Loop Diuretics Linked to Hip Bone Loss in Older Men

By Judith Groch
DERBY, Conn., 15April 2008 -- Men older than 65 who take loop diuretics for heart failure or hypertension have higher rates of bone loss at the hip than those not taking the drugs, a prospective study found.
Men taking loop diuretics had rates of hip bone loss almost three times that of nonusers after adjusting for age and baseline bone density, Lionel S. Lim, M.D., of Griffin Hospital here, and colleagues in the Osteoporotic Fractures in Men (MrOS) Study Group, reported in the April 14 issue of the Archives of Internal Medicine.
Loop diuretics have been associated with hip and other osteoporotic fractures in several observational studies. However, it is not certain whether this increased risk is caused by reduced bone mass, fall-related mechanisms, or associated comorbidities, the researchers said.
To test the hypothesis that loop diuretics reduce bone mineral density, the researchers measured bone density in 3,269 men, ages 65 and older (mean age 72.7), enrolled in the study.
The men were studied at baseline, 2000 through 2002, and at a mean follow-up of 4.6 years. All had bone mineral density measurements and verified loop diuretic use or nonuse at both visits.
Medication use was determined by an interviewer-administered questionnaire verified with inspection of medication containers. Bone mineral density was measured for the total hip and two subregions by dual-energy x-ray absorptiometry.
Eighty-four men were categorized as continuous users of loop diuretics, 181 as intermittent users, and 3,004 as nonusers.
Of the men, 91% were white. Of 265 continuous or intermittent users, 231 (87%) took furosemide (Lasix) as determined at the second visit.
The multivariable-adjusted rate of bone loss was about 2.5 times higher for continuous users than that of nonusers, and 1.5 times greater than that of intermittent users.
Compared with nonusers, the rate for intermittent diuretic use was about twice as great.
The average annual rate of decline in total hip bone mineral density increased steadily from -0.33% (95% CI -0.36% to -0.31%) for nonusers, to -0.58% (95% CI -0.69% to -0.47%) for intermittent users, to -0.78% (95% CI -0.96% to -0.60%) for continuous users.
This was after adjustment for age, baseline bone mineral density, body mass index, weight change from baseline, physical activity, clinic site, perceived health status, cigarette smoking status, diabetes, chronic obstructive pulmonary disease, congestive heart failure, hypertension, and statin use. Although these adjustments attenuated the results, the findings remained significant (P<0.01).
The findings were similar for change at the femoral neck and trochanter, the researchers said.
Future studies should address the underlying mechanisms of this bone loss, the researchers wrote.
Pointing to a study of postmenopausal women that found that long use of loop diuretics may decrease bone density by increasing urinary calcium excretion as well a parathyroid hormone-driven imbalance in bone turnover, the researchers said a similar mechanism might account for the bone loss in older men in the current study.
Study limitations included the slightly smaller proportion (8%) of loop diuretic users than in a recent sampling of older men (12%). Also, the analysis was limited to generally healthy, mostly white community-living older men who attended both visits and thus may not represent loop-diuretic users in general.
Because the investigators could not obtain information on diuretic dose, they could not assess a dose-response relationship.
They also pointed out that "analyses were adjusted for several factors to minimize confounding by indication and contraindication, but the possibilities of these biases cannot be eliminated without the use of a randomized, controlled trial design."
These findings suggest that the potential for bone loss and fracture risk should be considered when loop diuretics are prescribed for older patients in clinical practice, the investigators advised.
This study was supported by the National Institutes of Health.
The following institutes also provided support: the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, the National Cancer Institute, the National Center for Research Resources, and the NIH Roadmap for Medical Research. No financial disclosures were reported.

Primary source: Archives of Internal MedicineSource reference:Lim LS, et al "Loop diuretic use and increased rates of hip bone loss in older men" Arch Intern Med 2008; 168: 735-740.