Medicine:Heterotopic ossification

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Short description: Formation of bone tissue outside of the skeleton
Heterotopic ossification
Heterotopic ossification around the hip joint in a patient who has undergone hip arthroplasty

Heterotopic ossification (HO) is the process by which bone tissue forms outside of the skeleton in muscles and soft tissue.[1]

Symptoms

Causes

Heterotopic ossification often develops in patients with traumatic brain or spinal cord injuries, cerebral strokes or anoxia. Heterotopic ossifications associated with a sever injury of the central nervous system are called neurogenic heterotopic ossifications.[2][3][4] Neurogenic heterotopic ossification develop most commonly around the hips, but also elbow, knee, and shoulder in descending incidence.[3] This may account for the clinical observation that traumatic brain injuries cause accelerated fracture healing.[5] Heterotopic ossification also frequently develop followed extended severe body burns.[6][7]

The mechanisms by which neurogenic heterotopic ossification develop following a spinal cord injury have been studied in a mouse model. In this model, heterotopic ossifications develop after a dual injury of the central nervous system and muscle, with ossifications developing exclusively in injured muscles.[3] Mechanistically, heterotopic ossification is caused by a perversion of the muscle repair program. During normal muscle repair, muscle satellite cells, which are muscle stem cells, are induced to divide and then differentiate into myoblasts and myotubes to regenerate muscle fibres. This process is controlled by inflammatory macrophages and supportive myogenic growth and differentiation factors produced by muscle-specific mesenchymal progenitor cells called fibro-adipogenic progenitors or interstitial cells.[8] A key step during normal muscle repair is the programmed cell death (apoptosis) of these fibro-adipogenic progenitors triggered by tumor necrosis factor TNF secreted by inflammatory macrophages accumulating in the injured muscle, a process that prevents the development of muscle fibrosis.[9] However, following a spinal cord injury, fibro-adipogenic progenitors fail to undergo apoptosis and instead accumulate and differentiate into bone forming osteoblasts.[10] How a spinal cord injury perverts muscle repair to osteogenesis has recently been elucidated. The spinal cord injury stimulates the adrenal glands[11] to release the glucocorticoid corticosterone into the circulation. Excessive corticosterone causes an exacerbation of inflammation in the injured muscle with excessive release of oncostatin M and interleukin-1β.[12] Oncostatin M and interleukin-1 bind to their cognate receptors OSMR[13] and IL1R1[14] expressed by muscle fibro-adipogenic progenitors which in turn promote their proliferation and osteogenic differentiation. In support of this model, treatment with glucocorticoid receptor antagonists such as mifepristone or relacorilant or conditional deletion of the glucocorticoid receptor gene strongly inhibit the development of neurogenic heterotopic ossification after spinal cord injury in this mouse model.[12] Treatment with ruxolitinib, an inhibitor of JAK1 and JAK2 tyrosine kinases, which are activated downstream of OSMR, also reduces neurogenic heterotopic ossification in this model.[15] This mechanism also explains why infections, particularly with gram-negative bacteria, are associated with higher prevalence of neurogenic heterotopic ossifications in victims of traumatic brain and spinal cord injuries.[16][17][18][19] Lipopolysaccharides from gram-negative bacteria worsen heterotopic ossification by binding to their receptor Toll-like receptor 4 expressed by macrophages and muscle fibro-adipogenic progenitors and further increase oncostatin M and interleukin-1β release by macrophages.[19]

There are also rare genetic disorders causing heterotopic ossification such as fibrodysplasia ossificans progressiva (FOP), a condition that causes injured bodily tissues to be replaced by heterotopic bone. Characteristically exhibiting in the big toe at birth, it causes the formation of heterotopic bone throughout the body over the course of the sufferer's life, causing chronic pain and eventually leading to the immobilisation and fusion of most of the skeleton by abnormal growths of bone.[20]

Another rare genetic disorder causing heterotopic ossification is progressive osseous heteroplasia, is a condition characterized by cutaneous or subcutaneous ossification.[21]

Diagnosis

Heterotopic ossification of the elbow, after comminuted fracture and arthroplasty.
Heteropic ossification of the elbow, after comminuted fracture and arthroplasty.

