Etiology Of Heterotopic Ossification Research Articles

The impact of hypoxia on mesenchymal progenitor cells of human skeletal tissue in the pathogenesis of heterotopic ossification.

Mesenchymal progenitor cells (MPCs) are capable of differentiating into osteo/chondrogenic cells to contribute substantially to heterotopic ossification (HO). This study aimed to examine the impact of hypoxia on MPCs in the aetiology of HO. MPCs from human normal and HO skeletal tissue were cultivated under normoxia and hypoxia. Gene expression of factors which have a key role in HO aetiology (BMPs, COX-1 and COX-2, etc.) were examined by real-time PCR. Tissue of both groups was analysed by immunohistochemistry. Under hypoxia, COX-1, -2 and SOX-9 gene expression was elevated in HO MPCs, whereas in normal muscle tissue only COX-2 was upregulated. MPCs from HO had a significantly elevated gene expression of BMP-4 and decreased expression of BMP-1 and HIF-1 under hypoxia compared to normal MPCs. Immunohistochemistry detected no significant differences between normal and HO tissue. Hypoxia causes an enhanced gene expression of factors, which have a key role in HO pathophysiology. A better understanding of this entity will possibly allow reducing HO rates in orthopaedic and trauma surgery.

Pathogenesis and prevention strategies of heterotopic ossification in total hip arthroplasty: a narrative literature review and results of a survey in Germany.

Heterotopic ossification (HO) after THA can lead to pain, impaired range of motion and possibly revision surgery. This article summarizes current literature on the pathogenesis of HO in THA and trauma. Second, it presents the results of a survey on prophylactic concepts for HO in Germany. A narrative literature review was conducted by searching three databases (Pubmed, ScienceDirect, the Cochrane library) on the aetiology of HO. Between 2013 and 2014, a questionnaire was sent to 119 orthopaedic and trauma surgery departments in Germany. The acquired form of HO seems to develop after tissue trauma, which induces a local inflammation. A change in tissue conditions, multiple signalling pathways and involvement of several different cell types seem to promote enchondral ossification and finally HO formation. The feed back rate of the survey was 67%. Eighty-seven percent of all departments currently administer NSAIDs with a mean time span of 3 weeks after surgery for oral prophylaxis. Prophylactic perioperative irradiation is performed in 64% of trauma/orthopaedic departments if the patient is at risk for HO with a mean dosage of 7 Gy. Basic research detected new pathways and cell signalling mechanisms of HO pathogenesis, which could offer new treatment and prophylaxis options in the near future. So far, there is no uniform strategy for the clinical prophylaxis of HO in THA. Guidelines and new clinical trials need to be developed to further reduce HO rates in THA.

Fibrocytes participate in the development of heterotopic ossification.

Heterotopic ossification (HO) is a complication of musculoskeletal injury characterized by the formation of mature bone in soft tissues. The etiology of HO is unknown. We investigated the role of bone marrow derived progenitor cells in HO pathophysiology. We isolated the cells from HO specimens by cell explantation. Using flow cytometry and immunofluorescence microscopy, we found that 35 to 65% of the HO cells exhibit a bone marrow derived fibrocyte profile consisting in spindle-shaped morphology associated with type 1 pro-collagen and LSP1 expression. When cultured in osteogenic differentiation medium, active machinery for bone mineralization (high gene expression of Anx2, TNAP, and Pit-1), and calcium/phosphate deposits were found. Interestingly, interferon-alpha 2b significantly reduced the proliferation rate and COL1 gene expression in HO cells. We have characterized a novel subset of bone marrow derived progenitor cells in the HO specimens. The findings from this research study will provide new insights into the development of HO in burn patients.

