 10.1186/1471-2474-13-213.
BACKGROUND: This paper presents the model and results to evaluate the use of teriparatide as a first-line treatment of severe postmenopausal osteoporosis (PMO) and glucocorticoid-induced osteoporosis (GIOP). The study's objective was to determine if teriparatide is cost effective against oral bisphosphonates for two large and high risk cohorts. METHODS: A computer simulation model was created to model treatment, osteoporosis related fractures, and the remaining life of PMO and GIOP patients. Natural mortality and additional mortality from osteoporosis related fractures were included in the model. Costs for treatment with both teriparatide and oral bisphosphonates were included. Drug efficacy was modeled as a reduction to the relative fracture risk for subsequent osteoporosis related fractures. Patient health utilities associated with age, gender, and osteoporosis related fractures were included in the model. Patient costs and utilities were summarized and incremental cost-effectiveness ratios (ICERs) for teriparatide versus oral bisphosphonates and teriparatide versus no treatment were estimated.For each of the PMO and GIOP populations, two cohorts differentiated by fracture history were simulated. The first contained patients with both a historical vertebral fracture and an incident vertebral fracture. The second contained patients with only an incident vertebral fracture. The PMO cohorts simulated had an initial Bone Mineral Density (BMD) T-Score of -3.0. The GIOP cohorts simulated had an initial BMD T-Score of -2.5. RESULTS: The ICERs for teriparatide versus bisphosphonate use for the one and two fracture PMO cohorts were €36,995 per QALY and €19,371 per QALY. The ICERs for teriparatide versus bisphosphonate use for the one and two fracture GIOP cohorts were €20,826 per QALY and €15,155 per QALY, respectively. CONCLUSIONS: The selection of teriparatide versus oral bisphosphonates as a first-line treatment for the high risk PMO and GIOP cohorts evaluated is justified at a cost per QALY threshold of €50,000.
90Denosumab in the Treatment of Osteoporosis: 10 Years Later: A Narrative Review.PubMed
David L Kendler, Felicia Cosman, Robert Kees Stad, et al.
Adv Ther. 2022 Jan;39(1):58-74. doi: 10.1007/s12325-021-01936-y. Epub 2021 Nov 11.
The fully human monoclonal antibody denosumab was approved for treatment of osteoporosis in 2010 on the basis of its potent antiresorptive activity, which produces clinically meaningful increases in bone mineral density (BMD) and reduces fracture risk at key skeletal sites. At that time, questions remained regarding the long-term safety and efficacy of this receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor; and with clinical experience, new questions have arisen regarding its optimal use. Here, we examine these questions through the lens of data from the FREEDOM trial program and other studies to determine where denosumab fits in the osteoporosis treatment landscape. Clinical consensus and evidentiary support have grown for denosumab as a highly effective anti-osteoporosis therapy for patients at high risk of fracture. In the 10-year FREEDOM Extension study, denosumab treatment produced progressive incremental increases in BMD, sustained low rates of vertebral fracture, and further reduction in nonvertebral fracture risk without increased risk of infection, cancer, or immunogenicity. There was no evidence that suppression of bone turnover or mineralization was excessive, and rates of osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF) were very low. It is now recognized, however, that transitioning to another anti-osteoporosis therapy after denosumab discontinuation is essential to mitigate a transient rebound of bone turnover causing rapid BMD loss and increased risk of multiple vertebral fractures (MVFs). Taken together, the available data show that denosumab has a favorable benefit/risk profile and is a versatile agent for preventing osteoporotic fractures in the short and long term. Video abstract: Denosumab in the Treatment of Osteoporosis-10 Years Later (MP4 62727 KB).
91Management of postmenopausal osteoporosis and the prevention of fractures.PubMed
M Gambacciani, M Levancini
Panminerva Med. 2014 Jun;56(2):115-31. Epub 2014 Jun 19.
