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 changes in, and the association between, biochemical and histomorphometric indices of bone metabolism during the early stages of developing
tumor osteopathy. 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 killing on day 8. Serum
calcium (sCa),
alkaline phosphatase (sTAP), and
osteocalcin (sOC) and urinary
calcium (uCa),
deoxypyridinoline (uDPD), and
pyridinoline (uPYD) were measured daily. In a second semilongitudinal experiment (n = 70), the number of osteoclasts and osteoblasts (N.Oc, N.Ob), trabecular bone volume (BV/TV), and osteoid volume (O.Ar) were assessed by histomorphometry. In untreated
tumor-bearing animals, osteoclast numbers increased by 74% on day 3 (5.4 +/- 2.4 vs. 3.1 +/- 1.5/mm(2), p < 0.05), and trabecular bone volume fell by 24% on day 4 (12.5 +/- 2.0 vs. 15.8 +/- 1.2%, p < 0.05). 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/12 h, p < 0.05) and 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 +/- SD), whereas sOC remained unchanged until day 8. When combining the results of the two experiments, a high correlation was found between the number of osteoclasts and the urinary excretion of PYD (r = 0.91) and DPD (r = 0.89). Treatment with
ibandronate delayed
hypercalcemia, abolished
hypercalciuria, and accelerated
bone resorption. We conclude that osteoclast activation is an early event in
PTHrP-mediated
osteolysis, which is closely reflected by the renal excretion of pyridinium cross-links of
type I collagen. Therefore, specific
biochemical markers of
collagen breakdown may be useful as early indicators of developing
tumor osteopathy.