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Disorganization and Musculoskeletal Diseases: Novel Insights into the Enigma of Unexplained Bone Abnormalities and Fragility Fractures

  • BIOMECHANICS (JS Nyman and V Ferguson, Section Editors)
  • Published:
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Abstract

Purpose of Review

Describe the potential contribution of disorganized tissue to the pathogenesis of bone abnormalities and fractures. Especially, fractures that are unexplained by bone loss (osteoporosis) or structural deterioration.

Recent Findings

Currently, bone fragility is primarily viewed as due to loss, or decay (osteoporosis). However, it is also acknowledged that this view is limited because it does not explain many fractures or abnormalities such as necrosis, sclerosis, or infarcts. Atypical femoral fractures (AFFs) during antiresorptive therapy are an example. Hence, it is proposed that another distinct mechanism is responsible for bone diseases. A remarkable bone property distinct from mass and decay is the organization (arrangement) of its components. Components must be perfectly assembled or well-stacked to ensure “the right amount of bone, at the right place”. Disorganization is an aberration that is conspicuous in many diseases, more so in conditions poorly associated with bone mass and decay such as osteogenesis imperfecta, hypophosphatasia, and AFFs. However, despite the likely critical role of disorganization, this feature has received limited clinical attention.

Summary

This review focuses on the potential contribution of disorganization to bone in health and diseases. Particularly, we propose that disorganization, by causing ineffective transfer of loads, may produce not only bone abnormalities (pain, necrosis, infarct, sclerosis, delayed healing) but also fractures, especially AFFs or stress fractures. A disorganized element is one that is where it shouldn’t be (improperly stacked elements). Hence, disorganization can be measured by quantifying the extent to which a tissue (pixel within an image) is at an incorrect location.

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References

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

  1. Black DM, Thompson DE, Bauer DC, Ensrud K, Musliner T, Hochberg MC, Nevitt MC, Suryawanshi S, Cummings SR. Fracture Intervention Trial. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab. 2000;85(11):4118–24.

    Article  CAS  PubMed  Google Scholar 

  2. Samelson EJ, Broe KE, Xu H, Yang L, Boyd S, Biver E, Szulc P, Adachi J, Amin S, Atkinson E, Berger C, Burt L, Chapurlat R, Chevalley T, Ferrari S, Goltzman D, Hanley DA, Hannan MT, Khosla S, et al. Cortical and trabecular bone microarchitecture as an independent predictor of incident fracture risk in older women and men in the Bone Microarchitecture International Consortium (BoMIC): a prospective study. Lancet Diabetes Endocrinol. 2019;7(1):34–43.

    Article  PubMed  Google Scholar 

  3. Siris ES, Miller PD, Barrett-Connor E, et al. JAMA. 2001;286:2815–282.

    Article  CAS  PubMed  Google Scholar 

  4. Choksi P, Jepsen KJ, Clines GA. The challenges of diagnosing osteoporosis and the limitations of currently available tools. Clin Diabetes Endocrinol. 2018;4:12.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hernandez CJ, van der Meulen MC. Understanding bone strength is not enough. J Bone Miner Res. 2017;32(6):1157–62. Interesting review showing bone strength is not enough to explain bone.

  6. Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster DW, Ebeling PR, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Lane JM, McKiernan F, McKinney R, Ng A, 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. This a very interesting report that summarizes the current knowledge about atypical fractures, in particular during antiresorptives therapy.

  7. Zanchetta MB, Diehl M, Buttazzoni M, Galich A, Silveira F, Bogado CE, Zanchetta JR. Assessment of bone microarchitecture in postmenopausal women on long-term bisphosphonate therapy with atypical fractures of the femur. J Bone Miner Res. 2014;29(4):999–1004. This interesting shows that assessment of bone microarchitecture is not enough to comprehensively identify patients at risk for atypical fractures. This highlights the need to identify a novel mechanism responsible for this type of fracture.

