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      Romosozumab Treatment in Postmenopausal Women with Osteoporosis

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          Abstract

          Background Romosozumab, a monoclonal antibody that binds sclerostin, increases bone formation and decreases bone resorption. Methods We enrolled 7180 postmenopausal women who had a T score of -2.5 to -3.5 at the total hip or femoral neck. Patients were randomly assigned to receive subcutaneous injections of romosozumab (at a dose of 210 mg) or placebo monthly for 12 months; thereafter, patients in each group received denosumab for 12 months, at a dose of 60 mg, administered subcutaneously every 6 months. The coprimary end points were the cumulative incidences of new vertebral fractures at 12 months and 24 months. Secondary end points included clinical (a composite of nonvertebral and symptomatic vertebral) and nonvertebral fractures. Results At 12 months, new vertebral fractures had occurred in 16 of 3321 patients (0.5%) in the romosozumab group, as compared with 59 of 3322 (1.8%) in the placebo group (representing a 73% lower risk with romosozumab; P<0.001). Clinical fractures had occurred in 58 of 3589 patients (1.6%) in the romosozumab group, as compared with 90 of 3591 (2.5%) in the placebo group (a 36% lower risk with romosozumab; P=0.008). Nonvertebral fractures had occurred in 56 of 3589 patients (1.6%) in the romosozumab group and in 75 of 3591 (2.1%) in the placebo group (P=0.10). At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3325 patients] in the romosozumab group vs. 2.5% [84 of 3327] in the placebo group, a 75% lower risk with romosozumab; P<0.001). Adverse events, including instances of hyperostosis, cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and two cases of osteonecrosis of the jaw were observed in the romosozumab group. Conclusions In postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year. (Funded by Amgen and UCB Pharma; FRAME ClinicalTrials.gov number, NCT01575834 .).

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          Most cited references15

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          Romosozumab in postmenopausal women with low bone mineral density.

          Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation.
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            Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST).

            Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. By linkage analysis in one extended van Buchem family and two consanguineous sclerosteosis families we previously mapped both disease genes to the same chromosomal 17q12-q21 region, supporting the hypothesis that both conditions are caused by mutations in the same gene. After reducing the disease critical region to approximately 1 Mb, we used the positional cloning strategy to identify the SOST gene, which is mutated in sclerosteosis patients. This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif. Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients, but no mutations were found in a fourth sclerosteosis patient nor in the patients from the van Buchem family. As the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation. Therefore, this gene might become an important tool in the development of therapeutic strategies for osteoporosis.
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              Estimating hip fracture morbidity, mortality and costs.

              To estimate lifetime morbidity, mortality, and costs from hip fracture incorporating the effect of deficits in activities of daily living. Markov computer cohort simulation considering short- and long-term outcomes attributable to hip fractures. Data estimates were based on published literature, and costs were based primarily on Medicare reimbursement rates. Postacute hospital facility. Eighty-year-old community dwellers with hip fractures. Life expectancy, nursing facility days, and costs. Hip fracture reduced life expectancy by 1.8 years or 25% compared with an age- and sex-matched general population. About 17% of remaining life was spent in a nursing facility. The lifetime attributable cost of hip fracture was $81,300, of which nearly half (44%) related to nursing facility expenses. The development of deficits in ADLs after hip fracture resulted in substantial morbidity, mortality, and costs. Hip fractures result in significant mortality, morbidity, and costs. The estimated lifetime cost for all hip fractures in the United States in 1997 likely exceeded $20 billion. These results emphasize the importance of current and future interventions to decrease the incidence of hip fracture.
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                Author and article information

                Journal
                New England Journal of Medicine
                N Engl J Med
                Massachusetts Medical Society
                0028-4793
                1533-4406
                October 20 2016
                October 20 2016
                : 375
                : 16
                : 1532-1543
                Article
                10.1056/NEJMoa1607948
                27641143
                e8ab7076-9452-49ab-a193-c601367180a5
                © 2016
                History

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