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Functional Heterogeneity Within Osteoclast Populations—a Critical Review of Four Key Publications that May Change the Paradigm of Osteoclasts


Purpose of Review

In this review, we critically evaluate the literature for osteoclast heterogeneity, including heterogeneity in osteoclast behavior, which has hitherto been unstudied and has only recently come to attention. We give a critical review centered on four recent high-impact papers on this topic and aim to shed light on the elusive biology of osteoclasts and focus on the variant features of osteoclasts that diverge from the classical viewpoint.

Recent Findings

Osteoclasts originate from the myeloid lineage and are best known for their unique ability to resorb bone. For decades, osteoclasts have been defined simply as multinucleated cells positive for tartrate-resistant acid phosphatase activity and quantified relative to the bone perimeter or surface in histomorphometric analyses. However, several recent, high-profile studies have demonstrated the existence of heterogeneous osteoclast populations, with variable origins and functions depending on the microenvironment. This includes long-term persisting osteoclasts, inflammatory osteoclasts, recycling osteoclasts (osteomorphs), and bone resorption modes. Most of these findings have been revealed through murine studies and have helped identify new targets for human studies. These studies have also uncovered distinct sets of behavioral patterns in heterogeneous osteoclast cultures.


The underlying osteoclast heterogeneity likely drives differences in bone remodeling, altering patient risk for osteoporosis and fracture. Thus, identifying the underlying key features of osteoclast heterogeneity may help in better targeting bone diseases.

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Fig. 1


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

  1. Delaisse JM, Andersen TL, Kristensen HB, Jensen PR, Andreasen CM, Søe K. Re-thinking the bone remodeling cycle mechanism and the origin of bone loss. Bone [Internet]. Elsevier; 2020;141:115628. Available from:

  2. Isales CM, Seeman E. Modeling IB. Menopause and age - related bone loss. 2019;155–161.

  3. Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet. 2019;393:364–76.

    CAS  PubMed  Article  Google Scholar 

  4. Kanis JA, Norton N, Harvey NC, Jacobson T, Johansson H, Lorentzon M, et al. SCOPE 2021: a new scorecard for osteoporosis in Europe. Arch Osteoporos. 2021;16.

  5. Office of Disease Prevention and Health Promotion, Office of the Assistant Secretary for Health, Office of the Secretary USD of H and HS. Osteoporosis Workgroup. US Department of Health and Human Services [Internet]. 2020. Available from: the United States%2C an,at increased risk for osteoporosis.

  6. Schmidt CW. A measure of strength: developmental PFAS exposures and bone mineral content in adolescence. Environ Health Perspect. 2021;129:1–2.

    Google Scholar 

  7. Lewiecki EM, Ortendahl JD, Vanderpuye-Orgle J, Grauer A, Arellano J, Lemay J, Harmon AL, Broder MS, Singer AJ. Healthcare policy changes in osteoporosis can improve outcomes and reduce costs in the United States. JBMR Plus. 2019;3:1–7.

    Article  Google Scholar 

  8. Madsen CM, Jantzen C, Norring-Agerskov D, Vojdeman FJ, Abrahamsen B, Lauritzen JB, Jørgensen HL. Excess mortality following hip fracture in patients with diabetes according to age: a nationwide population-based cohort study of 154,047 hip fracture patients. Age Ageing. 2019;48:559–63.

    PubMed  Article  Google Scholar 

  9. Guzon-Illescas O, Perez Fernandez E, Crespí Villarias N, Quirós Donate FJ, Peña M, Alonso-Blas C, et al. Mortality after osteoporotic hip fracture: incidence, trends, and associated factors. J Orthop Surg Res. 2019;14:1–9.

    Article  Google Scholar 

  10. Bliuc D, Center JR. Determinants of mortality risk following osteoporotic fractures. Curr Opin Rheumatol United States. 2016;28:413–9.

    Article  Google Scholar 

  11. Cauley JA, Thompson DE, Ensrud KC, Scott JC, Black D. Risk of mortality following clinical fractures [Internet]. Osteoporos. Int. London : Springer-Verlag London Limited ; 2000. p. 556–561. Available from:

  12. Cummings SR, Lui LY, Eastell R, Allen IE. Association between drug treatments for patients with osteoporosis and overall mortality rates: a meta-analysis. JAMA Intern Med. 2019;179:1491–500.

