Advertisement

Inter-site Variability of the Human Osteocyte Lacunar Network: Implications for Bone Quality

  • Petar Milovanovic
  • Björn BusseEmail author
Osteocytes (J Klein Nulend, Section editor)
Part of the following topical collections:
  1. Topical Collection on Osteocytes

Abstract

Purpose of Review

This article provides a review on the variability of the osteocyte lacunar network in the human skeleton. It highlights characteristics of the osteocyte lacunar network in relation to different skeletal sites and fracture susceptibility.

Recent Findings

Application of 2D analyses (quantitative backscattered electron microscopy, histology, confocal laser scanning microscopy) and 3D reconstructions (microcomputed tomography and synchrotron radiation microcomputed tomography) provides extended high-resolution information on osteocyte lacunar properties in individuals of various age (fetal, children’s growth, elderly), sex, and disease states with increased fracture risk.

Summary

Recent findings on the distribution of osteocytes in the human skeleton are reviewed. Quantitative data highlighting the variability of the osteocyte lacunar network is presented with special emphasis on site specificity and maintenance of bone health. The causes and consequences of heterogeneous distribution of osteocyte lacunae both within specific regions of interest and on the skeletal level are reviewed and linked to differential bone quality factors and fracture susceptibility.

Keywords

Osteocyte distribution Inter-site differences Osteocyte lacunar number Mechanical loading Bone strength Aging Bone development 

Notes

Acknowledgments

The authors acknowledge the support from the German Research Foundation (DFG), the Alexander von Humboldt Foundation, and the Serbian Ministry of Education and Science (III45005).