The only definitive diagnostic test in the early acute stage is a bone scan, which will show heterotopic ossification 7 – 10 days earlier than an x-ray. The three-phase bone scan may be the most sensitive method of detecting early heterotopic bone formation. However, an abnormality detected in the early phase may not progress to the formation of heterotopic bone. Another finding, often misinterpreted as early heterotopic bone formation, is an increased (early) uptake around the knees or the ankles in a patient with a very recent spinal cord injury. It is not clear exactly what this means, because these patients do not develop heterotopic bone formation. It has been hypothesized that this may be related to the autonomic nervous system and its control over circulation.[22]

When the initial presentation is swelling and increased temperature in a leg, the differential diagnosis includes thrombophlebitis. It may be necessary to do both a bone scan and a venogram to differentiate between heterotopic ossification and thrombophlebitis, and it is even possible that both could be present simultaneously. In heterotopic ossification, the swelling tends to be more proximal and localized, with little or no foot/ankle edema, whereas in thrombophlebitis the swelling is usually more uniform throughout the leg.[23]

Treatment

The only curative treatment is surgical resection when possible depending on location and size of the heterotopic ossification.[3] However recurrence may occur with rates between 2% and 31% depending on the report.[24] Additional treatment with bisphosphonate (etidronate) or indomethacin after resection surgery do not significantly reduce the rate of recurrence.[24]

There is no established preventive treatment mostly because the cellular and molecular mechanisms leading to heterotopic ossifications have remained poorly understood. Originally, bisphosphonates were expected to be of value after hip surgery but there has been no convincing evidence of benefit, despite having been used prophylactically.[25]

Surgical removal of a Heterotopic Ossification fusing the right Humerus and Radius following a severe TBI and complete fracture of the Ulna.

Radiation Therapy.

Elbow heterotopic ossification radiation therapy field, status post surgery.

Prophylactic radiation therapy for the prevention of heterotopic ossification has been employed since the 1970s. A variety of doses and techniques have been used. Generally, radiation therapy should be delivered as close as practical to the time of surgery. A dose of 7-8 Gray in a single fraction within 24–48 hours of surgery has been used successfully. Treatment volumes include the peri-articular region, and can be used for hip, knee, elbow, shoulder, jaw or in patients after spinal cord trauma.

Single dose radiation therapy is well tolerated and is cost effective, without an increase in bleeding, infection or wound healing disturbances.[26]

Other possible treatments.

Non-steroidal anti-inflammatory drugs, such as indomethacin and ibuprofen, have shown some effect in preventing recurrence of heterotopic ossification after total hip replacement[27] or spinal cord injury.[28]

Conservative treatments such as passive range of motion exercises or other mobilization techniques provided by physical therapists or occupational therapists may also assist in preventing HO. A review article looked at 114 adult patients retrospectively and suggested that the lower incidence of HO in patients with a very severe TBI may have been due to early intensive physical and occupational therapy in conjunction with pharmacological treatment.[29] Another review article also recommended physiotherapy as an adjunct to pharmacological and medical treatments because passive range of motion exercises may maintain range at the joint and prevent secondary soft tissue contractures, which are often associated with joint immobility.[30]

