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

Introduction Patients 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 Analysis We 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 Dissemination The 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 Registration International Prospective Register for Systematic Reviews (PROSPERO) — CRD42019139320 Strengths and limitations of this study ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial CRD42019139320 ### Funding Statement No external funding was received for this study. ### Author Declarations All relevant ethical guidelines have been followed and any necessary IRB and/or ethics committee approvals have been obtained. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes Any clinical trials involved have been registered with an ICMJE-approved registry such as ClinicalTrials.gov and the trial ID is included in the manuscript. Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant Equator, ICMJE or other checklist(s) as supplementary files, if applicable. Yes Relevant data available upon request.