Newer Therapies for Osteoporosis
Bone undergoes a continuous remodeling process involving resorption and formation. Any process that disrupts this balance by increasing bone resorption relative to formation results in osteoporosis. Inadequate gonadal hormone production is a major cause of osteoporosis in men and women. Estrogen replacement therapy at menopause is a well-established means of preventing osteoporosis in the female, but many women fear its adverse effects, particularly the increased risk of breast cancer from con-tinued estrogen use (the well-demonstrated increased risk of endometrial cancer is prevented by combining the estrogen with a progestin) and do not like the persistence of menstrual bleeding that often accompanies this form of therapy. Medical enthusiasm for this treatment has waned with the demonstration that it does not protect against and may increase the risk of heart disease. Raloxifene is the first of the selective estrogen receptor modula-tors (SERMs;) to be approved for the prevention of osteoporosis. Raloxifene shares some of the beneficial effects of estrogen on bone without increasing the risk of breast or endo-metrial cancer (it may actually reduce the risk of breast cancer). Although not as effective as estrogen in increasing bone density, raloxifene has been shown to reduce vertebral fractures.
Nonhormonal forms of therapy for osteoporosis with proven efficacy in reducing fracture risk have also been developed. Bisphosphonates such as alendronate, risedronate, and iban-dronate have been conclusively shown to increase bone density and reduce fractures over at least 5 years when used continu-ously at a dosage of 10 mg/d or 70 mg/wk for alendronate; 5 mg/d or 35 mg/wk for risedronate; or 2.5 mg/d or 150 mg/month for ibandronate, and more recently intravenous zoledronate, 5 mgannually. Side-by-side trials between alendronate and calcitonin (another approved nonestrogen drug for osteoporosis) indicated a greater efficacy of alendronate. Bisphosphonates are poorly absorbed and must be given on an empty stomach or infused intravenously. At the higher oral doses used in the treatment of Paget’s disease, alendronate causes gastric irritation, but this is not a significant problem at the doses recommended for osteo-porosis when patients are instructed to take the drug with a glass of water and remain upright. Denosumab is a human monoclo-nal antibody directed against RANKL, and is very effective in inhibiting osteoclastogenesis and activity. Denosumab is given in 60 mg doses subcutaneously every 6 months. All of these drugs inhibit bone resorption with secondary effects to inhibit bone formation. On the other hand, teriparatide, the recombi-nant form of PTH 1-34, directly stimulates bone formation. However, teriparatide must be given daily by subcutaneous injection. Its efficacy in preventing fractures appears to be at least as great as that of the bisphosphonates. In all cases, ade-quate intake of calcium and vitamin D needs to be maintained.
Furthermore, there are several other forms of therapy in the pipeline. In Europe, strontium ranelate, a drug that appears to stimulate bone formation and inhibit bone resorption, has been used for several years with favorable results in large clinical trials; approval for use in the USA is expected. Additional promising new treatments undergoing clinical trials include an antibody against sclerostin (a protein produced by osteocytes that inhibits bone formation), that has been shown to stimulate bone forma-tion, and inhibitors of cathepsin K, an enzyme in osteoclasts that facilitates bone resorption