Molecular foundations of the etiology and pathogenesis of Legg-Calve-Perthes disease and prospects for targeted therapy: A literature review

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access


BACKGROUND: The etiology and pathogenesis of the development of Legg–Calve–Perthes disease, despite intensive research, remains not fully understood. Most studies have concluded about the multifactorial genesis of the development of hip osteochondropathy. Moreover, a complete understanding of all elements of pathogenesis leading to the manifestation and the progressive development of aseptic necrosis make it possible to develop targeted antiresorptive therapy. At present, several studies have investigated impaired functioning of signaling pathways that influence bone homeostasis during the development of Legg–Calve–Perthes disease. In addition, impaired metabolism in avascular necrosis is characterized by significant complexity and heterogeneity, which is based on aseptic inflammation associated with ischemic stress. Concepts of antiresorptive therapy were developed based on the results of studies on the pathogenesis of Legg–Calve–Perthes disease. Nevertheless, these treatment algorithms have not achieved wide practical application and require further investigation.

AIM: This study aimed to conduct a literary analysis of the molecular basis of the etiology and pathogenesis of Legg–Calve–Perthes disease and assess the prospects of therapy aimed at correcting bone homeostasis disorders.

MATERIALS AND METHODS: Data sources were PubMed, Medline, Scopus, Web of Science, and RSCI databases, without language restrictions.

RESULTS: The relationship between ischemic stress and the induction of a cytokine cascade with a predominance of the biological actions of proinflammatory cytokines, with parallel activation of intracellular regulatory networks that determine osteoresorptive processes, including due to pyroptosis, is shown. Data on the possibility of various variants of targeted antiresorptive therapy with the use of genetically engineered drugs are presented.

CONCLUSIONS: The pathogenesis of Legg–Calve–Perthes disease is characterized by significant genetic heterogeneity with the induction of various mediators of inflammation, angiogenesis, and osteogenesis, depending on the disease stage. Investigating features of impaired bone homeostasis regulation in the case of Legg–Calve–Perthes disease at the molecular and cellular level opens up opportunities for the development and clinical application of personalized therapy.

Full Text

Restricted Access

About the authors

Nikita A. Shabaldin

Kemerovo State Medical University

Author for correspondence.
ORCID iD: 0000-0001-8628-5649
SPIN-code: 6283-2581
Scopus Author ID: 57209570350

