Prevention and treatment of osteoporosis: efficacy of combination of hormone replacement therapy with other antiresorptive agents.

Osteoporosis is a debilitating disease characterized by decreased bone mineral density (BMD) leading to fractures. It primarily affects postmenopausal women and elderly men. Prevention of osteoporosis is very important because present therapies do not have the potential to mend damage to the bone microarchitecture caused by osteoporosis. The first line of prevention and treatment of osteoporosis is hormone replacement therapy (HRT). All of the approved drugs for the prevention and treatment of osteoporosis act as inhibitors of bone resorption; these drugs include HRT, selective estrogen receptor modulators, calcitonin, and bisphosphonates. The latter two drugs have also been shown to prevent fractures. This article discusses data from nine controlled prospective clinical studies. Study 1 was designed to assess the efficacy of combined HRT and bisphosphonate in preventing osteoporosis during the early stages of menopause. This combined therapy increased the lumbar spine BMD by 10.9% and femoral BMD by 7.3% over 4 yr, compared with 6.8 and 4.0% with HRT alone, and 6.8 and 1.2% with bisphosphonate alone. Study 2 was conducted on postmenopausal women with established osteoporosis. These results showed a 10.4 and 7.0% increase in BMD in vertebrae and femora, respectively, compared with 7.3 and 4.8% increases in the HRT group, and 6.8 and 0.9% in the bisphosphonate group. Data from study 3 demonstrated similar findings in that the combination of alendronate and HRT also enhanced BMD values. Studies 4 and 5 assessed the efficacy of the combined therapy of HRT and calcitonin in the prevention of early postmenopausal bone loss. Both studies demonstrated a significant increase in BMD over and above that observed with either HRT or calcitonin alone. Studies 6, 7, and 8 demonstrated that the addition of testosterone to estrogen therapy further increased BMD when compared to estrogen therapy alone, and also prevented the expected decreases in markers of bone formation in early postmenopausal women. Study 9 demonstrated a synergistic effect on BMD in postmenopausal women, when HRT was coadministered with monofluorophosphate. Other combination therapies may also enhance BMD (e.g., the combination of alendronate and parathyroid hormone [PTH]). However, some agents either lose their efficacy or have no added effects on BMD when they are coadministered (e.g., tiludronate and PTH, calcitonin and PTH, calcitonin and anabolic steroids). These studies illustrate that in a subgroup of patients (i.e., patients with high bone turnover and/or severe osteoporosis), specific combination treatments such as HRT with bis-phosphonates, calcitonin, or androgens (and perhaps also with PTH, fluoride, nitric oxide donors) provide additional beneficial effects over a single-drug therapy. Whether these combination therapies are more effective than individual drugs in reducing fractures still needs to be determined.