Compliance with Ethical Standards

Conflict of Interest

P. Milovanovic and B. Busse declare no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Currey JD. Bones: structure and mechanics. Princeton, N. J: Princeton University Press; 2002.Google Scholar
  2. 2.
    Busse B, Hahn M, Schinke T, Puschel K, Duda GN, Amling M. Reorganization of the femoral cortex due to age-, sex-, and endoprosthetic-related effects emphasized by osteonal dimensions and remodeling. J Biomed Mater Res A. 2010;92(4):1440–51.  https://doi.org/10.1002/jbm.a.32432.Google Scholar
  3. 3.
    Jobke B, Milovanovic P, Amling M, Busse B. Bisphosphonate-osteoclasts: changes in osteoclast morphology and function induced by antiresorptive nitrogen-containing bisphosphonate treatment in osteoporosis patients. Bone. 2014;59:37–43.  https://doi.org/10.1016/j.bone.2013.10.024.Google Scholar
  4. 4.
    Regelsberger J, Milovanovic P, Schmidt T, Hahn M, Zimmermann EA, Tsokos M, et al. Changes to the cell, tissue and architecture levels in cranial suture synostosis reveal a problem of timing in bone development. Eur Cell Mater. 2012;24:441–58.Google Scholar
  5. 5.
    Szulc P, Seeman E. Thinking inside and outside the envelopes of bone: dedicated to PDD. Osteoporos Int. 2009;20(8):1281–8.  https://doi.org/10.1007/s00198-009-0994-y.Google Scholar
  6. 6.
    Buenzli PR, Sims NA. Quantifying the osteocyte network in the human skeleton. Bone. 2015;75:144–50.  https://doi.org/10.1016/j.bone.2015.02.016.Google Scholar
  7. 7.
    Loiselle AE, Jiang JX, Donahue HJ. Gap junction and hemichannel functions in osteocytes. Bone. 2013;54(2):205–12.  https://doi.org/10.1016/j.bone.2012.08.132.Google Scholar
  8. 8.
    Santos A, Bakker A, Klein-Nulend J. The role of osteocytes in bone mechanotransduction. Osteoporos Int. 2009;20(6):1027–31.  https://doi.org/10.1007/s00198-009-0858-5.Google Scholar
  9. 9.
    Klein-Nulend J, Bonewald LF. The osteocyte. In: Bilezikian JP, Raisz LG, Martin TJ, editors. Principles of bone biology. 3rd ed. San Diego: Academic press; 2008. p. 153–74.Google Scholar
  10. 10.
    Bellido T. Osteocyte-driven bone remodeling. Calcif Tissue Int. 2014;94(1):25–34.  https://doi.org/10.1007/s00223-013-9774-y.Google Scholar
  11. 11.
    Dallas SL, Prideaux M, Bonewald LF. The osteocyte: An endocrine cell ... and more. Endocr Rev. 2013;34(5):658–90.  https://doi.org/10.1210/er.2012-1026.Google Scholar
  12. 12.
    Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26(2):229–38.  https://doi.org/10.1002/jbmr.320.Google Scholar
  13. 13.
    Bonewald LF, Wacker MJ. FGF23 production by osteocytes. Pediatr Nephrol. 2013;28(4):563–8.  https://doi.org/10.1007/s00467-012-2309-3.Google Scholar
  14. 14.
    Pereira RC, Juppner H, Azucena-Serrano CE, Yadin O, Salusky IB, Wesseling-Perry K. Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease. Bone. 2009;45(6):1161–8.  https://doi.org/10.1016/j.bone.2009.08.008.Google Scholar
  15. 15.
    Prideaux M, Findlay DM, Atkins GJ. Osteocytes: the master cells in bone remodelling. Curr Opin Pharmacol. 2016;28:24–30.  https://doi.org/10.1016/j.coph.2016.02.003.Google Scholar
  16. 16.
    • Milovanovic P, Zimmermann EA, vom Scheidt A, Hoffmann B, Sarau G, Yorgan T, et al. The formation of calcified nanospherites during micropetrosis represents a unique mineralization mechanism in aged human bone. Small. 2017;13(3):1602215.  https://doi.org/10.1002/smll.201602215 This study presents high-resolution data on the structure and composition of hypermineralized osteocyte lacunae as permanent traces of osteocyte apoptosis. Google Scholar
  17. 17.
