ORCID Profile
0000-0002-3099-8073
Current Organisation
University Medical Center Hamburg-Eppendorf
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Publisher: Wiley
Date: 22-11-2022
DOI: 10.1002/JBMR.4736
Abstract: Hyperthyroidism causes secondary osteoporosis through favoring bone resorption over bone formation, leading to bone loss with elevated bone fragility. Osteocytes that reside within lacunae inside the mineralized bone matrix orchestrate the process of bone remodeling and can themselves actively resorb bone upon certain stimuli. Nevertheless, the interaction between thyroid hormones and osteocytes and the impact of hyperthyroidism on osteocyte cell function are still unknown. In a preliminary study, we analyzed bones from male C57BL/6 mice with drug‐induced hyperthyroidism, which led to mild osteocytic osteolysis with 1.14‐fold larger osteocyte lacunae and by 108.33% higher tartrate‐resistant acid phosphatase (TRAP) activity in osteocytes of hyperthyroid mice compared to euthyroid mice. To test whether hyperthyroidism‐induced bone changes are reversible, we rendered male mice hyperthyroid by adding levothyroxine into their drinking water for 4 weeks, followed by a weaning period of 4 weeks with access to normal drinking water. Hyperthyroid mice displayed cortical and trabecular bone loss due to high bone turnover, which recovered with weaning. Although canalicular number and osteocyte lacunar area were similar in euthyroid, hyperthyroid and weaned mice, the number of terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling (TUNEL)‐positive osteocytes was 100% lower in the weaning group compared to euthyroid mice and the osteocytic TRAP activity was eightfold higher in hyperthyroid animals. The latter, along with a 3.75% lower average mineralization around the osteocyte lacunae in trabecular bone, suggests osteocytic osteolysis activity that, however, did not result in significantly enlarged osteocyte lacunae. In conclusion, we show a recovery of bone microarchitecture and turnover after reversal of hyperthyroidism to a euthyroid state. In contrast, osteocytic osteolysis was initiated in hyperthyroidism, but its effects were not reversed after 4 weeks of weaning. Due to the vast number of osteocytes in bone, we speculate that even minor in idual cell functions might contribute to altered bone quality and mineral homeostasis in the setting of hyperthyroidism‐induced bone disease. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.BONE.2015.08.002
Abstract: Bisphosphonates are widely used to treat osteoporosis, but have been associated with atypical femoral fractures (AFFs) in the long term, which raises a critical health problem for the aging population. Several clinical studies have suggested that the occurrence of AFFs may be related to the bisphosphonate-induced changes of bone turnover, but large discrepancies in the results of these studies indicate that the salient mechanisms responsible for any loss in fracture resistance are still unclear. Here the role of bisphosphonates is examined in terms of the potential deterioration in fracture resistance resulting from both intrinsic (plasticity) and extrinsic (shielding) toughening mechanisms, which operate over a wide range of length-scales. Specifically, we compare the mechanical properties of two groups of humeri from healthy beagles, one control group comprising eight females (oral doses of saline vehicle, 1 mL/kg/day, 3 years) and one treated group comprising nine females (oral doses of alendronate used to treat osteoporosis, 0.2mg/kg/day, 3 years). Our data demonstrate treatment-specific reorganization of bone tissue identified at multiple length-scales mainly through advanced synchrotron x-ray experiments. We confirm that bisphosphonate treatments can increase non-enzymatic collagen cross-linking at molecular scales, which critically restricts plasticity associated with fibrillar sliding, and hence intrinsic toughening, at nanoscales. We also observe changes in the intracortical architecture of treated bone at microscales, with partial filling of the Haversian canals and reduction of osteon number. We hypothesize that the reduced plasticity associated with BP treatments may induce an increase in microcrack accumulation and growth under cyclic daily loadings, and potentially increase the susceptibility of cortical bone to atypical (fatigue-like) fractures.
Publisher: American Chemical Society (ACS)
Date: 06-01-2021
Publisher: Springer Science and Business Media LLC
Date: 20-01-2020
DOI: 10.1038/S41598-019-57303-Z
Abstract: Osteophytes - bony outgrowths on joint structures - are found in healthy in iduals but are specifically present in late osteoarthritis (OA). Osteophyte development and function is not well understood, yet biomechanical stimuli are thought to be critical. Bone adapts to mechanical forces via the cellular network of osteocytes. The involvement of osteocytes in osteophyte formation and maturation has not been unravelled. Forty-three osteophytes from tibias of 23 OA patients (65 ± 9 years) were analysed. The trabecular bone structure of osteophytes presented with fewer trabeculae of lower bone mineral density compared to subchondral bone. We identified 40% early stage and 60% late stage osteophytes that significantly differed in their trabecular bone characteristics. Osteophyte bone revealed a higher number of osteocytes and a lower number of empty osteocyte lacunae per bone area than the subchondral bone. We found that OA osteophytes consist of younger bone material comprised of woven and lamellar bone with the capacity to develop into a late stage osteophyte potentially via the involvement of the osteocyte network. Our analysis of OA osteophytes implies a transition from woven to lamellar bone as in physiological bone growth within a pathological joint. Therefore, osteophyte development and growth present a valuable research subject when aiming to investigate the osteogenic signalling cascade.