  8. Black DM, Geiger EJ, Eastell R, Vittinghoff E, Li BH, Ryan DS, Dell RM, Adams AL. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med. 2020;383(8):743–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kostenuik PJ, Smith SY, Samadfam R, Jolette J, Zhou L, Ominsky MS. Effects of denosumab, alendronate, or denosumab following alendronate on bone turnover, calcium homeostasis, bone mass and bone strength in ovariectomized cynomolgus monkeys. J Bone Miner Res. 2015;30(4):657–69.

    Article  CAS  PubMed  Google Scholar 

  10. Törring O. Effects of denosumab on bone density, mass and strength in women with postmenopausal osteoporosis. Ther Adv Musculoskelet Dis. 2015;7(3):88–102.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Keaveny TM, Hoffmann PF, Singh M, Palermo L, Bilezikian JP, Greenspan SL, Black DM. Femoral bone strength and its relation to cortical and trabecular changes after treatment with PTH, alendronate, and their combination as assessed by finite element analysis of quantitative CT scans. J Bone Miner Res. 2008;23(12):1974–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zebaze R, Libanati C, McClung MR, Zanchetta JR, Kendler DL, Høiseth A, Wang A, Ghasem-Zadeh A, Seeman E. Denosumab reduces cortical porosity of the proximal femoral shaft in postmenopausal women with osteoporosis. J Bone Miner Res. 2016;31(10):1827–34.

    Article  CAS  PubMed  Google Scholar 

  13. Andika GD, Nugraha GKAS, Sunaria IM, Astawa P, Wiratnaya IGE, Maharjana MA. Pathological fracture of subtrochanter femur, soft tissue infection along the fracture site, shaft femur bone cortex thickening and blastic lesion on contralateral shaft femur due to renal osteodystrophy on the end stage renal disease patient: a case report. Int J Res Med Sci. 2020;8:3715–9.

    Article  Google Scholar 

  14. Nijhuis WH, Eastwood DM, Allgrove J, Hvid I, Weinans HH, Bank RA, Sakkers RJ. Current concepts in osteogenesis imperfecta: bone structure, biomechanics and medical management. J Child Orthop. 2019;13(1):1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Villa-Suárez JM, García-Fontana C, Andújar-Vera F, González-Salvatierra S, de Haro-Muñoz T, Contreras-Bolívar V, García-Fontana B, Muñoz-Torres M. Hypophosphatasia: a unique disorder of bone mineralization. Int J Mol Sci. 2021;22(9):4303.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Black DM, Bauer DC, Vittinghoff E, Lui LY, Grauer A, Marin F, Khosla S, de Papp A, Mitlak B, Cauley JA, McCulloch C, Eastell R, Bouxsein ML, Foundation for the National Institutes of Health Bone Quality Project. Foundation for the National Institutes of Health Bone Quality Project. Treatment-related changes in bone mineral density as a surrogate biomarker for fracture risk reduction: meta-regression analyses of individual patient data from multiple randomised controlled trials. Lancet Diabetes Endocrinol. 2020;8(8):672-682.

  17. Zebaze RM, Ghasem-Zadeh A, Bohte A, Iuliano-Burns S, Mirams M, Price RI, Mackie EJ, Seeman E. Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study. Lancet. 2010;375(9727):1729–36.

    Article  PubMed  Google Scholar 

  18. Allen D, Schriever WR. Progressive collapse, abnormal loads and building codes. In: Structural failures: modes, causes, responsibilities. New York, NY: American Society of Civil Engineers; 1973. p. 21–48.

    Google Scholar 

  19. Di Cataldo S, Ficarra E. Mining textural knowledge in biological images: applications, methods and trends. Comput Struct Biotechnol J. 2016;15:56–67. https://doi.org/10.1016/j.csbj.2016.11.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schousboe JT, Vo T, Taylor BC, Cawthon PM, Schwartz AV, Bauer DC, Orwoll ES, Lane NE, Barrett-Connor E, Ensrud KE, for the Osteoporotic Fractures in Men (MrOS) Study Research Group. Prediction of incident major osteoporotic and hip fractures by Trabecular Bone Score (TBS) and prevalent radiographic vertebral fracture in older men. J Bone Miner Res. 2016;31(3):690–7. https://doi.org/10.1002/jbmr.2713.