MD, PhD, Cand. Sci. (Med.), Assistant Professor

Russian Federation, Kemerovo

Andrei V. Shabaldin

Kemerovo State Medical University

ORCID iD: 0000-0002-8785-7896
SPIN-code: 5281-0065

MD, PhD, Dr. Sci. (Med.), Assistant Professor

Russian Federation, Kemerovo


  1. Wiig O, Terjesen T, Svenningsen S, Lie SA. The epidemiology and aetiology of Perthes’ disease in Norway. A nationwide study of 425 patients. J Bone Joint Surg Br. 2006;88:1217−1223. doi: 10.1302/0301-620X.88B9.17400
  2. Margetts BM, Perry CA, Taylor JF, Dangerfield PH. The incidence and distribution of Legg-Calvé-Perthes’ disease in Liverpool, 1982-95. Arch Dis Child. 2001;84(35):1−4.
  3. Gray IM, Lowry RB, Renwick DH. Incidence and genetics of Legg-Perthes disease (osteochondritisdeformans) in British Columbia: evidence of polygenic determination. J MedGenet. 1972;9:197−202.
  4. Perry DC. The epidemiology and etiology of Perthes’ Disease. Osteonecrosis. 2014:419–425. doi: 10.1007/978-3-642-35767-1_58
  5. Johansson T, Lindblad M, Bladh M, et al. Incidence of Perthes’ disease in children born between 1973 and 1993. Acta Orthop. 2017;88:96−100. doi: 10.1080/17453674.2016.1227055
  6. Randall T, Elaine N. The epidemiology and demographics of Legg–Calvé–Perthes disease. IRSN Orthop. 2011. doi: 10.5402/2011/504393
  7. Wiig O, Terjesen T, Svenningsen S. Prognostic factors and outcome of treatment in Perthes’ disease: a prospective study of 368 patients with five-year follow-up. J Bone Joint Surg Br. 2008;90(10):1364–1371. doi: 10.1302/0301-620X.90B10.20649
  8. Herring JA, Kim HT, Browne R. Legg-Calve-Perthes disease. Part II: prospective multicenter study of the effect of treatment on outcome. J Bone Joint Surg Am. 2004;86(10):2121–3214. doi: 10.1007/978-1-4471-5451-8_146
  9. Meiss AL, Barvencik F, Babin K, Eggers-Stroeder G. Denosumab and surgery for the treatment of Perthes’ disease in a 9-year-old boy: favorable course documented by comprehensive imaging – a case report. Acta Orthop. 2017;88(3):354−357. doi: 10.1080/17453674.2017.1298020
  10. Atsumi T, Yamano K, Muraki M, et al. The blood supply of the lateral epiphyseal arteries in Perthes’ disease. J Bone Joint Surg Br. 2000;82(3):392−398.
  11. Conway JJ. A scintigraphic classification of Legg-Calve-Perthes disease. Semin Nucl Med. 1993;23(4):274−295.
  12. Lamer S, Dorgeret S, Khairouni A, et al. Femoral head vascularisation in Legg-Calve-Perthes disease: comparison of dynamic gadolinium-enhanced subtraction MRI with bone scintigraphy. Pediatr Radiol. 2002;32(8):580−585.
  13. Lobov IL, Malkov АV, Lobov NI. Analysis of the physical growth and markers of connective tissue dysplasia in patients with Perthes disease. Pediatric Traumatology, Orthopaedics and Reconstructive Surgery. 2018;6(2):12−21. doi: 10.17816/PTORS6212-21. (In Russ.)
  14. Ponseti IV. Legg-Perthes disease; observations on pathological changes in two cases. J Bone Joint Surg Am. 1956;38(4):739–750.
  15. Kamiya N, Yamaguchi R, Adapala NS, et al. Legg-Calvé-Perthes disease produces chronic hip synovitis and elevation of interleukin-6 in the synovial fluid. J Bone Miner Res. 2015;30(6):1009–1013. doi: 10.1002/jbmr.2435
  16. Sanchis M, Zahir A, Freeman MA. The experimental simulation of Perthes disease by consecutive interruptions of the blood supply to the capital femoral epiphysis in the puppy. J Bone Joint Surg Am. 1973;55(2):335−342.
  17. Catterall A, Pringle J, Byers PD, et al. Perthes’ disease: is the epiphyseal infarction complete? J Bone Joint Surg Br. 1982;64(3):276−281.
