title: Bilateral tibial marrow ablation in rats induces a rapid hypercalcemia arising from extratibial bone resorption inhibitable by methylprednisolone or deflazacort.
abstract: The goals of this study were to quantitate biochemical markers of bone metabolism on days 1-15 after bilateral tibial marrow ablation surgery 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 time 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 ablation; however, the fact that both drugs produced a characteristic rapid 3- to 10-fold increase in the serum alpha 2-macroglobulin level demonstrates that the drugs rapidly reached the circulation. Both methylprednisolone and deflazacort also inhibited intramedullary deposition of collagen by 40-60% on day 7, a time near which operated control animals achieved maximal accumulation of new bone in this model. Histological comparisons among the three experimental groups were largely consistent with biochemical results. The urinary hydroxyproline/creatine ratio for the operated control group doubled on day 3 and then returned to presurgical levels on day 7 and later. The timing and size of the hydroxyproline/creatinine peak, as well as the fact that the intratibial osteoclastic response peaks on days 8-10 after ablation, suggests it results from extratibial bone resorption induced by marrow ablation. Consistent with this rationale, urinary calcium excretion in operated 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 presurgical level on day 15. Elevated excretion of calcium noted on days 9-15 in deflazacort-treated animals, which occurs in the absence of a detectable increase in resorption marker hydroxyproline, may however be due to the known action of glucocorticoids in increasing kidney filtration of calcium. In summary, this is the first report to show that bilateral 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 induced by circulating cytokines whose release from ablated tibias or osteoclastogenic action is inhibitable by methylprednisolone and deflazacort.
authors.affiliation: Division of Molecular Biology and Biochemistry, School of Biological Sciences, University of Missouri-Kansas City, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Magnuson
authors.forename: R
authors.initials: R
authors.lastname: Booth
authors.forename: S
authors.initials: S
authors.lastname: Porter
authors.forename: J P
authors.initials: JP
authors.lastname: Gorski
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism / Q000601:surgery*; D001862:Bone Resorption / Q000150:complications / Q000378:metabolism* / Q000517:prevention & control; D002118:Calcium / Q000097:blood / Q000652:urine; D004195:Disease Models, Animal; D017102:Fracture Healing / Q000187:drug effects / Q000502:physiology; D006909:Hydroxyproline / Q000737:chemistry / Q000652:urine; D006934:Hypercalcemia / Q000097:blood / Q000209:etiology* / Q000652:urine; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology*; D011282:Pregnenediones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013977:Tibia; D000511:alpha-Macroglobulins / Q000737:chemistry
chemical_list: D011282:Pregnenediones; D000511:alpha-Macroglobulins; C021988:deflazacort; D006909:Hydroxyproline; D002118:Calcium; D008775:Methylprednisolone