    Article  CAS  PubMed  Google Scholar 

  21. Li G, Yin J, Gao J, Cheng TS, Pavlos NJ, Zhang C, Zheng MH. Subchondral bone in osteoarthritis: insight into risk factors and microstructural changes. Arthritis Res Ther. 2013;15:223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Guilak F. Biomechanical factors in osteoarthritis. Best Pract Res Clin Rheumatol. 2011;25(6):815–23.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Li G, Yin J, Gao J, Cheng TS, Pavlos NJ, Zhang C, Zheng MH. Subchondral bone in osteoarthritis: insight into risk factors and microstructural changes. Arthritis Res Ther. 2013;15:223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Beck C, Morbach H, Wirth C, Beer M, Girschick HJ. Whole-body MRI in the childhood form of hypophosphatasia. Rheumatol Int 2011; 31:1315–1320.

  25. Sun HB. Mechanical loading, cartilage degradation, and arthritis. Ann N Y Acad Sci. 2010;1211:37–50.

    Article  CAS  PubMed  Google Scholar 

  26. Loi F, Córdova LA, Pajarinen J, Lin TH, Yao Z, Goodman SB. Inflammation, fracture and bone repair. Bone. 2016;86:119–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhu J, Zhu Y, Xiao W, Hu Y, Li Y. Instability and excessive mechanical loading mediate subchondral bone changes to induce osteoarthritis. Ann Transl Med. 2020;8(6):350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kelley N, Jeltema D, Duan Y, He Y. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int J Mol Sci. 2019;20(13):3328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang Z, Zhang S, Xiao Y, Zhang W, Wu S, Qin T, Yue Y, Qian W, Li L. NLRP3 inflammasome and inflammatory diseases. Oxid Med Cell Longev. 2020;2020:4063562–11.

    PubMed  PubMed Central  Google Scholar 

  30. Maruyama M, Rhee C, Utsunomiya T, Zhang N, Ueno M, Yao Z, Goodman SB. Modulation of the inflammatory response and bone healing. Front Endocrinol (Lausanne). 2020;11:386.

    Article  PubMed  Google Scholar 

  31. Nencini S, Ivanusic JJ. The physiology of bone pain. How much do we really know? Front Physiol. 2016;7:157.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Gowen M, Lazner F, Dodds R, Kapadia R, Feild J, Tavaria M, Bertoncello I, Drake F, Zavarselk S, Tellis I, Hertzog P, Debouck C, Kola I. Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res. 1999;14(10):1654–63.

    Article  CAS  PubMed  Google Scholar 

  33. Loder RT. The influence of diabetes mellitus on the healing of closed fractures. Clin Orthop Relat Res. 1988;232:210–6.

    Article  Google Scholar 

  34. Temponi EF, de Carvalho Junior LH, Costa LP. Atypical femoral fracture due to chronic use of bisphosphonates: case report. Rev Bras Ortop. 2015;50(4):482–5.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gregory DR, Sui LK, Hans-Christoph P. Periprosthetic fractures: epidemiology and future projections. J Orthop Trauma. 2011;25:S66–70.

    Article  Google Scholar 

  36. El Demellawy D, Davila J, Shaw A, Nasr Y. Brief review on metabolic bone disease. Acad Forensic Pathol. 2018;8(3):611–40.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Sato H, Kondo N, Wakamatsu A, Kobayashi D, Nakatsue T, Wada Y, Kuroda T, Suzuki Y, Nakano M, Endo N, Narita I. High bisphosphonate treatment rates and the prevalence of atypical femoral fractures in patients with systematic lupus erythematosus: a single-center retrospective study performed in Japan. Rheumatol Int. 2019;39(10):1803–10.

    Article  CAS  PubMed  Google Scholar 

  38. Koh JH, Myong JP, Jung SM, Lee J, Kwok SK, Park SH, Ju JH. Atypical femoral fracture in rheumatoid arthritis patients treated with bisphosphonates: a nested case-control study. Arthritis Rheumatol. 2016;68(1):77–82.