    •• Rolvien T, Vom Scheidt A, Stockhausen KE, Milovanovic P, Djonic D, Hubert J, et al. Inter-site variability of the osteocyte lacunar network in the cortical bone underpins fracture susceptibility of the superolateral femoral neck. Bone. 2018;112:187–93.  https://doi.org/10.1016/j.bone.2018.04.018 This study assessed cortical bone of the femoral neck—one of the most common fracture sites—from 12 female donors (age 34–86 years) with backscattered scanning electron microscopy and high-resolution microcomputed tomography (μ-CT). It highlights the lower osteocyte lacunar density in the superolateral subregion (lower habitual loading intensity) than in the inferomedial neck region (habitually highly loaded in compression), and suggests that reduced osteocyte numbers are linked to higher fragility of the superolateral neck. Google Scholar
  18. 18.
    Milovanovic P, Zimmermann EA, Hahn M, Djonic D, Püschel K, Djuric M, et al. Osteocytic canalicular networks: morphological implications for altered mechanosensitivity. ACS Nano. 2013;7(9):7542–51.  https://doi.org/10.1021/nn401360u.Google Scholar
  19. 19.
    Busse B, Bale HA, Zimmermann EA, Panganiban B, Barth HD, Carriero A, et al. Vitamin D deficiency induces early signs of aging in human bone, increasing the risk of fracture. Sci Transl Med. 2013;5(193):193ra88.  https://doi.org/10.1126/scitranslmed.3006286.Google Scholar
  20. 20.
    Burr DB, Turner CH, Naick P, Forwood MR, Ambrosius W, Sayeed Hasan M, et al. Does microdamage accumulation affect the mechanical properties of bone? J Biomech. 1998;31(4):337–45.  https://doi.org/10.1016/S0021-9290(98)00016-5.Google Scholar
  21. 21.
    Vashishth D, Verborgt O, Divine G, Schaffler MB, Fyhrie DP. Decline in osteocyte lacunar density in human cortical bone is associated with accumulation of microcracks with age. Bone. 2000;26(4):375–80.Google Scholar
  22. 22.
    Ashique AM, Hart LS, Thomas CDL, Clement JG, Pivonka P, Carter Y, et al. Lacunar-canalicular network in femoral cortical bone is reduced in aged women and is predominantly due to a loss of canalicular porosity. Bone Rep. 2017;7:9–16.  https://doi.org/10.1016/j.bonr.2017.06.002.Google Scholar
  23. 23.
    Bach-Gansmo FL, Brüel A, Jensen MV, Ebbesen EN, Birkedal H, Thomsen JS. Osteocyte lacunar properties and cortical microstructure in human iliac crest as a function of age and sex. Bone. 2016;91:11–9.  https://doi.org/10.1016/j.bone.2016.07.003.Google Scholar
  24. 24.
    • Rolvien T, Schmidt FN, Milovanovic P, Jähn K, Riedel C, Butscheidt S, et al. Early bone tissue aging in human auditory ossicles is accompanied by excessive hypermineralization, osteocyte death and micropetrosis. Sci Rep. 2018;8(1):1920.  https://doi.org/10.1038/s41598-018-19803-2 The study shows that in auditory ossicles, the majority of osteocytes die within the first months and years of life. Despite abundant osteocyte apoptosis, bone remodeling is not initiated, which presents a safety factor to conserve the architecture of the auditory ossicles and ensure stable sound transmission throughout life. Google Scholar
  25. 25.
    •• Milovanovic P, Zimmermann EA, Riedel C, Scheidt AV, Herzog L, Krause M, 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. Biomaterials. 2015;45:46–55.  https://doi.org/10.1016/j.biomaterials.2014.12.024 This study provides a detailed assessment of femoral cortex reorganization in young, aged, osteoporotic, and alendronate-treated female patients. Antiresorptive treatment showed favorable effects on osteocyte lacunar density and cell viability as reflected in a low occurrence of micropetrosis. Moreover, the study highlights differences in bone matrix mineralization between the femur, radius, iliac crest, and vertebral bone, and emphasizes differing trends in mineralization with bisphosphate treatment in relation to anatomical locations. Google Scholar
  26. 26.
    Tong X, Malo MKH, Burton IS, Jurvelin JS, Isaksson H, Kröger H. Histomorphometric and osteocytic characteristics of cortical bone in male subtrochanteric femoral shaft. J Anat. 2017;231(5):708–17.  https://doi.org/10.1111/joa.12670.Google Scholar
