Does Antihypertensive Medication Class Affect Fracture Risk?

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Researchers compared antihypertensive medication classes to evaluate fracture risk in users vs nonusers.
Researchers compared antihypertensive medication classes to evaluate fracture risk in users vs nonusers.

Thaizide-type diuretic therapy presents a lower hip and pelvic fracture risk compared to other hypertensive medications, according to research published in JAMA Internal Medicine.

Investigators from the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ClinicalTrials.gov identifier: NCT00000542) Collaborative Research Group used Veterans Affairs (VA) and Medicare insurance claims data to conduct a randomized, double-blind, active-controlled, clinical hypertension trial examining the link between thiazide diuretic use vs nonuse and fracture risk.

Study participants were randomly assigned to 1 of 3 first-step therapies: thiazide-type diuretic chlorthalidone (n=15,225), calcium channel blocker (CCB) amlodipine besylate (n=9048), or angiotensin-converting enzyme (ACE) inhibitor lisinopril. Assessment of a fourth therapy, α-receptor blocker doxazosin (n=9061), was stopped early due to an elevated cardiovascular disease risk compared with chlorthalidone.

Eligible participants were aged 55 years or older; had systolic and diastolic blood pressure readings of 140 mm Hg and 90 mm Hg, respectively; took medication for hypertension; and had at least 1 risk factor for coronary heart disease (CHD). Participants were recruited from 1994 to 1998, with in-trial follow-up concluding in 2002. Posttrial follow-up took place through the end of 2006, and was conducted using passive surveillance through national databases.

A total of 22,180 participants (age: 70.4±6.7 years; 43% women; 49.9% white) were followed for up to 8 years (mean follow-up: 4.9±1.5 years) during masked therapy. At the conclusion of the trial, 16,622 participants were followed for an additional 5 years (mean total follow-up: 7.8±3.1 years).

Among the in-trial cohort, 34 participants had pelvic fractures and 307 had hip fractures; 3 participants had both hip and pelvic fractures.

In analyses conducted after adjustment for demographic and clinical variables, data indicate that patients who received chlorthalidone vs amlodipine or lisinopril were found to have a lower risk of fracture (hazard ratio [HR]: 0.79; 95% confidence interval [CI], 0.63-0.98; P =.04); fracture risk was significantly lower in those receiving chlorthalidone vs lisinopril (HR: 0.75; 95% CI, 0.58-0.98; P =.04) but not significantly lower in those receiving chlorthalidone vs amlodipine (HR: 0.82; 95% CI, 0.63-1.08; P =.17). No significant difference was found when considering the effect of the addition of atenolol (adjusted HR: 1.29; 95% CI, 0.56-2.95).

In the cohort with both in-trial and post-trial follow-up, 70 pelvic fractures and 576 hip fractures were recorded. No significant difference was noted in fracture risk between those who received chlorthalidone vs amlodipine or lisinopril (adjusted HR: 0.87; 95% CI, 0.74-1.03; P =.10). Fracture risk in chlorthalidone vs lisinopril and chlorthalidone vs amlodipine was not significantly different (HR: 0.87; 95% CI, 0.71-1.09; P =.17 and HR: 0.87; 95% CI, 0.71-1.09; P =.16, respectively).

“This secondary analysis of a randomized clinical trial confirms previous observational reports that use of thiazide-type diuretics is associated with significantly lower risk of hip and pelvic fractures compared with treatment with an ACE inhibitors or a CCB,” the researchers concluded. “This effect is consistently observed in a variety of subgroups and appears to last for several years.”

Study Limitations

  • Analyses were conducted posthoc, meaning that results are subject to unmeasured bias
  • ALLHAT excluded several groups of participants at high risk for fracture (eg, patients with coronary artery disease, heart failure, or chronic kidney disease)
  • Databases, rather than medical records, were used to determine fracture occurrence.
  • There was crossover of medication use at 5 years, which would decrease differences in fracture outcomes between medication classes

Disclosures: Dr Cushman reports receiving honoraria from Takeda, and Dr Oparil reports receiving honoraria from Daiichi Sankyo and Novartis.

Reference

  1. Puttnam R, Davis BR, Pressel SL, et al, for the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Collaborative Research Group. Association of 3 different antihypertensive medications with hip and fracture risk in older adults. Secondary analysis of a randomized clinical trial. JAMA Intern Med. 2016 Nov 21. doi:10.1001/jamainternmed.2016.6821 [Epub ahead of print]
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