Association between histomorphometry and biochemical markers of bone turnover in a longitudinal rat model of parathyroid hormone-related peptide (PTHrP)-mediated tumor osteolysis

Advanced tumor osteopathy is characterized by abnormal bone turnover, Using a rat model of parathyroid hormone-related peptide (PTHrP)-mediated tumor osteolysis, the aim of the present study was to define the sequential chang es in, and the association between, biochemical and histomorphometric indic es of bone metabolism during the early stages of developing tumor osteopath y. Eight-month old Wistar rats (n = 48) were subcutaneously inoculated with either 2 x 10(6) cells of the Walker carcinosarcoma 256, or saline on day 0, and treated with either saline or the bisphosphonate ibandronate until k illing on day 8. Serum calcium (sCa), alkaline phosphatase (sTAP), and oste ocalcin (sOC) and urinary calcium (uCa), deoxypyridinoline (uDPD), and pyri dinoline (uPYD) were measured daily. In a second semilongitudinal experimen t (n = 70), the number of osteoclasts and osteoblasts (N.Oc, N.Ob), trabecu lar bone volume (BV/TV), and osteoid volume (O.Ar) were assessed by histomo rphometry. In untreated tumor-hearing animals, osteoclast numbers increased by 74% on day 3 (5.4 +/- 2.4 vs. 3.1 +/- 1.5/mm(2),p < 0.05), and trabecul ar bone volume fell by 24% on day 4 (12.5 +/- 2.0 vs. 15.8 +/- 1.2%,p < 0.0 5). Both time course and magnitude of these changes were closely reflected by an increase in uDPD (0.46 +/- 0.14 vs. 0.31 +/- 0.15 nmol/L, p < 0.05) a nd uPYD on day 4 (1.44 +/- 0.25 vs. 1.03 +/- 0.3 nmol/12 h,p < 0.05), sCa ( 3.8 +/- 0.52 vs. 3.0 +/- 0.13 mmol/L,p < 0.01), and uCa (0.13 +/- 0.08 vs. 0.03 +/- 0.01 mmol/12 h, p < 0.001) on day 6, and sTAP (254 +/- 127 vs. 120 +/- 40 U/L, p < 0.001) on day 7 (mean a SD), whereas sOC remained unchange d until day 8. When combining the results of the two experiments, a high co rrelation was found between the number of osteoclasts and the urinary excre tion of PYD (r = 0.91) and DPD (r = 0.89). Treatment,vith ibandronate delay ed hypercalcemia, abolished hypercalciuria, and accelerated bone resorption . We conclude that osteoclast activation is an early event in PTHrP-mediate d osteolysis, which is closely reflected by the renal excretion of pyridini um cross-links of type I collagen. Therefore, specific biochemical markers of collagen breakdown may be useful as early indicators of developing tumor osteopathy. (C) 2000 by Elsevier Science Inc. All rights reserved.