  27. 27.
    Akhter MP, Kimmel DB, Lappe JM, Recker RR. Effect of macroanatomic bone type and estrogen loss on osteocyte lacunar properties in healthy adult women. Calcif Tissue Int. 2017;100(6):619–30.  https://doi.org/10.1007/s00223-017-0247-6.Google Scholar
  28. 28.
    •• Hunter RL, Agnew AM. Intraskeletal variation in human cortical osteocyte lacunar density: Implications for bone quality assessment. Bone Rep. 2016;5:252–61.  https://doi.org/10.1016/j.bonr.2016.09.002 The results from this study show differences in osteocyte lacunar number per bone area between the femur, radius, and rib. The authors suggest that although these skeletal sites systemically experience declines in osteocyte lacunar density, specific characteristics can be found at each anatomical site potentially due to age-related changes in mechanical loading. Google Scholar
  29. 29.
    •• Gauthier R, Langer M, Follet H, Olivier C, Gouttenoire P-J, Helfen L, et al. 3D micro structural analysis of human cortical bone in paired femoral diaphysis, femoral neck and radial diaphysis. J Struct Biol. 2018;204:182–90.  https://doi.org/10.1016/j.jsb.2018.08.006 This SR-μCT study shows differences in osteocyte lacunar number per bone volume between paired femoral diaphysis, femoral neck, and radial diaphysis samples, suggesting that osteocyte characteristics at one skeletal site cannot be reliably transferred to other anatomical locations. Google Scholar
  30. 30.
    Bereshiem AC, Pfeiffer SK, Grynpas MD, Alblas A. Use of backscattered scanning electron microscopy to quantify the bone tissues of midthoracic human ribs. Am J Phys Anthropol. 2019;168(2):262–78.  https://doi.org/10.1002/ajpa.23716.Google Scholar
  31. 31.
    Zimmermann E, Riedel C, Stockhausen K, Chushkin Y, Schaible E, Schmidt F et al. Mechanical competence and bone quality develop during skeletal growth. J Bone Miner Res. 2019.  https://doi.org/10.1002/jbmr.3730.
  32. 32.
    Bernhard A, Milovanovic P, Zimmermann EA, Hahn M, Djonic D, Krause M, et al. Micro-morphological properties of osteons reveal changes in cortical bone stability during aging, osteoporosis, and bisphosphonate treatment in women. Osteoporos Int. 2013;24(10):2671–80.  https://doi.org/10.1007/s00198-013-2374-x.Google Scholar
  33. 33.
    Carter Y, Thomas CDL, Clement JG, Peele AG, Hannah K, Cooper DML. Variation in osteocyte lacunar morphology and density in the human femur — a synchrotron radiation micro-CT study. Bone. 2013;52(1):126–32.  https://doi.org/10.1016/j.bone.2012.09.010.Google Scholar
  34. 34.
    Carter Y, Suchorab JL, Thomas CDL, Clement JG, Cooper DML. Normal variation in cortical osteocyte lacunar parameters in healthy young males. J Anat. 2014;225(3):328–36.  https://doi.org/10.1111/joa.12213.Google Scholar
  35. 35.
    Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014;29(1):1–23.  https://doi.org/10.1002/jbmr.1998.Google Scholar
  36. 36.
    Donnelly E, Meredith DS, Nguyen JT, Gladnick BP, Rebolledo BJ, Shaffer AD, et al. Reduced cortical bone compositional heterogeneity with bisphosphonate treatment in postmenopausal women with intertrochanteric and subtrochanteric fractures. J Bone Miner Res. 2012;27(3):672–8.  https://doi.org/10.1002/jbmr.560.Google Scholar
  37. 37.
    Repp F, Kollmannsberger P, Roschger A, Kerschnitzki M, Berzlanovich A, Gruber GM, et al. Spatial heterogeneity in the canalicular density of the osteocyte network in human osteons. Bone Rep. 2017;6:101–8.  https://doi.org/10.1016/j.bonr.2017.03.001.Google Scholar
  38. 38.
    Rolvien T, Krause M, Jeschke A, Yorgan T, Puschel K, Schinke T, et al. Vitamin D regulates osteocyte survival and perilacunar remodeling in human and murine bone. Bone. 2017;103:78–87.  https://doi.org/10.1016/j.bone.2017.06.022.Google Scholar
  39. 39.
