Cumulative network meta-analyses, practice guidelines, and actual prescriptions for postmenopausal osteoporosis: a meta-epidemiological study
- 作者列表："Kataoka, Yuki","Luo, Yan","Chaimani, Anna","Onishi, Akira","Kimachi, Miho","Tsujimoto, Yasushi","Murad, Mohammad Hassan","Li, Tianjing","Cipriani, Andrea","Furukawa, Toshi A.
Summary We compared the cumulative network meta-analyses with the recommendations in postmenopausal osteoporosis practice guidelines and actual prescribing practices in the USA. There was no apparent discrepancy between guideline recommendations and drug prescribing rankings, with the exception of vitamin D and calcium, when we used cumulative NMAs as references. Purpose To compare the results of cumulative network meta-analyses (NMAs) with the recommendations in postmenopausal osteoporosis practice guidelines and actual prescribing practices in the USA. Methods MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus were searched to retrieve randomized controlled trials (RCTs) in July 2017. The Agency for Healthcare Research and Quality’s National Guideline Clearinghouse and associated society websites were searched to retrieve guidelines in June 2018. We used the Medical Expenditure Panel Survey (MEPS) to analyze prescription data from 1996 to 2015. Two independent investigators selected eligible RCTs. One investigator selected potential eligible guidelines, which were confirmed by another investigator. Two independent investigators extracted data from included RCTs. One investigator extracted recommendations from guidelines, which were confirmed by another investigator. (Registration: UMIN000031894) Results We analyzed data from 1995, 2000, 2005, 2010, and 2015. We chose hip fracture as the primary outcome of cumulative NMAs. We included 51 trials, 17 guidelines, and 5099 postmenopausal osteoporosis patients from the MEPS. Bisphosphonate, including alendronate, and combination of vitamin D and calcium (vDCa) were consistently recommendable from an efficacy viewpoint in NMAs and recommended in guidelines. Alendronate was the most prescribed drug (more than 30% over the observation period); however, vDCa was seldom prescribed. The maximum proportion was 5.3% from 2011 to 2015. Conclusions In postmenopausal osteoporosis, there was no apparent discrepancy between guideline recommendations and drug prescribing rankings, with the exception of vDCa, when we used cumulative NMAs as references.
总结我们比较了累积网络荟萃分析与美国绝经后骨质疏松症实践指南和实际处方实践中的建议。当我们使用累积 NMAs 作为参考时，指南建议和药物处方排名之间没有明显差异，维生素 D 和钙除外。目的比较累积网络荟萃分析 (NMAs) 的结果与美国绝经后骨质疏松症实践指南和实际处方实践中的建议。方法检索 MEDLINE 、 EMBASE 、 Cochrane Central Register of Controlled Trials 、 Web of Science 和 Scopus，检索 2017年7月随机对照试验 (RCTs)。2018年6月检索了医疗保健研究和质量机构的国家指南交换所和相关社会网站，以检索指南。我们使用医疗支出小组调查 (MEPS) 分析 1996年 2015年的处方数据。两名独立研究者选择了符合条件的 rct。一名研究者选择了潜在的合格指南，经另一名研究者确认。两名独立研究者从纳入的 rct 中提取数据。一名研究者从指南中提取建议，经另一名研究者确认。(注册: UMIN000031894) 结果我们分析了 2000 、 2005 、 2010 、 2015 和 1995年的数据。我们选择髋部骨折作为累积 NMAs 的主要结局。我们纳入了来自 mep 的 51 项试验、 17 项指南和 5099 例绝经后骨质疏松症患者。双膦酸盐，包括阿仑膦酸钠，以及维生素d 和钙的组合 (vDCa) 从 NMAs 的疗效观点来看是一致的推荐，并在指南中推荐。阿仑膦酸钠是处方最多的药物 (观察期超过 30%); 然而，很少开具 vDCa 处方。最高比例为 5.3% 2011年 2015年。结论在绝经后骨质疏松症中，当我们使用累积 NMAs 作为参考时，指南建议和药物处方排名之间没有明显差异，vDCa 除外。
METHODS::A major challenge in translating findings from genome-wide association studies (GWAS) to biological mechanisms is pinpointing functional variants because only a very small percentage of variants associated with a given trait actually impact the trait. We used an extensive epigenetics, transcriptomics, and genetics analysis of the TBX15/WARS2 neighbourhood to prioritize this region's best-candidate causal variants for the genetic risk of osteoporosis (estimated bone density, eBMD) and obesity (waist-hip ratio or waist circumference adjusted for body mass index). TBX15 encodes a transcription factor that is important in bone development and adipose biology. Manual