Heterotopic ossification

Heterotopic ossification (HO) is a result of one of three initial insults: a traumatic injury, a neurogenic injury, or a genetic predisposition. It is more common in men (3:2 male to female ratio), likely a result of increased muscle mass, increased physical activity, and hormonal signally pathways. It is also more commonly in those that suffer from prolonged intubation, likely from an anoxic brain injury or prolonged immobilization. It is a hard diagnosis to make due to its overlap in symptoms with other common conditions. In patients that suffered a forearm fracture, 20% of patients will likely develop HO as a complication. In patients that suffered a femoral shaft fracture, that percentage jumps to 52% of patients. Without a specific trauma or inciting event, patients will frequently develop arthritis in major joints (knees, hips and shoulders). This subjects them to eventual surgical treatment or joint replacement. In those patients, their ability to place weight on a joint or move their joint may be limited for a significant period of time. Therefore, this patient population is also subject to developing HO as a surgical complication. It was found that 44% of patients that received either a hip arthroscopy or total hip replacement developed HO. In patients that develop a lesion or injury to the nerves of their spinal cord, they can develop neurogenic heterotopic ossification. Neurologenic HO effects 20-29% of patients that developed a spinal cord injury (SCI). In an SCI, the spinal level of injury is important to know since complications typically arise distal or below the level of the injury. This is thought to be due to an impaired or abnormal healing response below the injury level. For this reason, the most common sites of HO in the SCI population are the hips and knees. This complication percentage increases as the burn percentage also increases. For burn patients, the most common site of HO is the elbow, likely due to increased motion at the joint to prevent flexure contractures. The elbow is a clinically significant site to monitor since this specific complication of HO can lead to cubital tunnel syndrome; other common, but less likely, sites are the shoulders, knees, forearms, and temporamandibular joint. == Presentation of symptoms ==

While heterotopic ossification is not a direct result of a traumatic injury, it also does not have to present with symptoms. In the population that is symptomatic, it commonly follows a standard progression of symptoms. Following the initial inciting traumatic or neurologic injury, there is a heightened inflammatory response. An abnormal or prolonged inflammatory response can lead to the early stages of HO. Typically within the first 6 to 12 weeks, symptoms will start to arise; this is considered early HO. Here, immature bone forms within the affect joint or tissue, leading to generalized inflammatory symptoms. This manifests as symptoms of redness, warmth, and swelling (37% of patients), pain (35% of patients), or generalized tenderness and decreased range of motion (49% of patients) in the affected joint or tissue. While these symptoms are more annoying than troubling in the context of HO, these symptoms can also be red flag signs for a more serious underlying condition and require medical evaluation. As time continues, symptoms will typically progress from a more generalized inflammatory response to a localized pain center. This presents as localized tenderness, pain, and painful or decreased range of motion in the tissue or joint affected. This is considered late HO. In all stages, if the abnormal bone formation grows to imping on surrounding structures, complications can arise depending on the structure involved. This can lead to nerve compression, vascular compression, pressure sores, lymphedema, ankylosis and present as pain, numbness, tingling, weakness, swelling, spasticity, decreased range of motion. Presentation of physical exam symptoms will depend on the location and severity of the HO. == Diagnosis ==

