Regulatory Perspectives in Pharmacometric Models of Osteoporosis

Abstract

Osteoporosis is a disorder of the bones in which they are weakened to the extent that they become more prone to fracture. There are various forms of osteoporosis: some of them are induced by drugs, and others occur as a chronic progressive disorder as an individual gets older. As the median age of the population rises across the world, the chronic form of the bone disease is drawing attention as an important worldwide health issue. Developing new treatments for osteoporosis and comparing them with existing treatments are complicated processes due to current acceptance by regulatory authorities of bone mineral density (BMD) and fracture risk as clinical end points, which require clinical trials to be large, prolonged, and expensive to determine clinically significant impacts in BMD and fracture risk. Moreover, changes in BMD and fracture risk are not always correlated, with some clinical trials showing BMD improvement without a reduction in fractures. More recently, bone turnover markers specific to bone formation and resorption have been recognized that reflect bone physiology at a cellular level. These bone turnover markers change faster than BMD and fracture risk, and mathematically linking the biomarkers via a computational model to BMD and/or fracture risk may help in predicting BMD and fracture risk changes over time during the progression of a disease or when under treatment. Here, we discuss important concepts of bone physiology, osteoporosis, treatment options, mathematical modeling of osteoporosis, and the use of these models by the pharmaceutical industry and the Food and Drug Administration.

Establishment of a Disease‐Drug Trial Model for Postmenopausal Osteoporosis: A Zoledronic Acid Case Study

“…It can also be seen that LSBMD (0.3 year) changes faster than THBMD (0.03 year). This is in line with the underlying bone physiology, where trabecular bone, which is more prevalent in the lumbar spine, is resorbed more rapidly than cortical bone, which is more prevalent in the hip 19,30 …”

“…This is in line with the underlying bone physiology, where trabecular bone, which is more prevalent in the lumbar spine, is resorbed more rapidly than cortical bone, which is more prevalent in the hip. 19,30 Compared to the original bone cell interaction model by Lemaire et al, 16 which required >25 structural parameters to be identified and estimated, the mathematically reduced model required only 5 (z s , D A , k B , Plc max, and k Plc ), which made it applicable to clinical data. At the same time, the reduction in the degrees of freedom to be spent on the estimation of structural parameters allowed for the estimation of variance parameters as well as evaluation of covariate relationships.…”

Pharmacometrics and systems pharmacology for metabolic bone diseases

“…A recent paper by the FDA sought to justify the use of a modelling and simulation (M&S) approach in the development of drugs for osteoporosis . An important point of that review was the FDA's optimistic view on the use of an M&S approach to better appreciate the applicability of various surrogate markers to predict fracture risk.…”

Prediction of Fracture Risk From Early‐Stage Bone Markers in Patients With Osteoporosis Treated With Once‐Yearly Administered Zoledronic Acid

“…The effectiveness of therapies is evident long after the initiation of treatment because improvements in bone strength require time. In contrast, changes in bone turnover markers (BTMs) are observed within a few weeks after the initiation of treatments, including bisphosphonate 3,4 …”

“…In the osteoporosis field, several previous studies have shown the importance and use of modeling and simulation. For example, Madrasi et al 4 suggested that although both short‐term BTMs and long‐term BMD could predict fracture risk, BTMs may be more useful because they change faster than BMD. In addition, Bauer et al 5 and Vasikaran et al 6 reported that short‐term decreases in bone resorption markers could predict fracture risk.…”