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339 DECREASED ANGIOGENESIS AND OSTEOCLASTOGENESIS IS ASSOCIATED WITH INCREASED TRABECULAR BONE VOLUME IN NEPHRECTOMIZED RATS GIVEN CALCIUM SUPPLEMENTATION
  1. P. Rianthavorn,
  2. W. G. Goodman,
  3. I. B. Salusky,
  4. H. Juppner,
  5. B. D. Kuizon
  1. Los Angeles, CA; Endocrine Unit

Abstract

Severe growth impairment and increased fracture risk have been reported in dialysis patients with adynamic bone (AD). Nephrectomized animals with AD have decreased osteoclastic activity and widening of growth plates. However, there is limited data regarding bone volume, angiogenesis and osteoclastogenesis in this condition. In order to study the change in trabecular bone volume and the role of angiogenesis and osteoclastogenesis in growing animals with AD, 47 rats underwent either sham procedure (Intact) or 5/6 subtotal Nephrectomy (Nx) to induce renal failure. Rats were given either control diet (C) containing 0.8% Calcium (Ca), 0.7% Phosphorus (P) or high calcium diet (Ca) containing 2.5% Ca, 0.7 % P for 4 weeks to induce AD. At sacrifice, blood was obtained for ionized Ca, P and PTH determinations. Tibiae were decalcified and embedded in paraffin. Femurs were embedded undecalcified in methylmethacrylate. Immunohistochemistry for Vascular Endothelial Growth Factor (VEGF) was done to assess angiogenesis. In situ hybridization was done using digoxigenin-labeled riboprobes for Osteoprotegerin (OPG). Histochemical staining for tartrate-resistant acid phosphatase (TRAP) was done to assess osteoclastic activity. Von Kossa staining was used to assess bone mineral content. Quantitative bone histomorphometry was done and the parameters measured include trabecular bone area, osteoid area and osteoid perimeter. Ionized Ca levels were higher, 1.49±0.07 mmol/L (SD) vs. 1.37±0.07 mmol/L (p≤0.001), whereas PTH levels were lower in Nx-Ca than in Nx-C, 35±28.3 pg/ml vs. 202±76.0 pg/ml (p≤0.001), consistent with the biochemical changes of AD. Serum P levels did not differ among groups. Staining for VEGF was markedly decreased whereas the expression for OPG was increased in Nx-Ca than in Nx-C. Osteoclastic activity was less in Nx-Ca than in Nx-C, 6±2.61 vs. 20.33±3.56 (p≤0.01). Nx-Ca had higher bone mineral content and trabecular bone area than Nx-C, 24.68±2.04 vs. 9.97±2.24 (p≤0.05). Osteoid area and perimeter were less in Nx-Ca than in Nx-C findings consistent with AD, 0.39±0.07 vs. 1.99±0.31 and 1.87±0.70 vs. 7.79±2.93, respectively (p≤0.05). There was no evidence of osteomalacia in Nx-Ca group. We conclude that, in a model that mimics AD; increased trabecular bone volume is associated with impaired angiogenesis, decreased osteoclastogenesis and upregulation of OPG.

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