Heterotopic Ossification Progression Research Articles

Radiological and clinical long-term results of heterotopic ossification following lumbar total disc replacement

BackgroundThe long-term results of heterotopic ossification (HO) following lumbar total disc replacement (TDR) and the corresponding clinical and radiological outcomes are unclear. PurposeThis study aimed to report the long-term results of HO following lumbar TDR and to analyze the clinical and radiological outcomes. Study Design/SettingA retrospective case review was performed for the consecutive patients who underwent lumbar TDR. Patient SampleThe study included 48 patients (60 segments) who underwent lumbar TDR. Outcome MeasuresThe time and location of HO development, segmental range of motion (ROM) of index level, the visual analog scale (VAS), and the Oswestry Disability Index (ODI) were analyzed. MethodsForty-eight patients (60 segments) were divided into HO and non-HO groups, and radiographs were used to measure the time and location of HO development. We compared segmental ROM between two groups using flexion-extension radiographs. Clinical outcomes were assessed using the VAS and the ODI. Furthermore, the segmental ROM, VAS, and ODI scores of each HO class were compared with those of the non-HO group. ResultsThe mean follow-up duration was 104.4 months. Heterotopic ossification was detected in 30 of 60 segments following lumbar TDR, and HO progression was noted in six segments. The mean segmental ROM was significantly lower in the HO group than in the non-HO group. The mean VAS and ODI scores were not significantly different between the two groups. Segmental ROM was significantly lower in the class III and IV of the HO group than in the non-HO group. The VAS and ODI scores were not significantly different among the different classes. ConclusionsWe found that the incidence of HO is the highest within 12 months after lumbar TDR, and the incidence might increase 5 years after surgery. Furthermore, HO progressed over time. Segmental ROM was decreased in the HO groups; however, the limitation in motion might have little clinical influence.

Retinoid roles and action in skeletal development and growth provide the rationale for an ongoing heterotopic ossification prevention trial.

The majority of skeletal elements develop via endochondral ossification. This process starts with formation of mesenchymal cell condensations at prescribed sites and times in the early embryo and is followed by chondrogenesis, growth plate cartilage maturation and hypertrophy, and replacement of cartilage with bone and marrow. This complex stepwise process is reactivated and recapitulated in physiologic conditions such as fracture repair, but can occur extraskeletally in pathologies including heterotopic ossification (HO), Ossification of the Posterior Longitudinal Ligament (OPLL) and Hereditary Multiple Exostoses (HME). One form of HO is common and is triggered by trauma, invasive surgeries or burns and is thus particularly common amongst severely wounded soldiers. There is also a congenital and very severe form of HO that occurs in children with Fibrodysplasia Ossificans Progressiva (FOP) and is driven by activating mutations in ACVR1 encoding the type I bone morphogenetic protein (BMP) receptor ALK2. Current treatments for acquired HO, including NSAIDs and local irradiation, are not always effective and can have side effects, and there is no effective treatment for HO in FOP. This review article describes the research path we took several years ago to develop a new and effective treatment for both congenital and acquired forms of HO and specifically, the testing of synthetic retinoid agonists to block the initial and critical chondrogenic step leading to HO onset and progression. We summarize studies with mouse models of injury-induced and congenital HO demonstrating the effectiveness and mode of action of the retinoid agonists, including Palovarotene. Our studies have provided the rationale for, directly led to, an ongoing phase 2 FDA clinical trial to test efficacy and safety of Palovarotene in FOP. Top-line results released a few months ago by the pharmaceutical sponsor Clementia are very encouraging. Given shared developmental pathways amongst pathologies of extraskeletal tissue formation, Palovarotene may also be effective in HME as preliminary in vitro data suggest.

