title: Chlorthalidone improves vertebral bone quality in genetic hypercalciuric stone-forming rats.
abstract: We have bred a strain of rats to maximize urine (u) calcium (Ca) excretion and model hypercalciuric nephrolithiasis. These genetic hypercalciuric stone-forming (GHS) rats excrete more uCa than control Sprague-Dawley rats, uniformly form kidney stones, and similar to patients, demonstrate lower bone mineral density. Clinically, thiazide diuretics reduce uCa and prevent stone formation; however, whether they benefit bone is not clear. We used GHS rats to test the hypothesis that the thiazide diuretic chlorthalidone (CTD) would have a favorable effect on bone density and quality. Twenty GHS rats received a fixed amount of a 1.2% Ca diet, and half also were fed CTD (4 to 5 mg/kg/d). Rats fed CTD had a marked reduction in uCa. The axial and appendicular skeletons were studied. An increase in trabecular mineralization was observed with CTD compared with controls. CTD also improved the architecture of trabecular bone. Using micro-computed tomography (µCT), trabecular bone volume (BV/TV), trabecular thickness, and trabecular number were increased with CTD. A significant increase in trabecular thickness with CTD was confirmed by static histomorphometry. CTD also improved the connectivity of trabecular bone. Significant improvements in vertebral strength and stiffness were measured by vertebral compression. Conversely, a slight loss of bending strength was detected in the femoral diaphysis with CTD. Thus results obtained in hypercalciuric rats suggest that CTD can favorably influence vertebral fracture risk. CTD did not alter formation parameters, suggesting that the improved vertebral bone strength was due to decreased bone resorption and retention of bone structure.
authors.affiliation: Nephrology Division, Department of Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA. David_Bushinsky@urmc.rochester.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Bushinsky
authors.forename: Thomas
authors.initials: T
authors.lastname: Willett
authors.forename: John R
authors.initials: JR
authors.lastname: Asplin
authors.forename: Christopher
authors.initials: C
authors.lastname: Culbertson
authors.forename: Sara P Y
authors.initials: SP
authors.lastname: Che
authors.forename: Marc
authors.initials: M
authors.lastname: Grynpas
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D002113:Calcification, Physiologic / Q000187:drug effects; D002129:Calcium Oxalate / Q000652:urine; D002130:Calcium Phosphates / Q000652:urine; D002752:Chlorthalidone / Q000494:pharmacology* / Q000627:therapeutic use*; D005265:Femoral Neck Fractures / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D005269:Femur / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D053565:Hypercalciuria / Q000150:complications* / Q000188:drug therapy / Q000235:genetics* / Q000652:urine; D007669:Kidney Calculi / Q000150:complications* / Q000188:drug therapy* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013131:Spine / Q000187:drug effects* / Q000503:physiopathology
chemical_list: D002130:Calcium Phosphates; D002129:Calcium Oxalate; C020243:calcium phosphate; D002752:Chlorthalidone