Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen am Rhein, Germany.
Analysis Group, Boston, Massachusetts, USA.
Clin Transl Sci. 2021 Jul;14(4):1452-1463. doi: 10.1111/cts.13006. Epub 2021 Apr 8.
Decline of bone mineral density (BMD) during menopause is related to increased risk of fractures in postmenopausal women, however, this relationship in premenopausal women has not been established. To quantify this relationship, real-world data (RWD) from the National Health and Nutrition Examination Survey (NHANES), and longitudinal data from the elagolix phase III clinical trials were modeled across a wide age range, and covariates were evaluated. The natural changes in femoral neck BMD (FN-BMD) were well-described by a bi-exponential relationship with first-order BMD formation (k ) and resorption (k ) rate constants. Body mass index (BMI) and race (i.e., Black) were significant predictors indicating that patients with high BMI or Black race experience a relatively lower BMD loss. Simulations suggest that untreated premenopausal women with uterine fibroids (UFs) from elagolix phase III clinical trials (median age 43 years [minimum 25-maximum 53]) lose 0.6% FN-BMD each year up to menopausal age. For clinical relevance, the epidemiological FRAX model was informed by the simulation results to predict the 10-year risk of major osteoporotic fracture (MOF). Premenopausal women with UFs, who received placebo only in the elagolix phase III trials, have a projected FN-BMD of 0.975 g/cm at menopause, associated with a 10-year risk of MOF of 2.3%. Integration of modeling, RWD, and clinical trials data provides a quantitative framework for projecting long-term postmenopausal risk of fractures, based on natural history of BMD changes in premenopausal women. This framework enables quantitative evaluation of the future risk of MOF for women receiving medical therapies (i.e., GnRH modulators) that adversely affect BMD.
绝经后骨密度（BMD）下降与绝经后妇女骨折风险增加有关，但这一关系在绝经前妇女中尚未确定。为了量化这种关系，使用来自国家健康和营养检查调查（NHANES）的真实世界数据（RWD）和 Elagolix 三期临床试验的纵向数据，在广泛的年龄范围内进行建模，并评估了协变量。股骨颈 BMD（FN-BMD）的自然变化通过双指数关系得到了很好的描述，其中包括一级 BMD 形成（k ）和吸收（k ）速率常数。体重指数（BMI）和种族（即黑人）是重要的预测指标，表明 BMI 高或黑种人患者经历相对较低的 BMD 丢失。模拟表明，来自 Elagolix 三期临床试验的未治疗的有子宫肌瘤（UFs）的绝经前妇女（中位年龄 43 岁[最小 25-最大 53]）每年 FN-BMD 丢失 0.6%，直至绝经年龄。就临床相关性而言，该流行病学 FRAX 模型是根据模拟结果得出的，用于预测 10 年主要骨质疏松性骨折（MOF）的风险。仅在 Elagolix 三期临床试验中接受安慰剂的有 UFs 的绝经前妇女，预计在绝经时 FN-BMD 为 0.975g/cm，10 年 MOF 风险为 2.3%。模型、RWD 和临床试验数据的整合提供了一种定量框架，用于预测基于绝经前妇女 BMD 变化自然史的长期绝经后骨折风险。该框架使我们能够定量评估接受不利影响 BMD 的医学治疗（即 GnRH 调节剂）的妇女未来 MOF 的风险。
