Dose-effect relations of loop- and thiazide-diuretics on calcium homeostasis: a randomized, double-blinded Latin-square multiple cross-over study in postmenopausal osteopenic women.
BACKGROUND
Thiazide diuretics (TDs) reduce whereas loop diuretics (LDs) increase urinary calcium. We studied the effects of different doses of a TD and LD on electrolytes, calcitropic hormones and biochemical bone markers.


METHODS
In a five-period crossover study, comparing four active doses with placebo, 40 postmenopausal women with osteopenia were treated with different doses of LD bumetanide (n = 20, 0.5-2.0 mg per day) or TD bendroflumethiazide (n = 20, 2.5-10 mg per day). Each treatment period lasted 1 week.


RESULTS
Urinary calcium decreased dose-dependently in response to the bendroflumethiazide. The best hypocalciuric effect was achieved by 5 mg day-1 of bendroflumethiazide. Total plasma calcium levels increased, whereas ionised calcium at ambient pH-values decreased because of increased pH-values in response to the bendroflumethiazide. Plasma PTH levels did not change, whereas a slight dose-dependent increase occurred in plasma 1,25(OH)2D levels. As a marker of bone formation, plasma osteocalcin levels increased. Conversely, bumetanide dose-dependently increased renal calcium losses with a concomitant increase in plasma PTH and 1,25(OH)2D levels. Plasma osteocalcin levels increased and bone-specific alkaline phosphatase levels decreased dose-dependently.


CONCLUSIONS
Whether a LD or TD is chosen as diuretic therapy affects calcium homeostasis. The effects of LDs are potentially harmful to bone. Further studies are needed to evaluate whether long-term treatment with LDs causes osteoporosis. Until then, we suggest using, if possible, a TD rather than a LD as diuretic therapy in order not to risk deleterious effects on bone metabolism.
Rejnmark
L
L
Department of Endocrinology anf Metabolism C, Aarhus Amtssygehus, University Hospital, Aarhus University, Tage-Hansens Gade 2, DK-80000 Aarhus C, Denmark. rejnmark@post6.tele.dk
Vestergaard
P
P
Pedersen
A R
AR
Heickendorff
L
L
Andreasen
F
F
Mosekilde
L
L
D000469:Alkaline Phosphatase / Q000097:blood; D001539:Bendroflumethiazide / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D001851:Bone Diseases, Metabolic / Q000378:metabolism / Q000503:physiopathology*; D002034:Bumetanide / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D018592:Cross-Over Studies; D004232:Diuretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D008875:Middle Aged; D015675:Osteocalcin / Q000097:blood; D010281:Parathyroid Hormone / Q000097:blood; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology*
D015415:Biomarkers; D004232:Diuretics; D010281:Parathyroid Hormone; D049993:Sodium Chloride Symporter Inhibitors; D002034:Bumetanide; D015675:Osteocalcin; D001539:Bendroflumethiazide; D000469:Alkaline Phosphatase; D002118:Calcium