Effects of short-term treatment with the bisphosphonates zoledronate and pamidronate on rat bone: A comparative histomorphometric study on the cancellous bone formed before, during, and after treatment

Abstract

To study the anti-resorptive effects of zoledronate and pamidronate on growing long bones we have performed a histomorphometric analysis of the three regions of the proximal tibial cancellous bone of bone formed before, during, and after drug treatment. Male rats (190-220 g) were treated subcutaneously for 10 days with zoledronate (0.028-2.8 g/kg) or pamidronate (3.7-370 g/kg) and sacrificed 5 days later. To delineate the three regions of cancellous bone, and for dynamic bone histomorphometry, calcein and demeclocycline were injected at various times. Both bisphosphonates caused a dose-dependent suppression of cancellous bone turnover and resorption to produce an increase in cancellous bone, but zoledronate was 100 times more potent than pamidronate. The increase in the bone amount and connectivity was more pronounced in the bone formed during treatment where transient bone resorption and normal bone formation led to a positive bone balance. In the bone formed before treatment, inhibition of bone resorption associated with reduced bone formation produced a net gain in amount of bone. Although both bone regions showed a positive bone balance, more bone accumulated in the bone formed during treatment probably because its trabecular bone surface was three times greater. In the primary spongiosa formed after treatment, a moderate increase in the bone amount and connectivity was observed only at the highest dose of both bisphosphonates. The bone formed before, during, and after treatment with bisphosphonates responds differently due to differences in bone architecture, rates of modeling and remodeling, and period of drug exposure. Anat. Rec. 249:458-468, 1997. 1997 Wiley-Liss, Inc. Key words: pamidronate; zoledronate; bisphosphonate; rat; bone histomorphometryThe bisphosphonate compound zoledronate (CGP 42446) is a very potent antiresorptive agent in several pharmacological models (Green et al., 1994). In a previous pilot experiment we studied the effects of zoledronate and pamidronate on static histomorphometric parameters of cancellous bone in rat tibia (Pataki et al., 1990). We reported that zoledronate and pamidronate induce a dose-dependent increase in the proximal tibial metaphyseal cancellous bone and that zoledronate was at least 100 times more potent than pamidronate in accumulating bone mass. Both compounds caused a dose-dependent decrease in osteoid perimeter and serum levels of osteocalcin, alkaline phosphates, and tartrate-resistant acid phosphates, suggesting that the increase in bone resulted from depression of bone resorption and formation. In the present study, both static and dynamic morphometric parameters were investigated after administration of zoledronate and compared to the effects of the reference drug pamidronate. In addition to morphometric investigations, the effects on cortical and cancellous bone were also analyzed chemically.Previous investigators characterized the effects of bisphosphonates on the entire metaphysis in growing rats. This is the first report that analyzes the his...

Can the increase of bone mineral density following bisphosphonates treatments be explained by biomechanical considerations?

“…Moreover, the developed approach could be generalized to other drugs affecting bone remodeling. For example, other bisphosphonates such as zoledronate and pamidronate (Pataki et al, 1997), different treatments inhibiting bone resorption such as calcitonin (Rodan and Martin, 2000) or recently interferon-b (Takayanagi et al, 2002), or even treatment favoring bone formation such as BMPs (Service, 2000) could be evaluated with the developed model if the BMD evolution is known. A numerical description of different drug effects on bone remodeling could then be performed.…”

Combined effects of zoledronate and mechanical stimulation on bone adaptation in an axially loaded mouse tibia

“…The aim of the present study was to assess the effect of zoledronate, the newer member of the third generation bisphosphonates Green, 1996;Pataki et al, 1997), on bone adaptation when a mechanical loading is applied. For this purpose, we used an in-vivo axial compression model of the mouse tibia (De Souza et al, 2005;Fritton et al, 2005, Stadelmann et al, 2009) and analyzed the effect of zoledronate on site-specific bone adaptation.…”

Effect of alendronate on the mandible and long bones: an experimental study in vivo

“…Clinical trials have posited that bisphosphonates may alter growth in these patients (11,14,15), and experimental studies on the subject have suggested they may be associated with a decrease in long-bone growth (16)(17)(18).…”