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      Definition and management of very high fracture risk in women with postmenopausal osteoporosis: a position statement from the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Association of Bone Assessment and Metabolism (ABRASSO)

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          ABSTRACT

          Several drugs are available for the treatment of osteoporosis in postmenopausal women. Over the last decades, most patients requiring pharmacological intervention were offered antiresorptive drugs as first-line therapy, while anabolic agents were considered a last resource for those with therapeutic failure. However, recent randomized trials in patients with severe osteoporosis have shown that anabolic agents reduce fractures to a greater extent than antiresorptive medications. Additionally, evidence indicates that increases in bone mineral density (BMD) are maximized when patients are treated with anabolic agents first, followed by antiresorptive therapy. This evidence is key, considering that greater increases in BMD during osteoporosis treatment are associated with a more pronounced reduction in fracture risk. Thus, international guidelines have recently proposed an individualized approach to osteoporosis treatment based on fracture risk stratification, in which the stratification risk has been refined to include a category of patients at very high risk of fracture who should be managed with anabolic agents as first-line therapy. In this document, the Brazilian Society of Endocrinology and Metabolism and the Brazilian Association of Bone Assessment and Metabolism propose the definition of very high risk of osteoporotic fracture in postmenopausal women, for whom anabolic agents should be considered as first-line therapy. This document also reviews the factors associated with increased fracture risk, trials comparing anabolic versus antiresorptive agents, efficacy of anabolic agents in patients who are treatment naïve versus those previously treated with antiresorptive agents, and safety of anabolic agents.

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          Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.

          Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown. We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry. New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache). Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.
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            Denosumab for prevention of fractures in postmenopausal women with osteoporosis.

            Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis. We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.) 2009 Massachusetts Medical Society
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              Romosozumab Treatment in Postmenopausal Women with Osteoporosis.

              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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                Author and article information

                Journal
                Arch Endocrinol Metab
                Arch Endocrinol Metab
                aem
                Archives of Endocrinology and Metabolism
                Sociedade Brasileira de Endocrinologia e Metabologia
                2359-3997
                2359-4292
                03 October 2022
                2022
                : 66
                : 5
                : 591-603
                Affiliations
                [1 ] orgnameSanta Casa de Belo Horizonte orgdiv1Unidade de Endocrinologia Belo Horizonte MG Brasil originalUnidade de Endocrinologia, Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brasil
                [2 ] orgnameHospital Felício Rocho orgdiv1Unidade de Endocrinologia Belo Horizonte MG Brasil originalUnidade de Endocrinologia, Hospital Felício Rocho, Belo Horizonte, MG, Brasil
                [3 ] orgnameCentro Universitário de Belo Horizonte orgdiv1Departamento de Medicina Belo Horizonte MG Brasil originalDepartamento de Medicina, Centro Universitário de Belo Horizonte (UNI-BH), Belo Horizonte, MG, Brasil
                [4 ] orgnameUniversidade Federal do Rio de Janeiro orgdiv1Divisão de Endocrinologia e Metabolismo Rio de Janeiro RJ Brasil originalDivisão de Endocrinologia e Metabolismo, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
                [5 ] orgnameUniversidade Federal do Ceará orgdiv1Departamento de Medicina Clínica Fortaleza CE Brasil originalDepartamento de Medicina Clínica, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brasil
                [6 ] orgnameUniversidade Federal de São Paulo orgdiv1Escola Paulista de Medicina orgdiv2Unidade de Endocrinologia São Paulo SP Brasil originalUnidade de Endocrinologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil
                [7 ] orgnameUniversidade Federal da Paraíba orgdiv1Divisão de Endocrinologia e Metabolismo João Pessoa PB Brasil originalDivisão de Endocrinologia e Metabolismo, Universidade Federal da Paraíba, João Pessoa, PB, Brasil
                [8 ] orgnameUniversidade Federal de São Paulo orgdiv1Escola Paulista de Medicina orgdiv2Divisão de Reumatologia São Paulo SP Brasil originalDivisão de Reumatologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil
                [9 ] orgnameCentro Paulista de Investigação Clínica São Paulo SP Brasil originalCentro Paulista de Investigação Clínica, São Paulo, SP, Brasil
                [10 ] orgnameUniversidade de São Paulo orgdiv1Faculdade de Medicina de Ribeirão Preto orgdiv2Departamento de Clínica Médica Ribeirão Preto SP Brasil originalDepartamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
                [11 ] orgnameUniversidade de Pernambuco orgdiv1Faculdade de Medicina orgdiv2Divisão de Endocrinologia e Metabolismo Recife PE Brasil originalDivisão de Endocrinologia e Metabolismo, Faculdade de Medicina, Universidade de Pernambuco, Recife, PE, Brasil
                Author notes
                Correspondence to: Barbara C. Silva, Rua Uberaba, 370, sala 705, Barro Preto 30180-080 – Belo Horizonte, MG, Brasil. barbarasilva2131@ 123456gmail.com
                [a]

                Member of the Sociedade Brasileira de Endocrinologia e Metabolismo (SBEM).

                [b]

                Member of the Associação Brasileira de Avaliação Óssea e Osteometabolismo (ABRASSO).

                Disclosure: Barbara C. Silva – Scientific lecture fees from Amgen. Miguel Madeira – No financial relationships or conflicts of interest. Catarina Brasil d’Alva – No financial relationships or conflicts of interest. Sergio Setsuo Maeda – Scientific lecture fees from Theramex. Narriane Chaves Pereira de Holanda – Scientific lecture fees from Amgen, AstraZeneca, Eli Lilly, and Novo Nordisk. Monique Nakayama Ohe – No financial relationships or conflicts of interest. Vera Szejnfeld – Scientific lecture fees from Amgen, Apsen, Zodiac, and Theramex; Member of the scientific advisory board, Apsen. Cristiano Zerbini – Research grants from Pfizer, Janssen, Amgen, Eli Lilly, GSK, and Novartis. Francisco José Albuquerque de Paula – No financial relationships or conflicts of interest. Francisco Bandeira – Scientific lecture fees from Amgen.

                Author information
                https://orcid.org/0000-0001-7276-581X
                https://orcid.org/0000-0001-6752-2880
                https://orcid.org/0000-0001-7332-9841
                https://orcid.org/0000-0002-2669-4245
                https://orcid.org/0000-0002-5724-8096
                https://orcid.org/0000-0003-4900-7185
                https://orcid.org/0000-0002-1743-6113
                https://orcid.org/0000-0001-6269-2354
                https://orcid.org/0000-0003-1262-3486
                https://orcid.org/0000-0003-0290-0742
                Article
                2359-3997000000522
                10.20945/2359-3997000000522
                10118822
                36191263
                a3e341f7-774b-436f-86ae-529e5c7431ea

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 November 2021
                : 25 April 2022
                Page count
                Figures: 0, Tables: 3, Equations: 0, References: 100
                Categories
                Consensus

                osteoporosis,very high risk of fracture,anabolic,teriparatide,romosozumab

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