Regulatory Perspectives in Pharmacometric Models of Osteoporosis.

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.