Integrating real-world data and modeling to project changes in femoral neck bone mineral density and fracture risk in premenopausal women

Abstract

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 (k1 ) and resorption (k2 ) 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/cm2 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.

Trial registration: ClinicalTrials.gov NCT01620528 NCT01931670 NCT02654054 NCT02691494.

Conflict of interest statement

D.B., I.W., N.M.M., P.N., S.E.C., C.O., and M.S. are employees of AbbVie and may hold AbbVie stock or stock options. W.G. is an employee of Analysis Group, Inc., which has received consulting fees from AbbVie.

© 2021 AbbVie Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

FIGURE 1

Observed and model‐predicted femoral neck bone mineral density (FN‐BMD) versus age using real‐world data. Boxes and horizontal lines represent the interquartile range (IQR; 25th and 75th percentiles) and median of observed FN‐BMD at each age category using National Health and Nutrition Examination Survey data. Lower and upper whiskers represent the smallest and largest value within 1.5‐times IQR. Outlying data are represented as black dots. Boxplots are overlaid with FN‐BMD data at baseline measured with Hologic machine type from elagolix clinical trials represented as colored dots (a) and with the median (solid line) of the model‐predicted data (b)

FIGURE 2

Observed and model‐predicted percentage change from baseline in femoral neck bone mineral density (FN‐BMD) at month 6 for the final model using clinical trials data of patients with uterine fibroids. Median (bar plots), 2.5th and 97.5th percentiles around the median (error bars) of the predicted percentage change from baseline in FN‐BMD from elagolix clinical trials at month 6 are compared with the observed data

FIGURE 3

Simulated femoral neck bone mineral density (FN‐BMD) and percentage change from baseline in FN‐BMD over time up to menopausal age for patients with uterine fibroids. Lines and shaded regions represent median and 95% confidence interval of the median. Dotted lines represent the 95% prediction interval

FIGURE 4

Predicted 10‐year risk of hip and major osteoporotic fractures and proportion of patients with uterine fibroids (UFs) in need of osteoporosis treatment up to postmenopausal age. Lines and shaded regions represent predicted median and 95% prediction interval of the median for femoral neck bone mineral density (FN‐BMD) (a), 10‐year risk of hip fractures and major osteoporotic fractures and proportion of patients in need of osteoporosis treatment (b). The dashed vertical lines represent the median age when a typical patient with UFs may reach menopause (i.e., 51 years) and the estimated median age when patients with UFs were recommended to initiate osteoporosis treatment (i.e., 72 years)