    PubMed  PubMed Central  Article  Google Scholar 

  13. Alarkawi D, Bliuc D, Tran T, Ahmed LA, Emaus N, Bjørnerem A, Jørgensen L, Christoffersen T, Eisman JA, Center JR. Impact of osteoporotic fracture type and subsequent fracture on mortality: the Tromsø Study. Osteoporos Int. 2020;31:119–30.

    CAS  PubMed  Article  Google Scholar 

  14. Zanker J, Duque G. Osteoporosis in older persons: old and new players. J Am Geriatr Soc. 2019;67:831–40.

    PubMed  Article  Google Scholar 

  15. de Vries TJ, Schoenmaker T, Hooibrink B, Leenen PJM, Everts V. Myeloid blasts are the mouse bone marrow cells prone to differentiate into osteoclasts. J Leukoc Biol. 2009;85:919–27.

    PubMed  Article  CAS  Google Scholar 

  16. Grigoriadis AE, Kennedy M, Bozec A, Brunton F, Stenbeck G, Park IH, Wagner EF, Keller GM. Directed differentiation of hematopoietic precursors and functional osteoclasts from human ES and iPS cells. Blood. 2010;115:2769–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Cairoli E, Eller-Vainicher C, Ulivieri FM, Zhukouskaya VV, Palmieri S, Morelli V, Beck-Peccoz P, Chiodini I. Factors associated with bisphosphonate treatment failure in postmenopausal women with primary osteoporosis. Osteoporos Int. 2014;25:1401–10.

    CAS  PubMed  Article  Google Scholar 

  18. Møller AMJ, Delaisse JM, Olesen JB, Bechmann T, Madsen JS, Søe K. Zoledronic acid is not equally potent on osteoclasts generated from different individuals. JBMR Plus. 2020;4:1–13. This paper studies the varying effect of zoledronic acid on osteoclasts obtained from different individuals in vitro.

  19. McDonald MM, Khoo WH, Ng PY, Xiao Y, Zamerli J, Thatcher P, et al. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell. 2021;184:1330-1347.e13. This paper studies the recycling of osteoclasts via daughter cells known as osteomorphs. Osteomorphs may be involved in the regulation of bone resorption.

  20. Madel MB, Ibáñez L, Ciucci T, Halper J, Rouleau M, Boutin A, et al. Dissecting the phenotypic and functional heterogeneity of mouse inflammatory osteoclasts by the expression of cx3cr1. Elife. 2020;9:1–22. This paper provides new insights into inflammatory osteoclast heterogeneity.

  21. Smieszek A, Marcinkowska K, Pielok A, Sikora M. The role of miR-21 in osteoblasts – osteoclasts. Cells. 2020;9:1–21.

    Article  CAS  Google Scholar 

  22. Møller AMJ, Delaissé JM, Olesen JB, Madsen JS, Canto LM, Bechmann T, et al. Aging and menopause reprogram osteoclast precursors for aggressive bone resorption. Bone Res [Internet]. Springer US; 2020;8. Available from: This paper studies the effect of age and menopause on osteoclast precursors and their subsequent effect leading to aggressive bone resorption.

  23. Yi L, Li Z, Jiang H, Cao Z, Liu J, Zhang X. Gene modification of transforming growth factor β (TGF-β) and interleukin 10 (IL-10) in suppressing Mt sonicate induced osteoclast formation and bone absorption. Med. Sci. Monit. 2018. p. 5200–7.

  24. Jacome-Galarza CE, Percin GI, Muller JT, Mass E, Lazarov T, Eitler J, et al. Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature [Internet]. Springer US; 2019;568:541–5. Available from: This paper studies the developmental origin and longevity of osteoclasts, but also looks at the mechanism behind the maintenance of bones after birth in mice.

  25. Parfitt AM. Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. J Cell Biochem. United States. 1994;55:273–86.

    CAS  Article  Google Scholar 

  26. Baron R, Tross R, Vignery A. Evidence of sequential remodeling in rat trabecular bone: morphology, dynamic histomorphometry, and changes during skeletal maturation. Anat Rec. 1984;208:137–45.

    CAS  PubMed  Article  Google Scholar 

  27. Sambrook PN, Hughes DR, Nelson AE, Robinson BG, Mason RS. Osteocyte viability with glucocorticoid treatment: relation to histomorphometry. Ann Rheum Dis. 2003;62:1215–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Hurley MM, Lee SK, Raisz LG, Bernecker P, Lorenzo J. Basic fibroblast growth factor induces osteoclast formation in murine bone marrow cultures. Bone [Internet]. 1998;22:309–316. Available from:

  29. Yaccoby S, Wezeman MJ, Henderson A, Cottler-Fox M, Yi Q, Barlogie B, Epstein J. Cancer and the microenvironment: myeloma-osteoclast interactions as a model. Cancer Res. 2004;64:2016–23.

