Keywords
Heterotopic ossification (HO) refers to the formation of bone in tissues that do not normally have ossifying properties. It includes heterotopic ossification secondary to muscle and bone injury; neurogenic heterotopic ossification; and progressive fibrous dysplasia ossificansprogressive (FOP). The main feature is the rapid formation of calcified bone in the soft tissue and the formation of ectopic bone tissue 3 to 12 weeks after the injury, causing symptoms such as periarticular swelling, pain, impaired joint movement, and even peripheral nerve impingement and pressure ulcers. The incidence of heterotopic ossification varies greatly in the literature, and the incidence of HO after total hip arthroplasty in patients with risk factors is 80% to 90%.
1. Pathology of HO, diagnosis and its grading
1.1 Pathology HO early local muscle necrosis, a large number of inflammatory cell infiltration, with a large number of fibroblast proliferation, a small amount of fibrous tissue formation. Mature HO is clearly demarcated from the surrounding soft tissues, with a white glossy cut surface and a typical stratification phenomenon: the core of the inner layer is soft tissue that can be penetrated by X-rays, containing a large number of proliferating undifferentiated mesenchymal cells, these shuttle cells are rich in chromatin, the nuclei are polymorphic, and sometimes mitotic images can be seen, but the cell morphology is normal; the middle layer has a large amount of bone-like tissue and abundant osteoblasts, and there are many slender cancellous bone The outer layer has a large amount of mineral deposits and forms a shell, and finally becomes dense plate-like bone, and osteoblasts and osteoclasts are seen to be active for bone remodeling.
1.2 Diagnosis
(1) Clinical manifestations: symptoms such as periarticular swelling, pain, joint mobility disorders, and even peripheral nerve impingement and pressure ulcers. It is similar to cellulitis, thrombophlebitis, osteomyelitis or tumor. It usually appears within 14 months after the injury, but it has also been reported after 1 year.
(2) Imaging: X-ray can clearly diagnose HO 4-6 weeks after the onset of ossification; CT can clarify the specific site of HO and the relationship with surrounding joints and muscles; bone scan can detect positive HO at 2.5 weeks after the onset of ossification and help determine the activity and maturity of HO.
(3) Laboratory tests:Measurement of 24h urinary prostaglandin E2 (PGE2), serum alkaline phosphatase (AKP), blood calcium level, and elevated 24h urinary PGE2 suggest that further tests should be performed.
1.3 Grading are graded according to the signs of X-ray plain film, and the following 2 are commonly used.
(1) Grading criteria for heterotopic ossification around the hip joint (Brooker 1993). grade 0: no soft tissue calcification; grade 1: small separated ossified lesions on the hip; grade 2: ossified images of the proximal femur pelvis more than 1 cm apart; grade 3: ossified images of the proximal femur pelvis less than 1 cm apart: grade 4: complete ossification of the proximal femur and pelvis, with joint ankylosis.
(2) Grading criteria for heterotopic ossification around the elbow joint (Hahi et al.) The angle between the edge of the lesion and the center line of the elbow joint on the lateral film is used as the criterion. grade 1: less than 30°; grade 2: 30-60°; grade 3: greater than 60°, but no ridge bridge formation; grade 4: ridge bridge formation in the humeral ulnar direction.
2, the occurrence mechanism of HO
Most of the mechanisms of HO occurrence are thought to be the result of a combination of bleeding, inflammatory response and cytokines after soft tissue injury.
2.1 Christophe et al. found that the expression levels of osteocalcin, osteonectin and type I collagen mRNA were significantly higher in ectopic osteoblasts than in normal osteoblasts. the formation of HO is closely related to its own osteogenic capacity, and Takashi et al, studied that the potential osteogenic capacity could promote the production of postoperative ectopic ossification. The cytokine bone morphogeneticprotein (BMP) has a significant ability to induce osteogenesis, and animal experiments have demonstrated that transplantation of BMP outside the skeletal system can form ectopic bone. In humans, overexpression of BMP-4 due to mutations in the BMP-4 gene is an important cause of heterotopic ossification. Intraoperative excision of bone, excessive stripping of the periosteum, and postoperative infection are also important causes of heterotopic ossification. Studies of HO markers and molecular levels can help to further understand the etiology of HO, which requires 3 prerequisites for the development of HO:
(1) Mesenchymal stem cells or precursor cells with multiple potentials.
