Osteopetrosis: classification, pathomorphology, genetic disorders, clinical manifestations (literature review and clinical case report)

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V.V. Povoroznyuk
N.V. Dedukh
M.A. Bystrytska
A.S. Musiienko


Osteopetrosis is a hereditary disease with an autosomal recessive or autosomal dominant type of inheritance, caused by a disruption in the functional activity of osteoclasts due to gene mutation. The article systematizes data on etiology, classification, pathomorphology, gene disorders based on the analysis of 38 sources of literature, and deals with the modern approa­ches to the treatment of osteopetrosis. Three types of osteopetrosis with different severity degrees of skeletal disorders and pathological severity are described. The main pathomorphological changes in the structural organization of bone tissue are presented and features of the state of osteoclasts are shown depending on the mutation of genes controlling their functional activity. There are no protocols for the treatment of this pathology, but treatment me­thods based on the use of hematopoietic stem cells are under development. The paper presents with clinical case report of a patient with marble bone disease.

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How to Cite
Povoroznyuk, V., N. Dedukh, M. Bystrytska, and A. Musiienko. “Osteopetrosis: Classification, Pathomorphology, Genetic Disorders, Clinical Manifestations (literature Review and Clinical Case Report)”. PAIN, JOINTS, SPINE, vol. 9, no. 2, July 2019, pp. 135-42, doi:10.22141/2224-1507.9.2.2019.172125.
Practical Medicine


Albers-Schonberg H. Rontgenbilder Einer Seltenen Knockenerkrankung. Munch Med Wochenschr. 1904;51:365-368.

Raynberg SA. Rentgenodiagnostika zabolevaniy kostey i sustavov [Radiodiagnosis of bones and joints diseases]. Moscow: Meditsina; 1964. 440 p. (in Russian).

Kalyagin AN, Belozertseva LV, Shchadneva SI, Katkova MI, Skatova OV, Parkhomenko YuV. Osteo-petrosis (marble bone disease). Sovremennaya Revmatologiya. 2014;8(1):23-26. doi: 10.14412/1996-7012-2014-1-23-26. (in Russian).

Shroff R, Beringer O, Rao K, Hofbauer LC, Schulz A. Denosumab for post-transplantation hyper-calcemia in osteopetrosis. N Engl J Med. 2012 Nov 1;367(18):1766-7. doi: 10.1056/NEJMc1206193.

Wu CC, Econs MJ, DiMeglio LA, et al. Diagnosis and Management of Osteopetrosis: Consensus Guide-lines From the Osteopetrosis Working Group. J Clin Endocrinol Metab. 2017 Sep 1;102(9):3111-3123. doi: 10.1210/jc.2017-01127.

Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis. 2009 Feb 20;4:5. doi: 10.1186/1750-1172-4-5.

Sobacchi C, Frattini A, Guerrini MM, et al. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet. 2007 Aug;39(8):960-2. doi:10.1038/ng2076.

Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000 Apr;21(2):115-37. doi:10.1210/edrv.21.2.0395.

Palagano E, Blair HC, Pangrazio A, et al. Buried in the Middle, But Guilty: Intronic Mutations in the TCIRG1 Gene Cause Human Autosomal Recessive Osteopetrosis. J Bone Miner Res. 2015 Oct;30(10):1814-21. doi: 10.1002/jbmr.2517.

Teitelbaum SL. Osteoclasts: what do they do and how do they do it? Am J Pathol. 2007 Feb;170(2):427-35. doi:10.2353/ajpath.2007.060834.

Osreopetroz [Osteopetrosis]. Art ORPHA2781. Available from: https://www.orpha.net/data/patho/RU/Osteopetrosis-RUrusAbs3700_.pdf. Accessed 16 Mar 2019 (in Russian).

Diniz G, Olukman O, Calkavur S, et al. A histologically Diagnosed Case with Infantile Osteopetrosis Complicated by Hypopituitarism. Case Rep Pathol. 2015;2015:786836. doi: 10.1155/2015/786836.

Dawar H, Mugalakhod V, Wani J, Raina D, Rastogi S, Wani S. Fracture management in osteopetrosis: an intriguing enigma. A guide for surgeons. Acta Orthop Belg. 2017 Sep;83(3):488-494.

Helfrich M, Perdu B, Coxon F. Human recessive osteopetrosis: new understanding of osteoclast func-tion through molecular and functional analysis of a rare genetic bone disease. Osteologie. 2009 Jan;18(4):260-267. doi: 10.1055/s-0037-1619909.

Mazzolari E, Forino C, Razza A, et al. A single-center experience in 20 patients with infantile malignant osteopetrosis. Am J Hematol. 2009 Aug;84(8):473-9. doi: 10.1002/ajh.21447.

Balemans W, Van Wesenbeeck L, Van Hul W. A clinical and molecular overview of the human osteo-petroses. Calcif Tissue Int. 2005 Nov;77(5):263-74. doi: 10.1007/s00223-005-0027-6.