Since heterotopic ossification can present similar to other more serious pathologies, a physical exam alone may not confirm the diagnosis. Utilizing laboratory testing and medical imaging together can provide a better picture to rule out more serious conditions and correctly identify the stage and severity of HO. However, it was found that in HO patients, alkaline phosphatase was elevated 2 weeks following their initial injury, peaked at 10 weeks post-injury, and returned to baseline by the 18 week post-injury mark. While it is not specific to HO, it was found that 12 weeks after a total hip replacement, an ESR above 35mm/hr was a reliable predictor for developing severe HO in patients. CK is an enzyme found in muscle tissue that, when found in the blood, can lead to believe there is active muscle damage. In addition to blood work, a urinalysis can identify certain byproducts of HO that a clinician may use to rule in or rule out its diagnosis. A 24-hour urine measurement for hydroxyproline can detect if one is building and breaking down bone at an increased rate compared to normal; however, this is not considered to be a reliable method to detect HO. While prostaglandin E2 is not specific for HO and is more associated with inflammatory conditions, its elevation has been associated with early HO. Genetic testing can be performed to confirm or rule-out either Fibrodysplasia ossificans progressiva (FOP), which is caused by a mutation in the ACVR1 gene, or Progressive osseous heteroplasia (POH), which is caused by a mutational spectrum in the GNAS-1 gene. In addition, a research paper published on the American Journal of Medical Genetics in May 2023 described a case where heterotopic ossification was associated with genetic variants of unknown significance in PDLIM-7, "...the gene encoding LMP-1 (LIM Mineralization Protein-1), an intracellular protein involved in the bone morphogenetic protein (BMP) pathway signaling and ossification." Imaging While laboratory studies are not reliable for diagnosing heterotopic ossification, medical imaging studies are more sensitive and specific for accurately diagnosing HO. Although it may be the simplest, most inexpensive method, an x-ray will not be helpful during the early stage. The only definitive diagnostic test in the early stage is a bone scan, which will show heterotopic ossification as early as 2.5 weeks post-injury, which is over 2 weeks sooner than detected by x-ray. While a bone scan is more specific less than one month post-injury, its use will be dependent on when symptoms begin. If symptoms arise after 4 weeks post-injury, and if the treatment team wants to rule out more serious complications, the team may begin with radiography or a CT scan. Their low cost and ability to detect immature bone formation while also checking for other diagnosis make them a useful tool to aid in the diagnosis. A treatment team may also utilize other imaging techniques such as an ultrasound or MRI to aid in the diagnosis process, more commonly used to rule out more serious, similarly presenting underlying conditions. When the initial presentation is swelling and increased temperature in a leg, thrombophlebitis or a deep vein clot cannot be ruled out with a clinical exam alone; therefore, ultrasound imaging may be necessary to differentiate. Similarly, osteomyelitis and malignant soft tissue masses can present similarly to HO; in this case, MRI has been found helpful in correctly diagnosis HO. == Classification types ==

Once heterotopic ossification has been diagnosed via imaging, the next step is assessing its severity and monitoring for progression of symptoms. There have been several classification systems identified, each dependent on the joint affected. The Brooker Classification System is utilized following total hip replacement to grade HO formation. The Hastings and Graham Classification System is utilized to grade HO formation at the elbow and forearm. == Management ==

Physical Therapy / Passive Range of Motion 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. For managing heterotopic ossification, there are mixed reviews in the literature about the success and efficacy of physical therapy (PT) and passive range of motion (PROM). In patients that had a total knee replacement, PT and PROM was found to be beneficial in preventing HO three months after surgery. In TBI patients that had HO of a joint, it was found that PROM of the joint did not worsen progression of HO; it was also found that when spasticity was not affecting the muscles of the affected joint, PROM under anesthesia improved joint motion. 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. 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. When comparing SCI patients, prophylactic NSAIDs compared to placebo showed statistically significant lowered incidence of HO in the prophylactic patient population. Bisphosphonates Bisphosphonates are the FDA approved medication for prevention and treatment of heterotopic ossification; they work by preventing bone growth in joints and soft tissues. Surgery The only curative treatment is surgical resection when possible depending on location and size of the heterotopic ossification. However recurrence may occur with rates between 2% and 31% depending on the report. Specific to the TBI population, surgical removal of the abnormal bone was the most effective treatment strategy. Additional treatment with bisphosphonate (etidronate) or indomethacin after resection surgery do not significantly reduce the rate of recurrence. == Patho-mechanism ==

The underlying mechanism by which heterotopic ossification forms is not fully understood but has been studied in a mouse model of neurogenic heterotopic ossification. In this model, heterotopic ossifications develop after a injury to the central nervous system such as the spinal cord and muscle, with bone developing exclusively in injured muscles. HO is thought to be caused by abnormal muscle repair. During normal muscle repair, muscle stem cells divide and differentiate to regenerate muscle fibres. This process is controlled by inflammatory cells and support muscle cell growth. A key step during normal muscle repair is the programmed cell death (apoptosis) triggered inflammatory cells to prevent the development of muscle fibrosis. However, following a spinal cord injury, fibro-adipogenic progenitors fail to undergo apoptosis and instead accumulate and differentiate into bone forming osteoblasts. The spinal cord injury stimulates the adrenal glands to release the glucocorticoid corticosterone into the circulation. Excessive corticosterone causes an exaggerated inflammation response in the injured muscle with excessive release of oncostatin M and interleukin-1β. Oncostatin M and interleukin-1 bind to their cognate receptors OSMR and IL1R1 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. 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. 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. 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. Another rare genetic disorder causing heterotopic ossification is progressive osseous heteroplasia, is a condition characterized by cutaneous or subcutaneous ossification. == See also ==