The Diuretic Indapamide Increases Bone Mass and Decreases Bone Resorption in Spontaneously Hypertensive Rats Supplemented with Sodium

Abstract

Clinical and epidemiological studies suggest that thiazide diuretics can prevent bone loss and decrease the incidence of hip fractures. However, the mechanism of the effect of diuretics on bone is not clearly established. Indapamide (IDP), a sulfonamide diuretic related to thiazides, is used to treat hypertension. Sixty spontaneously hypertensive rats (SHRs) were divided into four groups and treated with or without IDP (1.5 mg/kg/day) during 8 weeks in the presence or absence of a high sodium load (8% NaCl supplementation in the diet). Sodium and calcium excretions were increased in the rats receiving the high sodium load (SHR ؉ 8% NaCl) comparatively with control rats (SHR). IDP decreased and increased, respectively, calcium and sodium excretions. Serum parathyroid hormone (PTH) was unchanged in any group. Bone density was measured at the femur, tibia, and vertebrae, and bone morphometry was performed at the metaphysis of the femur to evaluate bone architecture. Rats fed a high sodium diet had an average 5.5% decreased bone density at every site except the femoral diaphysis. The trabecular bone volume was also decreased (SHR ؉ 8% NaCl vs. SHR, 11.99 ؎ 0.78 vs. 17.51 ؎ 1.5%, p < 0.05). An increase in trabecular separation suggested that these changes were due to increased bone resorption. In the SHR ؉ 8% NaCl ؉ IDP group, IDP increased bone density and trabecular bone volume (SHR ؉ 8% NaCl ؉ IDP vs. SHR ؉ 8% NaCl, 16.52 ؎ 1.04 vs. 11.99 ؎ 0.78%, p < 0.05). Trabecular separation and pyridinoline/creatinine excretion (SHR ؉ 8% NaCl ؉ IDP vs. SHR ؉ 8% NaCl, 136.39 ؎ 9.62 vs. 195.18 ؎ 22.34 nmol/mmol, p < 0.05) were also decreased by IDP. These results show that in rats receiving a high sodium diet, IDP can reverse sodium-induced bone loss and increased bone resorption independently of changes in serum PTH. (J Bone Miner

Fracture risk and the use of a diuretic (indapamide sr) ± perindopril: a substudy of the Hypertension in the Very Elderly Trial (HYVET)

“…In spontaneously hypertensive rats given large doses (1.5 mg/kg/day) of indapamide SR and a high salt intake, urinary calcium was decreased, sodium excretion increased and sodium-induced bone loss was prevented [44]. The studies in man suggest that thiazide diuretics and indapamide SR reduce calcium excretion in the urine by about 40–50% in patients with hypercalcuria and, in a very small study of patients with essential hypertension, reduce calcium excretion by about 20% [16].…”

Évolution de la densité minérale osseuse chez des hommes ostéoporotiques et hypercalciuriques traités par diurétiques thiazidiques

“…Le bénéfice osseux semble corrélé à l'augmentation de la réabsorption du calcium par le tubule rénal. Cette action rénale pourrait se traduire par une augmentation du taux de calcium ionisé à l'origine d'une diminution de la sécrétion de parathormone, et d'un ralentissement du remodelage osseux [24,25]. Ce dernier phénomène est à l'origine d'une diminution significative des marqueurs de résorption osseuse (N-télopeptide) et de formation osseuse (ostéocal-cine et phosphatases alcalines osseuses) [10].…”

Increased bone mineral density in a population‐based group of 70‐year‐old women on thiazide diuretics, independent of parathyroid hormone levels

“…Lalande et al . also showed that the thiazide‐related diuretic indapamide increased bone mass and decreased bone resorption in hypertensive rats independently of PTH levels [11]. Dawson‐Hughes et al ., however, found that thiazide users had lower serum levels of PTH during winter/spring compared with others [15].…”

“…Therefore, it is possible that some of these antihypertensive drugs might affect BMD. One possible way is through the calcium uptake, which occurs through nifedipine‐sensitive calcium channels [11]. A specific evidence for the role of calcium channel comes from the effects of calcium channel drugs on the production of bone matrix proteins and in vitro resorption.…”

“…The consequence of this cascade should be reduced bone remodelling rate [7]. However, the blunting effect of thiazide use on serum PTH levels has not been consistently found in human studies [8–10] or in animal studies [11]. Recently, Barry et al .…”