MANAGEMENT OF PRIMARY OSTEOPOROSIS

Abstract

Although there is a great need for better therapeutic approaches to the patient who presents with a fracture, osteoporotic fractures will remain a condition that is more amenable to prevention than treatment. Hormone replacement therapy (HRT) is still considered by many the mainstay for the prevention and the treatment of posrmenopausal osteoporosis. However, there are several controversies regarding HRT, especially the duration of treatment and the risks/benefits ratio. Recent studies have challenged the assumption that HRT conveys real long-term beneficial effects. Raloxifene or other“selective estrogen receptor modulators” (SERMs) should progressively replace HRT in elderly women. Bisphosphonates have demonstrated a clearcut efficacy in the treatment of osteoporosis. Alendronate and risedronate have been the most extensively studied bisphosphonates under randomized controlled trials conditions. Both agents can reduce the risk of vertebral and hip fractures by one-fourth to one-half. However, oral bisphosphonates are not without gastro-intestinal toxicity and strict adherence to constraining therapeutic schemes is mandatory. Intermittent treatments are alredy in use. Weekly alendronate is as efficient as daily therapy and improves treatment compliance. Newer more potent bisphosphonates, such as oral ibandronate or intravenous zoledronic acid, will allow much less frequent administration. The anti-fracture efficacy of yearly zoledronic acid infusions is thus currently tested. On the other hand, bone-forming agents, such as daily subcutaneous injections of teriparatide (rhPTH 1-34) offer exciting perspectives for the treatment of severe osteoporosis despite the complexity of such therapy.Osteoporosis is now defined as a disease characterized by a low bone mass and a microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk. Osteoporosis is a major public health problem and the current risk for a 50-yr old white woman to suffer from a hip, a vertebra or a wrist fracture is around 40%, 17.5% of which will be hip fractures. The incidence of fractures is about three times lower in men than in women but the mortality due to hip fractures is higher in men. The cost of osteoporotic fractures is considerable and is estimated in USA to be more than 20 x 109 $ per year (1). The different patterns of bone loss are the result of distinct cellular mechanisms and it is probably an oversimplification to consider primary osteoporosis as a single disease (2). The inexorable age-related bone loss seen in both sexes is the result of gradual thinning of trabeculae brought about by declining osteoblast function. Thus the osteoblast teams become less and less capable of refilling the resorption cavities created by the osteoclasts, so the thickness of the trabecular packets, and consequently the trabeculae themselves, declines. By contrast, the rapid postmenopausal bone loss is viewed as osteoclast- mediated. As estrogens concentrations fall, the osteoclasts become hyperactive, penetrate too deeply into the trabecular plates, and perforate them. Once the trabecular plate is perforated, the template for new bone formation is lost, formation and resorption are uncoupled, i.e. do not occur at the same remodeling site, and tissue is rapidly lost. The trabeculae become more widely separated and intertrabecular connectivity is reduced. As if that were not enough, the postmenopausal increase in activation frequency of remodelling units adds to the deleterious effects of the hyperactive osteoclasts. The rapid disruption of trabecular microarchitecture that occurs after menopause has more deleterious consequences for bone strength that does simple trabecular thinning. This fact accounts for the sharp rise in crush fractures of the vertebrae, which are rich in cancellous bone, among postmenopausal women. In contrast, the incidence of fractures characteristic of“age-related” osteoporosis, such as hip fracture, increases exponentially after 65 years.Bone mineral density (BMD) as measured by dualenergy X-ray absorptiometry (DXA) is the most common method for the diagnosis of osteoporosis and the threshold of a T-score (number of SD below the «peak bone mass») less than –2.5 is now classically used to establish the diagnosis. The ability of DEXA to predict fracture risk in an untreated population is well-characterized (3). However, changes in BMD following therapeutic intervention do not appear to predict fracture reduction as well as BMD predicts fracture risk prior to treatment (4). There is a growing interest in biochemical markers of bone turnover for that matter.This article will briefly review the recent therapeutic developments and the perspectives for the prevention and treatment of primary osteoporosis. For more complete assessments, the reader is referred to recent reviews (5).