Publisher: Wiley
Date: 02-05-2019
Publisher: Wiley
Date: 17-06-2019
DOI: 10.1002/JBMR.3730
Abstract: Bone fracture risk is influenced by bone quality, which encompasses bone's composition as well as its multiscale organization and architecture. Aging and disease deteriorate bone quality, leading to reduced mechanical properties and higher fracture incidence. Largely unexplored is how bone quality and mechanical competence progress during longitudinal bone growth. Human femoral cortical bone was acquired from fetal (n = 1), infantile (n = 3), and 2- to 14-year-old cases (n = 4) at the mid-diaphysis. Bone quality was assessed in terms of bone structure, osteocyte characteristics, mineralization, and collagen orientation. The mechanical properties were investigated by measuring tensile deformation at multiple length scales via synchrotron X-ray diffraction. We find dramatic differences in mechanical resistance with age. Specifically, cortical bone in 2- to 14-year-old cases exhibits a 160% greater stiffness and 83% higher strength than fetal/infantile cases. The higher mechanical resistance of the 2- to 14-year-old cases is associated with advantageous bone quality, specifically higher bone volume fraction, better micronscale organization (woven versus lamellar), and higher mean mineralization compared with fetal/infantile cases. Our study reveals that bone quality is superior after remodeling/modeling processes convert the primary woven bone structure to lamellar bone. In this cohort of female children, the microstructural differences at the femoral diaphysis were apparent between the 1- to 2-year-old cases. Indeed, the lamellar bone in 2- to 14-year-old cases had a superior structural organization (collagen and osteocyte characteristics) and composition for resisting deformation and fracture than fetal/infantile bone. Mechanistically, the changes in bone quality during longitudinal bone growth lead to higher fracture resistance because collagen fibrils are better aligned to resist tensile forces, while elevated mean mineralization reinforces the collagen scaffold. Thus, our results reveal inherent weaknesses of the fetal/infantile skeleton signifying its inferior bone quality. These results have implications for pediatric fracture risk, as bone produced at ossification centers during children's longitudinal bone growth could display similarly weak points. © 2019 American Society for Bone and Mineral Research.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Wiley
Date: 22-01-2015
DOI: 10.1002/JBMR.2340
Abstract: Paget's disease of bone (PDB) is the second most common bone disease mostly developing after 50 years of age at one or more localized skeletal sites it is associated with severely high bone turnover, bone enlargement, bowing/deformity, cracking, and pain. Here, to specifically address the origins of the deteriorated mechanical integrity, we use a cohort of control and PDB human biopsies to investigate multiscale architectural and compositional modifications to the bone structure (ie, bone quality) and relate these changes to mechanical property measurements to provide further insight into the clinical manifestations (ie, deformities and bowing) and fracture risk caused by PDB. Here, at the level of the collagen and mineral (ie, nanometer-length scale), we find a 19% lower mineral content and lower carbonate-to-phosphate ratio in PDB, which accounts for the 14% lower stiffness and 19% lower hardness promoting plastic deformation in pathological bone. At the microstructural scale, trabecular regions are known to become densified, whereas cortical bone loses its characteristic parallel-aligned osteonal pattern, which is replaced with a mosaic of lamellar and woven bone. Although we find this loss of anisotropic alignment produces a straighter crack path in mechanically-loaded PDB cases, cortical fracture toughness appears to be maintained due to increased plastic deformation. Clearly, the altered quality of the bone structure in PDB affects the mechanical integrity leading to complications such as bowing, deformities, and stable cracks called fissure fractures associated with this disease. Although the lower mineralization and loss of aligned Haversian structures do produce a lower modulus tissue, which is susceptible to deformities, our results indicate that the higher levels of plasticity may compensate for the lost microstructural features and maintain the resistance to crack growth.
Publisher: Springer Science and Business Media LLC
Date: 16-02-2016
DOI: 10.1038/SREP21072
Abstract: Bisphosphonates are a common treatment to reduce osteoporotic fractures. This treatment induces osseous structural and compositional changes accompanied by positive effects on osteoblasts and osteocytes. Here, we test the hypothesis that restored osseous cell behavior, which resembles characteristics of younger, healthy cortical bone, leads to improved bone quality. Microarchitecture and mechanical properties of young, treatment-naïve osteoporosis and bisphosphonate-treated cases were investigated in femoral cortices. Tissue strength was measured using three-point bending. Collagen fibril-level deformation was assessed in non-traumatic and traumatic fracture states using synchrotron small-angle x-ray scattering (SAXS) at low and high strain rates. The lower modulus, strength and fibril deformation measured at low strain rates reflects susceptibility for osteoporotic low-energy fragility fractures. Independent of age, disease and treatment status, SAXS revealed reduced fibril plasticity at high strain rates, characteristic of traumatic fracture. The significantly reduced mechanical integrity in osteoporosis may originate from porosity and alterations to the intra/extrafibrillar structure, while the fibril deformation under treatment indicates improved nano-scale characteristics. In conclusion, losses in strength and fibril deformation at low strain rates correlate with the occurrence of fragility fractures in osteoporosis, while improvements in structural and mechanical properties following bisphosphonate treatment may foster resistance to fracture during physiological strain rates.
