Long‐Term Immobilization in Elderly Females Causes a Specific Pattern of Cortical Bone and Osteocyte Deterioration Different From Postmenopausal Osteoporosis

Immobilization as a result of long‐term bed rest can lead to gradual bone loss. Because of their distribution throughout the bone matrix and remarkable interconnectivity, osteocytes represent the major mechanosensors in bone and translate mechanical into biochemical signals controlling bone remodeling. To test whether immobilization affects the characteristics of the osteocyte network in human cortical bone, femoral diaphyseal bone specimens were analyzed in immobilized female individuals and compared with age‐matched postmenopausal individuals with primary osteoporosis. Premenopausal and postmenopausal healthy individuals served as control groups. Cortical porosity, osteocyte number and lacunar area, the frequency of hypermineralized lacunae, as well as cortical bone calcium content (CaMean) were assessed using bone histomorphometry and quantitative backscattered electron imaging (qBEI). Bone matrix properties were further analyzed by Fourier transform infrared spectroscopy (FTIR). In the immobilization group, cortical porosity was significantly higher, and qBEI revealed a trend toward higher matrix mineralization compared with osteoporotic individuals. Osteocyte density and canalicular density showed a declining rate from premenopausal toward healthy postmenopausal and osteoporotic individuals with peculiar reductions in the immobilization group, whereas the number of hypermineralized lacunae accumulated inversely. In conclusion, reduced osteocyte density and impaired connectivity during immobilization are associated with a specific bone loss pattern, reflecting a phenotype clearly distinguishable from postmenopausal osteoporosis. Immobilization periods may lead to a loss of survival signals for osteocytes, provoking bone loss that is even higher than in osteoporosis states, whereas osteocytic osteolysis remains absent. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

[1]  K. Rockwood,et al.  Bed rest and accelerated aging in relation to the musculoskeletal and cardiovascular systems and frailty biomarkers: A review , 2019, Experimental Gerontology.

[2]  R. Ritchie,et al.  Mechanical Competence and Bone Quality Develop During Skeletal Growth , 2019, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[3]  R. Ritchie,et al.  On the Origins of Fracture Toughness in Advanced Teleosts: How the Swordfish Sword's Bone Structure and Composition Allow for Slashing under Water to Kill or Stun Prey , 2019, Advanced science.

[4]  P. Milovanović,et al.  Inter-site Variability of the Human Osteocyte Lacunar Network: Implications for Bone Quality , 2019, Current Osteoporosis Reports.

[5]  U. Siebert,et al.  Ultra-high matrix mineralization of sperm whale auditory ossicles facilitates high sound pressure and high-frequency underwater hearing , 2018, Proceedings of the Royal Society B.

[6]  L. Hofbauer,et al.  Differential effects of high-fat diet and exercise training on bone and energy metabolism. , 2018, Bone.

[7]  L. Bonewald,et al.  Physiological and pathological osteocytic osteolysis , 2018, Journal of musculoskeletal & neuronal interactions.

[8]  M. Djuric,et al.  Bone tissue aging affects mineralization of cement lines. , 2018, Bone.

[9]  P. Milovanović,et al.  Early bone tissue aging in human auditory ossicles is accompanied by excessive hypermineralization, osteocyte death and micropetrosis , 2018, Scientific Reports.

[10]  R. Gioia,et al.  Severely impaired bone material quality in Chihuahua zebrafish resembles classical dominant human osteogenesis imperfecta , 2018, bioRxiv.

[11]  M. Amling,et al.  Vitamin D regulates osteocyte survival and perilacunar remodeling in human and murine bone. , 2017, Bone.

[12]  L. Bonewald,et al.  Osteocytes Acidify Their Microenvironment in Response to PTHrP In Vitro and in Lactating Mice In Vivo , 2017, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[13]  D. Vashishth,et al.  Assessment of collagen quality associated with non-enzymatic cross-links in human bone using Fourier-transform infrared imaging. , 2017, Bone.

[14]  H. Birkedal,et al.  Immobilization and long-term recovery results in large changes in bone structure and strength but no corresponding alterations of osteocyte lacunar properties. , 2016, Bone.

[15]  Marc N. Wein,et al.  The Wnt Inhibitor Sclerostin Is Up-regulated by Mechanical Unloading in Osteocytes in Vitro* , 2015, The Journal of Biological Chemistry.

[16]  L. Bonewald.  Does Defective Bone Lead to Defective Muscle? , 2015, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[17]  Françoise Peyrin,et al.  Synchrotron X-ray phase nano-tomography-based analysis of the lacunar–canalicular network morphology and its relation to the strains experienced by osteocytes in situ as predicted by case-specific finite element analysis , 2014, Biomechanics and Modeling in Mechanobiology.

[18]  R. Ritchie,et al.  Multi-level characterization of human femoral cortices and their underlying osteocyte network reveal trends in quality of young, aged, osteoporotic and antiresorptive-treated bone. , 2015, Biomaterials.

[19]  Klaus Püschel,et al.  Trends in trabecular architecture and bone mineral density distribution in 152 individuals aged 30-90 years. , 2014, Bone.

[20]  Cesar Libanati,et al.  Romosozumab in postmenopausal women with low bone mineral density , 2014, The New England journal of medicine.

[21]  Michael Hahn,et al.  Osteocytic canalicular networks: morphological implications for altered mechanosensitivity. , 2013, ACS nano.

[22]  R. Ritchie,et al.  Proposed Pathogenesis for Atypical Femoral Fractures: Lessons from Materials Research , 2022 .