    Bell KL, Loveridge N, Power J, Garrahan N, Meggitt BF, Reeve J. Regional differences in cortical porosity in the fractured femoral neck. Bone. 1999;24(1):57–64.Google Scholar
  40. 40.
    Bell KL, Loveridge N, Power J, Garrahan N, Stanton M, Lunt M, et al. Structure of the femoral neck in hip fracture: cortical bone loss in the inferoanterior to superoposterior axis. J Bone Miner Res. 1999;14(1):111–9.  https://doi.org/10.1359/jbmr.1999.14.1.111.Google Scholar
  41. 41.
    Power J, Noble BS, Loveridge N, Bell KL, Rushton N, Reeve J. Osteocyte lacunar occupancy in the femoral neck cortex: an association with cortical remodeling in hip fracture cases and controls. Calcif Tissue Int. 2001;69(1):13–9.  https://doi.org/10.1007/s00223-001-0013-6.Google Scholar
  42. 42.
    Djuric M, Djonic D, Milovanovic P, Nikolic S, Marshall R, Marinkovic J, et al. Region-specific sex-dependent pattern of age-related changes of proximal femoral cancellous bone and its implications on differential bone fragility. Calcif Tissue Int. 2010;86(3):192–201.  https://doi.org/10.1007/s00223-009-9325-8.Google Scholar
  43. 43.
    Milovanovic P, Djonic D, Marshall RP, Hahn M, Nikolic S, Zivkovic V, et al. Micro-structural basis for particular vulnerability of the superolateral neck trabecular bone in the postmenopausal women with hip fractures. Bone. 2012;50(1):63–8.  https://doi.org/10.1016/j.bone.2011.09.044.Google Scholar
  44. 44.
    Busse B, Djonic D, Milovanovic P, Hahn M, Püschel K, Ritchie RO, et al. Decrease in the osteocyte lacunar density accompanied by hypermineralized lacunar occlusion reveals failure and delay of remodeling in aged human bone. Aging Cell. 2010;9(6):1065–75.  https://doi.org/10.1111/j.1474-9726.2010.00633.x.Google Scholar
  45. 45.
    Milovanovic P, Adamu U, Simon MJK, Rolvien T, Djuric M, Amling M, et al. Age- and sex-specific bone structure patterns portend bone fragility in radii and tibiae in relation to osteodensitometry: a high-resolution peripheral quantitative computed tomography study in 385 individuals. J Gerontol A Biol Sci Med Sci. 2015;70(10):1269–75.  https://doi.org/10.1093/gerona/glv052.Google Scholar
  46. 46.
    Milovanovic P, Djuric M, Neskovic O, Djonic D, Potocnik J, Nikolic S, et al. Atomic force microscopy characterization of the external cortical bone surface in young and elderly women: potential nanostructural traces of periosteal bone apposition during aging. Microsc Microanal. 2013;19(5):1341–9.  https://doi.org/10.1017/S1431927613001761.Google Scholar
  47. 47.
    Szulc P, Seeman E, Duboeuf F, Sornay-Rendu E, Delmas PD. Bone fragility: failure of oeriosteal apposition to compensate for increased endocortical resorption in postmenopausal women. J Bone Miner Res. 2006;21(12):1856–63.  https://doi.org/10.1359/jbmr.060904.Google Scholar
  48. 48.
    Verhulp E, van Rietbergen B, Huiskes R. Load distribution in the healthy and osteoporotic human proximal femur during a fall to the side. Bone. 2008;42(1):30–5.  https://doi.org/10.1016/j.bone.2007.08.039.Google Scholar
  49. 49.
    Rudman K, Aspden R, Meakin J. Compression or tension? The stress distribution in the proximal femur. Biomed Eng Online. 2006;5(1):12.Google Scholar
  50. 50.
    Mayhew PM, Thomas CD, Clement JG, Loveridge N, Beck TJ, Bonfield W, et al. Relation between age, femoral neck cortical stability, and hip fracture risk. Lancet. 2005;366(9480):129–35.Google Scholar
  51. 51.
    Djonic D, Milovanovic P, Nikolic S, Ivovic M, Marinkovic J, Beck T, et al. Inter-sex differences in structural properties of aging femora: implications on differential bone fragility: a cadaver study. J Bone Miner Metab. 2011;29(4):449–57.  https://doi.org/10.1007/s00774-010-0240-x.Google Scholar
  52. 52.
    Milovanovic P, Djonic D, Hahn M, Amling M, Busse B, Djuric M. Region-dependent patterns of trabecular bone growth in the human proximal femur: a study of 3D bone microarchitecture from early postnatal to late childhood period. Am J Phys Anthropol. 2017;164(2):281–91.  https://doi.org/10.1002/ajpa.23268.Google Scholar
