Skip to main content

Advertisement

SpringerLink
Log in

Potential Role of Perilacunar Remodeling in the Progression of Osteoporosis and Implications on Age-Related Decline in Fracture Resistance of Bone

  • Biomechanics (J Nyman and C Hernandez, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

We took an interdisciplinary view to examine the potential contribution of perilacunar/canalicular remodeling to declines in bone fracture resistance related to age or progression of osteoporosis.

Recent Findings

Perilacunar remodeling is most prominent as a result of lactation; recent advances further elucidate the molecular players involved and their effect on bone material properties. Of these, vitamin D and calcitonin could be active during aging or osteoporosis. Menopause-related hormonal changes or osteoporosis therapies affect bone material properties and mechanical behavior. However, investigations of lacunar size or osteocyte TRAP activity with age or osteoporosis do not provide clear evidence for or against perilacunar remodeling.

Summary

While the occurrence and potential role of perilacunar remodeling in aging and osteoporosis progression are largely under-investigated, widespread changes in bone matrix composition in OVX models and following osteoporosis therapies imply osteocytic maintenance of bone matrix. Perilacunar remodeling-induced changes in bone porosity, bone matrix composition, and bone adaptation could have significant implications for bone fracture resistance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

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

  1. Prior JC, Langsetmo L, Lentle BC, Berger C, Goltzman D, Kovacs CS, et al. Ten-year incident osteoporosis-related fractures in the population-based Canadian Multicentre Osteoporosis Study — comparing site and age-specific risks in women and men. Bone. 2015;71:237–43. https://doi.org/10.1016/j.bone.2014.10.026.

  2. Schuit SCE, Van Der Klift M, Weel AEAM, De Laet CEDH, Burger H, Seeman E, et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam study. Bone. 2004;34(1):195–202. https://doi.org/10.1016/j.bone.2003.10.001.

    Article  CAS  PubMed  Google Scholar 

  3. Amin S, Achenbach SJ, Atkinson EJ, Khosla S, Melton LJ. Trends in fracture incidence: a population-based study over 20 years. J Bone Miner Res. 2014;29(3):581–9. https://doi.org/10.1002/jbmr.2072.

    Article  PubMed  Google Scholar 

  4. Willie BM, Zimmermann EA, Vitienes I, Main RP, Komarova SV. Bone adaptation: safety factors and load predictability in shaping skeletal form. Bone. 2020;131:115114. https://doi.org/10.1016/j.bone.2019.115114

  5. Madel M-B, Ibáñez L, Wakkach A, De Vries TJ, Teti A, Apparailly F, et al. Immune function and diversity of osteoclasts in normal and pathological conditions. Front Immunol. 2019;10. https://doi.org/10.3389/fimmu.2019.01408.

  6. Xu F, Teitelbaum SL. Osteoclasts: new insights. Bone Res. 2013;1(1):11–26. https://doi.org/10.4248/br201301003.

    Article  CAS  PubMed Central  Google Scholar 

  7. Lian JB, Stein GS. Concepts of osteoblast growth and differentiation: basis for modulation of bone cell development and tissue formation. Crit Rev Oral Biol Med. 1992;3(3):269–305. https://doi.org/10.1177/10454411920030030501.

    Article  CAS  PubMed  Google Scholar 

  8. Riggs BL, Khosla S, Melton LJ. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev. 2002;23(3):279–302. https://doi.org/10.1210/edrv.23.3.0465.

    Article  CAS  PubMed  Google Scholar 

  9. Fink HA, Ewing SK, Ensrud KE, Barrett-Connor E, Taylor BC, Cauley JA, et al. Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. J Clin Endocrinol Metab. 2006;91(10):3908–15. https://doi.org/10.1210/jc.2006-0173.

  10. Michael H, Härkönen PL, Väänänen HK, Hentunen TA. Estrogen and testosterone use different cellular pathways to inhibit osteoclastogenesis and bone resorption. J Bone Miner Res. 2005;20(12):2224–32. https://doi.org/10.1359/jbmr.050803.

    Article  CAS  PubMed  Google Scholar 

  11. Hui SL, Slemenda CW, Johnston CC. Age and bone mass as predictors of fracture in a prospective study. J Clin Investig. 1988;81(6):1804–9. https://doi.org/10.1172/jci113523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kanis JA, Johnell O, Oden A, De Laet C, Dawson A, Jonsson B. Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int. 2001;12(12):989–95. https://doi.org/10.1007/s001980170006.

    Article  CAS  PubMed  Google Scholar 

  13. Curtis EM, Van Der Velde R, Moon RJ, Van Den Bergh JPW, Geusens P, De Vries F, et al. Epidemiology of fractures in the United Kingdom 1988–2012: variation with age, sex, geography, ethnicity and socioeconomic status. Bone. 2016;87:19–26. https://doi.org/10.1016/j.bone.2016.03.006.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Varga P, Hesse B, Langer M, Schrof S, Männicke N, Suhonen H, 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. Biomech Model Mechanobiol. 2015;14(2):267–82. https://doi.org/10.1007/s10237-014-0601-9.