    CAS  PubMed  Article  Google Scholar 

  30. Rissanen JP, Suominen MI, Peng Z, Halleen JM. Secreted tartrate-resistant acid phosphatase 5b is a marker of osteoclast number in human osteoclast cultures and the rat ovariectomy model. Calcif Tissue Int. 2008;82:108–15.

    CAS  PubMed  Article  Google Scholar 

  31. Jaworski ZFG. Physiology and pathology of bone remodeling: cellular basis of bone structure in health and in osteoporosis. Orthop Clin North Am [Internet]. 1981;12:485–512. Available from:

  32. Tonna EA. H3-histidine and H3-thymidine autoradiographic studies of the possibility of osteoclast aging. Lab Invest [Internet]. 1966;15:435—448. Available from:

  33. Thul PJ, Åkesson L, Wiking M, Mahdessian D, Geladaki A, Blal HA, et al. A subcellular map of the human proteome. Science (80- ). 2017;356:eaal3321.

  34. The Human Protein Atlas [Internet]. Available from:

  35. Tissue expression of VAV1 - Summary - The Human Protein Atlas. :2–4. Available from:

  36. Yahara Y, Barrientos T, Tang YJ, Puviindran V, Nadesan P, Zhang H, et al. Erythromyeloid progenitors give rise to a population of osteoclasts that contribute to bone homeostasis and repair. Nat Cell Biol [Internet]. Springer US; 2020;22:49–59. Available from: This paper identifies an erythromyeloid progenitor (EMP)-derived osteoclast precursor population, which arises independently of the hematopoietic stem cell (HSC) lineage.

  37. Flewitt* R. Conducting research with young children: some ethical considerations. Early Child Dev Care [Internet]. Routledge; 2005;175:553–65. Available from:

  38. Orcel P, Bielakoff J, De Vernejoul MC. Formation of multinucleated cells with osteoclast precursor features in human cord monocytes cultures. Anat Rec [Internet]. John Wiley & Sons, Ltd; 1990;226:1–9. Available from:

  39. Penolazzi L, Pocaterra B, Tavanti E, Lambertini E, Vesce F, Gambari R, et al. Human osteoclasts differentiated from umbilical cord blood precursors are less prone to apoptotic stimuli than osteoclasts from peripheral blood. Apoptosis [Internet]. 2008;13:553–61. Available from:

  40. Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol [Internet]. John Wiley & Sons, Ltd; 2000;109:235–42. Available from:

  41. Monaco MCG, Maric D, Salvucci O, Passeri CAL, Accorsi P, Major EO, et al. Identification of circulating CD31+CD45+ cell populations with the potential to differentiate into erythroid cells. Stem Cell Res Ther [Internet]. 2021;12:236. Available from:

  42. Yang C-T, French A, Goh PA, Pagnamenta A, Mettananda S, Taylor J, et al. Human induced pluripotent stem cell derived erythroblasts can undergo definitive erythropoiesis and co-express gamma and beta globins. Br J Haematol [Internet]. John Wiley & Sons, Ltd; 2014;166:435–48. Available from:

  43. Heppe DHM, Medina-Gomez C, de Jongste JC, Raat H, Steegers EAP, Hofman A, et al. Fetal and childhood growth patterns associated with bone mass in school-age children: the Generation R Study. J Bone Miner Res [Internet]. John Wiley & Sons, Ltd; 2014;29:2584–93. Available from:

  44. Vidulich L, Norris SA, Cameron N, Pettifor JM. Infant programming of bone size and bone mass in 10-year-old black and white South African children. Paediatr Perinat Epidemiol [Internet]. John Wiley & Sons, Ltd; 2007;21:354–62. Available from:

  45. Balasuriya CND, Evensen KAI, Mosti MP, Brubakk A-M, Jacobsen GW, Indredavik MS, et al. Peak bone mass and bone microarchitecture in adults born with low birth weight preterm or at term: a cohort study. J Clin Endocrinol Metab [Internet]. 2017;102:2491–500. Available from:

  46. Laitinen J, Kiukaanniemi K, Heikkinen J, Koiranen M, Nieminen P, Sovio U, et al. Body size from birth to adulthood and bone mineral content and density at 31 years of age: results from the northern Finland 1966 birth cohort study. Osteoporos Int [Internet]. 2005;16:1417–24. Available from:

  47. Bonjour JP, Chevalley T, Ferrari S, Rizzoli R. The importance and relevance of peak bone mass in the prevalence of osteoporosis. Salud Publica Mex. 2009;51:5–17.

