Thiazide-like diuretic associated with reduced fracture risk

Hip and Pelvic Fracture Risk Associated With Antihypertensive Medications | Cardiology | JAMA Internal Medicine | The JAMA Network

Here’s another medical oddity: a link between medication taken to treat high blood pressure and fewer bone fractures.

Question: Do thiazide diuretics protect against fracture risk?


Use of the thiazide-like diuretic chlorthalidone was associated with a 21% significantly lower risk of hip and pelvic fractures compared with either lisinopril or amlodipine and a significantly lower risk compared with lisinopril alone during approximately 4.9 years of follow-up.

During 5 additional years of posttrial follow-up, when medication use was not constrained by study protocol, fracture risk continued to be lower in users of chlorthalidone compared with lisinopril or amlodipine together or alone.  


The present results of short-term and long-term fracture protection with thiazide antihypertensive therapy compared with other antihypertensive medications strongly recommend use of a thiazide for hypertension treatment in addition to its long track record of cardiovascular protection.



On the basis of observational studies, the use of thiazide diuretics for the treatment of hypertension is associated with reduced fracture risk compared with nonuse. Data from randomized clinical trials are lacking.

Design, Setting, and Participants  

Using Veterans Affairs and Medicare claims data, this study examined hip and pelvic fracture hospitalizations in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial participants randomized to first-step therapy with

  1. a thiazide-type diuretic (chlorthalidone),
  2. a calcium channel blocker (amlodipine besylate), or
  3. an angiotensin-converting enzyme inhibitor (lisinopril).


A total of 22 180 participants were followed for up to 8 years during masked therapy. After trial completion, 16 622 participants for whom claims data were available were followed for up to 5 additional years.

During the trial, 338 fractures occurred. Participants randomized to receive chlorthalidone vs amlodipine or lisinopril had a lower risk of fracture on adjusted analyses

Risk of fracture was significantly lower in participants randomized to receive chlorthalidone vs lisinopril but not significantly different compared with those randomized to receive amlodipine.

similar results were obtained for in-trial and in-trial plus posttrial follow-up.

Conclusions and Relevance  

These findings from a large randomized clinical trial provide evidence of a beneficial effect of thiazide-type diuretic therapy in reducing hip and pelvic fracture risk compared with treatment with other antihypertensive medications.


Hypertension and osteoporotic fractures are age-related disorders whose incidences increase rapidly after the age of 65 years.

The conditions are interrelated because people with hypertension have more osteoporotic fractures than people without hypertension.1,2

A meta-analysis3 revealed that many nonrandomized, observational studies suggest that therapy with thiazide-type diuretics improves bone strength and reduces fracture risk.

A positive effect on calcium balance and a direct stimulatory effect on osteoblasts have been proposed as the biological basis for this putative beneficial effect.4 β-Blockers may also reduce fracture risk5 (possibly through β2-adrenergic blockade of receptors present on osteoclasts6), although a review article7 found that not all studies confirm this.

Less is known regarding the effects of angiotensin-converting enzyme inhibitors (ACEis) and calcium channel blockers (CCBs) on fracture risk despite their ubiquitous use in older adults with hypertension. Studies8,9 have found that ACEis exert a protective effect on bone strength through

blockade of local angiotensin production,

which stimulates osteoclast activity,


reduction of receptor activator nuclear factor–κβ ligand in osteoblasts,

which activates osteoclasts.

Several clinical studies suggest lower fracture risk with their use,10,11 although not all studies agree.1215

The large sample size, long follow-up, and randomized therapy provide a unique opportunity to examine post hoc the effects of the major classes of blood pressure–lowering medications on the incidence of hospitalizations for hip and pelvic fractures.

These fracture types are well captured in administrative data sets and are serious fracture types that can be associated with mortality.

We asked 3 questions:

Are hip and pelvic fractures less common during treatment with a thiazide-type diuretic compared with CCBs or ACEis?

Does the addition of a β-blocker to chlorthalidone further lower the risk of fracture?

Assuming a beneficial effect in the chlorthalidone group during the trial, would this pattern continue during the posttrial period (ie, is there a legacy effect)?

We hypothesized fewer in-trial fracture hospitalizations in those randomized to chlorthalidone vs comparators and that this benefit would persist into the posttrial surveillance period when participants were no longer randomized to study medications.


The step 1 study medications (chlorthalidone, 12.5-25 mg; amlodipine, 2.5-10 mg; and lisinopril, 10-40 mg) were formulated to look alike so that the identity of each agent was double-masked.

The doses were titrated to achieve a blood pressure lower than 140/90 mm Hg. If goal blood pressure was not achieved using the maximum tolerated dose, open-label step 2 (reserpine, clonidine, or atenolol) or step 3 (hydralazine) medications could be added.


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 ACEi or a CCB. This effect is consistently observed in a variety of subgroups and appears to last for several years.


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