  15. Yu B, Pacureanu A, Olivier C, Cloetens P, Peyrin F. Assessment of the human bone lacuno-canalicular network at the nanoscale and impact of spatial resolution. Sci Rep. 2020;10(1). https://doi.org/10.1038/s41598-020-61269-8.

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006;38(11):1310–5. https://doi.org/10.1038/ng1905.

  18. Bach-Gansmo FL, Weaver JC, Jensen MH, Leemreize H, Mader KS, Stampanoni M, et al. Osteocyte lacunar properties in rat cortical bone: differences between lamellar and central bone. J Struct Biol. 2015;191(1):59–67. https://doi.org/10.1016/j.jsb.2015.05.005.

  19. Milovanovic P, Busse B. Inter-site variability of the human osteocyte lacunar network: implications for bone quality. Curr Osteoporos Rep. 2019;17(3):105–15. https://doi.org/10.1007/s11914-019-00508-y.

  20. Zimmermann EA, Köhne 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.

  21. Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26(2):229–38. https://doi.org/10.1002/jbmr.320

  22. Belanger LF, Migicovsky BB. Histochemical evidence of proteolysis in bone: the influence of parathormone. J Histochem Cytochem. 1963;11(6):734–7. https://doi.org/10.1177/11.6.734.

    Article  CAS  Google Scholar 

  23. Rigal A, Vignal W. Recherches experimentales sur la formation du cal et sur les modifications des tissus dans les pseudoarthroses. Arch Physiol. 1881;8:419–58.

    Google Scholar 

  24. Recklinghausen FV. Untersuchungen uber rachitis und osteomalacia. Jena1910.

  25. Haller AC, Zimny ML. Effects of hibernation on interradicular alveolar bone. J Dent Res. 1977;56(12):1552–7. https://doi.org/10.1177/00220345770560122601.

    Article  CAS  PubMed  Google Scholar 

  26. Iagodovskiĭ VS, Triftanidi LA, Gorokhova GP. Effect of space flight on rat skeletal bones (an optical light and electron microscopic study). Kosm Biol Aviakosm Med. 1977;11(1):14–20.

    PubMed  Google Scholar 

  27. Bélanger LF, Drouin P. Osteolysis in the frog: The effects of parathormone. Can J Physiol Pharmacol. 1966;44(6):919–22. https://doi.org/10.1139/y66-114.

    Article  PubMed  Google Scholar 

  28. Baud CA. Structure and functions of osteocytes in normal conditions and under the influence of parathyroid extract. Schweiz Med Wochenschr. 1968;98(19):717–20.

    CAS  PubMed  Google Scholar 

  29. Krook L, Bélanger LF, Henrikson PA, Lutwak L, Sheffy BE. Bone flow. Rev Can Biol. 1970;29(2):157–67.

    CAS  PubMed  Google Scholar 

  30. Parfitt AM. The cellular basis of bone turnover and bone loss: a rebuttal of the osteocytic resorption--bone flow theory. Clin Orthop Relat Res. 1977;127:236–47.

    Google Scholar 

  31. Qing H, Ardeshirpour L, Divieti Pajevic P, Dusevich V, Jähn K, Kato S, et al. Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation. J Bone Miner Res. 2012;27(5):1018–29. https://doi.org/10.1002/jbmr.1567.

  32. • Tsourdi E, Jähn K, Rauner M, Busse B, Bonewald LF. Physiological and pathological osteocytic osteolysis. J Musculoskelet Neuronal Interact. 2018;18(3):292–303 Review on perilacunar remodeling in health and disease.

  33. Sano H, Kikuta J, Furuya M, Kondo N, Endo N, Ishii M. Intravital bone imaging by two-photon excitation microscopy to identify osteocytic osteolysis in vivo. Bone. 2015;74:134–9. https://doi.org/10.1016/j.bone.2015.01.013.

    Article  PubMed  Google Scholar 

  34. Jähn K, Kelkar S, Zhao H, Xie Y, Tiede-Lewis LM, Dusevich V, et al. Osteocytes acidify their microenvironment in response to PTHrP in vitro and in lactating mice in vivo. J Bone Miner Res. 2017;32(8):1761–72. https://doi.org/10.1002/jbmr.3167.

    Article  CAS  PubMed  Google Scholar 

  35. Nango N, Kubota S, Hasegawa T, Yashiro W, Momose A, Matsuo K. Osteocyte-directed bone demineralization along canaliculi. Bone. 2016;84:279–88. https://doi.org/10.1016/j.bone.2015.12.006.

    Article  CAS  PubMed  Google Scholar 

  36. Tang SY, Herber R-P, Ho SP, Alliston T. Matrix metalloproteinase-13 is required for osteocytic perilacunar remodeling and maintains bone fracture resistance. J Bone Miner Res. 2012;27(9):1936–50. https://doi.org/10.1002/jbmr.1646.

