Efficacy of 19-Nor-1,25-(OH)2D2 in the prevention and treatment of hyperparathyroid bone disease in experimental uremia.
BACKGROUND
The control of parathyroid hyperplasia and high circulating parathyroid hormone (PTH) levels is crucial in preventing secondary hyperparathyroidism (SH) in renal failure. Parathyroid gland enlargement and elevated levels of PTH are major contributors to increase bone resorption, a feature of renal osteodystrophy.


METHODS
These studies assessed the efficacy of the 1,25(OH)2D3 analog, 19-Nor-1,25(OH)2D2 (19-Nor), in the prevention (protocol I) and treatment (protocol II) of SH and renal osteodystrophy in uremic rats. In protocol I, normal and uremic rats were fed a high phosphorus diet for 2 months; uremic rats were administered intraperitoneal injections of either vehicle or 19-Nor (200 ng three times a week). In protocol II, normal and uremic rats were fed a high phosphorus diet for 4 months; 2 months after the onset of uremia, rats were administered either intraperitoneal vehicle or 19-Nor (200 ng three times a week). Serum PTH and bone histology were used to assess the degree of SH.


RESULTS
19-Nor was effective in preventing (protocol I) and suppressing (protocol II) the significant SH induced by uremia and further enhanced by a high phosphorus diet. In protocol I, bone histology in uremic controls showed a threefold increase in the cancellous bone mass compared to normal rats. This expansion in unmineralized bone was accompanied by 5-, 1.5-, and 7-fold increases in eroded surface, mineralization lag time (MLT), and bone formation rate (BFR/BS), respectively. Moreover, cortical bone porosity in untreated uremic rats increased 267-fold compared to normal animals. 19-Nor ameliorated these changes in cancellous and cortical bone. In protocol II, the reported indices worsened even further. In contrast, 2 months of 19-Nor treatment improved bone histology by reducing cortical bone porosity, woven bone formation, MLT, and BFR/BS.


CONCLUSIONS
In an experimental model of chronic renal failure (CRF), 19-Nor prevents SH and ameliorates the histomorphometric changes induced by uremia and high phosphorus diet. In addition, 19-Nor suppresses serum PTH and improves bone histology in uremic rats with established severe SH. Further studies in patients with CRF are necessary to define the clinical applicability of 19-Nor on bone histology in humans.
Slatopolsky
Eduardo
E
Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA. eslatopo@im.wustl.edu
Cozzolino
Mario
M
Lu
Yan
Y
Finch
Jane
J
Dusso
Andriana
A
Staniforth
Marc
M
Wein
Yoo
Y
Webster
Jee
J
D000818:Animals; D001847:Bone Diseases / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control*; D004872:Ergocalciferols / Q000494:pharmacology*; D005260:Female; D006961:Hyperparathyroidism / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control*; D007676:Kidney Failure, Chronic / Q000150:complications; D010281:Parathyroid Hormone / Q000097:blood / Q000378:metabolism; D016226:Phosphorus, Dietary / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014511:Uremia / Q000150:complications*
D004872:Ergocalciferols; D010281:Parathyroid Hormone; D016226:Phosphorus, Dietary; C084656:paricalcitol