  18. Inoue A, Freeman MA, Vernon-Roberts B, Mizuno S. The pathogenesis of Perthes’ disease. J Bone Joint Surg Br. 1976;58-B(4):453−461.
  19. Kim HK, Su PH. Development of flattening and apparent fragmentation following ischemic necrosis of the capital femoral epiphysis in a piglet model. J Bone Joint Surg Am. 2002;84(8):1329−1334.
  20. Kim HKW, Wiesman K, Kulkarni V, et al. Perfusion MRI in early stage of Legg-Calvé-Perthes disease to predict lateral pillar involvement. J Bone Joint Surg. 2014;96(14):1152-1160. doi: 10.2106/JBJS.M.01221
  21. Woratanarat P, Thaveeratitharm C, Woratanarat T, et al. Meta-analysis of hypercoagulability genetic polymorphisms in perthes disease. J Orthop Res. 2013;32(1):1−7. doi: 10.1002/jor.22473
  22. Balasa VV, Gruppo RA, Glueck CJ, et al. Legg-Calve-Perthes disease and thrombophilia. J Bone Joint Surg Am. 2004;86(12):2642−2647.
  23. Eldridge J, Dilley A, Austin H, et al. The role of protein C, protein S, and resistance to activated protein C in Legg-Perthes disease. Pediatrics. 2001;107:1329−1334.
  24. Nurullina GM, Ahmadullina GM. Bone remodeling in norm and in primary osteoporosis: the significance of bone remodeling markers. The Russian Archives of Internal Medicine. 2018;8(2):100−110. (In Russ.). doi: 10.20514/2226-6704-2018-8-2-100-110
  25. Gershtein ES, Timofeev YuS, Zuev AA, Kushlinskii NE. RANK/RANKL/OPG ligand-receptor system and its role in primary bone neoplasms (literature analysis and own data). Advances in Molecular Oncology. 2015;2(3):51–59. (In Russ.). doi: 10.17650/2313-805X-2015-2-3-51-59
  26. Korshunova EYu, Dmitrieva LA, Lebedev VF. Tsitokinovaya regulyatsiya metabolizma kostnoy tkani. Politravma. 2012;3:82−86. (In Russ.)
  27. Yamaguchi R, Kamiya N, Adapala NS, et al. HIF-1-dependent IL-6 activation in articular chondrocytes initiating synovitis in femoral head ischemic osteonecrosis. J Bone Joint Surg. 2016;98:1122−1131. doi: 10.2106/JBJS.15.01209
  28. Srzentic S, Spasovski V, Spasovski D, et al. Association of gene variants in TLR4 and IL-6 genes with Perthes disease. Srpski Arhiv Za Celokupno Lekarstvo. 2014;142(7−8):450−456. doi: 10.2298/SARH1408450S
  29. Adapala NS, Yamaguchi R, Phipps M, et al. Necrotic bone stimulates proinflammatory responses in macrophages through the activation of Toll-like receptor 4. Am J Pathol. 2016;186(11):2987−2999. doi: 10.1016/j.ajpath.2016.06.024
  30. Kamiya N, Kim HKW. Elevation of proinflammatory cytokine HMGB1 in the synovial fluid of patients with Legg-Calvé-Perthes disease and correlation with IL-6. JBMR Plus. 2021;5(2):e10429. doi: 10.1002/jbm4.10429
  31. Aleksandrova EN, Novikov AA, Nasonov EL. Current approaches to the laboratory diagnosis of rheumatic diseases: role of molecular and cellular biomarkers. Rheumatology Science and Practice. 2016;54(3):324−338. (In Russ.). doi: 10.14412/1995-4484-2016-324-338
  32. Torshin IYu, Gromova OA, Lila AM, et al. The results of postgenomic analysis of a glucosamine sulfate molecule indicate the prospects of treatment for comorbidities. Modern Rheumatology Journal. 2018;12(4):129−136. (In Russ.). doi: 10.14412/1996-7012-2018-4-129-136
  33. Gromova OA, Torshin IYu., Lila AM, et al. Standardised forms of chondroitin sulfate as a pathogenetic treatment of osteoarthritis in the context of post-genomic studies. Modern Rheumatology Journal. 2021;15(1):136−143. (In Russ.). doi: 10.14412/1996-7012-2021-1-136-143