Heterotopic ossification in cervical total disk replacement: A finite element analysis

Heterotopic ossification is one of the possible complications following cervical total disk replacement. Although there are numerous hypotheses regarding the etiology of heterotopic ossification, the main causes of heterotopic ossification remain unknown. In this study, we hypothesize that heterotopic ossification formation is related to external loading in the cervical vertebrae after total disk replacement. A two-dimensional finite element model of a cervical vertebra treated by total disk replacement in the sagittal plane was developed. The bone adaptation process of heterotopic ossification was simulated based on strain energy density under both compressive and shear forces. Different types of heterotopic ossification formation were analyzed according to the directions of forces. Two distinct types of heterotopic ossification following cervical total disk replacement were predicted, which was consistent with previous clinical studies. Type 1 heterotopic ossification was observed in the posterior upper part of the vertebra under compressive forces, while type 2 heterotopic ossification was detected mostly in the anterior upper part under shear forces. In addition, heterotopic ossification formation enhanced the strain energy distribution, which is known to be related to bone remodeling. This article presents the effects of different mechanical loading conditions on the occurrence of heterotopic ossification following cervical total disk replacement, and the results may be useful for the design of artificial disks that minimize heterotopic ossification.

A case of extensive heterotopic ossification following multiple ligament reconstruction after severe knee trauma

We present a case of extensive heterotopic ossification (HO) around the knee joint following multiple ligament reconstruction after severe trauma. A 50-year-old female sustained a motor vehicle accident and underwent multiple trauma. The initial diagnosis of the knee included avulsion fracture of the tibial attachment of the posterior cruciate ligament, multiple ligament injury including the anterior cruciate ligament and medial collateral ligament, medial and lateral meniscal tears, and the fracture of the inferior pole of the patella. The surgical treatment was delivered in 2 stages including reconstructions of the anterior and posterior cruciate ligaments reconstruction, and repair of the medial collateral ligament and menisci. At postoperative 2 months, HO was observed around the knee joint, especially on the medial and posterior aspect, and proceeded gradually. At postoperative 1 year, the ossification appears matured with clear trabeculation and round margin. The motion arc was fairly preserved from 20° to 70°. Considering the benefits and risks of the further operative management, the patient opted for conservative management. The etiology of HO is not thoroughly known, and its therapy is empiric. Although prevention is not always possible, feasible preventive measure should be exerted to avoid the irreversible pathology. This unique sequelae should be kept in mind of orthopedic surgeon to devise pertinent management plan and deliver it to the injured.

Free radical scavengers versus methylprednisolone in the prevention of experimentally induced heterotopic ossification

The etiology of heterotopic ossification (HO) is still obscure, it is difficult to devise an effective preventive or therapeutic approach. The options for the prevention of HO are still limited. The prophylactic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is insufficient. Moreover, NSAIDs increase the risk of nonunion and loosening in patients with multiple joint injuries. The present experimental study was designed to compare methylprednisolone with free radical scavengers for the prevention of HO. The model of Michelsson et al. was used to induce HO in the hind legs of 30 female New Zealand albino rabbits, weighing approx. 4 kg. The animals were randomized into three groups of 10 animals each, and received daily either placebo, a free radical scavenger cocktail [allopurinol and N-acetylcysteine (A/A)], or methylprednisolone in a randomized, double-blind fashion. Every four days, X-rays were obtained to measure the thickness and the length of new bone formation at the thigh. A statistically significant difference in thickness and length of newly formed bone was found between the three groups. In the placebo group HO increased from day 16 toward a medium length of 6 mm and a median thickness of 1.5 mm. In the A/A group, no signs of HO were found. In the methylprednisolone group, only one animal presented minor HO from day 32. Both free radical scavengers and methylprednisolone were found to inhibit HO, and may be considered effective measures for the prevention of heterotopic bone formation. However, it could not be demonstrated which of the two had the strongest inhibitory effect.

The United States Armed Forces Amputee Patient Care Program

United States military amputees are treated at either Walter Reed Army Medical Center (Washington, DC) or Brooke Army Medical Center (Fort Sam Houston, TX). At each center, a multidisciplinary team from more than a dozen specialties works together to address the psychological, social, vocational, and spiritual needs of our soldiers, marines, sailors, and airmen, as well as their physical rehabilitation. Excellent outcomes are being achieved with the current practices of the Armed Forces Amputee Care Program, but a great deal of evidence-based research must be done to determine the optimal time to close the wound, the etiology of heterotopic ossification in blast injury, the factors determining optimal socket design, and the best sequence and timing for introduction of different prosthetic technologies in the rehabilitation process.

