Juraschek M, Seibel M J, Woitge H W, Krempien B, Bauss F
Department of Medicine, University of Heidelberg, Heidelberg, Germany.
Bone. 2000 May;26(5):475-83. doi: 10.1016/S8756-3282(00)00259-3.
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.
晚期肿瘤性骨病的特征是骨转换异常。本研究利用甲状旁腺激素相关肽（PTHrP）介导的肿瘤性骨溶解大鼠模型，旨在确定肿瘤性骨病发展早期骨代谢生化指标和组织形态计量学指标的序贯变化及其之间的关联。8月龄Wistar大鼠（n = 48）于第0天皮下接种2×10⁶个Walker癌肉瘤256细胞或生理盐水，并于第8天处死前用生理盐水或双膦酸盐伊班膦酸钠进行处理。每天测量血清钙（sCa）、碱性磷酸酶（sTAP）、骨钙素（sOC）以及尿钙（uCa）、脱氧吡啶啉（uDPD）和吡啶啉（uPYD）。在第二项半纵向实验（n = 70）中，通过组织形态计量学评估破骨细胞和成骨细胞数量（N.Oc、N.Ob）、骨小梁体积（BV/TV）和类骨质体积（O.Ar）。在未治疗的荷瘤动物中，破骨细胞数量在第3天增加了74%（5.4±2.4对3.1±1.5/mm²，p < 0.05），骨小梁体积在第4天下降了24%（12.5±2.0对15.8±1.2%，p < 0.05）。这些变化的时间进程和幅度在第4天uDPD（0.46±0.14对0.31±0.15 nmol/12 h，p < 0.05）和uPYD增加（1.44±0.25对1.03±0.3 nmol/12 h，p < 0.05）、第6天sCa（3.8±0.52对3.0±0.13 mmol/L，p < 0.01）和uCa（0.13±0.08对0.03±0.01 mmol/12 h，p < 0.001）以及第7天sTAP（254±127对120±40 U/L，p < 0.001）（均值±标准差）中得到密切反映，而sOC直到第8天保持不变。综合两项实验结果发现，破骨细胞数量与PYD（r = 0.91）和DPD（r = 0.89）的尿排泄之间存在高度相关性。伊班膦酸钠治疗可延迟高钙血症、消除高钙尿症并加速骨吸收。我们得出结论，破骨细胞活化是PTHrP介导的骨溶解的早期事件，I型胶原吡啶交联的肾排泄密切反映了这一事件。因此，胶原降解的特定生化标志物可能作为肿瘤性骨病发展的早期指标。