  53. 53.
    Skedros JG, Baucom SL. Mathematical analysis of trabecular 'trajectories' in apparent trajectorial structures: the unfortunate historical emphasis on the human proximal femur. J Theor Biol. 2007;244(1):15–45.Google Scholar
  54. 54.
    Tsourdi E, Jähn K, Rauner M, Busse B, Bonewald LF. Physiological and pathological osteocytic osteolysis. J Musculoskelet Neuronal Interact. 2018;18(3):292–303.Google Scholar
  55. 55.
    Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, et al. Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/β-catenin signaling. J Bone Miner Res. 2009;24(10):1651–61.  https://doi.org/10.1359/jbmr.090411.Google Scholar
  56. 56.
    Moriishi T, Fukuyama R, Ito M, Miyazaki T, Maeno T, Kawai Y, et al. Osteocyte network; a negative regulatory system for bone mass augmented by the induction of Rankl in osteoblasts and Sost in osteocytes at unloading. PLoS One. 2012;7(6):e40143.Google Scholar
  57. 57.
    Gerbaix M, Gnyubkin V, Farlay D, Olivier C, Ammann P, Courbon G, et al. One-month spaceflight compromises the bone microstructure, tissue-level mechanical properties, osteocyte survival and lacunae volume in mature mice skeletons. Sci Rep. 2017;7(1):2659.  https://doi.org/10.1038/s41598-017-03014-2.Google Scholar
  58. 58.
    Gill TM, Allore H, Guo Z. The deleterious effects of bed rest among community-living older persons. J Gerontol A Biol Sci Med Sci. 2004;59(7):755–61.Google Scholar
  59. 59.
    Pfaff C, Schultz JA, Schellhorn R. The vertebrate middle and inner ear: a short overview. J Morphol. 2018.  https://doi.org/10.1002/jmor.20880.
  60. 60.
    Noble BS, Peet N, Stevens HY, Brabbs A, Mosley JR, Reilly GC, et al. Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone. Am J Phys Cell Physiol. 2003;284(4):C934–43.  https://doi.org/10.1152/ajpcell.00234.2002.Google Scholar
  61. 61.
    Tomkinson A, Reeve J, Shaw RW, Noble BS. The death of osteocytes via apoptosis accompanies estrogen withdrawal in human bone. J Clin Endocrinol Metab. 1997;82(9):3128–35.  https://doi.org/10.1210/jc.82.9.3128.Google Scholar
  62. 62.
    Noble BS, Stevens H, Loveridge N, Reeve J. Identification of apoptotic changes in osteocytes in normal and pathological human bone. Bone. 1997;20(3):273–82.Google Scholar
  63. 63.
    Tomkinson A, Gevers EF, Wit JM, Reeve J, Noble BS. The role of estrogen in the control of rat osteocyte apoptosis. J Bone Miner Res. 1998;13(8):1243–50.Google Scholar
  64. 64.
    Weinstein RS, Nicholas RW, Manolagas SC. Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab. 2000;85(8):2907–12.  https://doi.org/10.1210/jc.85.8.2907.Google Scholar
  65. 65.
    Kogianni G, Mann V, Noble BS. Apoptotic bodies convey activity capable of initiating osteoclastogenesis and localized bone destruction. J Bone Miner Res. 2008;23(6):915–27.  https://doi.org/10.1359/jbmr.080207.Google Scholar
  66. 66.
    Zimmermann EA, Kohne T, Bale HA, Panganiban B, Gludovatz B, Zustin J, et al. Modifications to nano- and microstructural quality and the effects on mechanical integrity in Paget’s disease of bone. J Bone Miner Res. 2015;30(2):264–73.  https://doi.org/10.1002/Jbmr.2340.Google Scholar
  67. 67.
    Hernandez CJ, Majeska RJ, Schaffler MB. Osteocyte density in woven bone. Bone. 2004;35(5):1095–9.  https://doi.org/10.1016/j.bone.2004.07.002.Google Scholar
  68. 68.
    Remaggi F, Canè V, Palumbo C, Ferretti M. Histomorphometric study on the osteocyte lacunocanalicular network in animals of different species. I. Woven-fibered and parallel-fibered bones. Ital J Anat Embryol. 1998;103:145–55.Google Scholar
  69. 69.
    Mulder L, Koolstra JH, den Toonder JMJ, van Eijden TMGJ. Relationship between tissue stiffness and degree of mineralization of developing trabecular bone. J Biomed Mater Res A. 2008;84A(2):508–15.  https://doi.org/10.1002/jbm.a.31474.Google Scholar
