Bone undergoes a continuous remodeling process involving resorption and formation. Any process that disrupts this bal-ance 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 continued 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 was the first of the selective estrogen receptor modulators (SERMs; see Chapter 40) to be approved for the prevention of osteoporosis. Raloxifene shares some of the beneficial effects of estrogen on bone with-out increasing the risk of breast or endometrial cancer (it may actually reduce the risk of breast cancer). Although not as effec-tive as estrogen in increasing bone density, raloxifene has been shown to reduce vertebral fractures. Nonhormonal forms of therapy for osteoporosis have been developed with proven efficacy in reducing fracture risk. Bisphosphonates such as alendronate, risedronate, ibandronate, and zoledronate have been conclusively shown to increase bone density and reduce fractures over at least 5 years when used continuously at a dosage of 10 mg/d or 70 mg/week for alendronate; 5 mg/d or 35 mg/week for risedronate; 2.5 mg/d or 150 mg/month for ibandronate; and 5 mg annually for intrave-nous zoledronate. Side-by-side trials between alendronate and calcitonin (another approved nonestrogen drug for osteoporo-sis) 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 irrita-tion, but this is not a significant problem at the doses recom-mended for osteoporosis when patients are instructed to take the drug with a glass of water and remain upright. Denosumab is a human monoclonal antibody directed against RANKL, and it 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 second-ary effects to inhibit bone formation. On the other hand, teripa-ratide, the recombinant form of PTH 1-34 and abaloparatide, an analog of PTHrP, directly stimulate bone formation as well as bone resorption. However, teriparatide and abaloparatide are given daily by subcutaneous injection. Their efficacy in prevent-ing fractures is at least as great as that of the bisphosphonates. In all cases, adequate intake of calcium and vitamin D needs to be maintained. Furthermore, there are several other forms of therapy in devel-opment. 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 tri-als; approval for use in the United States is expected. Additional promising new treatments undergoing clinical trials include antibodies against sclerostin. Romosozumab, for example, is showing promising results in phase 3 trials by stimulating bone formation and at least initially inhibiting bone resorption. Phase 3 trials with odanacatib, an inhibitor of cathepsin K, an enzyme in osteoclasts that facilitates bone resorption, showed efficacy with respect to fracture reduction. However, this drug also showed an unexpected increase in strokes, and it will not be further developed. In Japan, eldecalcitol, an analog of 1,25(OH)2D, has been approved for the treatment of osteoporo-sis with minimal effects on serum calcium. It is not yet available in the United States.