    Article  CAS  PubMed  Google Scholar 

  37. • Tokarz D, Martins JS, Petit ET, Lin CP, Demay MB, Liu ES. Hormonal regulation of osteocyte perilacunar and canalicular remodeling in the Hyp mouse model of X-linked hypophosphatemia. J Bone Miner Res. 2018;33(3):499–509. https://doi.org/10.1002/jbmr.3327Evidence for regulation of perilacunar remodeling by vitamin D and FGF23 in Hyp mice.

    Article  CAS  PubMed  Google Scholar 

  38. •• Lotinun S, Ishihara Y, Nagano K, Kiviranta R, Carpentier VT, Neff L, et al. Cathepsin K–deficient osteocytes prevent lactation-induced bone loss and parathyroid hormone suppression. J Clin Investig. 2019;129(8):3058–71. https://doi.org/10.1172/jci122936Osteocyte Cathepsin K has multiple roles in lactation-induced bone loss.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Krempien B, Friedrich E, Ritz E. Effect of PTH on osteocyte ultrastructure. Homeostasis of phosphate and other minerals. 1978;103:437–50. https://doi.org/10.1007/978-1-4684-7758-0_45.

    Article  CAS  Google Scholar 

  40. Tazawa K, Hoshi K, Kawamoto S, Tanaka M, Ejiri S, Ozawa H. Osteocytic osteolysis observed in rats to which parathyroid hormone was continuously administered. J Bone Miner Metab. 2004;22(6):524–9. https://doi.org/10.1007/s00774-004-0519-x.

    Article  CAS  PubMed  Google Scholar 

  41. Toverud SU, Cooper CW, Munson PL. Calcium metabolism during lactation: elevated blood levels of calcitonin*. Endocrinology. 1978;103(2):472–9. https://doi.org/10.1210/endo-103-2-472.

    Article  CAS  PubMed  Google Scholar 

  42. Clarke MV, Russell PK, Findlay DM, Sastra S, Anderson PH, Skinner JP, et al. A role for the calcitonin receptor to limit bone loss during lactation in female mice by inhibiting osteocytic osteolysis. Endocrinology. 2015;156(9):3203–14. https://doi.org/10.1210/en.2015-1345.

  43. Dole NS, Mazur CM, Acevedo C, Lopez JP, Monteiro DA, Fowler TW, et al. Osteocyte-intrinsic TGF-β signaling regulates bone quality through perilacunar/canalicular remodeling. Cell Rep. 2017;21(9):2585–96. https://doi.org/10.1016/j.celrep.2017.10.115.

  44. Kegelman CD, Coulombe JC, Jordan KM, Horan DJ, Qin L, Robling AG, et al. YAP and TAZ mediate osteocyte perilacunar/canalicular remodeling. J Bone Miner Res. 2020;35(1):196–210. https://doi.org/10.1002/jbmr.3876.

  45. Vahidi G, Rux C, Sherk VD, Heveran CM. Lacunar-canalicular bone remodeling: impacts on bone quality and tools for assessment. Bone. 2021;143:115663. https://doi.org/10.1016/j.bone.2020.115663.

    Article  CAS  PubMed  Google Scholar 

  46. • Yee CS, Schurman CA, White CR, Alliston T. Investigating osteocytic perilacunar/canalicular remodeling. Curr Osteoporos Rep. 2019;17(4):157–68. https://doi.org/10.1007/s11914-019-00514-0Review of approaches to study perilacunar remodeling.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Wojda SJ, Gridley RA, McGee-Lawrence ME, Drummer TD, Hess A, Kohl F, et al. Arctic ground squirrels limit bone loss during the prolonged physical inactivity associated with hibernation. Physiol Biochem Zool. 2016;89(1):72–80. https://doi.org/10.1086/684619.

    Article  PubMed  Google Scholar 

  48. Rodionova NV, Oganov VS, Zolotova NV. Ultrastructural changes in osteocytes in microgravity conditions. Adv Space Res. 2002;30(4):765–70. https://doi.org/10.1016/s0273-1177(02)00393-9.

    Article  CAS  PubMed  Google Scholar 

  49. Bach-Gansmo FL, Wittig NK, Brüel A, Thomsen JS, Birkedal H. Immobilization and long-term recovery results in large changes in bone structure and strength but no corresponding alterations of osteocyte lacunar properties. Bone. 2016;91:139–47. https://doi.org/10.1016/j.bone.2016.07.005.

    Article  PubMed  Google Scholar 

  50. Blaber EA, Dvorochkin N, Lee C, Alwood JS, Yousuf R, Pianetta P, et al. Microgravity induces pelvic bone loss through osteoclastic activity, osteocytic osteolysis, and osteoblastic cell cycle inhibition by CDKN1a/p21. PLoS ONE. 2013;8(4):e61372. https://doi.org/10.1371/journal.pone.0061372.

  51. Lloyd SA, Loiselle AE, Zhang Y, Donahue HJ. Evidence for the role of connexin 43-mediated intercellular communication in the process of intracortical bone resorption via osteocytic osteolysis. BMC Musculoskelet Disord. 2014;15(1):122. https://doi.org/10.1186/1471-2474-15-122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kogawa M, Wijenayaka AR, Ormsby RT, Thomas GP, Anderson PH, Bonewald LF, et al. Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2. J Bone Miner Res. 2013;28(12):2436–48. https://doi.org/10.1002/jbmr.2003.

