Assessment of effects of lanthanum carbonate with and without phosphate supplementation on bone mineralization in uremic rats.
OBJECTIVE
Previous studies have indicated that impaired bone mineralization in 5/6 th nephrectomized rats given high doses of lanthanum carbonate is due to phosphorus depletion caused by excessive binding to, and reduced absorption of, dietary phosphate. This study aimed to test this hypothesis by: 1) directly comparing the effects of a supratherapeutic dose of lanthanum carbonate or dietary phosphorus restriction on bone mineralization in a rodent model of chronic renal failure (CRF); and 2) investigating whether phosphorus supplementation would prevent the bone mineralization defect associated with lanthanum carbonate treatment.


METHODS
Male Sprague-Dawley rats were subjected to sham surgery or a two-step 5/6th nephrectomy to induce CRF and randomized across five treatment groups: sham, CRF, CRF + dietary phosphorus deficiency, CRF + lanthanum carbonate (1000 mg/kg/ day), and CRF + lanthanum carbonate + parenteral phosphorus repletion.


RESULTS
Rats with 5/6th nephrectomy had elevated serum creatinine, blood urea concentration, and urine volume and protein, consistent with impaired renal function, and increased urinary phosphorus and serum parathyroid hormone, consistent with hyperparathyroidism. Lanthanum carbonate and dietary phosphate insufficiency induced parallel changes in serum and urine markers of phosphate homeostasis and increased osteoid formation. These changes induced by lanthanum carbonate were normalized by systemic phosphate supplementation.


CONCLUSIONS
These findings provide further support for the concept that supratherapeutic doses of lanthanum carbonate induce effects on bone mineralization in uremic rats via an indirect pharmacological mechanism (phosphate depletion) and not via direct bone toxicity.
Damment
S J P
SJ
Department of Biosciences, Shire Pharmaceutical Development Ltd., Basingstoke, UK.
Shen
V
V
D000818:Animals; D002113:Calcification, Physiologic / Q000187:drug effects*; D004032:Diet; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007811:Lanthanum / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D009392:Nephrectomy; D010710:Phosphates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013977:Tibia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014511:Uremia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*
D010710:Phosphates; C119467:lanthanum carbonate; D007811:Lanthanum