Effect of paricalcitol and cinacalcet on serum phosphate, FGF-23, and bone in rats with chronic kidney disease.
Calcimimetics activate the calcium-sensing receptor (CaR) and reduce parathyroid hormone (PTH) by increasing the sensitivity of the parathyroid CaR to ambient calcium. The calcimimetic, cinacalcet, is effective in treating secondary hyperparathyroidism in dialysis patients [chronic kidney disease (CKD 5)], but little is known about its effects on stage 3-4 CKD patients. We compared cinacalcet and paricalcitol in uremic rats with creatinine clearances "equivalent" to patients with CKD 3-4. Uremia was induced in anesthetized rats using the 5/6th nephrectomy model. Groups were 1) uremic control, 2) uremic + cinacalcet (U+Cin; 15 mg x kg(-1) x day(-1) po for 6 wk), 3) uremic + paricalcitol (U+Par; 0.16 microg/kg, 3 x wk, ip for 6 wk), and 4) normal. Unlike U+Par animals, cinacalcet promoted hypocalcemia and marked hyperphosphatemia. The Ca x P in U+Cin rats was twice that of U+Par rats. Both compounds suppressed PTH. Serum 1,25-(OH)(2)D(3) was decreased in both U+Par and U+Cin rats. Serum FGF-23 was increased in U+Par but not in U+Cin, where it tended to decrease. Analysis of tibiae showed that U+Cin, but not U+Par, rats had reduced bone volume. U+Cin rats had similar bone formation and reduced osteoid surface, but higher bone resorption. Hypocalcemia, hyperphosphatemia, low 1,25-(OH)(2)D(3), and cinacalcet itself may play a role in the detrimental effects on bone seen in U+Cin rats. This requires further investigation. In conclusion, due to its effects on bone and to the hypocalcemia and severe hyperphosphatemia it induces, we believe that cinacalcet should not be used in patients with CKD without further detailed studies.
Finch
Jane L
JL
Renal Division, Washington University Medical School, St. Louis, Missouri 63110, USA.
Tokumoto
Masanori
M
Nakamura
Hironori
H
Yao
Wei
W
Shahnazari
Mohammad
M
Lane
Nancy
N
Slatopolsky
Eduardo
E
D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001862:Bone Resorption / Q000139:chemically induced / Q000378:metabolism; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000652:urine; D000069449:Cinacalcet; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004872:Ergocalciferols / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood*; D006961:Hyperparathyroidism / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054559:Hyperphosphatemia / Q000139:chemically induced / Q000378:metabolism; D006996:Hypocalcemia / Q000139:chemically induced / Q000378:metabolism; D009281:Naphthalenes / Q000009:adverse effects / Q000494:pharmacology*; D009392:Nephrectomy; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000097:blood* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000819:agonists / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D013977:Tibia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014511:Uremia / Q000188:drug therapy / Q000378:metabolism
D015415:Biomarkers; D004872:Ergocalciferols; C505605:Fgf23 protein, rat; D009281:Naphthalenes; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D010758:Phosphorus; D005346:Fibroblast Growth Factors; C084656:paricalcitol; D003404:Creatinine; D002117:Calcitriol; D002118:Calcium; D000069449:Cinacalcet