  53. Kogawa M, Khalid KA, Wijenayaka AR, Ormsby RT, Evdokiou A, Anderson PH, et al. Recombinant sclerostin antagonizes effects of ex vivo mechanical loading in trabecular bone and increases osteocyte lacunar size. Am J Physiol Cell Physiol. 2018;314(1):C53–61. https://doi.org/10.1152/ajpcell.00175.2017.

  54. Mosey H, Núñez JA, Goring A, Clarkin CE, Staines KA, Lee PD, et al. Sost deficiency does not alter bone’s lacunar or vascular porosity in mice. Front Mater. 2017;4. https://doi.org/10.3389/fmats.2017.00027.

  55. Talmage RV, Doppelt SH, Fondren FB. An interpretation of acute changes in plasma45Ca following parathyroid hormone administration to thyroparathyroidectomized rats. Calcif Tissue Res. 1977;22(1):117–28. https://doi.org/10.1007/bf02010351.

    Article  Google Scholar 

  56. Meunier P, Bernard J, Vignon G. The measurement of periosteocytic enlargement in primary and secondary hyperparathyroidism. Isr J Med Sci. 1971;7(3):482–5.

    CAS  PubMed  Google Scholar 

  57. Mosekilde L, Melsen F. A tetracycline-based histomorphometric evaluation of bone resorption and bone turnover in hyperthyroidism and hyperparathyroidism. Acta Med Scand. 2009;204(1-6):97–102. https://doi.org/10.1111/j.0954-6820.1978.tb08406.x.

    Article  Google Scholar 

  58. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Investig. 1998;102(2):274–82. https://doi.org/10.1172/jci2799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Xia X, Kar R, Gluhak-Heinrich J, Yao W, Lane NE, Bonewald LF, et al. Glucocorticoid-induced autophagy in osteocytes. J Bone Miner Res. 2010;25(11):2479–88. https://doi.org/10.1002/jbmr.160.

  60. Jia J, Yao W, Guan M, Dai W, Shahnazari M, Kar R, et al. Glucocorticoid dose determines osteocyte cell fate. FASEB J. 2011;25(10):3366–76. https://doi.org/10.1096/fj.11-182519.

  61. Lane NE, Yao W, Balooch M, Nalla RK, Balooch G, Habelitz S, et al. Glucocorticoid-treated mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice. J Bone Miner Res. 2005;21(3):466–76. https://doi.org/10.1359/jbmr.051103.

  62. Sun B, Sun J, Han X, Liu H, Li J, Du J, et al. Immunolocalization of MMP 2, 9 and 13 in prednisolone induced osteoporosis in mice. Histol Histopathol. 2016;31(6):647–56. https://doi.org/10.14670/hh-11-702.

    Article  CAS  PubMed  Google Scholar 

  63. Farr JN, Fraser DG, Wang H, Jaehn K, Ogrodnik MB, Weivoda MM, et al. Identification of senescent cells in the bone microenvironment. J Bone Miner Res. 2016;31(11):1920–9. https://doi.org/10.1002/jbmr.2892.

  64. 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/jcem.82.9.4200.

    Article  CAS  PubMed  Google Scholar 

  65. • Ru J-Y, Wang Y-F. Osteocyte apoptosis: the roles and key molecular mechanisms in resorption-related bone diseases. Cell Death Dis. 2020;11(10). https://doi.org/10.1038/s41419-020-03059-8Review on the role of osteocyte apoptosis in bone diseases.

  66. Onal M, Piemontese M, Xiong J, Wang Y, Han L, Ye S, et al. Suppression of autophagy in osteocytes mimics skeletal aging. J Biol Chem. 2013;288(24):17432–40. https://doi.org/10.1074/jbc.M112.444190.

  67. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA. Matrix-embedded cells control osteoclast formation. Nat Med. 2011;17(10):1235–41. https://doi.org/10.1038/nm.2448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 2011;17(10):1231–4. https://doi.org/10.1038/nm.2452.

    Article  CAS  PubMed  Google Scholar 

  69. Emerton KB, Hu B, Woo AA, Sinofsky A, Hernandez C, Majeska RJ, et al. Osteocyte apoptosis and control of bone resorption following ovariectomy in mice. Bone. 2010;46(3):577–83. https://doi.org/10.1016/j.bone.2009.11.006.

  70. •• McCutcheon S, Majeska RJ, Spray DC, Schaffler MB, Vazquez M. Apoptotic osteocytes induce RANKL production in bystanders via purinergic signaling and activation of pannexin channels. J Bone Miner Res. 2020;35(5):966–77. https://doi.org/10.1002/jbmr.3954ATP released from apoptotic osteocytes via Panx1 channels triggers RANKL expression in neighboring osteocytes.