[23]  P. Pajevic,et al.  Osteocyte biology and space flight. , 2013, Current biotechnology.

[24]  R. Ritchie,et al.  Vitamin D Deficiency Induces Early Signs of Aging in Human Bone, Increasing the Risk of Fracture , 2013, Science Translational Medicine.

[25]  Piero Pianetta,et al.  Microgravity Induces Pelvic Bone Loss through Osteoclastic Activity, Osteocytic Osteolysis, and Osteoblastic Cell Cycle Inhibition by CDKN1a/p21 , 2013, PloS one.

[26]  J. Kanis,et al.  Standardized nomenclature, symbols, and units for bone histomorphometry: A 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee , 2013, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[27]  Mark L. Johnson,et al.  Skeletal muscle secreted factors prevent glucocorticoid-induced osteocyte apoptosis through activation of β-catenin. , 2012, European cells & materials.

[28]  M. Bouxsein,et al.  Serum sclerostin increases in healthy adult men during bed rest. , 2012, Journal of Clinical Endocrinology and Metabolism.

[29]  N. Fazzalari,et al.  Increased proportion of hypermineralized osteocyte lacunae in osteoporotic and osteoarthritic human trabecular bone: implications for bone remodeling. , 2012, Bone.

[30]  P. Schneider,et al.  Serial FIB/SEM imaging for quantitative 3D assessment of the osteocyte lacuno-canalicular network. , 2011, Bone.

[31]  T. Rachner,et al.  Osteoporosis: now and the future , 2011, The Lancet.

[32]  Michael Hahn,et al.  Decrease in the Osteocyte Lacunar Density Accompanied by Hypermineralized Lacunar Occlusion Reveals Failure and Delay of Remodeling in Aged Human Bone , 2022 .

[33]  D. Kubek,et al.  Methodological assessment of acid‐etching for visualizing the osteocyte lacunar‐canalicular networks using scanning electron microscopy , 2009, Microscopy research and technique.

[34]  G. Duda,et al.  Reorganization of the femoral cortex due to age-, sex-, and endoprosthetic-related effects emphasized by osteonal dimensions and remodeling. , 2009, Journal of biomedical materials research. Part A.

[35]  R. Wolfe,et al.  Functional impact of 10 days of bed rest in healthy older adults. , 2008, The journals of gerontology. Series A, Biological sciences and medical sciences.

[36]  P. Fratzl,et al.  Bone mineralization density distribution in health and disease. , 2008, Bone.

[37]  L. Bonewald.  Osteocytes as Dynamic Multifunctional Cells , 2007, Annals of the New York Academy of Sciences.

[38]  Minqi Li,et al.  Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. , 2007, Cell metabolism.

[39]  A. Boskey,et al.  FT-IR imaging of native and tissue-engineered bone and cartilage. , 2007, Biomaterials.

[40]  A. Parfitt,et al.  Osteocyte Apoptosis Is Induced by Weightlessness in Mice and Precedes Osteoclast Recruitment and Bone Loss , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[41]  D. Fyhrie,et al.  The morphological association between microcracks and osteocyte lacunae in human cortical bone. , 2005, Bone.

[42]  Peng Liu,et al.  Sclerostin Binds to LRP5/6 and Antagonizes Canonical Wnt Signaling* , 2005, Journal of Biological Chemistry.

[43]  Jenneke Klein-Nulend,et al.  Shear stress inhibits while disuse promotes osteocyte apoptosis. , 2004, Biochemical and biophysical research communications.

[44]  D. Rao,et al.  Reduced Iliac Cancellous Osteocyte Density in Patients With Osteoporotic Vertebral Fracture , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[45]  D. Bikle,et al.  The impact of skeletal unloading on bone formation. , 2003, Gravitational and space biology bulletin : publication of the American Society for Gravitational and Space Biology.

[46]  L. Lanyon,et al.  Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone. , 2003, American journal of physiology. Cell physiology.

[47]  N. Rushton,et al.  Osteocyte Lacunar Occupancy in the Femoral Neck Cortex: An Association with Cortical Remodeling in Hip Fracture Cases and Controls. , 2001, Calcified Tissue International.

[48]  Laurence Vico,et al.  Effects of long-term microgravity exposure on cancellous and cortical weight-bearing bones of cosmonauts , 2000, The Lancet.

[49]  J. Zerwekh,et al.  The Effects of Twelve Weeks of Bed Rest on Bone Histology, Biochemical Markers of Bone Turnover, and Calcium Homeostasis in Eleven Normal Subjects , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[50]  R Huiskes,et al.  Osteocyte density changes in aging and osteoporosis. , 1996, Bone.

[51]  R T Turner,et al.  Spaceflight results in depressed cancellous bone formation in rat humeri. , 1995, Aviation, space, and environmental medicine.

[52]  Richard Mendelsohn,et al.  An FT-IR microscopic investigation of the effects of tissue preservation on bone , 1992, Calcified Tissue International.

[53]  M. Spector,et al.  Spaceflight Results in Formation of Defective Bone 1 , 1985, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[54]  D R Carter,et al.  Effects of Spaceflight on Structural and Material Strength of Growing Bone , 1983, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[55]  T. Wronski,et al.  Effect of spaceflight on periosteal bone formation in rats. , 1983, The American journal of physiology.

[56]  M. Schweizer,et al.  The Formation of Calcified Nanospherites during Micropetrosis Represents a Unique Mineralization Mechanism in Aged Human Bone. , 2017, Small.

[57]  Anna Teti,et al.  Do osteocytes contribute to bone mineral homeostasis? Osteocytic osteolysis revisited. , 2009, Bone.