Pathogenesis of osteoporosis: concepts, conflicts, and prospects (original) (raw)

Prior to the introduction of BMD measurements, the diagnosis of osteoporosis was only made when fragility fractures occurred in an appropriate clinical setting, largely in postmenopausal women and older men. Today we use BMD to diagnose osteoporosis and osteopenia before fractures occur, as well as to confirm the diagnosis in patients with fragility fractures (109). Our goal is to identify those individuals most likely to have fractures in the future and to treat them appropriately so that their fracture risk will be reduced.

While low BMD is an important risk factor, many other factors have been identified in epidemiologic studies, including age, low body weight, and smoking. Many drugs and diseases that can aggravate bone loss and fragility are also important in predicting future fracture risk, such as glucocorticoid or thyroid hormone excess and chronic inflammatory disorders (109). Another key predictor is the rate of bone remodeling. Increased rates of osteoclastic bone resorption, measured by the level of collagen breakdown products, as well as increased bone formation, measured by bone-specific alkaline phosphatase, osteocalcin, or procollagen peptide levels, are associated with an increase in risk for bone loss and fragility fractures. Techniques that can analyze the microarchitecture of bone are being developed that could further improve diagnosis (110). In the future, it may be possible to identify genetic profiles that predict greater or lesser risk of fractures.

At present the therapy of osteoporosis is directed at the major pathogenetic mechanisms outlined here, with a strong emphasis on prevention of bone loss and fractures (111). While the first major pathogenetic mechanism, failure to achieve optimal peak bone mass, is determined largely by our genes, nutrition and lifestyle can have an effect during growth and development. Moreover, adequate calcium and vitamin D intake and appropriate physical activity may not only increase peak bone mass but also slow bone loss and reduce fracture risk throughout life.

Pharmacotherapy for osteoporosis has been focused mainly on interventions that could reverse the second pathogenetic mechanism, excessive bone resorption (112). In the past, estrogen replacement was the most widely used therapy. Ironically, the first study that truly established the antifracture efficacy of estrogen has also resulted in its being largely abandoned as the primary therapy for osteoporosis (113). Data from the Women’s Health Initiative indicated that the estrogen, particularly when combined with progestins, increased the risk of breast cancer and cardiovascular disease, which outweighed the benefits to the skeleton. The fact that much lower doses of estrogen can prevent bone loss in postmenopausal women (13) suggests that the cost/benefit ratio might be reversed with such therapy, but appropriate long-term studies have not yet been carried out. One alternative is the use of selective estrogen receptor modulators. One of these, raloxifene, has been shown to decrease the risk of vertebral fracture and does not appear to increase the risk of breast cancer (114).

The discovery that calcitonin is a selective inhibitor of osteoclastic activity more than 40 years ago led to the concept that calcitonin deficiency might be the cause of osteoporosis and that its administration might be the cure. However, calcitonin deficiency was not found in osteoporotic patients, and calcitonin therapy has been less effective than other antiresorptive agents, possibly because osteoclasts can escape calcitonin inhibition (112, 114).

The clinical trials showing that bisphosphonates could provide effective and relatively safe antiresorptive therapy have had an enormous impact on the management of osteoporosis. The currently FDA-approved bisphosphonates — alendronate, risedronate, and ibandronate — have been shown to reduce the incidence of fractures, including both vertebral and nonvertebral fractures, particularly hip fractures (112, 114). These agents bind to the bone surface and then are taken up by osteoclasts, leading to their inactivation and programmed cell death. Potent bisphosphonates have now been in use for more than 10 years, and there is some concern that prolonged use may cause excessive inhibition of bone remodeling and slow the repair of fractures and of microdamage (115).

Effective treatment for the third pathogenetic mechanism, impaired bone formation, has only become available recently. Although it was shown more than 60 years ago that intermittent administration of low doses of PTH could increase bone mass in animals, an effective clinical approach was only developed and approved by the FDA in 2002. Daily subcutaneous injections of the synthetic N-terminal portion of PTH, teriparatide, can increase bone mass and strength by markedly increasing bone formation, while only modestly increasing bone resorption (116). This therapy is as effective as bisphosphonates in fracture reduction. Extensive studies on the mechanism of action of PTH are underway and should help us in identifying the critical pathways that regulate bone formation and are abnormal in osteoporotic patients. Another putative anabolic agent, strontium ranelate, has recently been approved for treatment of osteoporosis in several countries outside the US (117). Its mechanism of action is not well understood.

New antiresorptive approaches are being investigated, including selective inhibitors of osteoclastic hydrogen ion transport and cathepsin K as well as antagonists to the αvβ3 integrins that are necessary for osteoclast adherence and motility (118). New anabolic approaches are likely to emerge from further study of the transcriptional regulation of osteoblasts.

While improvements in diagnosis and therapy are important, it is equally true that we have sufficient tools today to assess fracture risk and prevent or treat osteoporosis to reduce that risk. Thus, there are 2 challenges: (a) to develop better diagnostic tools and treatment; and (b) to apply our current knowledge more broadly in the community. The latter is far from being met. Moreover, it is critical that we meet both these challenges in the coming decades if we are to deal effectively with the increase in osteoporosis and fractures that is projected as our population ages (111).