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.BIOMATERIALS.2014.03.066
Abstract: While most fracture-mechanics investigations on bone have been performed at low strain rates, physiological fractures invariably occur at higher loading rates. Here, at strain rates from 10(-5) to 10(-1) s(-1), we investigate deformation and fracture in bone at small length-scales using in situ small-angle x-ray scattering (SAXS) to study deformation in the mineralized collagen fibrils and at the microstructural level via fracture-mechanics experiments to study toughening mechanisms generating toughness through crack-tip shielding. Our results show diminished bone toughness at increasing strain rates as cracks penetrate through the osteons at higher strain rates instead of deflecting at the cement lines, which is a prime toughening mechanism in bone at low strain rates. The absence of crack deflection mechanisms at higher strain rates is consistent with lower intrinsic bone matrix toughness. In the SAXS experiments, higher fibrillar strains at higher strain rates suggest less inelastic deformation and thus support a lower intrinsic toughness. The increased incidence of fracture induced by high strain rates can be associated with a loss in toughness in the matrix caused by a strain rate induced stiffening of the fibril ductility, i.e., a "locking-up" of the viscous sliding and sacrificial bonding mechanisms, which are the origin of inelastic deformation (and toughness) in bone at small length-scales.
Publisher: Proceedings of the National Academy of Sciences
Date: 31-07-2017
Abstract: Since the first reports of atypical femoral fractures (AFFs), a clinical phenomenon in which patients experience catastrophic brittle fractures of the femoral shaft with minimal trauma, the risk associated with bisphosphonates, the most widely prescribed pharmaceuticals for osteoporosis, has become increasingly well-established. However, the underlying cause of AFFs and their causal relationship to bisphosphonates is unknown. Here we examine bone tissue from women with AFFs and show that long-term bisphosphonate treatment degrades the fracture-resistance toughening mechanisms that are inherent to healthy bone. Our work resolves the apparent paradox of AFFs as a side effect of the most common osteoporosis treatment by clarifying the differing effects of bisphosphonates on bone tissue structure and mechanical properties across multiple length scales.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.BONE.2019.07.003
Abstract: In osteoporosis patients, antiresorptive treatments such as alendronate reduce the resorption of trabecular bone and thus minimize vertebral fracture risk. However, fracture risk reduction efficacy of antiresorptive drugs varies between skeletal sites and is highest for vertebral bone. In human vertebrae, cancellous bone is distributed heterogeneously between regions. This microstructural heterogeneity is changing with patient age and is likely to play a major role in vertebral failure mechanisms and fracture susceptibility. Whether antiresorptive treatment affects the heterogeneity of vertebral microstructure in osteoporosis has not been unraveled. Our aim was to assess whether antiresorptive treatment would have a region-dependent influence on vertebral trabecular bone. Therefore, we used high-resolution peripheral quantitative computed tomography (HR-pQCT), microcomputed tomography (microCT) and uniaxial compression testing to determine the structure and mechanical properties of trabecular bone cores from anterior and posterior regions of 22 lumbar vertebrae from elderly osteoporotic women. We analyzed age-matched ex vivo bone s les from bisphosphonate-treated female osteoporosis patients (age: 82 ± 7y, bisphosphonate treatment period: 4 ± 2 years) along treatment-naïve female controls (82 ± 7y). MicroCT analysis showed a significantly lower bone volume fraction (p = 0.006) and lower trabecular number (p = 0.003) for the anterior bone cores compared to posterior bone cores in the treatment-naïve group. The bisphosphonate-treated group had a more homogeneous bone volume distribution and did not show significant regional differences in bone volume, it however also displayed significantly different trabecular numbers (p = 0.016). In bone cores of the bisphosphonate-treated group, trabeculae were thicker in comparison to treatment-naïve controls (p = 0.011). Differences in bone volume further resulted in different maximum forces during compression testing between the s les. In addition, the percental difference between BV/TV In conclusion, regional trabecular bone microstructure in lumbar vertebrae of bisphosphonate-treated women was more homogeneous compared to treatment-naïve controls. Bisphosphonate treatment, which specifically targets resorption surfaces common in anterior vertebral bone, might have resulted in a region-specific preservation of vertebral microstructure and loading capacity. This could have positive implications for the reduction of wedge fracture risk and add to the explanation of the higher efficacy of fracture risk reduction in vertebrae in comparison to other fracture regions.
No related grants have been discovered for Björn Busse.