    Article  CAS  PubMed  Google Scholar 

  71. Tiede-Lewis LM, Xie Y, Hulbert MA, Campos R, Dallas MR, Dusevich V, et al. Degeneration of the osteocyte network in the C57BL/6 mouse model of aging. Aging. 2017;9(10):2190–208. https://doi.org/10.18632/aging.101308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Heveran CM, Rauff A, King KB, Carpenter RD, Ferguson VL. A new open-source tool for measuring 3D osteocyte lacunar geometries from confocal laser scanning microscopy reveals age-related changes to lacunar size and shape in cortical mouse bone. Bone. 2018;110:115–27. https://doi.org/10.1016/j.bone.2018.01.018.

    Article  PubMed  PubMed Central  Google Scholar 

  73. 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. 2016;91:11–9. https://doi.org/10.1016/j.bone.2016.07.003.

    Article  Google Scholar 

  74. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  75. 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.

  76. Carter Y, Thomas CDL, Clement JG, Cooper DML. Femoral osteocyte lacunar density, volume and morphology in women across the lifespan. J Struct Biol. 2013;183(3):519–26. https://doi.org/10.1016/j.jsb.2013.07.004.

    Article  PubMed  Google Scholar 

  77. 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.

  78. Mullender MG, Van Der Meer DD, Huiskes R, Lips P. Osteocyte density changes in aging and osteoporosis. Bone. 1996;18(2):109–13. https://doi.org/10.1016/8756-3282(95)00444-0.

    Article  CAS  PubMed  Google Scholar 

  79. Vashishth D, Gibson GJ, Fyhrie DP. Sexual dimorphism and age dependence of osteocyte lacunar density for human vertebral cancellous bone. Anat Rec. 2005;282A(2):157–62. https://doi.org/10.1002/ar.a.20146.

    Article  Google Scholar 

  80. Milovanovic P, Zimmermann EA, Hahn M, Djonic D, Püschel K, Djuric M, et al. Osteocytic canalicular networks: morphological implications for atered mechanosensitivity. ACS Nano. 2013;7(9):7542–51. https://doi.org/10.1021/nn401360u.

  81. McCreadie BR, Hollister SJ, Schaffler MB, Goldstein SA. Osteocyte lacuna size and shape in women with and without osteoporotic fracture. J Biomech. 2004;37(4):563–72. https://doi.org/10.1016/s0021-9290(03)00287-2.

    Article  PubMed  Google Scholar 

  82. • Hemmatian H, Laurent MR, Bakker AD, Vanderschueren D, Klein-Nulend J, Van Lenthe GH. Age-related changes in female mouse cortical bone microporosity. Bone. 2018;113:1–8. https://doi.org/10.1016/j.bone.2018.05.003Quantification of density, morphology and spatial position of vascular and lacunar porosity in young and aged C57Bl/6 mice.

    Article  PubMed  Google Scholar 

  83. Solberg LB, Brorson S-H, Stordalen GA, Bækkevold ES, Andersson G, Reinholt FP. Increased tartrate-resistant acid phosphatase expression in osteoblasts and osteocytes in experimental osteoporosis in rats. Calcif Tissue Int. 2014;94(5):510–21. https://doi.org/10.1007/s00223-013-9834-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Van Schoor NM, Visser M, Pluijm SMF, Kuchuk N, Smit JH, Lips P. Vitamin D deficiency as a risk factor for osteoporotic fractures. Bone. 2008;42(2):260–6. https://doi.org/10.1016/j.bone.2007.11.002.

    Article  CAS  PubMed  Google Scholar 

  85. Rolvien T, Krause M, Jeschke A, Yorgan T, Püschel 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.

  86. Misof BM, Blouin S, Hofstaetter JG, Roschger P, Zwerina J, Erben RG. No role of osteocytic osteolysis in the development and recovery of the bone phenotype induced by severe secondary hyperparathyroidism in vitamin D receptor deficient mice. Int J Mol Sci. 2020;21(21). https://doi.org/10.3390/ijms21217989.

  87. Brickley M, Mays S, Ives R. An investigation of skeletal indicators of vitamin D deficiency in adults: Effective markers for interpreting past living conditions and pollution levels in 18th and 19th century Birmingham. England. Am J Phys Anthropol. 2007;132(1):67–79. https://doi.org/10.1002/ajpa.20491.

    Article  PubMed  Google Scholar 

  88. 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):193ra88–8. https://doi.org/10.1126/scitranslmed.3006286.

  89. White KE, Evans WE, O'Riordan JLH, Speer MC, Econs MJ, Lorenz-Depiereux B, et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26(3):345–8. https://doi.org/10.1038/81664.

  90. Wang H, Yoshiko Y, Yamamoto R, Minamizaki T, Kozai K, Tanne K, et al. Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro. J Bone Miner Res. 2008;23(6):939–48. https://doi.org/10.1359/jbmr.080220.

  91. Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol. 2006;17(5):1305–15. https://doi.org/10.1681/asn.2005111185.

  92. Pereira RC, Jűppner 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Nat Acad Sci. 2001;98(11):6500–5. https://doi.org/10.1073/pnas.101545198.

