Bone growth in the rat mandible following every-day or alternate-day methylprednisolone treatment schedules

Abstract

The effects of a short-acting corticosteroid, methylprednisolone sodium succinate (MPSS), on alveolar and cortical bone growth in rats were tested within a chronopharmacologic context. Different groups of rats were injected intraperitoneally at 1 of 6 circadian stages, 4 h apart, daily (ED) or on alternate days (AD). The doses of MPSS were progressively raised from 0.25 – 0.50 mg/kg ED-AD to 40–80 mg/kg ED-AD within 26 days, and the total duration of the study was 46 days. Controls received daily saline injections. Tetracycline was injected at 6–10 day intervals to provide biological time-markers for each change in the MPSS dose level. Mandibular growth in rats treated with MPSS (either ED or AD) was generally less than that in saline-treated controls, except perhaps when the injections occurred early in the daily light span. Low doses (first 6 days) injected 1–5 h after the onset of the environmental photofraction, stimulated cortical appositional bone growth, but at other circadian times the same dose level appeared to be inhibitory. In the case of mandible length and cortical bone growth, the response of control animals to saline injection also exhibited a statistically-significant circadian rhythm, with highest values during the early or middle light span. The presence of this rhythm suggests that saline injections per se were a disturbance, the effects of which were mediated by endogenous corticosterone production; it provides additional evidence for a circadian stage dependence of bone response to corticosteroid, whether of endogenous or exogenous origin. The circadian rhythm in growth response was consistently most pronounced in the rats treated with MPSS daily, as indicated by higher amplitudes and lower probability values for fitted 24-h cosines. The temporal optimization of steroid effects in the rat jaw may be more readily achieved with ED dose schedules than with AD schedules.