The prevention of fractures is the ultimate goal of osteoporosis treatments. To achieve this objective, developing a method to predict fracture risk in the early stage of osteoporosis treatment would be clinically useful. This study aimed to develop a mathematical model quantifying the long-term fracture risk after 2 annual doses of 5 mg of once-yearly administered zoledronic acid or placebo based on the short-term measurement of bone turnover markers or bone mineral density (BMD). The data used in this analysis were obtained from a randomized, placebo-controlled, double-blind, 2-year study of zoledronic acid that included 656 patients with primary osteoporosis. Two-year individual bone resorption marker (tartrate-resistant acid phosphatase 5b [TRACP-5b]) and lumbar spine (L2-L4) BMD profiles were simulated using baseline values and short-term measurements (at 3 months for TRACP-5b and 6 months for BMD) according to the pharmacodynamic model. A new parametric time-to-event model was developed to describe the risk of clinical fractures. Fracture risk was estimated using TRACP-5b or BMD and the number of baseline vertebral fractures. As a result, the fracture risk during the 2 years was successfully predicted using TRACP-5b or BMD. The 90% prediction intervals well covered the observed fracture profiles in both models. Therefore, TRACP-5b or BMD is useful to predict the fracture risk of patients with osteoporosis, and TRACP-5b would be more useful because it is an earlier marker. Importantly, the developed model allows clinicians to inform patients of their predicted response at the initial stage of zoledronic acid treatment.
Keywords: bone turnover marker; fracture risk assessment; osteoporosis; time-to-event analysis.
© 2020 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.