Alterations in canine vertebral bone turnover, microdamage accumulation, and biomechanical properties following 1-year treatment with clinical treatment doses of risedronate or alendronate

Abstract

One year of treatment with bisphosphonates at 5x the dose used for post-menopausal osteoporosis significantly increases failure load and microdamage, and decreases toughness at multiple skeletal sites in intact female beagles. The goal of this study was to determine if similar changes occur with doses equivalent to those used for PMO treatment. Skeletallymature female beagles were treated daily for one year with vehicle (VEH) or one of three doses of risedronate (RIS; 0.05, 0.10, 0.50 mg/kg/day) or alendronate (ALN; 0.10, 0.20, 1.00 mg/kg/day). Doses of ALN corresponded to treatment dose for PMO, ½ that dose, and 5x that dose on a mg/kg basis; RIS was given at a dose-equivalent to ALN. Vertebral density, geometry, percent ash, static/dynamic histology, microdamage, and biomechanical parameters were quantified. Trabecular bone activation frequency (Ac.f) was dosedependently lower in RIS-treated groups (-40%,-66%,-84%, p < 0.05 vs VEH) while the three ALN groups were all similarly lower compared to VEH (-65%,-71%,-76%; p < 0.05). Crack surface density (Cr.S.Dn) was significantly higher than VEH for all doses of RIS and ALN (+2.9 to 5.4-fold vs VEH). Stiffness was significantly increased with both agents while there were no significant changes in any other structural or estimated material properties. Cr.S.Dn and Ac.f exhibited a significant non-linear correlation (r 2 =0.21; p<0.001) while there was no relationship between Cr.S.Dn and any mechanical properties. These results document that 1-year of bisphosphonate treatment at clinical doses allows significant accumulation of microdamage in the vertebra but this is offset by increases in bone volume and mineralization such that there is no significant impairment of mechanical properties. 45

Atypical subtrochanteric and diaphyseal femoral fractures: Report of a task force of the american society for bone and mineral Research

“…(48,53,54) Following 1 to 3 years of BP treatment at doses similar to or greater than those used in postmenopausal women, toughness was 20% to 30% lower than in control animals. (48,53) It was thought initially that the decline in toughness was related to the well-documented accumulation of microdamage that was observed in lumbar vertebrae and other bones of dogs treated with BPs, (48,54,55) although changes to both mineralization and collagen cross-linking also occur. More recent data show that toughness continues to decline in animals with long-term BP treatment without an increase in microdamage accumulation or a further increase in secondary mineralization.…”

“…This accumulation of damage is nonlinear and increases more quickly the more that remodeling is suppressed. (48) However, marked reduction of turnover is not necessary to induce a significant accumulation of microdamage. Reducing trabecular bone activation frequency in the canine vertebra by approximately 40% with risedronate is associated with a threefold increase in microdamage compared with untreated controls, (48) and suppression by approximately 20% with raloxifene is associated with a doubling of microdamage.…”

“…(48) However, marked reduction of turnover is not necessary to induce a significant accumulation of microdamage. Reducing trabecular bone activation frequency in the canine vertebra by approximately 40% with risedronate is associated with a threefold increase in microdamage compared with untreated controls, (48) and suppression by approximately 20% with raloxifene is associated with a doubling of microdamage. (49) Studies of iliac crest biopsies provide conflicting data about whether microdamage accumulates with BP treatment in humans.…”

“…(28) In a 1-year study using various doses of alendronate or risedronate, there was minimal correspondence between changes in microdamage accumulation and material-level toughness in vertebrae from several groups of BP-treated dogs. (48) Likewise, animals not treated with BPs have an age-related threefold increase in microdamage accumulation without a change in bone toughness. (28) These lines of evidence suggest that neither microdamage nor increased secondary mineralization is solely responsible for the change in bone material properties with BP therapy, leaving changes in collagen or interactions among all these properties as likely reasons for the progressive decline in toughness.…”

The Effect of Antiresorptives on Bone Quality

“…Microdamage can be both good and bad for mechanical integrity [69]. Some animal studies of BPs show whole-bone mechanical strength and toughness are improved by BP treatment despite an increase in the amount of microdamage [5,48]. Extensive reviews of the physiology of microdamage and its mechanical effects are available [18,19,39,48,65].…”