    Article  CAS  PubMed  Google Scholar 

  39. Oh D, Huh SJ. Insufficiency fracture after radiation therapy. Radiat Oncol J. 2014;32(4):213–20. https://doi.org/10.3857/roj.2014.32.4.213.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Celii FG, Beckmann NM. Radiation-induced insufficiency fracture of the femur 18 years after radiation therapy. Radiol Case Rep. 2018;14(2):179–83.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Howland WJ, Loeffler RK, Starchman DE, Johnson RG. Post irradiation atrophic changes of bone and related complications. Radiology. 1975;117(3 Pt 1):677–85.

    Article  CAS  PubMed  Google Scholar 

  42. Pastores GM, Einhorn TA. Skeletal complications of Gaucher disease: pathophysiology, evaluation, and treatment. Sem Hematol. 1995;32(Suppl 1):20–7.

    Google Scholar 

  43. van der Veer E, van der Goot W, de Monchy JG, Kluin-Nelemans HC, van Doormaal JJ. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy. 2012;67(3):431–8.

    Article  PubMed  Google Scholar 

  44. Hughes RA. Arthritis precipitated by isotretinoin treatment for acne vulgaris. J Rheumatol. 1993;20(7):1241–2.

    CAS  PubMed  Google Scholar 

  45. Krebs NM, Krebs RC, Yaish AM. Femoral osteomyelitis presenting as a pathologic fracture in a 53-year-old male: a rare case report. J Orthop Case Rep. 2017;7(6):85–8. https://doi.org/10.13107/jocr.2250-0685.962.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Bouchette P, Boktor SW. Paget disease. 2021 Jul 13. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–.

  47. Appelman-Dijkstra NM, Papapoulos SE. Paget’s disease of bone. Best Pract Res Clin Endocrinol Metab. 2018;32(5):657–68.

    Article  PubMed  Google Scholar 

  48. Sepehri NZ, Raeisi T, Razi B, Janmohammadi P, Darand M, Alizadeh S. The association between psoriasis and psoriatic arthritis with the risk of osteoporosis, osteopenia and bone fractures: a systematic review and meta-analysis. Int J Clin Pract. 2021;75(11):e14630.

    Article  PubMed  Google Scholar 

  49. Caffarelli C, Gonnelli S, Tomai Pitinca MD, Francolini V, Fui A, Bargagli E, Refini RM, Bennett D, Nuti R, Rottoli P. Idiopathic pulmonary fibrosis a rare disease with severe bone fragility. Intern Emerg Med. 2016;11(8):1087–94.

    Article  PubMed  Google Scholar 

  50. Atteritano M, Sorbara S, Bagnato G, Miceli G, Sangari D, Morgante S, Visalli E, Bagnato G. Bone mineral density, bone turnover markers and fractures in patients with systemic sclerosis: a case control study. PLoS ONE. 2013;8(6):e66991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Beck BR, Daly RM, Singh MA, Taaffe DR. Exercise and Sports Science Australia (ESSA) position statement on exercise prescription for the prevention and management of osteoporosis. J Sci Med Sport. 2017;20(5):438–45.

    Article  PubMed  Google Scholar 

  52. Limaiem F, Byerly DW, Singh R. Osteoblastoma. 2022 May 2. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing

  53. Wordsworth P, Chan M. Melorheostosis and osteopoikilosis: a review of clinical features and pathogenesis. Calcif Tissue Int. 2019;104:530–43.

    Article  CAS  PubMed  Google Scholar 

  54. Slavchev SA, Georgiev GP. A non-ossifying fibroma and a stress fracture of the femur mimicking bone malignancy in a child. Cureus. 2020;12(4):e7652. Published 2020 Apr 12. https://doi.org/10.7759/cureus.7652.

  55. Chiu E, Cabanero M, Sidhu G. Paradoxical stress fracture in a patient with multiple myeloma and bisphosphonate use. Cureus. 2020;12(8):e9837. Published 2020 Aug 18. https://doi.org/10.7759/cureus.9837.

  56. Gartrell BA, Saad F. Pathologic fracture in patients with metastatic prostate cancer. Curr Opin Urol. 2014;24(6):595–600.

    Article  PubMed  Google Scholar 

  57. Seref-Ferlengez Z, Kennedy OD, Schaffler MB. Bone microdamage, remodeling and bone fragility: how much damage is too much damage? Bonekey Rep. 2015;4:644. https://doi.org/10.1038/bonekey.2015.11.

