Inter-site Variability of the Human Osteocyte Lacunar Network: Implications for Bone Quality
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.
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.
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.
KeywordsOsteocyte distribution Inter-site differences Osteocyte lacunar number Mechanical loading Bone strength Aging Bone development
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.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Currey JD. Bones: structure and mechanics. Princeton, N. J: Princeton University Press; 2002.Google Scholar
- 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
- 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
- 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.•• 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
- 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
- 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.•• 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
- 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.•• 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
- 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.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
- 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
- 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
- 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
- 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.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.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
- 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.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
- 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.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.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
- 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.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.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.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.
- 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.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
- 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
- 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.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.• 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.• 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.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.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
- 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
- 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
- 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
- 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
- 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.Noble B. Bone microdamage and cell apoptosis. Eur Cell Mater. 2003;6:46–55.Google Scholar
- 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.
- 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