curation of 692 GWAS-derived variants gave eight strong candidates for causal SNPs that modulate TBX15 transcription in subcutaneous adipose tissue (SAT) or osteoblasts, which highly and specifically express this gene. None of these SNPs were prioritized by Bayesian fine-mapping. The eight regulatory causal SNPs were in enhancer or promoter chromatin seen preferentially in SAT or osteoblasts at TBX15 intron-1 or upstream. They overlap strongly predicted, allele-specific transcription factor binding sites. Our analysis suggests that these SNPs act independently of two missense SNPs in TBX15. Remarkably, five of the regulatory SNPs were associated with eBMD and obesity and had the same trait-increasing allele for both. We found that WARS2 obesity-related SNPs can be ascribed to high linkage disequilibrium with TBX15 intron-1 SNPs. Our findings from GWAS index, proxy, and imputed SNPs suggest that a few SNPs, including three in a 0.7-kb cluster, act as causal regulatory variants to fine-tune TBX15 expression and, thereby, affect both obesity and osteoporosis risk.
METHODS:PURPOSE:Systemic mastocytosis (SM) is characterized by the expansion of clonal mast cells that infiltrate various organ systems. The extent of organ infiltration and subsequent organ damage distinguishes between indolent SM (ISM) defined by a nearly normal life expectancy and advanced SM (AdvSM) defined by poor prognosis. In ISM, measurement of the bone mineral density (BMD) frequently reveals osteoporosis. In contrast, the clinical implication of an increased BMD and osteosclerosis remains unclear. METHODS:BMD was evaluated in 61 patients with mastocytosis (ISM, n = 29, 48%; AdvSM, n = 32, 52%). We correlated the prevalence of osteoporosis, increased BMD and osteosclerosis with clinical parameters, disease variant and prognosis. RESULTS:Osteoporosis was detected in 11/29 (38%) patients with ISM but only in 2/32 (6%) patients with AdvSM (p = 0.004). An increased BMD was detected in 1/29 (3%) patients with ISM and 24/32 (75%) patients with AdvSM (p < 0.001) while osteosclerosis was only detected in AdvSM patients (16/32, 50%). AdvSM patients with increased BMD had higher levels of bone marrow mast cell infiltration, higher serum tryptase and alkaline phosphatase levels compared to ISM as well as higher number of high-molecular risk mutations (p < 0.05). In addition, we found that the prognosis of AdvSM patients with increased BMD is inferior compared to those without increased BMD (median overall survival 3.6 years versus not reached, p = 0.031). CONCLUSIONS:Osteoporosis is a common feature in ISM but not in AdvSM. An increased BMD is frequently present in AdvSM but not in ISM and is associated with more advanced disease and inferior outcome.
METHODS::We present salmon calcitonin (SCT) loaded Hydroxyapatite nanoparticles (HAP-NPs) for sublingual osteoporosis therapy. Surface stabilized HAP-NPs were prepared by aqueous precipitation. SCT was loaded by ionic complexation, as confirmed by FTIR. SCT-HAP-NPs exhibited high loading efficiency (~85%), average size (~100nm), and zeta potential (~-25 mv). Stability of SCT was established by circular dichroism spectroscopy and HPLC analysis. Confocal laser scanning microscopy confirmed deep penetration of SCT-HAP-NPs into the mucosa with >4-fold enhancement in permeability relative to SCT solution. Sublingual SCT-HAP-NPs revealed relative bioavailability of ~15% compared to the subcutaneous injection in rabbits (200iu). Significant and comparable improvement in serum biomarkers with increase in bone mass and mechanical strength and decreased bone erosion compared to subcutaneous SCT was confirmed in ovariectomized (OVX) osteoporosis rat model. Such comparable pharmacodynamic effect at the same dose suggested targeted bone delivery and promise of sublingual SCT-HAP-NPs as a non-invasive alternative to the injection.