  58. Cohen-Solal M, Funck-Brentano T, Ureña TP. Bone fragility in patients with chronic kidney disease. Endocr Connect. 2020;9(4):R93–R101. https://doi.org/10.1530/EC-20-0039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Liu YZ, Akhter MP, Gao X, Wang XY, Wang XB, Zhao G, Wei X, Wu HJ, Chen H, Wang D, Cui L. Glucocorticoid-induced delayed fracture healing and impaired bone biomechanical properties in mice. Clin Interv Aging. 2018;13:1465–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Dubrovsky AM, Nyman JS, Uppuganti S, Chmiel KJ, Kimmel DB, Lane NE. Bone strength/bone mass discrepancy in glucocorticoid-treated adult mice. JBMR Plus. 2020;5(3):e10443.

    PubMed  PubMed Central  Google Scholar 

  61. Kim JT, Cha YH, Jeong S, Yoo JI, Park CH. Subtrochanteric atypical femoral fracture induced solely by glucocorticoid without bisphosphonate treatment: a case report. Osteoporos Int. 2021;32(10):2115–8.

    Article  PubMed  Google Scholar 

  62. Allon M, Litovsky SH, Tey JCS, Sundberg CA, Zhang Y, Chen Z, Fang Y, Cheung AK, Shiu YT. Abnormalities of vascular histology and collagen fiber configuration in patients with advanced chronic kidney disease. J Vasc Access. 2019;20(1):31–40.

    Article  PubMed  Google Scholar 

  63. Aoki C, Uto K, Honda K, Kato Y, Oda H. Advanced glycation end products suppress lysyl oxidase and induce bone collagen degradation in a rat model of renal osteodystrophy. Lab Invest. 2013;93:1170–83.

    Article  CAS  PubMed  Google Scholar 

  64. Ketteler M, Leonard MB, Block GA, Shroff R, Evenepoel P, Tonelli MA. KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl (2011). 2017;7(1):1–59.

    Article  Google Scholar 

  65. Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol. 2014;18(1):1–14. https://doi.org/10.4196/kjpp.2014.18.1.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hsieh CL, Yang MH, Chyau CC, Chiu CH, Wang HE, Lin YC, Chiu WT, Peng RY. Kinetic analysis on the sensitivity of glucose- or glyoxal-induced LDL glycation to the inhibitory effect of Psidium guajava extract in a physiomimic system. Biosystems. 2007;88:92–100.

    Article  CAS  PubMed  Google Scholar 

  67. Avery NC, Bailey AJ. The effects of the Maillard reaction on the physical properties and cell interactions of collagen. Pathol Biol (Paris). 2006;54(7):387–95.

    Article  CAS  PubMed  Google Scholar 

  68. Acevedo C, Sylvia M, Schaible E, Graham JL, Stanhope KL, Metz LN, Gludovatz B, Schwartz AV, Ritchie RO, Alliston TN, Havel PJ, Fields AJ. Contributions of material properties and structure to increased bone fragility for a given bone mass in the UCD-T2DM rat model of type 2 diabetes. J Bone Miner Res. 2018;33(6):1066–75.

    Article  CAS  PubMed  Google Scholar 

  69. Willett TL, Voziyan P, Nyman JS. Causative or associative: a critical review of the role of advanced glycation end-products in bone fragility. Bone. 2022;163:116485. https://doi.org/10.1016/j.bone.2022.116485.

    Article  CAS  PubMed  Google Scholar 

  70. Ghebremariam YT, Cooke JP, Gerhart W, Griego C, Brower JB, Doyle-Eisele M, Moeller BC, Zhou Q, Ho L, de Andrade J, Raghu G, Peterson L, Rivera A, Rosen GD. Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis. J Transl Med. 2015;13:249.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Sugiyama T, Watarai K, Oda T, Kim YT, Oda H. Proton pump inhibitors and fracture: they impair bone quality and increase fall risk? Osteoporos Int. 2016;27:1675–6.