    Article  Google Scholar 

  48. Marks SC, Seifert MF. The lifespan of osteoclasts: experimental studies using the giant granule cytoplasmic marker characteristic of beige mice. Bone [Internet]. 1985;6:451–5 Available from:

    PubMed  Article  Google Scholar 

  49. Jaworski ZFG, Duck B, Sekaly G. Kinetics of osteoclasts and their nuclei in evolving secondary Haversian systems. J Anat. 1981;133:397–405.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang B, Jin H, Zhu M, Li J, Zhao L, Zhang Y, et al. Chondrocyte β-catenin signaling regulates postnatal bone remodeling through modulation of osteoclast formation in a murine model. Arthritis Rheumatol [Internet]. John Wiley & Sons, Ltd; 2014;66:107–20. Available from:

  51. Rauch F. The dynamics of bone structure development during pubertal growth. J Musculoskelet Neuronal Interact. 2012;12:1–6.

    CAS  PubMed  Google Scholar 

  52. Suda T, Takahashi N, Martin TJ. Modulation of osteoclast differentiation. Endocr Rev [Internet]. 1992;13:66–80. Available from:

  53. Mizuno H, Kikuta J, Ishii M. In vivo live imaging of bone cells. Histochem Cell Biol [Internet]. Springer Berlin Heidelberg; 2018;149:417–22. Available from:

  54. Khosla S, Hofbauer LC. Osteoporosis treatment: recent developments and ongoing challenges. Lancet Diabetes Endocrinol [Internet]. Elsevier Ltd; 2017;5:898–907. Available from:

  55. Bi H, Chen X, Gao S, Yu X, Xiao J, Zhang B, Liu X, Dai M. Key triggers of osteoclast-related diseases and available strategies for targeted therapies: a review. Front Med. 2017;4:1–10.

    Article  Google Scholar 

  56. Ishii M, Egen JG, Klauschen F, Meier-Schellersheim M, Saeki Y, Vacher J, et al. Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature. Nature Publishing Group; 2009;458:524–528.

  57. Ishii M, Kikuta J, Shimazu Y, Meier-Schellersheim M, Germain RN. Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo. J Exp Med. 2010;207:2793–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Vico L, Hargens A. Skeletal changes during and after spaceflight. Nat Rev Rheumatol [Internet]. Nature Publishing Group; 2018;14:229–45. Available from:

  59. Baron R, Vignery A. Behavior of osteoclasts during a rapid change in their number induced by high doses of parathyroid hormone or calcitonin in intact rats. Metab Bone Dis Relat Res. 1981;2:339–46.

    CAS  Article  Google Scholar 

  60. Jansen IDC, Vermeer JAF, Bloemen V, Stap J, Everts V. Osteoclast fusion and fission. Calcif Tissue Int. 2012;91:159.

    CAS  PubMed Central  Article  Google Scholar 

  61. Solari F, Domenget C, Gire V, Woods C, Lazarides E, Rousset B, Jurdic P. Multinucleated cells can continuously generate mononucleated cells in the absence of mitosis: a study of cells of the avian osteoclast lineage. J Cell Sci. 1995;108:3233–41.

    CAS  PubMed  Article  Google Scholar 

  62. Burckhardt P, Faouzi M, Buclin T, Lamy O. Fractures after denosumab discontinuation: a retrospective study of 797 cases. J Bone Miner Res. 2021;36:1717–28.

    CAS  PubMed  Article  Google Scholar 

  63. Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD, Yang YC, Grazette L, San Martin J, Gallagher JC. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96:972–80.

    CAS  PubMed  Article  Google Scholar 

  64. Dufrançais O, Mascarau R, Poincloux R, Maridonneau-Parini I, Raynaud-Messina B, Vérollet C. Cellular and molecular actors of myeloid cell fusion: podosomes and tunneling nanotubes call the tune. Cell Mol Life Sci [Internet]. Springer International Publishing; 2021;78:6087–104. Available from:

  65. Huynh N, Vonmoss L, Smith D, Rahman I, Felemban MF, Zuo J, et al. Characterization of regulatory extracellular vesicles from osteoclasts. J Dent Res. 2016;95:673–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Sasaki A, Boyce BF, Story B, Wright KR, Chapman M, Boyce R, Mundy GR, Yoneda T. Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res. 1995;55:3551–7.