See also

References

  1. ↑ Brance ML, Cóccaro NM, Casalongue AN, Durán A, Brun LR. Extensive progressive heterotopic ossification post-Covid-19 in a man. Bone. 2022 Feb;155:116287. DOI: 10.1016/j.bone.2021.116287. PMID 34896358.
  2. ↑ Alexander, Kylie A.; Tseng, Hsu-Wen; Salga, Marjorie; Genêt, François; Levesque, Jean-Pierre (December 2020). "When the Nervous System Turns Skeletal Muscles into Bones: How to Solve the Conundrum of Neurogenic Heterotopic Ossification" (in en). Current Osteoporosis Reports 18 (6): 666–676. doi:10.1007/s11914-020-00636-w. ISSN 1544-1873. PMID 33085000. https://link.springer.com/10.1007/s11914-020-00636-w. 
  3. ↑ 3.0 3.1 3.2 3.3 Genêt, François; Jourdan, Claire; Schnitzler, Alexis; Lautridou, Christine; Guillemot, Didier; Judet, Thierry; Poiraudeau, Serge; Denormandie, Philippe (2011-01-31). Feany, Mel. ed. "Troublesome Heterotopic Ossification after Central Nervous System Damage: A Survey of 570 Surgeries" (in en). PLOS ONE 6 (1). doi:10.1371/journal.pone.0016632. ISSN 1932-6203. PMID 21304993. Bibcode: 2011PLoSO...616632G. 
  4. ↑ Genêt, François; Minooee, Kambiz; Jourdan, Claire; Ruet, Alexis; Denormandie, Philippe; Schnitzler, Alexis (2015-07-03). "Troublesome heterotopic ossification and stroke: Features and risk factors. A case control study" (in en). Brain Injury 29 (7–8): 866–871. doi:10.3109/02699052.2015.1005133. ISSN 0269-9052. PMID 25915823. http://www.tandfonline.com/doi/full/10.3109/02699052.2015.1005133. 
  5. ↑ Hofman, Martijn; Koopmans, Guido; Kobbe, Philipp; Poeze, Martijn; Andruszkow, Hagen; Brink, Peter R. G.; Pape, Hans-Christoph (January 2015). Gram, Hermann. ed. "Improved Fracture Healing in Patients with Concomitant Traumatic Brain Injury: Proven or Not?" (in en). Mediators of Inflammation 2015 (1). doi:10.1155/2015/204842. ISSN 0962-9351. PMID 25873754. 
  6. ↑ Thefenne, Laurent; de Brier, Gratiane; Leclerc, Thomas; Jourdan, Claire; Nicolas, Claire; Truffaut, Stéphanie; Lapeyre, Eric; Genet, Francois (2017-08-04). Kou, Yu Ru. ed. "Two new risk factors for heterotopic ossification development after severe burns" (in en). PLOS ONE 12 (8). doi:10.1371/journal.pone.0182303. ISSN 1932-6203. PMID 28777823. Bibcode: 2017PLoSO..1282303T. 
  7. ↑ Levi, Benjamin; Jayakumar, Prakash; Giladi, Avi; Jupiter, Jesse B.; Ring, David C.; Kowalske, Karen; Gibran, Nicole S.; Herndon, David et al. (November 2015). "Risk factors for the development of heterotopic ossification in seriously burned adults: A National Institute on Disability, Independent Living and Rehabilitation Research burn model system database analysis" (in en). Journal of Trauma and Acute Care Surgery 79 (5): 870–876. doi:10.1097/TA.0000000000000838. ISSN 2163-0755. PMID 26496115. 
  8. ↑ Joe, Aaron W. B.; Yi, Lin; Natarajan, Anuradha; Le Grand, Fabien; So, Leslie; Wang, Joy; Rudnicki, Michael A.; Rossi, Fabio M. V. (February 2010). "Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis" (in en). Nature Cell Biology 12 (2): 153–163. doi:10.1038/ncb2015. ISSN 1465-7392. PMID 20081841. 
  9. ↑ Lemos, Dario R; Babaeijandaghi, Farshad; Low, Marcela; Chang, Chih-Kai; Lee, Sunny T; Fiore, Daniela; Zhang, Regan-Heng; Natarajan, Anuradha et al. (July 2015). "Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors" (in en). Nature Medicine 21 (7): 786–794. doi:10.1038/nm.3869. ISSN 1078-8956. PMID 26053624. https://www.nature.com/articles/nm.3869. 
