Anti-Diabetic and Antiresorptive Pharmacotherapies for Prevention and Treatment of Type 2 Diabetes-Induced Bone Disease: Protocol for a Two-Part Systematic Review and Network Meta-Analysis

IntroductionPatients with type 2 diabetes mellitus (T2DM) are at risk for a variety of severe debilitating effects. One of the most serious complications experienced by T2DM patients are skeletal diseases caused by changes in the bone microenvironment. As a result, T2DM patients are at risk for higher prevalence of fragility fractures.There are a variety of treatments available for counteracting this effect. Some anti-diabetic medications, such as metformin, have been shown to have a positive effect on bone health without the addition of additional drugs into patients’ treatment plans. Chinese randomized controlled trial (RCT) studies have also proposed antiresorptive pharmacotherapies as a viable alternative treatment strategy. Previous network meta-analyses (NMAs) and meta-analyses regarding this topic did not include all available RCT trials, or only performed pairwise comparisons. We present a protocol for a two-part NMA that incorporates all available RCT data to provide the most comprehensive ranking of anti-diabetics (Part I) and antiresorptive (Part II) pharmacotherapies in terms of their ability to decrease fracture incidences, increase bone mineral density (BMD), improve indications of bone turnover markers (BTMs), and decrease pain in adult T2DM patients.Methods and AnalysisWe will search MEDLINE, EMBASE, PubMed, Web of Science, CINAHL, CENTRAL and Chinese literature sources (CNKI, CQVIP, Wanfang Data, Wanfang Med Online) for randomized controlled trials (RCTs) which fit our criteria. We will include adult T2DM patients who have taken anti-diabetics (Part I) or antiresorptive (Part II) therapies with relevant outcome measures in our study.We will perform title/abstract and full-text screening as well as data extraction in duplicate. Risk of bias (RoB) will be evaluated in duplicate for each study, and the quality of evidence will be examined using CINeMA in accordance to the GRADE framework. We will use R and gemtc to perform the NMA. We will report changes in BMD, BTM and pain scores in either weighted or standardized mean difference, and we will report fracture incidences as odds ratios. We will use the surface under the cumulative ranking curve (SUCRA) scores to provide numerical estimates of the rankings of interventions.Ethics and DisseminationThe study will not require ethics approval. The findings of the two-part NMA will be disseminated in peer-reviewed journals and presented at conferences. We aim to produce the most comprehensive quantitative analysis regarding the management of T2DM bone disease. Our analysis should be able to provide physicians and patients with up-to-date recommendations for anti-diabetic medications and antiresorptive pharmacotherapies for maintaining bone health in T2DM patients.Systematic Review RegistrationInternational Prospective Register for Systematic Reviews (PROSPERO) — CRD42019139320ARTICLE SUMMARYStrengths and limitations of this studyLiterature search in Chinese databases will yield new RCT evidence regarding the efficacy of anti-diabetics in treating T2DM bone diseaseUsing network meta-analytical techniques to analyze the relative efficacy of antiresorptive therapies will allow us to include new treatment arms, such as zoledronic acid and risedronate.Only RCTs will be included and the quality of trials and networks will be evaluated using Risk of Bias, GRADE and comparison-adjusted funnel plots.Chinese clinicians may not use the same procedures and practices as Western clinicians, therefore the outcomes from Chinese RCTs may not apply to the Western healthcare systems.The study design does not allow the comparison of anti-diabetics with antiresorptive therapies or combinations of the two.