  34. Huang Q, Lia B, Lin C, Chen X, et al. MicroRNA sequence analysis of plasma exosomes in early Legg–Calvé–Perthes disease. Cellular Signalling. 2022;91. doi: 10.1016/j.cellsig.2021.110184
  35. Hufeland M, Rahner N, Krauspe R. Trichorhinophalangeal syndrome type I: a novel mutation and Perthes-like changes of the hip in a family with 4 cases over 3 generations. J Pediatr Orthop. 2015;35(1):e1−5. doi: 10.1097/BPO.0000000000000330
  36. Gilman JL, Newman HA, Freeman R, et al. Two cases of Legg-Perthes and intellectual disability in Tricho-Rhino-Phalangeal syndrome type 1 associated with novel TRPS1 mutations. Am J Med Genet A. 2017;173(6):1663−1667. doi: 10.1002/ajmg.a.38204
  37. Kung LHW, Sampurnoa L, Yamminec KM, et al. CRISPR/Cas9 editing to generate a heterozygous COL2A1 p.G1170S human chondrodysplasia iPSC line, MCRIi019-A-2, in a control iPSC line, MCRIi019-A. Stem Cell Research. 2020;48. doi: 10.1016/j.scr.2020.101962
  38. Kannu P, Irving M, Aftimos S, Savarirayan R. Two novel COL2A1 mutations associated with a Legg-Calvé-Perthes disease-like presentation. Clin Orthop Relat Res. 2011;469(6):1785−1790.
  39. Su P, Li R, Liu S, et al. Age at onset-dependent presentations of premature hip osteoarthritis, avascular necrosis of the femoral head, or Legg-Calve-Perthes disease in a single family, consequent upon a p.Gly1170Ser mutation of COL2A1. Arthritis Rheum. 2008;58(6):1701−1706.
  40. Higuchi Y, Hasegawa K, Yamashita M, et al. A novel mutation in the COL2A1 gene in a patient with Stickler syndrome type 1: a case report and review of the literature. J Med Case Rep. 2017;11. doi: 10.1186/s13256-017-1396-y
  41. Dasa V, Eastwood JRB, Podgorski M, et al. Exome sequencing reveals a novel COL2A1 mutation implicated in multiple epiphyseal dysplasia. Am J Med Genet. 2019;179(4):534−541. doi: 10.1002/ajmg.a.61049
  42. Adapala NS, Kim HKW. Comprehensive genome-wide transcriptomic analysis of immature articular cartilage following ischemic osteonecrosis of the femoral head in piglets. Plos One. 2016;11(4):e0153174. doi: 10.1371/journal.pone.0153174
  43. Gromova OA, Torshin IYu, Lila AM, Gromov AN. Molecular mechanisms of action of glucosamine sulfate in the treatment of degenerative-dystrophic diseases of the joints and spine: results of proteomic analysis. Neurology, Neuropsychiatry, Psychosomatics. 201810(2):38−44. (In Russ.). doi: 10.14412/2074-2711-2018-2-38-44
  44. Pastushkova LH, Goncharova AG, Vasilyeva GYu, et al. Search for blood proteome proteins involved in the regulation of bone remodeling in astronauts. Human Physiology. 2019;45(5):91−98. (In Russ.). doi: 10.1134/S0131164619050126
  45. Young ML, Little DG, Kim HKW. Evidence for using bisphosphonate to treat Legg-Calvé-Perthes disease. Clin Orthop Relat Res. 2012;470:2462–2475. doi: 10.1007/s11999-011-2240-0
  46. Kim HKW, Sanders M, Athavale S, et al. Local bioavailability and distribution of systemically (parenterally) administered ibandronate in the infarcted femoral head. Bone. 2006;39(1):205−212. doi: 10.1016/j.bone.2005.12.019
  47. Vandermeer JS, Kamiya N, Aya-ay J, et al. Local administration of ibandronate and bonemorphogenetic protein-2 after ischemic osteonecrosis of the immature femoral head: a combined therapy that stimulates bone formation and decreases femoral head deformity. J Bone Joint Surg Am. 2011;93(10):905−913. doi: 10.2106/JBJS.J.00716
  48. Little DG, Peat RA, Mcevoy A, et al. Zoledronic acid treatment results in retention of femoral head structure after traumatic osteonecrosis in young Wistar rats. J Bone Miner Res. 2009;18(11):2016–2022. doi: 10.1359/jbmr.2003.18.11.2016