The function of proprioceptors in bone organization: A possible explanation for neurogenic heterotopic ossification in patients with neurological damage

Neurogenic heterotopic ossification is characterized by the formation of extra osseous bone in soft tissue surrounding peripheral joints in neurological patients. It occurs in 25% of spinal cord injury patients, and in 20% of these the pathologic process is severe enough to cause limitations in joint motion. Vascular and metabolic changes resulting from autonomic nervous system impairment may play a role in the etiology of heterotopic ossification. Repetitive vigorous passive manipulation of the joint to preserve range of motion, in the presence of reduced defense mechanisms, may also traumatize soft tissue, thereby initiating the pathological process. Nerve terminals within ligaments and capsules that allow for proprioception have a determinant role in triggering on and off muscle contraction, permitting acceleration and deceleration during gait. The Sarah Network of Rehabilitation Hospitals has treated over 20,000 patients with spinal cord and brain injury in the past 20 years. Based on the observation of heterotopic ossification development in some of these patients, and its tendency to relapse, this present article speculates whether, after an interruption in the neural pathways: (1) altered proprioception can forge a different relationship between tissues; and (2) chaotic new bone formation can occur. We postulate that heterotopic ossification in patients with injury to the central nervous system (CNS) may be related to a dysfunction of proprioception. With interruption of the neural tract of a given limb, ligaments lose control and coordination of their proprioceptive function and begin to react to direct stimulus in an independent, isolated and haphazard way. Free of CNS control and directly stimulated by such independent signals, mesenchymal osteoprogenitor cells located in soft tissues begin to occasion tissue maturation and differentiation into bone: heterotopic bone.

Radiation therapy for inflammatory arthritis

Radiation therapy for inflammatory arthritis

Chronic abdominal pain caused by heterotopic ossification with functioning bone marrow: a case report and review of the literature.

Heterotopic ossification is rarely seen after midline abdominal surgery. The etiology of heterotopic ossification is unknown. Although it is well recognized that heterotopic ossification may contain osteogenic cells and/or hematopoietic cells, to our knowledge, no case has ever been reported to have histologic evidence of hematopoiesis. We report the occurrence of heterotopic bone with bone marrow showing normal trilineage hematopoiesis in the incision scar of a woman who underwent gastric reduction surgery for the treatment of obesity. The literature regarding heterotopic ossification and extramedullary hematopoiesis is reviewed in this report, and discussion focuses on the mechanism of this pathophysiologic process.

Prevention and Treatment Of Heterotopic Ossification After Spinal Cord Injury

Background/Objectives: Heterotopic ossification (HO) is a frequent, irreversible complication afterspinal cord injury (SCI). The objective of this article is to explain the etiology of HO; present new advances in prevention, diagnosis, and management of this complication; and provide a suggested algorithm for clinical management.Etiology: Although still hypothetical, trauma and overexpression of bone morphogenic protein(s) in traumatized soft tissue appear to play important roles as initiating factors of HO.Prevention: Preventive use of nonsteroidal antiinflammatory agents (NSAIDs) reduces the incidence of HO by a magnitude of 2 to 3.Management: Early determination of serum creatine phosphokinase may have a diagnostic value in predicting the onset and severity of HO, and an NSAID may be added to etidronate therapy in the initial inflammatory phase of HO formation until C-reactive protein Ieveis return to normal range. Surgery is indicated in a subset of patients, and a regimenthat includes radiation therapy may prevent postoperative recurrence.Conclusion: Significant progress has been made in the early prevention and management of HO. Further studies are needed to elucidate the etiology.

Elbow heterotopic ossification in head-trauma patients: diagnosis and treatment.

Heterotopic ossification is a disorder characterized histologically and radiographically by normal bone formation in soft tissues that normally have no ossification properties. In severe head-trauma patients, a high incidence of heterotopic ossification occurs. The diagnosis of this pathology in these patients often is difficult for residual neurological damage. The etiology of heterotopic ossification following head trauma is unknown. Similarities have been found between heterotopic ossification and myositis ossificans, a hereditary autosomal dominant disease.