  94. Rowe PSN. Regulation of bone-renal mineral and energy metabolism: The PHEX, FGF23, DMP1, MEPE ASARM pathway. Crit Rev Eukaryot Gene Expr. 2012;22(1):61–86. https://doi.org/10.1615/CritRevEukarGeneExpr.v22.i1.50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Mohammadi Z, Fayyazbakhsh F, Ebrahimi M, Amoli MM, Khashayar P, Dini M, et al. Association between vitamin D receptor gene polymorphisms (Fok1 and Bsm1) and osteoporosis: a systematic review. J Diabetes Metab Disord. 2014;13(1):98. https://doi.org/10.1186/s40200-014-0098-x.

  96. Ralston SH. Genetic regulation of bone mass and susceptibility to osteoporosis. Genes Dev. 2006;20(18):2492–506. https://doi.org/10.1101/gad.1449506.

  97. Fang Y, van Meurs JBJ, d'Alesio A, Jhamai M, Zhao H, Rivadeneira F, et al. Promoter and 3′-untranslated-region haplotypes in the vitamin D receptor gene predispose to osteoporotic fracture: the Rotterdam study. Am J Hum Genet. 2005;77(5):807–23. https://doi.org/10.1086/497438.

  98. Gooi JH, Chia LY, Walsh NC, Karsdal MA, Quinn JMW, Martin TJ, et al. Decline in calcitonin receptor expression in osteocytes with age. J Endocrinol. 2014;221(2):181–91. https://doi.org/10.1530/joe-13-0524.

  99. Sapir-Koren R, Livshits G. Is interaction between age-dependent decline in mechanical stimulation and osteocyte–estrogen receptor levels the culprit for postmenopausal-impaired bone formation? Osteoporos Int. 2013;24(6):1771–89. https://doi.org/10.1007/s00198-012-2208-2.

    Article  CAS  PubMed  Google Scholar 

  100. Zimmermann EA, Busse B, Ritchie RO. The fracture mechanics of human bone: influence of disease and treatment. BoneKEy Rep. 2015;4:743. https://doi.org/10.1038/bonekey.2015.112.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Weiner S, Wagner HD. The material bone: structure-mechanical function relations. Annu Rev Mater Sci. 1998;28(1):271–98. https://doi.org/10.1146/annurev.matsci.28.1.271.

    Article  CAS  Google Scholar 

  102. Skedros JG, Holmes JL, Vajda EG, Bloebaum RD. Cement lines of secondary osteons in human bone are not mineral-deficient: new data in a historical perspective. Anat Rec. 2005;286A(1):781–803. https://doi.org/10.1002/ar.a.20214.

    Article  Google Scholar 

  103. Zimmermann EA, Schaible E, Bale H, Barth HD, Tang SY, Reichert P, et al. Age-related changes in the plasticity and toughness of human cortical bone at multiple length scales. Proc Nat Acad Sci. 2011;108(35):14416–21. https://doi.org/10.1073/pnas.1107966108.

  104. Zimmermann EA, Ritchie RO. Bone as a structural material. Adv Healthc Mater. 2015;4(9):1287–304. https://doi.org/10.1002/adhm.201500070.

  105. Gupta HS, Wagermaier W, Zickler GA, Raz-Ben Aroush D, Funari SS, Roschger P, et al. Nanoscale deformation mechanisms in bone. Nano Letters. 2005;5(10):2108–11. https://doi.org/10.1021/nl051584b.

  106. Zimmermann EA, Riedel C, Schmidt FN, Stockhausen KE, Chushkin Y, Schaible E, et al. Mechanical competence and bone quality develop during skeletal growth. J Bone Miner Res. 2019;34(8):1461–72. https://doi.org/10.1002/jbmr.3730.

  107. Poundarik AA, Diab T, Sroga GE, Ural A, Boskey AL, Gundberg CM, et al. Dilatational band formation in bone. Proc Nat Acad Sci. 2012;109(47):19178–83. https://doi.org/10.1073/pnas.1201513109.

  108. Fantner GE, Hassenkam T, Kindt JH, Weaver JC, Birkedal H, Pechenik L, et al. Sacrificial bonds and hidden length dissipate energy as mineralized fibrils separate during bone fracture. Nat Mater. 2005;4(8):612–6. https://doi.org/10.1038/nmat1428.

  109. Paschalis EP, Fratzl P, Gamsjaeger S, Hassler N, Brozek W, Eriksen EF, et al. Aging versus postmenopausal osteoporosis: bone composition and maturation kinetics at actively-forming trabecular surfaces of female subjects aged 1 to 84 years. J Bone Miner Res. 2016;31(2):347–57. https://doi.org/10.1002/jbmr.2696.

  110. 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.

  111. Vashishth D, Gibson GJ, Khoury JI, Schaffler MB, Kimura J, Fyhrie DP. Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone. 2001;28(2):195–201. https://doi.org/10.1016/s8756-3282(00)00434-8.

