BILATERAL TIBIAL MARROW ABLATION IN RATS INDUCES A RAPID HYPERCALCEMIA ARISING FROM EXTRATIBIAL BONE-RESORPTION INHIBITABLE BY METHYLPREDNISOLONE OR DEFLAZACORT

The goals of this study were to quantitate biochemical markers of bone metabolism on days 1-15 after bilateral tibial marrow ablation surger y in young adult rats and to determine the effect of a single dose of methylprednisolone (2 mg/kg) or deflazacort (2.5 mg/kg) given at the t ime of ablation, Unexpectedly, serum calcium levels rose to a maximum of 15.9 mg/dl on day 7 after marrow ablation and remained above normal through day 15. This increase was blocked by a single intramedullary injection of methylprednisolone or deflazacort immediately following a blation; however, the fact that both drugs produced a characteristic r apid 3- to 10-fold increase in the serum alpha(2)-macroglobulin level demonstrates that the drugs rapidly reached the circulation, Both meth ylprednisolone and deflazacort also inhibited intramedullary depositio n of collagen by 40-60% on day 7, a time near which operated control a nimals achieved maximal accumulation of new bone in this model, Histol ogical comparisons among the three experimental groups were largely co nsistent with biochemical results, The urinary hydroxyproline/creatini ne ratio for the operated control group doubled on day 3 and then retu rned to presurgical levels on day 7 and later, The timing and size of the hydroxyproline/creatinine peak, as well as the fact that the intra tibial osteoclastic response peaks on days 8-10 after ablation, sugges ts it results from extratibial bone resorption induced by marrow ablat ion, Consistent with this rationale, urinary calcium excretion in oper ated controls rose 9-fold from day 0 to day 3 and appeared to plateau over the period from day 3 to day 9, before returning to a near presur gical level on day 15. Elevated excretion of calcium noted on days 9-1 5 in deflazacort-treated animals, which occurs in the absence of a det ectable increase in resorption marker hydroxyproline, may however be d ue to the known action of glucocorticoids in increasing kidney filtrat ion of calcium, In summary, this is the first report to show that bila teral tibial marrow ablation in rats causes a rapid hypercalcemia and calciuria which is accompanied initially by a peak of bone resorption marker urinary hydroxyproline, We speculate that the source of calcium and hydroxyproline is extratibial osteoclastic bone resorption induce d by circulating cytokines whose release from ablated tibias or osteoc lastogenic action is inhibitable by methylprednisolone and deflazacort .