  70. 70.
    van Oers RFM, Wang H, Bacabac RG. Osteocyte shape and mechanical loading. Curr Osteoporos Rep. 2015;13(2):61–6.  https://doi.org/10.1007/s11914-015-0256-1.Google Scholar
  71. 71.
    Bacabac RG, Mizuno D, Schmidt CF, MacKintosh FC, Loon JJWAV, Klein-Nulend J, et al. Round versus flat: bone cell morphology, elasticity, and mechanosensing. J Biomech. 2008;41(7):1590–8.Google Scholar
  72. 72.
    Vatsa A, Breuls RG, Semeins CM, Salmon PL, Smit TH, Klein-Nulend J. Osteocyte morphology in fibula and calvaria — is there a role for mechanosensing? Bone. 2008;43(3):452–8.Google Scholar
  73. 73.
    • Hemmatian H, Jalali R, Semeins CM, JMA H, van Lenthe GH, Klein-Nulend J, et al. Mechanical loading differentially affects osteocytes in fibulae from lactating mice compared to osteocytes in virgin mice: possible role for lacuna size. Calcif Tissue Int. 2018;103(6):675–85.  https://doi.org/10.1007/s00223-018-0463-8 These results suggest that osteocytes in fibulae from lactating mice with large lacunae respond more distinct to mechanical loading than those from virgin mice, as evidenced via sclerostin expression. The authors conclude that osteocytes residing in large lacunae show an effective response to mechanical loading. Google Scholar
  74. 74.
    • Wu V, van Oers RFM, Schulten EAJM, Helder MN, Bacabac RG, Klein-Nulend J. Osteocyte morphology and orientation in relation to strain in the jaw bone. Int J Oral Sci. 2018;10(1):2.  https://doi.org/10.1038/s41368-017-0007-5 This study reports osteocyte data in relation to jaws in areas where a single tooth was missing or where several rear teeth were missing. The authors linked osteocyte characteristics to strain distribution as shown in a finite element model. Google Scholar
  75. 75.
    Milovanovic P, Rakocevic Z, Djonic D, Zivkovic V, Hahn M, Nikolic S, et al. Nano-structural, compositional and micro-architectural signs of cortical bone fragility at the superolateral femoral neck in elderly hip fracture patients vs. healthy aged controls. Exp Gerontol. 2014;55:19–28.Google Scholar
  76. 76.
    PMd B, Manske SL, Ebacher V, Oxland TR, Cripton PA, Guy P. During sideways falls proximal femur fractures initiate in the superolateral cortex: evidence from high-speed video of simulated fractures. J Biomech. 2009;42(12):1917–25.Google Scholar
  77. 77.
    Tang T, Cripton PA, Guy P, McKay HA, Wang R. Clinical hip fracture is accompanied by compression induced failure in the superior cortex of the femoral neck. Bone. 2018;108:121–31.  https://doi.org/10.1016/j.bone.2017.12.020.Google Scholar
  78. 78.
    Zani L, Erani P, Grassi L, Taddei F, Cristofolini L. Strain distribution in the proximal Human femur during in vitro simulated sideways fall. J Biomech. 2015;48(10):2130–43.  https://doi.org/10.1016/j.jbiomech.2015.02.022.Google Scholar
  79. 79.
    Kheirollahi H, Luo Y. Identification of high stress and strain regions in proximal femur during single-leg stance and sideways fall using QCT-based finite element model. Int J Med Health Biomedi Bioeng Pharm Eng. 2015;9(8):633–40.Google Scholar
  80. 80.
    Milovanovic P, vom Scheidt A, Mletzko K, Sarau G, Püschel K, Djuric M, et al. Bone tissue aging affects mineralization of cement lines. Bone. 2018;110:187–93.  https://doi.org/10.1016/j.bone.2018.02.004.Google Scholar
  81. 81.
    Thomas CDL, Mayhew PM, Power J, Poole KES, Loveridge N, Clement JG, et al. Femoral neck trabecular bone: loss with aging and role in preventing fracture. J Bone Miner Res. 2009;24(11):1808–18.  https://doi.org/10.1359/jbmr.090504.Google Scholar
  82. 82.
    Ye T, Cao P, Qi J, Zhou Q, Rao DS, Qiu S. Protective effect of low-dose risedronate against osteocyte apoptosis and bone loss in ovariectomized rats. PLoS One. 2017;12(10):e0186012.Google Scholar