Radiotherapy for the Prophylaxis of Heterotopic Ossification: A Systematic Review and Meta-analysis of Randomized Controlled trials

Abstract Introduction Heterotopic ossification (HO) involves the formation of lamellar bone in nonosseous tissue. For HO, radiotherapy has been shown to be an effective prophylactic modality. Objective To compare HO outcomes following radiotherapy and to investigate the comparative efficacy of preoperative versus postoperative radiotherapy. Methods A systematic search was conducted on Ovid MEDLINE, EMBASE and Cochrane CENTRAL. Studies were included if they were randomized controlled trials (RCTs) that included patients who were prescribed prophylactic radiation for whom relevant HO progression outcomes were reported. Results From a literature search of 528 articles, 12 RCTs were included. There was a statistically significant reduction in HO prevalence with multiple as opposed to single fraction radiotherapy ( p =0.04), however there was no statistically significant difference when examining HO progression ( p =0.34). There was no statistically significant difference in HO progression when comparing a biologically effective radiation dose (BED) of >2500cGy versus ⩽2500cGy ( p =0.28). As well, no statistically significant difference existed in HO progression between postoperative versus preoperative radiation ( p =0.43). Conclusion There was no difference between postoperative or preoperative radiotherapy in preventing HO progression. There seems to be no relationship between BED greater or less than 2500cGy and the efficacy of HO prophylaxis. Multiple fractions seem to be more effective than single fraction radiotherapy in preventing HO progression.

Characterization of Heterotopic Ossification Using Radiographic Imaging: Evidence for a Paradigm Shift.

Heterotopic ossification (HO) is the growth of extra-skeletal bone which occurs following trauma, burns, and in patients with genetic bone morphogenetic protein (BMP) receptor mutations. The clinical and laboratory evaluation of HO is dependent on radiographic imaging to identify and characterize these lesions. Here we show that despite its inadequacies, plain film radiography and single modality microCT continue to serve as a primary method of HO imaging in nearly 30% of published in vivo literature. Furthermore, we demonstrate that detailed microCT analysis is superior to plain film and single modality microCT radiography specifically in the evaluation of HO formed through three representative models due to its ability to 1) define structural relationships between growing extra-skeletal bone and normal, anatomic bone, 2) provide accurate quantification and growth rate based on volume of the space-occupying lesion, thereby facilitating assessments of therapeutic intervention, 3) identify HO at earlier times allowing for evaluation of early intervention, and 4) characterization of metrics of bone physiology including porosity, tissue mineral density, and cortical and trabecular volume. Examination of our trauma model using microCT demonstrated two separate areas of HO based on anatomic location and relationship with surrounding, normal bone structures. Additionally, microCT allows HO growth rate to be evaluated to characterize HO progression. Taken together, these data demonstrate the need for a paradigm shift in the evaluation of HO towards microCT as a standard tool for imaging.

Early detection of heterotopic ossification using near‐infrared optical imaging reveals dynamic turnover and progression of mineralization following Achilles tenotomy and burn injury

Heterotopic ossification (HO) is the abnormal formation of bone in soft tissue. Current diagnostics have low sensitivity or specificity to incremental progression of mineralization, especially at early time points. Without accurate and reliable early diagnosis and intervention, HO progression often results in incapacitating conditions of limited range of motion, nerve entrapment, and pain. We hypothesized that non-invasive near-infrared (NIR) optical imaging can detect HO at early time points and monitor heterotopic bone turnover longitudinally. C57BL6 mice received an Achilles tenotomy on their left hind limb in combination with a dorsal burn or sham procedure. A calcium-chelating tetracycline derivative (IRDye 680RD BoneTag) was injected bi-weekly and imaged via NIR to measure accumulative fluorescence for 11 wk and compared to in vivo microCT images. Percent retention of fluorescence was calculated longitudinally to assess temporal bone resorption. NIR detected HO as early as five days and revealed a temporal response in HO formation and turnover. MicroCT could not detect HO until 5 wk. Confocal microscopy confirmed fluorophore localization to areas of HO. These findings demonstrate the ability of a near-infrared optical imaging strategy to accurately and reliably detect and monitor HO in a murine model.

