Department of Orthopaedic Surgery, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands.
Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands.
J Bone Miner Res. 2021 Sep;36(9):1729-1738. doi: 10.1002/jbmr.4380. Epub 2021 Jun 10.
Denosumab (Dmab) treatment can benefit patients with fibrous dysplasia/McCune-Albright syndrome (FD/MAS) by suppressing the receptor activator of nuclear factor κB ligand (RANKL)-mediated increased bone resorption. However, limited data of two pediatric cases indicate that a rebound phenomenon may occur after withdrawal. Therefore we studied the safety of Dmab discontinuation in FD/MAS. Thirty-seven patients using Dmab, mostly after unsuccessful bisphosphonate (BP) treatment, were included. Health records were screened for pain scores, side effects, and bone turnover markers (BTMs) (calcium, alkaline phosphatase [ALP], procollagen 1 N-terminal propeptide [P1NP], and β-crosslaps [B-CTX, also termed β-C-terminal telopeptide]) during treatment, and for BTMs and clinical rebound effects after withdrawal. BTM levels after withdrawal were compared to pretreatment values. Data were calculated as median (interquartile range [IQR]). BTMs normalized in two-thirds of patients and pain scores decreased significantly during treatment (p = 0.002). One patient (2.7%) developed osteonecrosis of the jaw. Sixteen patients discontinued Dmab treatment after a median of 1.6 years (IQR 1.0 years) because of insufficient effect on pain (n = 10, 63%), side effects (n = 4, 25%), or other reasons (n = 4, 25%). Follow-up posttreatment was 3.2 (2.8) years, wherein no fractures, pain flares, or lesion progression occurred. Calcium remained normal in all but one patient, who had a mild asymptomatic hypercalcemia (2.73 mmol/L) 5 months after discontinuation. ALP passed pretreatment levels in five of 11 patients (46%), increased most after 6 months by 18 (43) U/L, and returned to baseline levels thereafter. P1NP exceeded pretreatment levels in four of nine patients (44%), CTX in eight of nine patients (89%). P1NP rose most after 3 months and stabilized thereafter. CTX showed the highest relative elevation. Patients with high pretreatment levels responding well to Dmab seemed to have the highest rebound. These results suggest beneficial effects of Dmab on pain and BTMs, and show a biochemical but asymptomatic rebound phenomenon after withdrawal in adults with FD/MAS, mainly in case of high pretreatment levels, good response, and multiple injections. Further studies on the safety of Dmab and withdrawal are needed and ongoing. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
地舒单抗（Dmab）通过抑制核因子 κB 配体受体激活剂（RANKL）介导的骨吸收增加，可使纤维性骨发育不良/麦卡恩-阿尔布赖特综合征（FD/MAS）患者受益。然而，两项儿科病例的有限数据表明，停药后可能会出现反弹现象。因此，我们研究了 FD/MAS 停药的安全性。37 例患者使用地舒单抗，主要是在双膦酸盐（BP）治疗失败后使用。筛选健康记录以评估治疗期间的疼痛评分、副作用和骨转换标志物（BTM）（钙、碱性磷酸酶[ALP]、I 型前胶原 N 端前肽[P1NP]和 β 交联 C 端肽[β-CTX，也称为β-C 端肽]），以及停药后的 BTM 和临床反弹效应。将停药后的 BTM 水平与治疗前的值进行比较。数据以中位数（四分位距[IQR]）表示。有三分之二的患者的 BTM 水平恢复正常，疼痛评分在治疗期间显著下降（p=0.002）。1 例（2.7%）患者发生下颌骨坏死。16 例患者在中位 1.6 年（IQR 1.0 年）后停止地舒单抗治疗（n=16，63%），原因是疼痛缓解不足（n=10，63%）、副作用（n=4，25%）或其他原因（n=4，25%）。治疗后随访 3.2（2.8）年，无骨折、疼痛加重或病变进展。除 1 例患者（2.7%）外，所有患者的血钙均正常，该患者停药后 5 个月出现轻度无症状高钙血症（2.73mmol/L）。11 例患者中有 5 例（46%）的 ALP 超过治疗前水平，停药后 6 个月增加最多 18（43）U/L，此后恢复至基线水平。9 例患者中有 4 例（44%）的 P1NP 超过治疗前水平，9 例患者中有 8 例（89%）的 CTX 超过治疗前水平。CTX 在 3 个月后升高最多，此后稳定。CTX 显示出最高的相对升高。对 Dmab 反应良好的高治疗前水平患者似乎反弹最明显。这些结果表明 Dmab 对疼痛和 BTM 有有益的影响，并表明成人 FD/MAS 停药后存在生化但无症状的反弹现象，主要发生在高治疗前水平、良好反应和多次注射的情况下。需要并正在进行 Dmab 安全性和停药的进一步研究。
