The effect of long-term bisphosphonate therapy on trabecular bone strength and microcrack density

Abstract

ObjectivesBisphosphonates (BP) are the first-line treatment for preventing fragility fractures. However, concern regarding their efficacy is growing because bisphosphonate is associated with over-suppression of remodelling and accumulation of microcracks. While dual-energy X-ray absorptiometry (DXA) scanning may show a gain in bone density, the impact of this class of drug on mechanical properties remains unclear. We therefore sought to quantify the mechanical strength of bone treated with BP (oral alendronate), and correlate data with the microarchitecture and density of microcracks in comparison with untreated controls.MethodsTrabecular bone from hip fracture patients treated with BP (n = 10) was compared with naïve fractured (n = 14) and non-fractured controls (n = 6). Trabecular cores were synchrotron scanned and micro-CT scanned for microstructural analysis, including quantification of bone volume fraction, microarchitecture and microcracks. The specimens were then mechanically tested in compression.ResultsBP bone was 28% lower in strength than untreated hip fracture bone, and 48% lower in strength than non-fractured control bone (4.6 MPa vs 6.4 MPa vs 8.9 MPa). BP-treated bone had 24% more microcracks than naïve fractured bone and 51% more than non-fractured control (8.12/cm2 vs 6.55/cm2 vs 5.25/cm2). BP and naïve fracture bone exhibited similar trabecular microarchitecture, with significantly lower bone volume fraction and connectivity than non-fractured controls.ConclusionBP therapy had no detectable mechanical benefit in the specimens examined. Instead, its use was associated with substantially reduced bone strength. This low strength may be due to the greater accumulation of microcracks and a lack of any discernible improvement in bone volume or microarchitecture. This preliminary study suggests that the clinical impact of BP-induced microcrack accumulation may be significant.Cite this article: A. Jin, J. Cobb, U. Hansen, R. Bhattacharya, C. Reinhard, N. Vo, R. Atwood, J. Li, A. Karunaratne, C. Wiles, R. Abel. The effect of long-term bisphosphonate therapy on trabecular bone strength and microcrack density. Bone Joint Res 2017;6:602–609. DOI: 10.1302/2046-3758.610.BJR-2016-0321.R1.

Human mesenchymal stem cells differentiate into an osteogenic lineage in presence of strontium containing bioactive glass nanoparticles

“…Current treatments target reduction of bone resorption by, for example, suppressing osteoclast activities, such as treatment with oestrogen, calcitonin, and bisphosphonates [7]. Bisphosphonates can strongly bind to bone mineral [8] and are retained within it [9], reducing rate of bone resorption by osteoclasts [8,[10][11][12][13]. Alendronate, risedronate and zoledronate have been demonstrated, in clinical trials of 3-5 years duration, to be effective drugs in terms of stabilising bone loss and maintain bone mineral density [10,14].…”

Analysis of Trabecular Microstructure and Vascular Distribution of Capital Femoral Epiphysis Relevant to Legg–Calve–Perthes Disease

“…The micro‐tomography data was then analyzed with the use of the CTVox program (Bruker) to assess the epiphyses for four markers of trabecular architecture, which have been previously utilized in microstructural studies of the glenoid, distal radius, and femoral head : bone volume fraction (BV/TV, %), trabecular thickness (TbTh, µm), trabecular separation (TbSp, µm), and trabecular number (TbN, 1/mm). Comparisons were then performed between each of the four quadrants.…”

The lack of neuropeptide Y‐Y 1 receptor signaling modulates the chemical and mechanical properties of bone matrix

“…In the case of osteopetrosis, bones display an abnormally dense matrix; however the susceptibility to fracture is insurmountably amplified . In addition, in the clinics it has been reported that the treatment of osteoporosis, a disease characterized by a low bone mass and high fracture incidence, with bisphosphonates failed to restore bone ECM properties, and consequently bone strength . Of note, the observed defective matrix properties have been generally attributed to abnormal osteoclastic differentiation and matrix resorptive malfunction …”

“…19 In addition, in the clinics it has been reported that the treatment of osteoporosis, a disease characterized by a low bone mass and high fracture incidence, with bisphosphonates failed to restore bone ECM properties, and consequently bone strength. 20 Of note, the observed defective matrix properties have been generally attributed to abnormal osteoclastic differentiation and matrix resorptive malfunction. 19,20 Although the high bone mass phenotype exhibited by Y 1 R knockout (Y 1 R −/− ) mice has been mainly attributed to enhanced osteoblastic activity, 14 our previous functional studies reported that the osteoclastic function and activity is also impaired.…”

“…20 Of note, the observed defective matrix properties have been generally attributed to abnormal osteoclastic differentiation and matrix resorptive malfunction. 19,20 Although the high bone mass phenotype exhibited by Y 1 R knockout (Y 1 R −/− ) mice has been mainly attributed to enhanced osteoblastic activity, 14 our previous functional studies reported that the osteoclastic function and activity is also impaired. 9 The Y 1 R sympathetic signaling deficiency in male mice stimulates the formation of giant multinucleated osteoclasts, with reduced capacity to resorb bone matrix as appreciated by the formation of poorly demineralized eroded pits, and markedly smaller pits in terms of area, volume, and depth, as determined by quantitative 3D analysis using a computational tool.…”