  83. 83.
    Bellido T, Plotkin LI. Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability. Bone. 2011;49(1):50–5.  https://doi.org/10.1016/j.bone.2010.08.008.Google Scholar
  84. 84.
    Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone. 2001;28(5):524–31.  https://doi.org/10.1016/S8756-3282(01)00414-8.Google Scholar
  85. 85.
    Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res. 2000;15(4):613–20.  https://doi.org/10.1359/jbmr.2000.15.4.613.Google Scholar
  86. 86.
    Krause M, Soltau M, Zimmermann EA, Hahn M, Kornet J, Hapfelmeier A, et al. Effects of long-term alendronate treatment on bone mineralisation, resorption parameters and biomechanics of single human vertebral trabeculae. Eur Cell Mater. 2014;28:152–63 discussion 63-5.Google Scholar
  87. 87.
    Ritchie RO. The conflicts between strength and toughness. Nat Mater. 2011;10(11):817–22.  https://doi.org/10.1038/nmat3115.Google Scholar
  88. 88.
    Ma S, Goh EL, Jin A, Bhattacharya R, Boughton OR, Patel B, et al. Long-term effects of bisphosphonate therapy: perforations, microcracks and mechanical properties. Sci Rep. 2017;7:43399.  https://doi.org/10.1038/srep43399.Google Scholar
  89. 89.
    Jan GH, Michael F, Eilis F, Thomas CL, David T. Microdamage: a cell transducing mechanism based on ruptured osteocyte processes. J Biomech. 2006;39(11):2096–103.Google Scholar
  90. 90.
    Noble B. Bone microdamage and cell apoptosis. Eur Cell Mater. 2003;6:46–55.Google Scholar
  91. 91.
    Taylor D, Mulcahy L, Presbitero G, Tisbo P, Dooley C, Duffy G, Lee TC The scissors model of microcrack detection in bone: work in progress. MRS Online Proc Lib 2010;1274.  https://doi.org/10.1557/PROC-1274-QQ08-01.
  92. 92.
    Dooley C, Tisbo P, Lee T, Taylor D. Rupture of osteocyte processes across microcracks: the effect of crack length and stress. Biomech Model Mechanobiol. 2012;11(6):759–66.  https://doi.org/10.1007/s10237-011-0349-4.Google Scholar
  93. 93.
    Colopy SA, Benz-Dean J, Barrett JG, Sample SJ, Lu Y, Danova NA, et al. Response of the osteocyte syncytium adjacent to and distant from linear microcracks during adaptation to cyclic fatigue loading. Bone. 2004;35(4):881–91.  https://doi.org/10.1016/j.bone.2004.05.024.Google Scholar
  94. 94.
    Klein-Nulend J, Bakker A. Osteocytes: mechanosensors of bone and orchestrators of mechanical adaptation. Clin Rev Bone Miner Metab. 2007;5(4):195–209.  https://doi.org/10.1007/s12018-008-9014-6.Google Scholar
  95. 95.
    Brock GR, Kim G, Ingraffea AR, Andrews JC, Pianetta P, van der Meulen MCH. Nanoscale examination of microdamage in sheep cortical bone using synchrotron radiation transmission x-ray microscopy. PLoS One. 2013;8(3):e57942.  https://doi.org/10.1371/journal.pone.0057942.Google Scholar
  96. 96.
    Reilly GC. Observations of microdamage around osteocyte lacunae in bone. J Biomech. 2000;33(9):1131–4.  https://doi.org/10.1016/s0021-9290(00)00090-7.Google Scholar
  97. 97.
    Cummings SR, Nevitt MC. Non-skeletal determinants of fractures: the potential importance of the mechanics of falls. Osteoporos Int. 1994;4(1):S67–70.  https://doi.org/10.1007/bf01623439.Google Scholar
  98. 98.
    Greenspan SL, Myers ER, Kiel DP, Parker RA, Hayes WC, Resnick NM. Fall direction, bone mineral density, and function: risk factors for hip fracture in frail nursing home elderly. Am J Med. 1998;104(6):539–45.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Osteology and BiomechanicsUniversity Medical Center Hamburg-EppendorfHamburgGermany
  2. 2.Laboratory for Anthropology and Skeletal Biology, Institute of Anatomy, Faculty of MedicineUniversity of BelgradeBelgradeSerbia
  3. 3.Forum Medical Technology Health Hamburg (FMTHH), Heisenberg Research Group of Biomedical SciencesUniversity Medical Center Hamburg-EppendorfHamburgGermany

Personalised recommendations