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    Original Investigation
    November 13, 2019

    Association of Receiving Multiple, Concurrent Fracture-Associated Drugs With Hip Fracture Risk

    Author Affiliations
    • 1The Dartmouth Institute for Health Policy and Clinical Practice, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire
    • 2Division of Geriatric and Palliative Medicine, Internal Medicine, Institute of Healthcare Policy and Innovation, University of Michigan, Ann Arbor
    • 3Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough
    • 4now with Microsoft Artificial Intelligence and Research, Healthcare NeXT, Redmond, Washington
    JAMA Netw Open. 2019;2(11):e1915348. doi:10.1001/jamanetworkopen.2019.15348
    Key Points español 中文 (chinese)

    Question  Is the concurrent receipt of 2 fracture-associated drugs associated with increased risk of hip fracture?

    Findings  In this cohort study, 11 million person-years of Medicare data revealed that the receipt of multiple fracture-associated drugs was common among older US residents. Concurrent receipt of 2 or more such drugs was associated with a more than 2-fold increase in hip fracture risk, with some specific combinations appearing especially hazardous, including commonly prescribed drugs, such as opioids, antidepressants, and sedatives.

    Meaning  If confirmed, results of this cohort study suggest caution when combining fracture-associated medications, especially when use is discretionary, alternatives exist, or baseline fracture risk is high.


    Importance  Many prescription drugs increase fracture risk, which raises concern for patients receiving 2 or more such drugs concurrently. Logic suggests that risk will increase with each additional drug, but the risk of taking multiple fracture-associated drugs (FADs) is unknown.

    Objective  To estimate hip fracture risk associated with concurrent exposure to multiple FADs.

    Design, Setting, and Participants  This cohort study used a 20% random sample of Medicare fee-for-service administrative data for age-eligible Medicare beneficiaries from 2004 to 2014. Sex-stratified Cox regression models estimated hip fracture risk associated with current receipt of 1, 2, or 3 or more of 21 FADs and, separately, risk associated with each FAD and 2-way FAD combination vs no FADs. Models included sociodemographic characteristics, comorbidities, and use of non-FAD medications. Analyses began in November 2018 and were completed April 2019.

    Exposure  Receipt of prescription FADs.

    Main Outcomes and Measures  Hip fracture hospitalization.

    Results  A total of 11.3 million person-years were observed, reflecting 2 646 255 individuals (mean [SD] age, 77.2 [7.3] years, 1 615 613 [61.1%] women, 2 136 585 [80.7%] white, and 219 579 [8.3%] black). Overall, 2 827 284 person-years (25.1%) involved receipt of 1 FAD; 1 322 296 (11.7%), 2 FADs; and 954 506 (8.5%), 3 or more FADs. In fully adjusted, sex-stratified models, an increase in hip fracture risk among women was associated with the receipt of 1, 2, or 3 or more FADs (1 FAD: hazard ratio [HR], 2.04; 95% CI, 1.99-2.11; P < .001; 2 FADs: HR, 2.86; 95% CI, 2.77-2.95; P < .001; ≥3 FADs: HR, 4.50; 95% CI, 4.36-4.65; P < .001). Relative risks for men were slightly higher (1 FAD: HR, 2.23; 95% CI, 2.11-2.36; P < .001; 2 FADs: HR, 3.40; 95% CI, 3.20-3.61; P < .001; ≥3 FADs: HR, 5.18; 95% CI, 4.87-5.52; P < .001). Among women, 2 individual FADs were associated with HRs greater than 3.00; 80 pairs of FADs exceeded this threshold. Common, risky pairs among women included sedative hypnotics plus opioids (HR, 4.90; 95% CI, 3.98-6.02; P < .001), serotonin reuptake inhibitors plus benzodiazepines (HR, 4.50; 95% CI, 3.76-5.38; P < .001), and proton pump inhibitors plus opioids (HR, 4.00; 95% CI, 3.56-4.49; P < .001). Receipt of 1, 2, or 3 or more non-FADs was associated with a small, significant reduction in fracture risk compared with receipt of no non-FADs among women (1 non-FAD: HR, 0.93; 95% CI, 0.90-0.96; P < .001; 2 non-FADs: HR, 0.84; 95% CI, 0.81-0.87; P < .001; ≥3 non-FADs: HR, 0.74; 95% CI, 0.72-0.77; P < .001).

    Conclusions and Relevance  Among older adults, FADs are commonly used and commonly combined. In this cohort study, the addition of a second and third FAD was associated with a steep increase in fracture risk. Many risky pairs of FADs included potentially avoidable drugs (eg, sedatives and opioids). If confirmed, these findings suggest that fracture risk could be reduced through tighter adherence to long-established prescribing guidelines and recommendations.