    Article  CAS  PubMed  Google Scholar 

  112. •• Farlay D, Bala Y, Rizzo S, Bare S, Lappe JM, Recker R, et al. Bone remodeling and bone matrix quality before and after menopause in healthy women. Bone. 2019;128:115030. https://doi.org/10.1016/j.bone.2019.08.003Bone composition, remodeling rates, and microhardness measurements in paired biopsies from women before menopause, one year after menopause and 14 years after menopause.

    Article  CAS  PubMed  Google Scholar 

  113. Misof BM, Roschger P, Blouin S, Recker R, Klaushofer K. Bone matrix mineralization is preserved during early perimenopausal stage in healthy women: a paired biopsy study. Osteoporos Int. 2016;27(5):1795–803. https://doi.org/10.1007/s00198-015-3446-x.

    Article  CAS  PubMed  Google Scholar 

  114. Gamsjaeger S, Brozek W, Recker R, Klaushofer K, Paschalis EP. Transmenopausal changes in trabecular bone quality. J Bone Miner Res. 2014;29(3):608–17. https://doi.org/10.1002/jbmr.2073.

    Article  CAS  PubMed  Google Scholar 

  115. •• Paschalis EP, Gamsjaeger S, Condon K, Klaushofer K, Burr D. Estrogen depletion alters mineralization regulation mechanisms in an ovariectomized monkey animal model. Bone. 2019;120:279–84. https://doi.org/10.1016/j.bone.2018.11.004Bone composition assessed with Raman spectroscopy in bone regions with similar tissue age, established with fluorescent calcein labels, in ovariectomized or sham-operated monkeys.

    Article  CAS  PubMed  Google Scholar 

  116. Diab T, Vashishth D. Morphology, localization and accumulation of in vivo microdamage in human cortical bone. Bone. 2007;40(3):612–8. https://doi.org/10.1016/j.bone.2006.09.027.

    Article  PubMed  Google Scholar 

  117. Schaffler MB, Choi K, Milgrom C. Aging and matrix microdamage accumulation in human compact bone. Bone. 1995;17(6):521–5. https://doi.org/10.1016/8756-3282(95)00370-3.

    Article  CAS  PubMed  Google Scholar 

  118. Wasserman N, Brydges B, Searles S, Akkus O. In vivo linear microcracks of human femoral cortical bone remain parallel to osteons during aging. Bone. 2008;43(5):856–61. https://doi.org/10.1016/j.bone.2008.07.238.

    Article  PubMed  Google Scholar 

  119. Qiu S, Sudhaker Rao D, Fyhrie DP, Palnitkar S, Parfitt AM. The morphological association between microcracks and osteocyte lacunae in human cortical bone. Bone. 2005;37(1):10–5. https://doi.org/10.1016/j.bone.2005.01.023.

    Article  PubMed  Google Scholar 

  120. 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. https://doi.org/10.1016/s8756-3282(00)00236-2.

    Article  CAS  PubMed  Google Scholar 

  121. Burr DB. Stress concentrations and bone microdamage: John Currey’s contributions to understanding the initiation and arrest of cracks in bone. Bone. 2019;127:517–25. https://doi.org/10.1016/j.bone.2019.07.015.

    Article  PubMed  Google Scholar 

  122. Currey JD. Stress concentrations in bone. J Cell Sci. 1962;s3-103:111–33.

    Article  Google Scholar 

  123. Zioupos P, Wang X, Currey J. The accumulation of fatigue microdamage in human cortical bone of two different ages in vitro. Clin Biomech. 1996;11(7):365–75. https://doi.org/10.1016/0268-0033(96)00010-1.

    Article  CAS  Google Scholar 

  124. 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.

    Article  CAS  PubMed  Google Scholar 

  125. Nicolella DP, Moravits DE, Gale AM, Bonewald LF, Lankford J. Osteocyte lacunae tissue strain in cortical bone. J Biomech. 2006;39(9):1735–43. https://doi.org/10.1016/j.jbiomech.2005.04.032.

    Article  PubMed  Google Scholar 

  126. Koester KJ, Ager JW, Ritchie RO. The true toughness of human cortical bone measured with realistically short cracks. Nat Mater. 2008;7(8):672–7. https://doi.org/10.1038/nmat2221.

    Article  CAS  PubMed  Google Scholar 

  127. Zimmermann EA, Launey ME, Barth HD, Ritchie RO. Mixed-mode fracture of human cortical bone. Biomaterials. 2009;30(29):5877–84. https://doi.org/10.1016/j.biomaterials.2009.06.017.

    Article  CAS  PubMed  Google Scholar 

  128. Nalla RK, Kinney JH, Ritchie RO. Mechanistic fracture criteria for the failure of human cortical bone. Nat Mater. 2003;2(3):164–8. https://doi.org/10.1038/nmat832.

    Article  CAS  PubMed  Google Scholar 

  129. Nalla RK, Kruzic JJ, Kinney JH, Balooch M, Ager JW, Ritchie RO. Role of microstructure in the aging-related deterioration of the toughness of human cortical bone. Mater Sci Eng C. 2006;26(8):1251–60. https://doi.org/10.1016/j.msec.2005.08.021.

