Co-Treatment of PTH With Osteoprotegerin or Alendronate Increases Its Anabolic Effect on the Skeleton of Oophorectomized Mice

Abstract

We examined the effects of 60 days of co-treatment of PTH with either OPG or alendronate in oophorectomized mice. Compared with PTH alone, co-treatment of PTH with either of these two mechanistically distinct anti-catabolics improved bone volume, mechanical strength, and appendicular and axial mineralization and prolonged the beneficial effect of PTH on BMD.Introduction: Conflicting evidence exists as to whether the anabolic effect of PTH is inhibited by the action of anti-catabolics. To examine this issue, we assessed the effects of alendronate and osteoprotegerin (OPG), two anti-catabolics with different modes of action, on the anabolic activity of PTH(1-34) in the skeleton of 4-month-old oophorectomized mice. Materials and Methods: Mice treated with vehicle alone (PBS), alendronate alone (100 g/kg/week), OPG alone (10 mg/kg twice a week), or PTH alone (80 g/kg/day) were compared with each other and with animals administered PTH plus alendronate or PTH plus OPG. We assessed lumbar spine and femoral BMD at 0, 30, and 60 days. Contact radiography, histology, and histomorphometry, three-point bending assay of the femur, and serum osteocalcin and TRACP5b assays were performed at 2 months. Results: Although alendronate and OPG each suppressed bone turnover, at the doses used, this was more profound with OPG. Increases in lumbar spine and femoral BMD and in trabecular bone volume were at least as great with OPG as with alendronate, and mechanical indices of femoral bone strength improved only with OPG. Both produced a plateau in spine and femoral BMD increases by 30 days. Co-treatment of PTH with each anti-catabolic produced additive increases in BMD in the femur and supra-additive increases in the lumbar spine with no plateau effects. Neither anti-catabolic impeded the PTH-induced increase in bone volume or the increase in mechanical strength of the femur. Conclusions: These studies show that the highly potent anti-catabolic OPG can produce dramatic increases in BMD and bone strength; that the temporal pattern of activity of bone formation and resorption modulators may have major influence on net skeletal accrual; and that, depending on timing, inhibition of osteoclastic activity may markedly augment the anabolic action of PTH.

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

“…In that study it was shown that PTH increased osteoblast number and bone formation rate in femoral bone of both wild type and CREM/ICER null mice, but the increase in osteoclasts was much greater in the latter. The findings in these two mouse models of attenuated negative feedback signaling support the notion that the degree of bone anabolism caused by intermittent PTH can be limited by the ability of the hormone to also stimulate bone resorption -a phenomenon that may contribute to the gradual loss of anabolism with continued administration of the hormone [1,45].…”

“…RANKL may also stimulate the secretion of an osteoblastogenic factor from osteoclasts [106]. Evidence that bisphosphonates attenuated the anabolic effect of intermittent PTH in animal models and humans is consistent with the involvement of osteoclasts in the anabolic effect [107][108][109][110][111], but such inhibition was not seen in other studies [45,[112][113][114]. Indeed, both OPG and alendronate prolonged the duration of the anabolic effect in ovariectomized mice, apparently by preventing the increased bone resorption that occurs in the later stages of treatment [45].…”

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

“…Although it has been shown that bisphosphonates may clinically impair the anabolic actions of PTH, this is not always the case in rodent models. Studies have shown that co-treatment with PTH and alendronate increased its anabolic effect [37], whereas pre-treatment with bisphosphonates blunted but did not abolish the anabolic response to PTH on the skeleton of oophorectomized mice [38]. In the present study, the concurrent initiation of PTH therapy and therapy with ZA increased percent bone volume in comparison to ossicles treated with PTH or ZA alone.…”

Alendronate Affects Osteoblast Functions by Crosstalk through EphrinB1-EphB

“…The dose of alendronate used in humans is approximately 1 mg/kg/wk orally (Huang et al, 2005). Our dosage in mice approximated the human dose (Samadfam et al, 2007).…”