Treatment with a sclerostin antibody increases cancellous bone formation and bone mass regardless of marrow composition in adult female rats.

The current report describes the skeletal effects of a sclerostin monoclonal antibody (Scl-AbIII) treatment at a yellow (fatty) marrow skeletal site in adult female rats. Ten-month-old female Sprague-Dawley rats were treated with vehicle or Scl-AbIII at 5 or 25 mg/kg, twice per week by s.c. injection for 4 weeks. Trabecular bone from a yellow (fatty) marrow site, the 5th caudal vertebral body (CVB), was processed undecalcified for quantitative bone histomorphometric analysis. Compared to vehicle controls, Scl-AbIII at both doses significantly increased bone formation parameters and trabecular bone volume and thickness and decreased bone resorption parameter in the trabecular bone of the CVB. As a reference, we also found that the Scl-AbIII at both doses significantly decreased bone resorption and increased bone formation and bone volume in a red (hematopoietic) marrow site, the 4th lumber vertebral body (LVB). It appears that the percentage of increase in trabecular bone volume induced by Scl-AbIII treatment was slightly larger in the LVB than in the CVB. In summary, these preclinical findings show that antibody-mediated sclerostin inhibition has significant bone anabolic effects at both red and yellow marrow skeletal sites.

Alfacalcidol treatment increases bone mass from anticatabolic and anabolic effects on cancellous and cortical bone in intact female rats.

It has been reported that alfacalcidol had an anticatabolic and anabolic effect on bone in ovariectomized and aged male rat models, but this has not been tested on intact female rats. The current study was to determine the effects of alfacalcidol on cancellous and cortical bone in intact female rats with or without exercise. Seventy-four, 8.5-month-old, intact female rats were orally treated with 0, 0.005, 0.025, 0.05, or 0.1 microg/kg alfacalcidol alone or in combination with raised cage (RC) exercise for 3 months. In vivo peripheral quantitative computerized tomography (pQCT) of the proximal tibial metaphyses (PTM) and ex vivo histomorphometric analyses of the PTM and tibial shaft (TX) were performed. Only the 0.1 microg alfacalcidol/kg dose proved to be anabolic. pQCT analysis showed that this dose increased total and cortical bone mineral content and density and trabecular bone mineral density. Histomorphometrically, it induced an anabolic response by increased trabecular mass and microarchitecture from stimulated cancellous bone and bone bouton formations, and suppressed bone resorption more than bone formation on the trabecular and endocortical surfaces, to produce a positive bone balance. A positive correlation between trabecular connectivity and bone bouton numbers occurred. These findings suggest alfacalcidol treatment augments bone mass by increased cancellous bone mass and improved trabecular architecture through its anticatabolic and anabolic properties in the intact adult female rat. Last, raised cage exercise alone or the combination of raised cage and alfacalcidol was no more effective than alfacalcidol alone.

Alfacalcidol-stimulated focal bone formation on the cancellous surface and increased bone formation on the periosteal surface of the lumbar vertebrae of adult female rats.

PURPOSE: To investigate the skeletal effects of alfacalcidol alone or in combination with exercise in intact adult female rats. METHODS: Seventy-four 8.5-month-old rats were orally administered 0, 0.005, 0.025, 0.05 or 0.1 microg/kg of alfacalcidol for 12 weeks, alone or in combination with exercise. Cancellous bone histomorphometric measurements were performed on the second lumbar vertebra. RESULTS: At 0.05 and 0.1 microg/kg, alfacalcidol caused a significant increase in cancellous bone volume, accompanied by an increase in trabecular architecture. Percent eroded surface, bone resorption and formation were suppressed by alfacalcidol treatment. However, mineral apposition rate was significantly increased, indicating osteoblast activity was increased. A positive balance between bone formation and resorption was observed in the rats treated with the highest dose of alfacalcidol. Alfacalcidol induced a unique bone formation site ("bouton") on the cancellous surface. These boutons connected adjacent trabeculae and increased trabecular thickness. They exhibited both smooth and scalloped cement lines, suggesting that they were formed by minimodeling- and remodeling-based bone formation. Furthermore, alfacalcidol at 0.1 microg/kg increased periosteal bone formation of the lumbar transverse processes. Bipedal stance exercise alone did not have an effect on bone balance and bone turnover. There were no interactions between alfacalcidol and bipedal stance exercise except for a decrease in bone resorption. CONCLUSION: Alfacalcidol exhibited both anti-catabolic and anabolic effects on bone in intact female rats. The effect of combined treatment with alfacalcidol and bipedal stance exercise was no better than that of alfacalcidol alone.

Risedronate did not block the maximal anabolic effect of PTH in aged rats.

The study was designed to investigate if pre-treating rats with a therapeutic equivalent dose of risedronate blunted the anabolic effects of PTH, and whether a withdrawal period prior to PTH treatment would alter any effect of risedronate on PTH treatment. Skeletally mature rats were treated for 18 weeks with vehicle, risedronate, or risedronate for 8 weeks followed by vehicle for 10 weeks (withdrawal period). At the end of this period, animals were treated for a further 12 weeks with PTH or PTH vehicle. Trabecular and cortical bone mass were monitored by serial pQCT, or by DXA and microCT. Bone histomorphometry was performed on the proximal tibiae and tibial shafts for bone turnover parameters at week 40. Risedronate alone moderately increased while PTH alone markedly increased trabecular bone mass at the proximal tibial (35% and 200%, respectively) and lumbar vertebral body (14% and 36%, respectively). The maximum bone gains were similar with and without pretreatment with risedronate as compared to the PTH alone. Continuous administration of risedronate for 18 weeks prior to PTH treatment had lower percentage increases in proximal tibial BMD during the first 8 weeks of PTH treatments, and had lower active bone forming surface and bone formation rates after being treated with PTH 12 weeks as compared to the PTH alone group. However, with the 10-week withdrawal period, risedronate did not blunt the stimulatory effect of PTH on osteoblast activity as shown by similar bone formation rates as with PTH alone. Our findings suggest that while risedronate pretreatment may slow the bone anabolic response to PTH, a withdrawal period prior to PTH treatment allows osteoblastic activity to respond normally to PTH stimulation.