Pangrazio A, Pusch M, Caldana E, et al. Molecular and clinical heterogeneity in CLCN7-dependent os-teopetrosis: report of 20 novel mutations. Hum Mutat. 2010 Jan;31(1):E1071-80. doi: 10.1002/humu.21167.

Cotter M, Connell T, Colhoun E, Smith OP, McMahon C. Carbonic anhydrase II deficiency: a rare auto-somal recessive disorder of osteopetrosis, renal tubular acidosis, and cerebral calcification. J Pediatr Hematol Oncol. 2005 Feb;27(2):115-7. doi: 10.1097/01.mph.0000154068.86987.47.

Farfán MA, Olarte CM, Pesantez RF, Suárez S, Vallejo L. Recommendations for fracture management in patients with osteopetrosis: case report. Arch Orthop Trauma Surg. 2015 Mar;135(3):351-6. doi: 10.1007/s00402-014-2144-z.

Pangrazio A, Fasth A, Sbardellati A, et al. SNX10 mutations define a subgroup of human autosomal re-cessive osteopetrosis with variable clinical severity. J Bone Miner Res. 2013 May;28(5):1041-9. doi: 10.1002/jbmr.1849.

Shapiro F. Osteopetrosis. Current Clinical Considerations. Clin Orthop Relat Res. 1993 Sep;(294):34-44.

Bollerslev J, Henriksen K, Nielsen MF, Brixen K, Van Hul W. Autosomal dominant osteopetrosis revis-ited: lessons from recent studies. Eur J Endocrinol. 2013 Jul 13;169(2):R39-57. doi: 10.1530/EJE-13-0136.

Spichak II, Bogacheva MV, Toporkov DI. Osteopetrosis - rare inherited disorder (literature review and clinical observations). Pediatricheskiy vestnik Yuzhnogo Urala. 2016;(2):106-114. (in Russian).

Benichou OD, Laredo JD, de Vernejoul MC. Type II autosomal dominant osteopetrosis (Albers-Schonberg disease): clinical and radiological manifestations in 42 patients. Bone. 2000 Jan;26(1):87-93. doi: 10.1016/S8756-3282(99)00244-6.

Tolar J, Teitelbaum SL, Orchard PJ. Osteopetrosis. N Engl J Med. 2004 Dec 30;351(27):2839-49. doi:10.1056/NEJMra040952.

Van Wesenbeeck L, Cleiren E, Gram J, et al. Sixnovel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet. 2003 Mar;72(3):763-71. doi:10.1086/368277.

Frattini A, Pangrazio A, Susani L, et al. Chloride channel CLCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis. J Bone Miner Res. 2003 Oct;18(10):1740-7. doi: 10.1359/jbmr.2003.18.10.1740.

Steward CG. Hematopoietic stem cell transplantation for osteopetrosis. Pediatr Clin North Am. 2010 Feb;57(1):171-80. doi: 10.1016/j.pcl.2009.11.006.

Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. 2003 Aug;4(8):638-49. doi:10.1038/nrg1122.

Waguespack SG, Hui SL, Dimeglio LA, Econs MJ. Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7gene mutation. J Clin Endocrinol Metab. 2007 Mar;92(3):771-8. doi:10.1210/jc.2006-1986.

Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S. Bisphosphonate-induced osteopetrosis. N Engl J Med. 2003 Jul 31;349(5):457-63. doi:10.1056/NEJMoa023110.

Driessen GJ, Gerritsen EJ, Fischer A, et al. Long-term outcome of haematopoieticstem cell transplanta-tion in autosomal recessive osteopetrosis: an EBMT report. Bone Marrow Transplant. 2003 Oct;32(7):657-63. doi:10.1038/sj.bmt.1704194.

Steward CG. Neurological aspects of osteopetrosis. Neuropathol Appl Neurobiol. 2003 Apr;29(2):87-97.

AlkhiaryYM, Gerstenfeld LC, Krall E, et al. Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34). J Bone Joint Surg Am. 2005 Apr;87(4):731-41. doi: 10.2106/JBJS.D.02115.

Sen RK, Gopinathan NR, Kumar R, Saini UC. Simple reproducible technique in treatment for osteo-petrotic fractures. Musculoskelet Surg. 2013 Aug;97(2):117-21. doi: 10.1007/s12306-012-0222-3.

Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH. Osteopetrosis: genetics, treatment and new in-sights into osteoclast function. Nat Rev Endocrinol. 2013 Sep;9(9):522-36. doi: 10.1038/nrendo.2013.137.

Alam I, McQueen AK, Acton D, et al. Phenotypic severity of autosomal dominant osteopetrosis type II (ADO2) mice on different genetic backgrounds recapitulates the features of human disease. Bone. 2017 Jan;94:34-41. doi: 10.1016/j.bone.2016.10.016.

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