  10. ↑ Tseng, Hsu-Wen; Girard, Dorothée; Alexander, Kylie A.; Millard, Susan M.; Torossian, Frédéric; Anginot, Adrienne; Fleming, Whitney; Gueguen, Jules et al. (2022-02-25). "Spinal cord injury reprograms muscle fibroadipogenic progenitors to form heterotopic bones within muscles" (in en). Bone Research 10 (1): 22. doi:10.1038/s41413-022-00188-y. ISSN 2095-6231. PMID 35217633. 
  11. ↑ Debaud, Charlotte; Tseng, Hsu-Wen; Chedik, Malha; Kulina, Irina; Genêt, François; Ruitenberg, Marc J.; Levesque, Jean-Pierre (2021-08-01). "Local and Systemic Factors Drive Ectopic Osteogenesis in Regenerating Muscles of Spinal-Cord–Injured Mice in a Lesion-Level–Dependent Manner" (in en). Journal of Neurotrauma 38 (15): 2162–2175. doi:10.1089/neu.2021.0058. ISSN 0897-7151. https://www.liebertpub.com/doi/10.1089/neu.2021.0058. 
  12. ↑ 12.0 12.1 Alexander, Kylie A.; Tseng, Hsu-Wen; Lao, Hong Wa; Girard, Dorothée; Barbier, Valérie; Ungerer, Jacobus P.J.; McWhinney, Brett C.; Samuel, Selwin G. et al. (2024). "A glucocorticoid spike derails muscle repair to heterotopic ossification after spinal cord injury" (in en). Cell Reports Medicine 5 (12). doi:10.1016/j.xcrm.2024.101849. PMID 39657663. 
  13. ↑ Torossian, Frédéric; Guerton, Bernadette; Anginot, Adrienne; Alexander, Kylie A.; Desterke, Christophe; Soave, Sabrina; Tseng, Hsu-Wen; Arouche, Nassim et al. (2017-11-02). "Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications" (in en). JCI Insight 2 (21). doi:10.1172/jci.insight.96034. ISSN 2379-3708. PMID 29093266. 
  14. ↑ Tseng, Hsu-Wen; Kulina, Irina; Girard, Dorothée; Gueguen, Jules; Vaquette, Cedryck; Salga, Marjorie; Fleming, Whitney; Jose, Beulah et al. (2020-12-01). "Interleukin-1 Is Overexpressed in Injured Muscles Following Spinal Cord Injury and Promotes Neurogenic Heterotopic Ossification" (in en). Journal of Bone and Mineral Research 37 (3): 531–546. doi:10.1002/jbmr.4482. ISSN 0884-0431. PMID 34841579. https://academic.oup.com/jbmr/article/37/3/531-546/7516831. 
  15. ↑ Alexander, Kylie A.; Tseng, Hsu-Wen; Fleming, Whitney; Jose, Beulah; Salga, Marjorie; Kulina, Irina; Millard, Susan M.; Pettit, Allison R. et al. (2019). "Inhibition of JAK1/2 Tyrosine Kinases Reduces Neurogenic Heterotopic Ossification After Spinal Cord Injury". Frontiers in Immunology 10. doi:10.3389/fimmu.2019.00377. ISSN 1664-3224. PMID 30899259. 
  16. ↑ Dizdar, Dilek; Tiftik, Tülay; Kara, Murat; Tunç, Hakan; Ersöz, Murat; Akkuş, Selami (2013). "Risk factors for developing heterotopic ossification in patients with traumatic brain injury" (in en). Brain Injury 27 (7–8): 807–811. doi:10.3109/02699052.2013.775490. ISSN 0269-9052. PMID 23730889. http://www.tandfonline.com/doi/full/10.3109/02699052.2013.775490. 
  17. ↑ Reznik, J. E.; Biros, E.; Marshall, R.; Jelbart, M.; Milanese, S.; Gordon, S.; Galea, M. P. (2014). "Prevalence and risk-factors of neurogenic heterotopic ossification in traumatic spinal cord and traumatic brain injured patients admitted to specialised units in Australia". Journal of Musculoskeletal & Neuronal Interactions 14 (1): 19–28. ISSN 1108-7161. PMID 24583537. 
  18. ↑ Citak, Mustafa; Suero, Eduardo M.; Backhaus, Manuel; Aach, Mirko; Godry, Holger; Meindl, Renate; Schildhauer, Thomas A. (2012). "Risk Factors for Heterotopic Ossification in Patients With Spinal Cord Injury: A Case-Control Study of 264 Patients" (in en). Spine 37 (23): 1953–1957. doi:10.1097/BRS.0b013e31825ee81b. ISSN 0362-2436. PMID 22614800. http://journals.lww.com/00007632-201211010-00005. 