  49. Kim HK, Randall TS, Bian H, et al. Ibandronate for prevention of femoral head deformity after ischemic necrosis of the capital femoral epiphysis in immature pigs. J Bone Joint Surg. 2005;87(3):550–557. doi: 10.2106/JBJS.D.02192
  50. Aruwajoye O, Aswath PB, Kim HK. Material properties of bone in the femoral head treated with ibandronate and BMP-2 following ischemic osteonecrosis. J Orthop Res. 2017;35(7):1453–1460. doi: 10.1002/jor.23402
  51. Kim HK, Aruwajoye O, Du J, Kamiya N. Local administration of bone morphogenetic protein-2 and bisphosphonate during non-weight-bearing treatment of ischemic osteonecrosis of the femoral head: an experimental investigation in immature pigs. J Bone Joint Surg Am. 2014;96(18):1515–1524. doi: 10.2106/JBJS.M.01361
  52. Chen CH, Chang JK, Lai KA, et al. Alendronate in the prevention of collapse of the femoral head in nontraumatic osteonecrosis: a two-year multicenter, prospective, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2012;64(5):1572–1578. doi: 10.1002/art.33498
  53. Yuan HF, Guo CA, Yan ZQ. The use of bisphosphonate in the treatment of osteonecrosis of the femoral head: a meta-analysis of randomized control trials. Osteoporos Int. 2016;27:295–299. doi: 10.1007/s00198-015-3317-5
  54. Li D, Yang Z, Wei Z, Kang P. Efficacy of bisphosphonates in the treatment of femoral head osteonecrosis: A PRISMA – compliant meta-analysis of animalstudies and clinical trials. Scientific Reports. 2018;8:1450. doi: 10.1038/s41598-018-19884-z
  55. Russell RG, Xia Z, Dunford JE, et al. Bisphosphonates: an update on mechanisms of action and how these relate toclinical efficacy. Ann NY Acad Sci. 2007;1117(1):209−257. doi: 10.1196/annals.1402.089
  56. Polyzosa SA, Makras P, Tournis S, Anastasilakis AD. Off-label uses of denosumab in metabolic bone diseases. Bone. 2019;129:115048. doi: 10.1016/j.bone.2019.115048
  57. Ren Y, Deng Z, Gokani V, et al. Anti-interleukin-6 therapy decreases hip synovitis and bone resorption and increases bone formation following ischemic osteonecrosis of the femoral head. J Bone Miner Res. 2021;36(2):357−368. doi: 10.1002/jbmr.4191
  58. Kuroyanagia G, Adapala NS, Yamaguchi R, et al. Interleukin-6 deletion stimulates revascularization and new bone formation following ischemic osteonecrosis in a murine model. Bone. 2018;116:221−231. doi: 10.1016/j.bone.2018.08.011
  59. Klinicheskie rekomendatsii. Yunosheskiy artrit s sistemnym nachalom. 2021-2022-2023 (29.06.2021). [cited 2022 July 14]. Available from:
  60. Kostik MM, Isupova EА, Chikova IА, et al. Evaluation of the efficiency and safety of tocilizumab therapy in patients with systemic-onset juvenile idiopathic arthritis: results of a retrospective follow-up. Modern Rheumatology Journal. 2017;11(4):30–39. (In Russ.). DOI: 10/14412/1996-7012-2017-4-30-39
  61. Kaneshiro S, Ebina K, Shi K, et al. IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro. J Bone Miner Metab. 2014;32(4):378–392.
  62. Patel NM, Feldman DS. Biologic and pharmacologic treatment of Legg-Calvé-Perthes disease. Legg-Calvé-Perthes disease. New York: Springer; 2020. doi: 10.1007/978-1-0716-0854-8_10

Supplementary files

There are no supplementary files to display.

Copyright (c) 2022 Shabaldin N.A., Shabaldin A.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС77-54261 от 24 мая 2013 г.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies