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      Efficacy and Safety of Postmenopausal Osteoporosis Treatments: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

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          Abstract

          Although a range of pharmacological interventions is available, it remains uncertain which treatment for osteoporosis is more effective. This network meta-analysis study aimed to compare different drug efficacy and safety in randomized controlled trials (RCTs) for the treatment of postmenopausal osteoporosis. PubMed, EMBASE, MEDLINE, Clinicaltrial.gov, Cochrane library, Google scholar were searched up to 31 October 2020. Randomized placebo-controlled trials that reported measures of bone mineral density (BMD) percentage change and/or numbers of adverse events of postmenopausal osteoporosis patients were included. Network meta-analysis was conducted using frequentist approach. Ninety-four RCTs comprising 15,776 postmenopausal osteoporosis females were included in the network meta-analysis. Compared with placebo, most interventions showed increase in BMD change. According to surfaces under the cumulative ranking curves (SUCRAs), strontium ranelate, fluoride, and hormone replacement therapy were most effective in increasing total hip, lumbar spine, and distal radius BMD, respectively. Parathyroid hormone (PTH) was most effective in preventing new hip fracture. When taking into account all anatomic sites, bisphosphonate (BP), monoclonal antibody (mAb), and fluoride have a balanced efficacy in increasing BMD at all sites. Considering both the effectiveness of increasing BMD and preventing hip fracture, mAb, BP, and PTH are more favorable among all interventions. The treatment effects of different medications on BMD percentage change are anatomic site-dependent. After weighing anti-osteoporosis treatment efficacy against risk of complications, BP and mAb are the more favorable interventions to increase BMD at all sites and reduce the risks of hip fracture and death.

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          Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

          David Moher and colleagues introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses
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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

                Contributors
                Role: Academic Editor
                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                08 July 2021
                July 2021
                : 10
                : 14
                : 3043
                Affiliations
                [1 ]Department of Dentistry, MacKay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei 10449, Taiwan; aaa1212p@ 123456gmail.com
                [2 ]School of Dentistry, College of Medicine, National Taiwan University, No. 1, Chang-De Street, Taipei 10048, Taiwan; orthodaniel@ 123456yahoo.com.tw (M.-C.H.); blr1350@ 123456gmail.com (S.-F.C.)
                [3 ]Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan; tsuangfy@ 123456gmail.com
                [4 ]Department of Orthopedic Surgery, College of Medicine, China Medical University, No. 2, Yu-Der Rd., Taichung 40447, Taiwan
                [5 ]Department of Orthopedic Surgery, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan
                Author notes
                [* ]Correspondence: jennyzc@ 123456ms3.hinet.net (J.Z.-C.C.); drjssun@ 123456gmail.com (J.-S.S.); Tel.: +886-4-22062121 (J.-S.S.)
                [†]

                These authors contributed equally.

                Author information
                https://orcid.org/0000-0002-7694-3860
                https://orcid.org/0000-0001-5797-1885
                Article
                jcm-10-03043
                10.3390/jcm10143043
                8305263
                34300210
                958fe4e2-885b-464a-a1f6-55e9a75534f5
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 20 May 2021
                : 05 July 2021
                Categories
                Article

                network meta-analysis,randomized controlled trial,osteoporosis,bone mineral density,risks of complications

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