Differential maintenance of cortical and cancellous bone strength following discontinuation of bone-active agents

Abstract

Osteoporotic patients treated with antiresorptive or anabolic agents experience an increase in bone mass and a reduction in incident fractures. However, the effects of these medications on bone quality and strength after a prolonged discontinuation of treatment are not known. We evaluated these effects in an osteoporotic rat model. Six-month-old ovariectomized (OVX) rats were treated with placebo, alendronate (ALN, 2 µg/kg), parathyroid hormone [PTH(1–34); 20 µg/kg], or raloxifene (RAL, 2 mg/kg) three times a week for 4 months and withdrawn from the treatments for 8 months. Treatment with ALN, PTH, and RAL increased the vertebral trabecular bone volume (BV/TV) by 47%, 53%, and 31%, with corresponding increases in vertebral compression load by 27%, 51%, and 31%, respectively (p < .001). The resulting bone strength was similar to that of the sham-OVX control group with ALN and RAL and higher (p < .001) with PTH treatment. After 4 months of withdrawal, bone turnover (BFR/BS) remained suppressed in the ALN group versus the OVX controls (p < .001). The vertebral strength was higher than in the OVX group only in ALN-treated group (p < .05), whereas only the PTH-treated animals showed a higher maximum load in tibial bending versus the OVX controls (p < .05). The vertebral BV/TV returned to the OVX group level in both the PTH and RAL groups 4 months after withdrawal but remained 25% higher than the OVX controls up to 8 months after withdrawal of ALN (p < .05). Interestingly, cortical bone mineral density increased only with PTH treatment (p < .05) but was not different among the experimental groups after withdrawal. At 8 months after treatment withdrawal, none of the treatment groups was different from the OVX control group for cortical or cancellous bone strength. In summary, both ALN and PTH maintained bone strength (maximum load) 4 months after discontinuation of treatment despite changes in bone mass and bone turnover; however, PTH maintained cortical bone strength, whereas ALN maintained cancellous bone strength. Additional studies on the long-term effects on bone strength after discontinuation and with combination of osteoporosis medications are needed to improve our treatment of osteoporosis. © 2011 American Society for Bone and Mineral Research.

Effect of sequential treatments with alendronate, parathyroid hormone (1–34) and raloxifene on cortical bone mass and strength in ovariectomized rats

“…The boundary conditions that defined the load platen-specimen interface were assumed to be frictionless. Total strength and the load-carrying capacity of the vertebral trabecular bone were calculated from finite-element analyses, as previously [54, 72, 89]. …”

“…Osteoporosis patients now routinely cycle through bone active medications [68–72]. It is extremely difficult to do direct studies of fracture risk associated with such sequential treatments in humans, because of the large samples sizes required.…”

Combined treatment with a traditional Chinese medicine, Hachimi-jio-gan (Ba-Wei-Di-Huang-Wan) and alendronate improves bone microstructure in ovariectomized rats

“…The OVX group was a positive control to study changes occurring during the development of osteoporosis following OVX and to compare the effect of treatments. The differences between OVX and sham groups have been well-characterized from previous studies using micro-CT (Boyd et al, 2006;Shahnazari et al, 2011). The beneficial effect of bisphosphonates on the structural biomechanical properties of osteoporosis has also been extensively studied (Allen and Burr, 2007;Ito et al, 2005;Shahnazari et al, 2010).…”

“…ALN (2.0 mg/kg/dose three times per week) was given subcutaneously. The dose of ALN was determined from the previous studies that demonstrated significant inhibition of bone loss in OVX rats (Fuchs et al, 2008;Iwata et al, 2006;Shahnazari et al, 2011). HJG of 0.05% aqueous solution was administered orally as the drinking fluid for twelve weeks continuously.…”

“…After the operations, OVX rats were pair-fed with the sham-operated rats, to prevent postovariectomy hyperphagia, with approximately 18 g chow/day per rat, tap water was supplied ad libitum (Shahnazari et al, 2011). All rats were untreated for eight weeks after the operation to allow for the development of osteopenia.…”