    Article  CAS  Google Scholar 

  130. Zioupos P, Currey JD. Changes in the stiffness, strength, and toughness of human cortical bone with age. Bone. 1998;22(1):57–66. https://doi.org/10.1016/s8756-3282(97)00228-7.

    Article  CAS  PubMed  Google Scholar 

  131. Wang X, Shen X, Li X, Mauli AC. Age-related changes in the collagen network and toughness of bone. Bone. 2002;31(1):1–7. https://doi.org/10.1016/s8756-3282(01)00697-4.

    Article  PubMed  Google Scholar 

  132. Koester KJ, Barth HD, Ritchie RO. Effect of aging on the transverse toughness of human cortical bone: evaluation by R-curves. J Mech Behav Biomed Mater. 2011;4(7):1504–13. https://doi.org/10.1016/j.jmbbm.2011.05.020.

    Article  CAS  PubMed  Google Scholar 

  133. Kaya S, Basta-Pljakic J, Seref-Ferlengez Z, Majeska RJ, Cardoso L, Bromage TG, et al. Lactation-induced changes in the volume of osteocyte lacunar-canalicular space alter mechanical properties in cortical bone tissue. J Bone Miner Res. 2017;32(4):688–97. https://doi.org/10.1002/jbmr.3044.

  134. • Taylor EA, Donnelly E, Yao X, Johnson ML, Amugongo SK, Kimmel DB, et al. Sequential treatment of estrogen deficient, osteopenic rats with alendronate, parathyroid hormone (1–34), or raloxifene alters cortical bone mineral and matrix composition. Calcif Tissue Int. 2020;106(3):303–14. https://doi.org/10.1007/s00223-019-00634-wRaman measurements of bone composition at perilacunar and non-perilacunar bone regions in rats treated with OVX and sequential osteorporosis treatment.

    Article  CAS  PubMed  Google Scholar 

  135. • Stern AR, Yao X, Wang Y, Berhe A, Dallas M, Johnson ML, et al. Effect of osteoporosis treatment agents on the cortical bone osteocyte microenvironment in adult estrogen-deficient, osteopenic rats. Bone Rep. 2018;8:115–24. https://doi.org/10.1016/j.bonr.2018.02.005Nanoindentation as a function of distance from lacunae and finite element model of lacunar mechanical environment in rats treated with OVX and sequential osteorporosis treatment.

    Article  PubMed  PubMed Central  Google Scholar 

  136. •• Gardinier JD, Al-Omaishi S, Rostami N, Morris MD, Kohn DH. Examining the influence of PTH(1-34) on tissue strength and composition. Bone. 2018;117:130–7. https://doi.org/10.1016/j.bone.2018.09.019Investigation of the effects of PTH(1-34) treatment in mice on Raman spectroscopy measured bone composition in perilacunar vs non-perilacunar bone and on resistance to microdamage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. • Kola SK, Begonia MT, Tiede-Lewis LM, Laughrey LE, Dallas SL, Johnson ML, et al. Osteocyte lacunar strain determination using multiscale finite element analysis. Bone Rep. 2020;12:100277. https://doi.org/10.1016/j.bonr.2020.100277Finite element model of bone matrix, perilacunar bone matrix and porosity at the micron-scale to parametrically determine the effects of lacunar orientation, lacunar size and perilacunar bone modulus on strain distribution in perilacunar bone matrix.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Zhang S, Bach-Gansmo FL, Xia D, Besenbacher F, Birkedal H, Dong M. Nanostructure and mechanical properties of the osteocyte lacunar-canalicular network-associated bone matrix revealed by quantitative nanomechanical mapping. Nano Res. 2015;8(10):3250–60. https://doi.org/10.1007/s12274-015-0825-8.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. S. Komarova for the thoughtful discussions as well as Dr. B. Busse and the Universitätsklinikum Hamburg-Eppendorf Microscopy Imaging Facility for the support in obtaining the image shown in Fig. 1.

Author information

Authors and Affiliations

  1. Heisenberg Research Group, Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestr. 55a, 22529, Hamburg, Germany

    Katharina Jähn-Rickert

  2. Mildred Scheel Cancer Career Center Hamburg, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Katharina Jähn-Rickert

  3. Faculty of Dentistry, McGill University, Strathcona Anatomy and Dentistry Building, 3640 Rue University, Montreal, Canada

    Elizabeth A. Zimmermann

Authors
  1. Katharina Jähn-Rickert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth A. Zimmermann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Katharina Jähn-Rickert or Elizabeth A. Zimmermann.

Ethics declarations

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.

Conflict of Interest

Katharina Jähn-Rickert declares no conflict of interest. Elizabeth Zimmermann reports grants and non-financial support from Mereo BioPharma, outside the submitted work.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Biomechanics

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jähn-Rickert, K., Zimmermann, E.A. Potential Role of Perilacunar Remodeling in the Progression of Osteoporosis and Implications on Age-Related Decline in Fracture Resistance of Bone. Curr Osteoporos Rep 19, 391–402 (2021). https://doi.org/10.1007/s11914-021-00686-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-021-00686-8

Keywords

Search

Navigation