Present and future of osteoporosis therapy

Abstract

In the 50-year “modern” history of osteoporosis, there have been about 17 antifracture studies with sufficient attention to design to allow inference regarding efficacy. Antivertebral fracture efficacy has been reported with etidronate, estrogen patch, calcitonin, and 1,25-dihydroxyvitamin D. Two studies using fluoride were positive, and two were negative. Hip fractures have been neglected. One study showed efficacy of hip protectors, one showed efficacy of vitamin D and calcium in nursing home dwellers. The source of most hip fractures is the community. One community based antihip fracture efficacy study using annual injections of vitamin D was positive. There have been no antivertebral or antihip fracture studies in men, or in corticosteroid-related osteoporosis in men or women. Lack of independently repeated demonstration of efficacy, small fracture numbers, and data pooling in some of these (the best) studies leave great uncertainty. Estrogen and bisphosphonates appear to be the best options at this time. New data suggest that calcium supplementation is likely to reduce the rate of bone loss and perhaps reduce fracture rates. The challenge is to maintain and restore the constituents of bone mineral density (BMD), that is: to promote periosteal and endosteal bone formation; reduce endosteal bone resorption and cortical porosity; and increase trabecular thickness, number, and connectivity. There are many opportunities, for instance, intermittent parathyroid hormone (PTH) increases bone strength and, with estrogen, may increase connectivity. The anabolic effects of PTH may be partly mediated by IGF-1. IGF-1 increases periosteal, endosteal, and trabecular bone formation, cortical and trabecular width, and trabecular and endocortical connectivity. With bisphosphonate, IGF-1 may increase bone area and strength as the bisphosphonate decreases medullary area while IGF-1 increases subperiosteal area. Anabolic effects of fluoride warrant further study provided that the study design addresses the issue of bone strength, the narrow toxic-therapeutic window, and cortical bone loss. Aluminum, a constituent of zeolite, has anabolic effects which may be partly mediated by TGF-β. Prostaglandin E2 increases periosteal and endosteal bone formation but may increase cortical porosity. More data are needed regarding these growth factors, silicon compounds, strontium salts, and flavenoids. The effects of medroxyprogesterone and 19 norprogestins on BMD have not been compared. Raloxifene, a new estrogen agonist free of endometrial hyperplastic effects, is being studied. Most treated individuals with osteoporosis (i.e., low BMD with or without a fracture) will not suffer a fracture so treatment must be safe. Success—absence of fracture—will be measured by the epidemiologist because it is difficult to distinguish efficacy from chance in an individual as the peak incidence of fractures in the community is usually only about 1–4/100 per year.