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.
Subject(s)
Blood Glucose/metabolism , Bone Density Conservation Agents/administration & dosage , Fasting/blood , Fractures, Bone/prevention & control , Osteoporosis, Postmenopausal/blood , Osteoporosis, Postmenopausal/drug therapy , Aged , Animals , Body Weight/drug effects , Bone Density Conservation Agents/adverse effects , Diabetes Mellitus/blood , Diabetes Mellitus/chemically induced , Disease Models, Animal , Female , Follow-Up Studies , Fractures, Bone/blood , Fractures, Bone/epidemiology , Humans , Incidence , Insulin Resistance , Mice , Middle Aged , Osteoporosis, Postmenopausal/epidemiology , Time FactorsABSTRACT
OBJECTIVES: To determine whether resting heart rate is associated with several types of osteoporotic fractures, mortality, and cause-specific mortality in older women. DESIGN: A prospective cohort study. SETTING: Four communities across the United States. PARTICIPANTS: We prospectively assessed resting pulse rate in 9,702 women aged 65 and older enrolled in the Study of Osteoporotic Fractures. MEASUREMENTS: Resting pulse was measured in the supine position. Hip, humerus, pelvis, rib, ankle, and wrist fractures were identified by self-report and validated by radiographs. Incident vertebral fractures were assessed by quantitative morphometry. Cause-specific mortality was assessed from death certificates and hospital discharge summaries. RESULTS: Women with resting heart rates of greater than 80 beats per minute (bpm) (n = 1,140 (12%)) had an adjusted 1.6-fold (95% confidence interval (CI) = 1.2-2.0) increased risk of either a hip, pelvis, or rib fracture and a 1.9-fold (95% CI = 1.4-2.5) increased risk of vertebral fracture. A heart rate of 80 bpm or greater was also associated with 1.4-fold (95% Cl = 1.2-1.5) increased all-cause mortality and 1.5-fold (95% CI = 1.2-2.1) increased coronary heart disease mortality. Investigating resting heart rate as a continuous variable, we detected a general pattern of increasing risks with higher heart rate that could not be explained by age, weight, poor health, physical activity, hyperthyroidism, or smoking. CONCLUSIONS: Older women with resting heart rates of 80 bpm or more have an increased risk of several osteoporotic fractures and of mortality that is not explained by other risk factors. Heart rate may be a simple tool for assessing risk of fracture and of death from coronary heart disease in older women.