    Article  CAS  PubMed  Google Scholar 

  72. Jo Y, Park E, Ahn SB, Jo YK, Son B, Kim SH, Park YS, Kim HJ. A proton pump inhibitor’s effect on bone metabolism mediated by osteoclast action in old age: a prospective randomized study. Gut Liver. 2015;9(5):607–14. https://doi.org/10.5009/gnl14135.

    Article  CAS  PubMed  Google Scholar 

  73. Gaston MS, Simpson AH. Inhibition of fracture healing. J Bone Joint Surg Br. 2007;89(12):1553–60.

    Article  CAS  PubMed  Google Scholar 

  74. Liu W, Kang N, Seriwatanachai D, Dong Y, Zhou L, Lin Y, Ye L, Liang X, Yuan Q. Chronic kidney disease impairs bone defect healing in rats. Sci Rep. 2016;6:23041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Helfrich MH. Osteoclast diseases. Microsc Res Tech. 2003;61(6):514–32.

    Article  PubMed  Google Scholar 

  76. Teti A, Econs ME. Osteopetroses, emphasizing potential approaches to treatment. Bone. 2017;102:50–9.

    Article  CAS  PubMed  Google Scholar 

  77. Wu CC, Econs MJ, DiMeglio LA, Insogna KL, Levine MA, Orchard PJ, Miller WP, Petryk A, Rush ET, Shoback DM, Ward LM, Polgreen LE. Diagnosis and management of osteopetrosis: consensus guidelines from the Osteopetrosis Working Group. J Clin Endocrinol Metab. 2017;102(9):3111–23.

    Article  PubMed  Google Scholar 

  78. Drake MT, Clarke BL, Oursler MJ, Khosla S. Cathepsin K inhibitors for osteoporosis: biology, potential clinical utility, and lessons learned. Endocr Rev. 2017;38(4):325–50.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Fratzl-Zelman N, Valenta A, Roschger P, Nader A, Gelb BD, Fratzl P, Klaushofer K. Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis. J Clin Endocrinol Metab. 2004;89(4):1538–47.

    Article  CAS  PubMed  Google Scholar 

  80. Bizaoui V, Michot C, Baujat G, Amouroux C, Baron S, Capri Y, Cohen-Solal M, Collet C, Dieux A, Genevieve D, Isidor B, Monnot S, Rossi M, Rothenbuhler A, Schaefer E, Cormier-Daire V. Pycnodysostosis: natural history and management guidelines from 27 French cases and a literature review. Clin Genet. 2019;96:309–16.

    Article  CAS  PubMed  Google Scholar 

  81. Black DM, Abrahamsen B, Bouxsein ML, Einhorn T, Napoli N. Atypical femur fractures: review of epidemiology, relationship to bisphosphonates, prevention, and clinical management. Endocr Rev. 2019;40(2):333–68.

    Article  PubMed  Google Scholar 

  82. Lo JC, Grimsrud CD, Ott SM, Chandra M, Hui RL, Ettinger B. Atypical femur fracture incidence in women increases with duration of bisphosphonate exposure. Osteoporos Int. 2019;30(12):2515–20. https://doi.org/10.1007/s00198-019-05112-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Anastasilakis AD, Makras P, Yavropoulou MP, Tabacco G, Naciu AM, Palermo A. Denosumab discontinuation and the rebound phenomenon: a narrative review. J Clin Med. 2021;10(1):152. https://doi.org/10.3390/jcm10010152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Black DM, Geiger EJ, Eastell R, Vittinghoff E, Li BH, Ryan DS, Dell RM, Adams AL. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med. 2020;383(8):743–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. van de Laarschot DM, McKenna MJ, Abrahamsen B, et al. Medical management of patients after atypical femur fractures: a systematic review and recommendations from the European Calcified Tissue Society. J Clin Endocrinol Metab. 2020;105(5):1682–99.

    Article  PubMed  Google Scholar 

  86. Ettinger B, Burr DB, Ritchie RO. Proposed pathogenesis for atypical femoral fractures: lessons from materials research. Bone. 2013;55(2):495–500. https://doi.org/10.1016/j.bone.2013.