    CAS  PubMed  Google Scholar 

  67. Stegelmeier AA, van Vloten JP, Mould RC, Klafuric EM, Minott JA, Wootton SK, Bridle BW, Karimi K. Myeloid cells during viral infections and inflammation. Viruses. 2019;11.

  68. Madel MB, 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;10:1–18.

    Article  CAS  Google Scholar 

  69. Ibáñez L, Abou-Ezzi G, Ciucci T, Amiot V, Belaïd N, Obino D, et al. Inflammatory osteoclasts prime TNFα-producing CD4+ T cells and express CX3CR1. J Bone Miner Res. 2016;31:1899–908. This paper studies CX3CR1 as a marker of inflammatory osteoclasts and demonstrates that the differentiation of CX3CR1+ osteoclasts is controlled by IL-17 in vitro.

  70. Borggaard XG, Pirapaharan DC, Delaissé JM, Søe K. Osteoclasts’ ability to generate trenches rather than pits depends on high levels of active cathepsin k and efficient clearance of resorption products. Int J Mol Sci. 2020;21:1–18. This study presents some molecular and mechanistic characteristics of osteoclasts in trench mode and highlights the importance of cathepsin K.

  71. Panwar P, Søe K, Guido RV, Bueno RVC, Delaisse JM, Brömme D. A novel approach to inhibit bone resorption: exosite inhibitors against cathepsin K. Br J Pharmacol. 2016;173:396–410.

    CAS  PubMed  Article  Google Scholar 

  72. Søe K, Merrild DMH, Delaissé JM. Steering the osteoclast through the demineralization-collagenolysis balance. Bone [Internet]. The Authors; 2013;56:191–8. Available from:

  73. Delaisse JM, Søe K, Andersen TL, Rojek AM, Marcussen N. The mechanism switching the osteoclast from short to long duration bone resorption. Front Cell Dev Biol. 2021;9:1–17.

    Article  Google Scholar 

  74. Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun [Internet]. Nature Publishing Group; 2016;7:1–10. Available from:

  75. Sawant A, Deshane J, Jules J, Lee CM, Harris BA, Feng X, Ponnazhagan S. Myeloid-derived suppressor cells function as novel osteoclast progenitors enhancing bone loss in breast cancer. Cancer Res. 2013;73:672–82.

    CAS  PubMed  Article  Google Scholar 

  76. Zhuang J, Zhang J, Lwin ST, Edwards JR, Edwards CM, Mundy GR, Yang X. Osteoclasts in multiple myeloma are derived from Gr-1+CD11b+myeloid-derived suppressor cells. PLoS One. 2012;7:e48871.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Okuma A, Hanyu A, Watanabe S, Hara E. P16Ink4a and p21Cip1/Waf1 promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis. Nat Commun [Internet]. Springer US; 2017;8. Available from:

  78. Madel MB, Ibáñez L, Rouleau M, Wakkach A, Blin-Wakkach C. A novel reliable and efficient procedure for purification of mature osteoclasts allowing functional assays in mouse cells. Front Immunol. 2018;9:1–12.

    Article  CAS  Google Scholar 

  79. Meirow Y, Jovanovic M, Zur Y, Habib J, Colombo DF, Twaik N, et al. Specific inflammatory osteoclast precursors induced during chronic inflammation give rise to highly active osteoclasts associated with inflammatory bone loss. Bone Res. Springer Nature; 2022;10.

  80. Møller AMJ, Delaissé JM, Olesen JB, Canto LM, Rogatto SR, Madsen JS, Søe K. Fusion potential of human osteoclasts in vitro reflects age, menopause, and in vivo bone resorption levels of their donors—a possible involvement of dc-stamp. Int J Mol Sci. 2020;21:1–16.

    Google Scholar 

  81. Boissy P, Saltel F, Bouniol C, Jurdic P, Machuca-Gayet I. Transcriptional activity of nuclei in multinucleated osteoclasts and its modulation by calcitonin. Endocrinology. 2002;143:1913–21.

    CAS  PubMed  Article  Google Scholar 

  82. Søe K, Delaissé JM. Glucocorticoids maintain human osteoclasts in the active mode of their resorption cycle. J Bone Miner Res. 2010;25:2184–92.

    PubMed  Article  CAS  Google Scholar 

  83. Søe K, Delaissé JM. Time-lapse reveals that osteoclasts can move across the bone surface while resorbing. J Cell Sci. 2017;130:2026–35.

