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Effects of antiresorptive therapies on glucose metabolism: results from the FIT, HORIZON-PFT, and FREEDOM trials
Journal article   Open access   Peer reviewed

Effects of antiresorptive therapies on glucose metabolism: results from the FIT, HORIZON-PFT, and FREEDOM trials

Ann V Schwartz, Anne L Schafer, Andrew Grey, Eric Vittinghoff, Lisa Palermo, Li-Yung L Lui, Robert B Wallace, Steven R Cummings, Dennis M Black, Douglas C Bauer, …
Journal of bone and mineral research, Vol.28(6), pp.1348-1354
06/2013
DOI: 10.1002/jbmr.1865
PMID: 23322676
url
https://doi.org/10.1002/jbmr.1865View
Published (Version of record) Open Access

Abstract

In rodent models, undercarboxylated osteocalcin (ucOC) acts as a hormone that promotes insulin sensitivity and secretion. If ucOC plays a similar role in humans, then antiresorptive therapies, which reduce ucOC levels, may increase the risk of insulin resistance and diabetes. We tested whether antiresorptive therapies result in higher fasting glucose, increased weight, or greater diabetes incidence in post hoc analyses of three randomized, placebo-controlled trials in postmenopausal women: Fracture Intervention Trial (FIT) (N = 6151) of alendronate (4 years), Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT) (N = 7113) of zoledronic acid (3 years), and Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial (N = 7076) of denosumab (3 years). Fasting glucose was measured annually in FIT and HORIZON in a subset of women, and every 6 months in FREEDOM in all participants. Weight was measured annually in all trials. Incident diabetes was identified from adverse event reports, initiation of diabetes medication, or elevated fasting glucose. Differences in fasting glucose changes from randomization to trial conclusion between treatment and placebo groups were not statistically significant: -0.47 mg/dL in FIT, 0.20 mg/dL in HORIZON-PFT, and 0.09 mg/dL in FREEDOM, all p > 0.6. Weight change differed between treatment and placebo groups in FIT (0.32 kg, p = 0.003) and FREEDOM (0.31 kg, p = 0.023) but not in HORIZON-PFT (0.15 kg, p = 0.132). In the three trials combined, diabetes occurred in 203 and 225 women assigned to treatment or placebo, respectively. Diabetes incidence was not increased in any of the treatment groups or in the pooled estimate (pooled relative risk [RR] = 0.90; 95% confidence interval [CI] 0.74-1.10). Antiresorptive therapy does not have a clinically important effect on fasting glucose, weight, or diabetes risk in postmenopausal women. Contrary to predictions from mouse models, reduced bone turnover does not appear to play a significant role in glucose metabolism in humans.
 Aged Animals Blood Glucose - metabolism Body Weight - drug effects Bone Density Conservation Agents - administration & dosage Bone Density Conservation Agents - adverse effects Diabetes Mellitus - blood Diabetes Mellitus - chemically induced Disease Models, Animal Fasting - blood Female Follow-Up Studies Fractures, Bone - blood Fractures, Bone - epidemiology Fractures, Bone - prevention & control Humans Incidence Insulin Resistance Mice Middle Aged Osteoporosis, Postmenopausal - blood Osteoporosis, Postmenopausal - drug therapy Osteoporosis, Postmenopausal - epidemiology Time Factors

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