Postmenopausal osteoporosis affects millions of women, being estrogen deficiency the key factor in the pathogenesis of involutional osteoporosis. Fracture prevention is one of the public health priorities worldwide. Different treatments for osteoporosis are available. The various options are aimed to maintain bone health and decrease the risk of fractures. The majority of these drugs are antiresorptive agents, i.e., drugs that lower bone turnover, inhibiting osteoclastic bone resorption. Dietary sources of calcium intake and vitamin D are ideal, while pharmachological supplements should be used if diet alone cannot provide the recommended daily intake. Bisphosphonates are first-line therapy for patients with established osteoporosis at high risk of fracture. Some serious, but rare, adverse events have been associated with their long-term administration. The monoclonal antibody to RANKL, named denosumab, administered as a 60-mg subcutaneous injection every 6 months, is a valuable option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, who are unable to take other osteoporosis treatments. Teriparatide (PTH 1-34) is the only available osteoanabolic drugs for osteoporosis treatment at present. Its use is limited to severe osteoporosis because of the high cost of the treatment. In climacteric women, in different stages of menopausal transition, and beyond, hormone replacement therapy at different doses (HRT) rapidly normalizes turnover, preventing and/or treating osteoporosis. HRT is able to preserve and even increase BMD at all skeletal sites, leading to a significant reduction in vertebral and non-vertebral fractures. Selective estrogen modulators (SERMs) as raloxifene and bazedoxifene reduce bone turnover and maintains or increases vertebral and femoral BMDs in comparison to placebo and reduces the risk of vertebral and new vertebral fractures, in high risk women. The combination of a SERM with an estrogen has been defined as tissue selective estrogen complex (TSEC). The bazedoxifene with conjugated estrogen is able to reduce climacteric symptoms, reducing bone turnover and preserving BMD. Studies investigating the actions of phytoestrogens on BMD or bone turnover are largely contradictory, making them inconclusive. At the present time, phytoestrogens cannot be recommended for postmenopausal osteoporosis. In conclusion, the use of HRT for osteoporosis prevention is based on biology, epidemiology, animal and preclinical data, observational studies and randomized, clinical trials. Osteoporosis prevention can actually be considered as a major additional effect in climacteric women who use HRT for treatment of climacteric symptoms. Bone protection is one of the major benefits of HRT. The possibility that low dose HRT or TSEC causes a decrease in fracture risk is not demonstrated but the scientific evidence is compelling. Conversely, established osteoporosis, often occurring in elderly women, can better be treated with specific treatments, such as bisphosphonates or, in more severe and selected cases, anabolic agents (teriparatide).
92Romosozumab Treatment in Postmenopausal Women with Osteoporosis.PubMed
Felicia Cosman, Daria B Crittenden, Jonathan D Adachi, et al.
N Engl J Med. 2016 Oct 20;375(16):1532-1543. doi: 10.1056/NEJMoa1607948. Epub 2016 Sep 18.
BACKGROUND: Romosozumab, a monoclonal antibody that binds sclerostin, increases bone formation and decreases bone resorption. METHODS: We enrolled 7180 postmenopausal women who had a T score of -2.5 to -3.5 at the total hip or femoral neck. Patients were randomly assigned to receive subcutaneous injections of romosozumab (at a dose of 210 mg) or placebo monthly for 12 months; thereafter, patients in each group received denosumab for 12 months, at a dose of 60 mg, administered subcutaneously every 6 months. The coprimary end points were the cumulative incidences of new vertebral fractures at 12 months and 24 months. Secondary end points included clinical (a composite of nonvertebral and symptomatic vertebral) and nonvertebral fractures. RESULTS: At 12 months, new vertebral fractures had occurred in 16 of 3321 patients (0.5%) in the romosozumab group, as compared with 59 of 3322 (1.8%) in the placebo group (representing a 73% lower risk with romosozumab; P<0.001). Clinical fractures had occurred in 58 of 3589 patients (1.6%) in the romosozumab group, as compared with 90 of 3591 (2.5%) in the placebo group (a 36% lower risk with romosozumab; P=0.008). Nonvertebral fractures had occurred in 56 of 3589 patients (1.6%) in the romosozumab group and in 75 of 3591 (2.1%) in the placebo group (P=0.10). At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3325 patients] in the romosozumab group vs. 2.5% [84 of 3327] in the placebo group, a 75% lower risk with romosozumab; P<0.001). Adverse events, including instances of hyperostosis, cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and two cases of osteonecrosis of the jaw were observed in the romosozumab group. CONCLUSIONS: In postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year. (Funded by Amgen and UCB Pharma; FRAME ClinicalTrials.gov number, NCT01575834 .).
93Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis.PubMed
Kenneth G Saag, Jeffrey Petersen, Maria Luisa Brandi, et al.
N Engl J Med. 2017 Oct 12;377(15):1417-1427. doi: 10.1056/NEJMoa1708322. Epub 2017 Sep 11.
BACKGROUND: Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption. METHODS: We enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in ≥330 patients). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated. RESULTS: Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2047 patients]) (P<0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P<0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; P=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed. CONCLUSIONS: In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. (Funded by Amgen and others; ARCH ClinicalTrials.gov number, NCT01631214 .).