    Article  CAS  PubMed  Google Scholar 

  87. Allen MR, Gineyts E, Leeming DJ, Burr DB, Delmas PD. Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra. Osteoporos Int. 2008;19(3):329–37.

    Article  CAS  PubMed  Google Scholar 

  88. Jo Y, Park E, Ahn SB, Jo YK, Son B, Kim SH, Park YS, Kim HJ. A proton pump inhibitor’s effect on bone metabolism mediated by osteoclast action in old age: a prospective randomized study. Gut Liver. 2015;9(5):607–14. https://doi.org/10.5009/gnl14135.

    Article  CAS  PubMed  Google Scholar 

  89. Bi H, Chen X, Gao S, et al. Key triggers of osteoclast-related diseases and available strategies for targeted therapies: a review. Front Med (Lausanne). 2017;4:234.

    Article  PubMed  Google Scholar 

  90. Hinton A, Bond S, Forgac M. V-ATPase functions in normal and disease processes. Pflugers Arch. 2009;457(3):589–98.

    Article  CAS  PubMed  Google Scholar 

  91. Gregory DR, Sui LK, Hans-Christoph P. Periprosthetic fractures: epidemiology and future projections. J Orthop Trauma. 2011;25:S66–70.

    Article  Google Scholar 

  92. Bokov A, Isrelov A, Skorodumov A, Aleynik A, Simonov A, Mlyavykh S. An analysis of reasons for failed back surgery syndrome and partial results after different types of surgical lumbar nerve root decompression. Pain Phys. 2011;14:545–57.

    Article  Google Scholar 

  93. Koc D, Dogan A, Bek B. Bite force and influential factors on bite force measurements: a literature review. Eur J Dent. 2010 Apr;4(2):223-232.

  94. Bauer A, Jäncke L, Kalveram KT. Mechanical perturbation of jaw movements during speech: effects on articulation and phonation. Percept Motor Skills. 1995;80(3_suppl):1108-1112.

  95. Chang J, Hakam AE, McCauley LK. Current understanding of the pathophysiology of osteonecrosis of the jaw. Curr Osteoporos Rep. 2018;16(5):584–95.

    Article  CAS  PubMed  Google Scholar 

  96. Ryan JL, Larson E. Osteonecrosis of the torus palatinus in the setting of long-term oral bisphosphonate use--a case report. S D Med. 2016;69(1):23–5.

    PubMed  Google Scholar 

  97. Sim IW, Borromeo GL, Tsao C, Hardiman R, Hofman MS, Papatziamos Hjelle C, Siddique M, Cook GJR, Seymour JF, Ebeling PR. Teriparatide promotes bone healing in medication-related osteonecrosis of the jaw: a placebo-controlled, randomized trial. J Clin Oncol. 2020;38(26):2971–80. https://doi.org/10.1200/JCO.19.02192.

    Article  PubMed  Google Scholar 

  98. Zebaze R, Nguyen HH, Shore-Lorenti C, Chiang C, Napoli N, Milat F, Ebeling PR. Misalignment by producing ineffective load conduction may be responsible for atypical femoral fractures (AFFs). The 22nd World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, WCO-IOF-ESCEO 2022, Berlin, Germany.

  99. Khosla S, Shane E. A crisis in the treatment of osteoporosis. J Bone Miner Res. 2016;31(8):1485–7. This interesting review highlights problems in the treatment of patients with osteoporosis due to the inability of current tools to identify the minority that sustains atypical fracture.

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Authors and Affiliations

  1. Department of Medicine, School of Clinical Sciences, Monash University, Level 5, Block E, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, 3168, Australia

    Roger Zebaze & Peter Robert Ebeling

  2. Department of Endocrinology, Monash Health, Clayton, Victoria, Australia

    Peter Robert Ebeling

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  1. Roger Zebaze
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  2. Peter Robert Ebeling
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Correspondence to Roger Zebaze.

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Zebaze, R., Ebeling, P.R. Disorganization and Musculoskeletal Diseases: Novel Insights into the Enigma of Unexplained Bone Abnormalities and Fragility Fractures. Curr Osteoporos Rep 21, 154–166 (2023). https://doi.org/10.1007/s11914-022-00759-2

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