    PubMed  PubMed Central  Google Scholar 

  84. Merrild DMH, Pirapaharan DC, Andreasen CM, Kjærsgaard-Andersen P, Møller AMJ, Ding M, Delaissé JM, Søe K. Pit- and trench-forming osteoclasts: a distinction that matters. Bone Res. 2015;3:1–11.

    Article  CAS  Google Scholar 

  85. Vanderoost J, Søe K, Merrild DMH, Delaissé JM, Van Lenthe GH. Glucocorticoid-induced changes in the geometry of osteoclast resorption cavities affect trabecular bone stiffness. Calcif Tissue Int. 2013;92:240–50.

    CAS  PubMed  Article  Google Scholar 

  86. Møller AMJ, Füchtbauer EM, Brüel A, Andersen TL, Borggaard XG, Pavlos NJ, Thomsen JS, Pedersen FS, Delaisse JM, Søe K. Septins are critical regulators of osteoclastic bone resorption. Sci Rep. 2018;8:1–15.

    Google Scholar 

  87. Panwar P, Xue L, Søe K, Srivastava K, Law S, Delaisse JM, Brömme D. An ectosteric inhibitor of cathepsin K inhibits bone resorption in ovariectomized mice. J Bone Miner Res. 2017;32:2415–30.

    CAS  PubMed  Article  Google Scholar 

  88. Gentzsch C, Junge M, Pueschel K, Delling G, Kaiser E. A scanning electron microscopy-based approach to quantify resorption lacunae applied to the trabecular bone of the femoral head. J Bone Miner Metab. 2005;23:205–11.

    PubMed  Article  Google Scholar 

  89. Gentzsch C, Delling G, Kaiser E. Microstructural classification of resorption lacunae and perforations in human proximal femora. Calcif Tissue Int. 2003;72:698–709.

    CAS  PubMed  Article  Google Scholar 

  90. Mosekilde L. Consequences of the remodelling process for vertebral trabecular bone structure: a scanning electron microscopy study (uncoupling of unloaded structures). Bone Miner. 1990;10:13–35.

    CAS  PubMed  Article  Google Scholar 

  91. Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, Cesari M, Nourhashemi F. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc. 2013;14:877–82.

    PubMed  Article  Google Scholar 

  92. Abdelmagid SM, Barbe MF, Safadi FF. Role of inflammation in the aging bones. Life Sci. 2015;123:25–34.

    CAS  PubMed  Article  Google Scholar 

  93. Hasegawa T, Kikuta J, Sudo T, Matsuura Y, Matsui T, Simmons S, et al. Identification of a novel arthritis-associated osteoclast precursor macrophage regulated by FoxM1. Nat Immunol [Internet]. Springer US; 2019;20:1631–43. Available from:

  94. Novak S, Roeder E, Kalinowski J, Jastrzebski S, Aguila HL, Lee S-K, Kalajzic I, Lorenzo JA. Osteoclasts derive predominantly from bone marrow–resident CX 3 CR1 + precursor cells in homeostasis, whereas circulating CX 3 CR1 + cells contribute to osteoclast development during fracture repair. J Immunol. 2020;204:868–78.

    CAS  PubMed  Article  Google Scholar 

  95. Tsukasaki M, Huynh NCN, Okamoto K, Muro R, Terashima A, Kurikawa Y, et al. Stepwise cell fate decision pathways during osteoclastogenesis at single-cell resolution. Nat Metab [Internet]. Springer US; 2020;2:1382–90. Available from:

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We wish to thank Jean-Marie Delaissé for critical reading and commenting on our manuscript.


Neha Sharma, Megan Weivoda, and Kent Søe are all supported by the National Institutes of Health (R01AR077538-01A1), while Megan Weivoda is also financed by NIH-U01 AG075227, R61 AR078073, P30 AR069620, AFAR Junior Faculty Award, and the Mayo Clinic. Kent Søe is funded by the University of Southern Denmark. Megan Weivoda has received honoraria from Amgen Europe for lectures.

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Sharma, N., Weivoda, M.M. & Søe, K. Functional Heterogeneity Within Osteoclast Populations—a Critical Review of Four Key Publications that May Change the Paradigm of Osteoclasts. Curr Osteoporos Rep (2022).

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  • Osteoclast
  • Inflammatory osteoclasts
  • Osteomorphs
  • Erythromyeloid
  • Longevity
  • Bone resorption