Long-Term Treatment of Incadronate Disodium Accumulates Microdamage but Improves the Trabecular Bone Microarchitecture in Dog Vertebra

Abstract

This study aimed to investigate the effect of long-term suppression of bone resorption by bisphosphonate on the microstructure, accumulation of microdamage, and mechanical properties of trabecular bone. Twentynine 1-year-old beagles (15 males, 14 females) were divided into three groups. The control group (CNT) was treated daily with vehicle, and the other two groups were treated with incadronate at a dose of 0.3 mg/kg/day (LOW) or 0.6 mg/kg/day (HIGH) orally for 3 years. After death, the second thoracic vertebra was scanned with microcomputed tomography (micro-CT) and assigned to histomorphometric and microdamage measurements. The fourth lumbar vertebra was mechanically tested by compression. Incadronate concentration in bone was measured in the 11th thoracic vertebra. Micro-CT analysis demonstrated a platelike trabecular structure and increased concave surface of trabeculae in the thoracic vertebra of incadronate-treated groups. Three-year incadronate treatment significantly suppressed trabecular activation rates by 56% in LOW and 67% in HIGH without impairment of mineralization, and increased microdamage accumulation in both incadronate-treated groups. Trabecular bone volume was significantly increased in both LOW and HIGH groups, and vertebral strength was significantly increased in the HIGH group compared with the CNT group. However, intrinsic material properties such as normalized ultimate stress and normalized toughness were reduced in incadronate-treated groups. Incadronate concentration in bone was dose-dependent. This study suggests that long-term suppression of bone remodeling increases microdamage accumulation, but this is not necessarily associated with vertebral fragility because of compensated increase of bone mass and improved microarchitecture. (J Bone Miner Res 2003;18:512-520)

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

“…(50) In support of this, several studies have suggested that long-term inhibition of bone turnover by bisphosphonates may result in increased microfracture accumulation and, in some cases, decreased bone strength. (51)(52)(53) At the dosing schedule used here, dasatinib treatment of normal rats decreased OC numbers and serum CTX-1 levels by 50%. In contrast, there were no changes in OB activity in dasatinib-treated animals, as determined by the serum markers osteocalcin and P1NP and by the dynamic measurements MS/BS Ã , BFR Ã , and MAR Ã , suggesting that bone turnover still may have been occurring.…”

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

“…Data from biomechanical tests performed on the vertebrae of beagle dogs treated with bisphosphonates [1][2][3][4] consistently indicate that there is a reduction in toughness. However, reports of bisphosphonate-induced changes in rib toughness have thus far been discordant [5,6].…”

“…Following one year of treatment at doses equivalent to or below those used to treat postmenopausal osteoporosis, bisphosphonates non-significantly reduced (-6 to -20%) vertebral bone toughness [1]; higher doses significantly reduced vertebral toughness (-21%) [2]. Bisphosphonate treatment for three years significantly reduced vertebral toughness compared to vehicle-treated controls at doses both equivalent to (-27%) and above (-30 to -40%) those used to treat patients with osteoporosis [3,4].…”

A biomechanical perspective on bone quality

“…Although a number of studies have looked at the effects of bisphosphonates on trabecular bone biomechanics in large animals [50][51][52][53][54][55][56][57], we could find only two that looked specifically for differences in mechanical properties relative to density [49,58]. Neither of the studies observed significant changes in the relationships as a result of treatment.…”