Osteoporosis is a systemic skeletal disease characterized by decreasing bone mass and microarchitectural deterioration of bone tissue, with consequent increases in bone fragility and susceptibility to fracture. In addition to fractures, the clinical complications of osteoporosis include disability and chronic pain. Approximately 52 million people in the United States are affected by osteoporosis or low bone density. It is especially common in postmenopausal women, but one in five men will experience an osteoporosis-related fracture at some point in his lifetime. The economic burden of osteoporosis is large and growing: the most recent estimate of U.S. annual costs due to fractures alone have been nearly $20 billion. A recent projection of the burden and costs of incident osteoporosis-related fractures in the United States from 2005 to 2025 estimates more than 2 million fractures in 2010, with direct medical costs of more than $18 billion (more than 25 percent attributable to men). Although the bulk of these costs are incurred by individuals 65 and older, direct costs and productivity loss among working women under 65 are considerable. Since the release of the original report, several of the bisphosphonates have become available in new, less frequently administered, forms, and a new biological agent, denosumab, is now available. In addition, new data have been released on adverse events associated with bisphosphonates. The update search identified new data on effectiveness and adverse effects. Thus the following questions guided the current report. Key Question 1: What are the comparative benefits in fracture risk reduction among the following therapeutic modalities for low bone density: Bisphosphonate medications, specifically: Alendronate (Fosamax(r), oral), Risedronate (Actonel(r); oral once-a-week), Ibandronate (Boniva(r)), Zoledronic acid (Reclast(r)IV); Denosumab (Prolia(r)); Menopausal estrogen therapy for women (numerous brands and routes of administration); Parathyroid hormone (PTH), 1-34 (teriparatide) (Forteo(r)); Selective estrogen receptor modulators (SERMs), specifically, Raloxifene (Evista(r)); Calcium; Vitamin D; Combinations or sequential use of above; Exercise in comparison to above agents. Key Question 2: How does fracture risk reduction resulting from treatments vary between individuals with different risks for fracture as determined by the following factors: Bone mineral density; FRAX or other risk assessment score; Prior fractures (prevention vs. treatment); Age; Sex; Race/ethnicity; Glucocorticoid use; Other factors (e.g., whether the individuals were community dwelling vs. institutionalized, vitamin D deficient vs. not). Key Question 3: Regarding treatment adherence and persistence, What are the levels of adherence to and persistence with medications for the treatment and prevention of osteoporosis? What factors affect adherence and persistence? What are the effects of adherence and persistence on the risk of fractures? Key Question 4: What are the short- and long-term harms (adverse effects) of the above therapies (when used specifically to treat or prevent low bone density/osteoporotic fracture); and do these vary by any specific subpopulations (e.g., the subpopulations identified in Key Question 2)? Key Question 5: With regard to treatment for preventing osteoporotic fracture: How often should patients be monitored (via measurement of bone mineral density) during therapy; how does bone density monitoring predict antifracture benefits during pharmacotherapy; and does the ability of monitoring to predict antifracture effects of a particular pharmacologic agent vary among the pharmacotherapies? How does the antifracture benefit vary with long-term continued use of pharmacotherapy, and what are the comparative antifracture effects of continued long-term therapy with the various pharmacother