(2) The presence of stimulating factors. The main stimulating factors are bonemor-phogeneticprotein (BMP), insulin-likegrowthfactortype-1 (IGF-1), transferergrowthfactor (TGF) and prolactin. （prolactin, etc.
(3) Suitable environment for bone formation, the occurrence of HO is also related to the local tissue environmental conditions. Biopsies of skin and soft tissue at the site of ectopic ossification revealed changes in the endothelium and basement membrane of capillaries and small vessels, which can cause hypoxia in the soft tissues around the joint, leading to metabolic changes and contributing to the development of HO.
2.2 The main HO-related stimulating factors are:
(1) BMP gene:Among the many known stimulators of ectopic ossification, BMP gene is most closely related to ectopic ossification and has the ability to significantly induce bone formation. deletion of BMP-2 and BMP-4 genes can lead to embryonic death. rats with deletion of BMP-7 gene exhibit deformities of the skull, thorax, hind limbs, etc. Studies of progressive ossifying fibrous dysplasia disease have found that increased expression of BMP-4 mRNA in patient cells causes overexpression of BMP-4, resulting in ectopic ossification. bmp, a member of the TGF-β superfamily, is a diffusible protein molecule that, when secreted, creates a local concentration gradient that affects the development or differentiation of surrounding cells toward osteoblasts through some signaling pathway.
(2) c-fos gene:c-fos gene also plays an important role in normal bone development.
(3) Msx2: Liu et al. found that overexpression of Msx2 caused premature closure of the cranial suture in developing rats, along with ectopic ossification on the midline surface of the sagittal suture of the skull.
(4) BMP antagonist genes:It was found that downregulation of BMP antagonists can also cause ectopic ossification. 5 BMP antagonists including Nogginization have been identified, and these antagonists have different affinities with different BMPs. Mutations in the Noggin gene have been found in patients with FOP, and mice with knockout Noggin genes can develop features similar to those seen in patients with progressive ossifying fibrous dysplasia.
3. Prevention and treatment of HO
3.1 Prevention of HO is a common complication in orthopedic clinics, and preventive treatments have been used to reduce trauma and intraoperative bleeding by improving surgical techniques and flushing bone fragments from the surgical area with adequate saline; medications: tetraphosphonates (diphos-phonates-EHDP), non-steroidal anti-inflammatory analgesics (NSAIDs); radiation therapy; and for joint movement affecting surgical excision of ectopic ossified tissue that interferes with joint movement. However, the results have been less than satisfactory and have not reduced the formation of HO.
3.2 Drug treatment
(1) Tetraphosphonates (diphosphonates-EHDP) can inhibit the conversion of amorphous calcium phosphate into hydroxyl phosphate lime, thus preventing the mineralization of bone matrix, but not its synthesis, and HO is easy to recur after stopping the drug.
(2) Non-steroidal anti-inflammatory analgesics (NSAIDs) are currently recognized as the most effective drugs to prevent the formation of HO. Their mechanism of action is to block the synthesis of prostaglandins by inhibiting cyclooxygenase, thereby altering the local inflammatory response that triggers bone reconstruction and inhibiting the differentiation of mesenchymal cells into osteoblasts. Animal experiments have found that this differentiation begins as early as 16-32 h after injury, so the application of NSAIDs should be started on postoperative day 1. The commonly used clinical drug is indomethacin, which is administered for 2 to 6 weeks, with emphasis on starting administration 1 to 2 d after surgery; if the drug is started 5 to 7 d after surgery, it will not prevent HO formation. The main side effect of NSAIDs is gastrointestinal reaction, and about 30% of patients cannot complete the course of treatment because of gastrointestinal reaction. Concerns persist about whether the application of NSAIDs after prosthetic arthroplasty may affect bone growth into the surface of the prosthesis, thereby increasing aseptic loosening and poor healing at the greater trochanteric osteotomy, and short-term follow-up results suggest that this possibility is not increased, but further support is needed from long-term follow-up studies.