  19. ↑ 19.0 19.1 Salga, Marjorie; Samuel, Selwin G; Tseng, Hsu-Wen; Gatin, Laure; Girard, Dorothée; Rival, Bastien; Barbier, Valérie; Bisht, Kavita et al. (2023). "Bacterial Lipopolysaccharides Exacerbate Neurogenic Heterotopic Ossification Development" (in en). Journal of Bone and Mineral Research 38 (11): 1700–1717. doi:10.1002/jbmr.4905. ISSN 0884-0431. PMID 37602772. https://academic.oup.com/jbmr/article/38/11/1700-1717/7610375. 
  20. ↑ Pignolo, Robert J; Shore, Eileen M; Kaplan, Frederick S (2011). "Fibrodysplasia Ossificans Progressiva: Clinical and Genetic Aspects" (in en). Orphanet Journal of Rare Diseases 6 (1): 80. doi:10.1186/1750-1172-6-80. ISSN 1750-1172. PMID 22133093. 
  21. ↑ Pignolo, Robert; Ramaswamy, Girish; Fong, John; Shore, Eileen; Kaplan, Frederick (January 2015). "Progressive osseous heteroplasia: diagnosis, treatment, and prognosis" (in en). The Application of Clinical Genetics 8: 37–48. doi:10.2147/TACG.S51064. ISSN 1178-704X. PMID 25674011. 
  22. ↑ "Heterotopic Ossification – SCI InfoSheet #12". http://www.spinalcord.uab.edu/show.asp?durki=21485. 
  23. ↑ "Heterotopic Ossification". http://www.spinalcord.ar.gov/Publications/FactSheets/sheets1-5/fact1.html. 
  24. ↑ 24.0 24.1 Azhideh, Arash; Chansky, Howard; Yousefiasl, Maryam; Haseli, Sara; Mirghaderi, Peyman; Hernandez, Nicholas M.; Elahi, Reza; Nabipoor, Ali et al. (2025-10-24). "Recurrence of neurogenic heterotopic ossification after surgical excision and preventive strategies: A systematic review and meta-analysis" (in en). The Journal of Spinal Cord Medicine: 1–13. doi:10.1080/10790268.2025.2571821. ISSN 1079-0268. PMID 41134066. https://www.tandfonline.com/doi/full/10.1080/10790268.2025.2571821. 
  25. ↑ Metabolic Bone and Stone Disease. BEC Nordin, AG NEED, HA Morris: Churchill Livingstone, 1993. p 328-9
  26. ↑ Principles and Practice of Radiation Oncology Fifth Edition, Perez and Brady, Lippincott pp. 1955–56
  27. ↑ Joice, M.; Vasileiadis, G. I.; Amanatullah, D. F. (July 2018). "Non-steroidal anti-inflammatory drugs for heterotopic ossification prophylaxis after total hip arthroplasty: a systematic review and meta-analysis" (in en). The Bone & Joint Journal 100-B (7): 915–922. doi:10.1302/0301-620X.100B7.BJJ-2017-1467.R1. ISSN 2049-4394. PMID 29954195. https://online.boneandjoint.org.uk/doi/10.1302/0301-620X.100B7.BJJ-2017-1467.R1. 
  28. ↑ Zakrasek, Elissa C.; Yurkiewicz, Shara M.; Dirlikov, Ben; Pence, B. Tim; Crew, James D. (March 2019). "Use of nonsteroidal anti-inflammatory drugs to prevent heterotopic ossification after spinal cord injury: a retrospective chart review" (in en). Spinal Cord 57 (3): 214–220. doi:10.1038/s41393-018-0199-3. ISSN 1362-4393. PMID 30254206. https://www.nature.com/articles/s41393-018-0199-3. 
  29. ↑ Simonsen, L.L., Sonne-Holm, S., Krasheninnikoff, M., Engberg, A.W. (2007). "Symptomatic heterotopic ossification after very severe traumatic brain injury in 114 patients: Incidence and risk factors". Injury, Int. J. Care Injured 38: 1146–1150.
  30. ↑ Cipriano, C.A., Pill, S.G., Keenan, M.A. (2009). "Heterotopic ossification following traumatic brain injury and spinal cord injury". J Am Acad Orthop Surg 17 (11): 689-697.
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