Thiazides and bone.

During the past decade, the use of thiazide diuretics in the treatment of essential hypertension has decreased, despite their established antihypertensive efficacy, positive benefit in coronary heart disease, and low cost, and widespread recommendations for their use. That decrease may be, in part, the result of concern about their effects on lipid and carbohydrate metabolism, and, especially, by the promotion of newer classes of antihypertensive medications. However, thiazides have antihypertensive efficacy and cardiovascular benefit in doses below those that produce potentially adverse metabolic effects. Thiazides have another potential benefit, namely the prevention and treatment of age-related osteoporosis and fractures. Thiazides decrease renal calcium excretion, without reducing intestinal calcium absorption, thereby shifting external calcium balance in a positive direction (1). Because calcium deficiency is a major risk factor for age-related osteoporosis, and because calcium intake in older adults is often suboptimal, it is reasonable to consider whether thiazides are osteoprotective. Evidence from several observational studies indicate that patients treated with thiazides, predominantly for hypertension, have significantly greater bone mineral density, lower rates of bone loss, and fewer hip fractures than those not on thiazides (2– 4). Not all studies have confirmed those findings, however (5). Nevertheless, if critically analyzed observational studies were an acceptable basis for making therapeutic decisions (6), thiazides might be a recommended treatment for osteoporosis. But the consensus view remains that treatment recommendations require randomized trials. Until this issue of the Journal, only one such trial of the effects of thiazide on bone had been reported. In a small number of subjects whose bone density was assessed at one site only (forearm) (7), the expected age-related bone loss was slowed for 6 months but was not sustained thereafter. Accordingly, the article by Reid et al (8) in this issue of The Green Journal makes an important contribution by reporting the effect of thiazide (hydrochlorothiazide, 50 mg per day) on bone mineral density at several sites in a placebo-controlled randomized study of 185 postmenopausal women who were followed for 2 years. The investigators found significant benefits on total skeletal mineral density, as well as at sites that consist of predominantly cortical bone (legs and forearm). Benefit was not observed at sites richer in trabecular bone (lumbar spine, 65% trabecular; femoral neck, 25% trabecular). All of the benefits occurred during the first 6 months, with no loss of this benefit during the subsequent 18 months of treatment. The beneficial effects of thiazide correlated with the extent of urine calcium lowering, which persisted for 2 years, and urinary excretion of a highly specific marker of bone resorption, N-telopeptide, was reduced. The investigators draw the appropriately tempered conclusion that, in normal postmenopausal women, hydrochlorothiazide might be considered for prevention of age-related cortical bone loss at several sites. But their findings give little encouragement that thiazides might prevent bone loss at the spine or hip, or by inference, osteoporotic fractures at those sites. They were encouraged by the observed benefit in the skeleton as a whole, which they point out is similar in degree to that observed with established antiresorptive treatments. But without evidence of benefit at the spine and hip, it is difficult to agree with their argument that their results justify a large study to assess the effects of thiazides on fracture risk at those sites. In retrospect, several considerations not discussed by Reid et al might have been made in designing a randomized trial of thiazide’s effect on bone in postmenopausal women. The first would be to consider supplementing dietary calcium during the trial, to achieve at least the 1,500 mg per day total calcium intake recommended for postmenopausal women. If thiazides exert their osteoprotective effect in part by improving calcium balance, greater intakes of calcium might augment that effect. From the data presented by Reid et al, one can estimate that calcium intake was very low (less than 500 mg per day) in approximately 25% of their subjects. Perhaps those were the same subjects who had minimal benefits from thiazide administration. Although thiazides do not reduce intestinal calcium absorption in younger subjects (1), they might in older subjects (9), in whom intestinal calcium absorption may be impaired, which would offset the benefit from reducing urine calcium. Calcium supplementation might guard against that possibility. Although Reid et al did not detect a thiazide-induced decrease in serum levels of calcitriol, the major hormone regulator of intestinal calcium absorption, such a negative finding should be interpreted cautiously when the sample size is small. A second design point would be to consider co-administration of potassium with thiazide, at least in amounts that prevent thiazide-induced reductions in serum potassium concentration and body potassium content. PotasAm J Med. 2000;109:429 – 430. From the University of California, San Francisco, and the General Clinical Research Center, San Francisco, California. Requests for reprints should be addressed to Anthony Sebastian, MD, University of California, San Francisco, 1202 Moffitt Hospital, Box 0126, San Francisco, California 94143.