3.3 Gene therapy for HO is at the experimental stage, and the factors found to reduce or prevent the occurrence of HO are basicgibroblastgrowthfactor (bFGF); hNOG [Delta] B2; Noggin; gene therapy awaits further study.
3.4 Surgical treatment Surgical resection is the only treatment for patients with severe joint dysfunction resulting from HO formation. Surgery should be performed after the maturity of ectopic ossification, and studies have shown that the maturity of the lesion can be accurately determined by measuring the metabolic activity ratio of HO to normal bone through serial bone scans. Surgery should be performed in the absence of acute phase manifestations such as local fever and erythema, normal AKP, and bone scan showing normal or near normal; series of quantitative bone scan indexes should be performed after 2 to 3 months of decline from the stable phase. garland considers the time of surgery for heterotopic ossification as: 6 months after trauma; 12 months after spinal cord injury; and 18 months after traumatic brain injury. The surgical approach for the removal of heterotopic ossification in the elbow and hip is also described. Elbow:postero-lateral approach:for lesions on the posterior lateral side of the elbow; antero-lateral approach:for lesions on the anterior side of the elbow; medial approach:for lesions on the medial and posterior medial sides of the elbow, and cases with anterior displacement of the ulnar nerve. Hip: anterior approach: suitable for anterior and medial-inferior lesions; posterior approach: suitable for posterior lesions. The main complications of surgical resection include bleeding, infection, fracture and postoperative recurrence. To reduce the postoperative recurrence rate, NSAIDs or radiotherapy, or a combination of both, should be routinely administered in the early postoperative period [.
3.5 The mechanism of action of radiation therapy is to prevent the differentiation of pluripotent mesenchymal cells to osteoblasts by changing the structure of DNA of rapidly differentiating cells. Regarding the safety of radiotherapy, there is a consensus that a dose of 3000 cGy or less will not induce the development of sarcoma.
(1) Radiation therapy is performed with a 4-10mV linear gas pedal or 60Co treatment machine. The irradiation methods include preoperative radiotherapy and postoperative radiotherapy.
(2) Postoperative irradiation: postoperative fractionated prophylactic irradiation, irradiation time within 4h before total hip arthroplasty and started within 48h after surgery, irradiation dose 7-8Gy once, no significant difference in the incidence of grade 3-4 HO. The literature reported postoperative irradiation of DT20Gy, 2Gy. times, completed in 10 sessions; postoperative DT10Gy, 2Gy. times, completed in 5 sessions; postoperative 1-time irradiation of DT7-8Gy, with similar preventive effect and no statistical difference. Postoperative irradiation was given DT5.5Gy once and DT7Gy once, respectively. The results showed that the preventive efficacy of postoperative irradiation DT5.5Gy once was significantly inferior to that of the DT7Gy once group, regardless of whether it was accompanied by high-risk factors, and the differences were significant, and the timing of postoperative radiotherapy should be started within 4 d after surgery.
(3) Preoperative irradiation: Studies have shown that preoperative irradiation of 8Gy can effectively inhibit HO formation, Schneider et al. compared the 2 groups of rabbits, there was no difference in the preventive effect between preoperative single dose irradiation of DT8Gy and postoperative fractionated irradiation, and preoperative irradiation should be performed within 4h before surgery.
Summary
There is no reliable treatment for HO once it has developed except surgical resection, so the focus is on prevention of HO occurrence. The more feasible methods to prevent the appearance of HO are non-steroidal anti-inflammatory analgesics and local radiation therapy, while non-steroidal anti-inflammatory analgesics can lead to gastrointestinal bleeding, and more importantly, the systemic use of drugs will prevent fracture healing, which is unfavorable to the healing of fractures in other parts of the body. For HO in the extremities (such as elbow joint, etc.), preoperative irradiation did not prolong the operation time and intraoperative bleeding did not increase because there was no contraindication to radiotherapy. It does not affect postoperative wound healing, and 7-8 Gy for 1 preoperative radiotherapy is the preferred method, with a postoperative follow-up of more than 6 months. HO after hip arthroplasty may have adverse effects on radiotherapy for patients of childbearing age, and postoperative nonsteroidal anti-inflammatory analgesic prophylaxis is considered.