Continuous Treatment with a Low-Dose β-Agonist Reduces Bone Mass by Increasing Bone Resorption Without Suppressing Bone Formation

The sympathetic nervous system regulates bone remodeling through the beta-adrenergic receptor (beta-AR). However, the systemic roles of adrenergic actions on bone remodeling through the beta-AR are largely unknown. In this study, we examined the dose effect of continuous treatment with isoprenaline, a nonspecific beta-AR agonist, on bone remodeling. Male C57BL/6J mice were intrasubcutaneously administrated with four different doses (5, 25, 50, or 100 mu g/g daily) of isoprenaline or vehicle using an osmotic pump for 2 weeks. The region of high-turnover cancellous bone was analyzed by microcomputed tomography (mu CT). Continuous isoprenaline treatment caused a similar to 35.7% decline in the femoral cancellous bone volume fraction (BV/TV) at all doses (5-100 mu g/g daily). Furthermore, continuous isoprenaline treatment weakened the bone mechanical properties in the trunk of lumbar vertebra 4 (L4). These parameters did not show significant differences between doses. Histomorphometric analysis revealed that isoprenaline doses of 50 mu g/g daily or less did not significantly inhibit bone formation parameters, such as bone formation rate (BFR) and mineral surface/bone surface (MS/BS). Only the highest dose (100 mu g/g daily) of isoprenaline significantly inhibited BFR and MS/BS. On the other hand, osteoclast number/bone surface (Oc.N/BS) was enhanced approximately 2.4-fold and osteoclast surface/bone surface (Oc.S/BS) was increased 2.0-fold by all doses of continuous isoprenaline treatment. The osteoclast parameters plateaued at the lowest dose (5 mu g/g daily) of continuous isoprenaline treatment. These results indicate that chronic stimulation of beta-AR with low-dose agonist treatment induces bone loss mainly via enhanced bone resorption.