Suppressed Bone Turnover by Long-Term Bisphosphonate Treatment Accumulates Microdamage but Maintains Intrinsic Material Properties in Cortical Bone of Dog Rib

Abstract

Effects of long-term suppression of bone remodeling by bisphosphonate were investigated in cortical bone of dog rib. Although microdamage was accumulated, BMD was increased without increasing cortical bone area. Consequently, the intrinsic material properties were not reduced.Introduction: Recently, we have reported that long-term suppression of bone remodeling increases microdamage accumulation but is not necessarily associated with vertebral fragility because of compensated increase of bone mass and improved microarchitecture. This study aimed to investigate the effect of long-term suppression of bone remodeling by bisphosphonate on the degree of mineralization, accumulation of microdamage, and mechanical properties of cortical bone in the same dogs. Materials and Methods: Twenty-nine 1-year-old beagles (15 males, 14 females) were divided into three groups and treated daily with vehicle (CNT) or with incadronate at a dose of 0.3 (LOW) or 0.6 mg/kg/day (HIGH) orally for 3 years. After death, pQCT, histomorphometry, microdamage measurements, and three-point bending mechanical test were performed using the ninth rib. Results: Cortical BMD was increased in the incadronate-treated groups. Cortical activation frequency was suppressed by 82% and 70% in HIGH and LOW, respectively, compared with CNT, without impairment of mineralization. Microdamage accumulation was increased in both incadronate-treated groups. Although there were no significant differences in total and cortical area among the three groups, structural mechanical properties were significantly increased after incadronate treatment while intrinsic material properties were not changed in the incadronate-treated groups. Conclusion: This study suggests that long-term suppression of bone remodeling by bisphosphonate increases microdamage accumulation. However, this was not necessarily associated with a reduction of intrinsic material properties probably because of an increased degree of mineralization.

Local alendronate increases fixation of implants inserted with bone compaction: 12‐week canine study

“…26,27 One of our concerns regarding the use of bisphosphonate as adjuvant in implant fixation is the effect of decreasing bone turnover. An impaired bone turnover might lead to increased bone fragility and accumulation of microfractures, 28 resulting in reduced long-term implant fixation. However, in a 10-year follow-up study, where the effect of oral alendronate treatment for osteoporosis was investigated in postmenopausal women, no association between prolonged use of alendronate and excess fracture risk was found.…”

Alendronate Reduces Bone Toughness of Ribs without Significantly Increasing Microdamage Accumulation in Dogs Following 3 Years of Daily Treatment

“…Displacement, energy absorption, and toughness parameters were calculated for the entire test (to fracture) as well as separately for the pre-yield and post-yield portions of the curve with the yield point defined using the 2% offset criterion [11]. Equations used to calculate material properties are identical to those used previously for testing dog ribs via three-point bending [5,6].…”

“…Significant reductions in toughness (-20%) of ribs from beagle dogs were shown after one year of alendronate treatment at doses exceeding those used clinically for postmenopausal osteoporosis [5]. In contrast, following three years of high dose incadronate treatment, no significant difference in rib toughness was shown between treated and non-treated animals [6]. Although these latter data were touted in an editorial to point to a new 'vista' with respect to the negative effects of bisphosphonates on material properties [7], in actuality the manner in which toughness was calculated in these two papers was significantly different.…”

“…In contrast, following three years of high dose incadronate treatment, no significant difference in rib toughness was shown between treated and non-treated animals [6]. Although these latter data were touted in an editorial to point to a new 'vista' with respect to the negative effects of bisphosphonates on material properties [7], in actuality the manner in which toughness was calculated in these two papers was significantly different. In three point bending tests, the load-deformation curve describes forces and moments that can be used to depict stresses and strains.…”

“…Mashiba et al defined toughness as the area under the stress-strain curve to fracture, therefore encompassing both pre-yield and post-yield regions [5]. Komatsubara et al defined toughness as the area under the stress-strain curve to ultimate stress [7]. Given that yield and ultimate stress are nearly identical in these rib three point bending tests, the values reported by Komatsubara reflect mainly the pre-yield portion of the curve.…”