Heterotopic ossification and rhabdomyolysis

Heterotopic ossification and rhabdomyolysis are well described entities but, as far as we know, their association has never been described in the literature. We recently treated a patient who presented with this association. After a suicide attempt, this patient developed rhabdomyolysis of the left upper and lower limbs with peripheral neurological impairment. Two months later radiographs showed ectopic ossification around the left hip. Rhabdomyolysis is underdiagnosed, and is due to local disturbance of the calcium-phosphorus metabolism resulting in soft tissue calcifications. Underlying rhabdomyolysis may be a possible aetiology of heterotopic ossification. Recognition of this may help us to understand the pathophysiology and to improve the management of heterotopic ossification.

Neurogenic Heterotopic Ossification

Heterotopic ossification (HO) following neurological injury is defined as soft tissue bone formation which is most often seen after spinal cord or head injury and reported to occur after numerous other neurological insults. It can result in ankylosis of associated joints restricting patient mobility. Lesions present with signs of local inflammation. Evidence of ossification is noted on Technetium 99 bone scan and then on X-ray. Serum alkaline phosphatase may be elevated. Although it resembles the histopathology of myositis ossificans traumatica, its pathogenesis remains unclear. Current research favors exercise of joints to attenuate loss in range of motion. Ethane-1-hydroxy-1, 1-diphosphonic acid, a diphosphonate analogue of pyrophosphate, is the only medical treatment specifically indicated in heterotopic ossification. It has not been as effective as first hoped. Nonsteroidal anti-inflammatory drugs, warfarin, and X-radiation therapy hold promise as treatments. Surgical excision to remove ankylosing ectopic bone has been plagued by reoccurrence. Studies to better elucidate the etiology of HO, accelerate diagnosis of the condition, and accurately determine its risk of reoccurrence are needed. Further controlled studies of the various treatments are also warranted.

Ultrasound in the early diagnosis of heterotopic ossification in patients with spinal injuries.

Heterotopic ossification (HO) is a potentially disabling complication of spinal injuries and other chronic disorders. It is of unknown aetiology and currently there is no easy or convenient diagnostic method that will allow very early confirmation of the inflammatory changes that precede osteoid and, later, true bone formation. Clinical experience, however, indicates that early treatment with radiotherapy, antiinflammatory agents or diphosphonates is needed to control the progression. This study was undertaken to assess the role of ultrasound (US) in the very early diagnosis of HO in patients with spinal injuries. US was found to be very sensitive in detecting focal soft tissue abnormalities around joints and in the muscles of these patients. If combined with a Doppler study to exclude deep venous thrombosis (DVT), and infection or tumour could be excluded clinically, US was extremely accurate in predicting the presence or absence of early HO changes within hours of the clinical manifestation. In 2 patients it successfully predicted HO in the opposite leg before clinical signs were evident. This study also provided supportive evidence of the theory of microtrauma in the aetiology of HO. As ultrasound is portable, safe, cheap, reproducible and accurate, it is the method of choice in the early diagnosis of HO. It allows early treatment to prevent the formation of osteoid and subsequent bone formation.

Pseudoarthrosis in Heterotopic Ossification in Spinal Cord-Injured Patients

Heterotopic ossification (HO) of proximal joints is a common complication of spinal cord injury, traumatic brain injury, and burns, and is also seen among an array of other clinical conditions. Of the patients with HO, 3-8% develop ankylosis of the joint involved. Although the etiology of HO is not known, the main goal in its management is to retain the maximum possible functional range of movement in the joint involved. Toward this end, surgical resection of HO with etidronate disodium treatment to mobilize ankylosed joints has been reported, as has forceful joint manipulation in head-injured adults with HO. This paper presents two cases of extensive HO formation around hip and knee joints in patients who developed pseudoarthrosis. Cinradiographic assessment of the joints involved revealed pseudoarthrosis formation at the same axis as the normal anatomical plane of the joint, thus permitting functional range of movement.