Early development and progression of heterotopic ossification in cervical total disc replacement

The purpose of cervical total disc replacement (TDR) is to decrease the incidence of adjacent segment disease through motion preservation. Heterotopic ossification (HO) is a well-known complication after hip and knee arthroplasties. There are few reports regarding HO in patients undergoing cervical TDR, however; and the occurrence of HO and its effects on cervical motion have rarely been reported. Moreover, temporal progression of HO has not been fully addressed. One goal of this study involved determining the incidence of HO following cervical TDR, as identified from plain radiographs, and demonstrating the progression of HO during the follow-up period. A second goal consisted of determining whether segmental motion could be preserved and identifying the relationship between HO and clinical outcomes. The authors conducted a retrospective clinical and radiological study of 28 consecutive patients who underwent cervical TDR with Mobi-C prostheses (LDR Medical) between September 2006 and October 2008. Radiological outcomes were evaluated using lateral dynamic radiographs obtained preoperatively and at 1, 3, 6, 12, and 24 months postoperatively. The occurrence of HO was interpreted on lateral radiographs using the McAfee classification. Cervical range of motion (ROM) was also measured. The visual analog scale (VAS) and Neck Disability Index (NDI) were used to evaluate clinical outcome. The mean follow-up period was 21.6 ± 7.0 months, and the mean occurrence of HO was at 8.0 ± 6.6 months postoperatively. At the last follow-up, 18 (64.3%) of 28 patients had HO: Grade I, 6 patients; Grade II, 8 patients; Grade III, 3 patients; and Grade IV, 1 patient. Heterotopic ossification progression was proportional to the duration of follow-up; HO was present in 3 (10.7%) of 28 patients at 1 month; 7 (25.0%) of 28 patients at 3 months; 11 (42.3%) of 26 patients at 6 months; 15 (62.5%) of 24 patients at 12 months; and 17 (77.3%) of 22 patients at 24 months. Cervical ROM was preserved in Grades I and II HO but was restricted in Grades III and IV HO. Clinical improvement according to the VAS and NDI was not significantly correlated with the occurrence of HO. The overall incidence of HO after cervical TDR was relatively high. Moreover, HO began unexpectedly to appear early after surgery. Heterotopic ossification progression was proportional to the time that had elapsed postoperatively. Grade III or IV HO can restrict the cervical ROM and may lead to spontaneous fusion; however, the occurrence of HO did not affect clinical outcome. The results of this study indicate that a high incidence of HO with the possibility of spontaneous fusion is to be expected during long-term follow-up and should be considered before performing cervical TDR.

Shielding of the Hip Prosthesis During Radiation Therapy for Heterotopic Ossification is Associated with Increased Failure of Prophylaxis

Radiation therapy (RT) is frequently administered to prevent heterotopic ossification (HO) after total hip arthroplasty (THA). The purpose of this study was to determine if there is an increased risk of HO after RT prophylaxis with shielding of the THA components. This is a retrospective analysis of THA patients undergoing RT prophylaxis of HO at Brigham and Women's Hospital between June 1994 and February 2004. Univariate and multivariate logistic regressions were used to assess the relationships of all variables to failure of RT prophylaxis. A total of 137 patients were identified and 84 were eligible for analysis (61%). The median RT dose was 750 cGy in one fraction, and the median follow-up was 24 months. Eight of 40 unshielded patients (20%) developed any progression of HO compared with 21 of 44 shielded patients (48%) (p = 0.009). Brooker Grade III-IV HO developed in 5% of unshielded and 18% of shielded patients (p = 0.08). Multivariate analysis revealed shielding (p = 0.02) and THA for prosthesis infection (p = 0.03) to be significant predictors of RT failure, with a trend toward an increasing risk of HO progression with age (p = 0.07). There was no significant difference in the prosthesis failure rates between shielded and unshielded patients. A significantly increased risk of failure of RT prophylaxis for HO was noted in those receiving shielding of the hip prosthesis. Shielding did not appear to reduce the risk of prosthesis failure.