title: Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials.
abstract: To evaluate the comparative effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on risk of bone fracture in patients with type 2 diabetes mellitus (T2DM).
  
  
  
  PubMed, EMBASE, CENTRAL and ClinicalTrials.gov were systematically searched from inception to 27 January 2016 to identify randomized controlled trials (RCTs) reporting the outcome of fracture in patients with T2DM treated with SGLT2 inhibitors. Pairwise and network meta-analyses, as well as a cumulative meta-analysis, were performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs).
  
  
  
  A total of 38 eligible RCTs (10 canagliflozin, 15 dapagliflozin and 13 empagliflozin) involving 30 384 patients, with follow-ups ranging from 24 to 160 weeks, were included. The fracture event rates were 1.59% in the SGLT2 inhibitor groups and 1.56% in the control groups. The incidence of fracture events was similar among these three SGLT2 inhibitor groups. Compared with placebo, canagliflozin (OR 1.15; 95% CI 0.71-1.88), dapagliflozin (OR 0.68; 95% CI 0.37-1.25) and empagliflozin (OR 0.93; 95% CI 0.74-1.18) were not significantly associated with an increased risk of fracture. Our cumulative meta-analysis indicated the robustness of the null findings with regard to SGLT2 inhibitors.
  
  
  
  Our meta-analysis based on available RCT data does not support the harmful effect of SGLT2 inhibitors on fractures, although future safety monitoring from RCTs and real-world data with detailed information on bone health is warranted.
authors.affiliation: Department of Pharmacy, Peking University Third Hospital, Beijing, China.|Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, USA.|Center for Pharmacoepidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, USA.
authors.forename: H L
authors.initials: HL
authors.lastname: Tang
authors.affiliation: Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: D D
authors.initials: DD
authors.lastname: Li
authors.affiliation: Division of Nephrology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: Hebrew Seniorlife Institute for Aging Research and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Y H
authors.initials: YH
authors.lastname: Hsu
authors.affiliation: Department of Pharmacy Administration and Clinical Pharmacy, Peking University Health Science Center, Beijing, China.
authors.forename: T S
authors.initials: TS
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Peking University Third Hospital, Beijing, China.
authors.forename: S D
authors.initials: SD
authors.lastname: Zhai
authors.affiliation: Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, USA.|Center for Pharmacoepidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, USA.
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Song
mesh_terms: D001559:Benzhydryl Compounds / Q000627:therapeutic use; D000068896:Canagliflozin / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D050723:Fractures, Bone / Q000453:epidemiology*; D005960:Glucosides / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D015994:Incidence; D016017:Odds Ratio; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin; C529054:dapagliflozin; C570240:empagliflozin
keywords: 
  SGLT2 inhibitor; fracture; meta-analysis; type 2 diabetes