Thiazide Treatment Protects Against Hip Fracture

Summarized by Robert W. Griffith, MD
January 29, 2004

Introduction

Hip fractures are common in the elderly, and most are associated with osteoporosis. One strategy to lower the frequency of hip fractures might be to decrease the accelerated bone loss seen with osteoporosis. Thiazide diuretics, which are widely used as antihypertensive agents in the elderly, are thought to reduce urinary calcium excretion. The possibility that they might have a protective effect on hip fractures was examined as part of the Rotterdam Study, and the results published in the Annals of Internal Medicine.

Method

In the well-known Rotterdam study, all inhabitants over 55 in a particular suburb of this Netherlands city were invited to participate in 1990. A total of 7,891 subjects were enrolled, and provided a full medical history and underwent a complete physical examination. Subsequent interviews and medical examinations were done at regular intervals. Medication usage was documented during the study from computerized pharmacy records.

For this part of the study, all participants were followed until they had a hip fracture, died, or reached the end of the study in December 1999, whichever came first.

Exposure to thiazides (including chlorthalidone¹) was classified in one of 7 mutually exclusive ways: never used, currently used for 1 to 42 days, currently used for 43 to 365 days, currently used for more than 365 days, discontinued since 1 to 60 days, discontinued since 61 to 120 days, and discontinued for more than 120 days. The occurrence of hip fractures in relation to this classification of thiazide use was examined statistically.

Baseline patient characteristics included Mini-Mental State examination score, use of a walking aid, previous fractures, thyroid disease, smoking, alcohol intake, and history of dizziness and falling. Other possible confounding factors searched for included evidence of Parkinson's disease, diabetes, hypertension, and the medications used to treat these conditions, as well as estrogen use and calcium intake.

Results

There were 281 hip fractures in the 7,891 subjects during a total of 58,009 patient-years.

The hazard ratios for hip fracture in association with thiazide use are given in the table below:

Thiazide Use	Patients with hip fractures	Hazard Ratio	95% Confidence Interval
Never used	202	1.00 (reference)
Ever used	79	0.94	0.72-1.24
Current users	26	0.71	0.47-1.06
Current use 1-42 d	6	1.17	0.52-2.63
Current use 43-365 d	13	0.81	0.46-1.42
Current use > 365 d	7	0.46	0.21-0.96

The risks for hip fracture for ever-use of thiazides (yes or no) and for current use of thiazides (regardless of duration of use) were reduced, but the differences did not reach statistical significance. For current users, there was a statistically significant inverse relationship between increased duration of use and the risk for hip fracture. And for those taking thiazides for more than a year, there was a statistically significant reduction in risk to 0.46.

The strongest protective effect of thiazides was seen in people over 80, although the difference from younger people was not significant. Bone density didn't affect the results, but higher calcium intake was associated with a slightly lowered risk of fracture.

After discontinuation of thiazides, the protective effect disappeared after 4 months.

Comment

A protective effect of thiazide diuretics on hip fractures has been reported before, but this is the first study to examine the duration of thiazide intake and the duration of the protection.

How do thiazides act in this way? Thiazides can reduce renal calcium excretion, helping to create a positive calcium balance. However, in this study there was a greater thiazide effect in people with a higher calcium intake, suggesting that an additional mechanism may be at work. In this regard, in vitro studies have shown that thiazides directly inhibit the osteocalcin secretion of osteoblasts.

Whatever the mechanism, it seems clear that thiazide diuretics, widely recommended as basic treatment for hypertension, can significantly reduce the incidence of hip fracture. They are relatively cheap and free from side effects, and thus may have several relevant advantages over the more recently introduced antihypertensives.

Source

• Thiazide diuretics and the risk for hip fracture. MWCJ. Schoofs, M. van der Klift, A. Hofman,  et al., Ann Intern Med, 2003, vol. 139, pp. 476--482

Footnotes
1. Chlorthalidone is formally not a thiazide, but has similar effects on calcium excretion

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