Heterotopic Ossification Research Articles

Macrophage migration inhibitory factor promotes heterotopic ossification by mediating ROS/HIF-1α positive feedback loop and activating Wnt/β-catenin signaling pathway.

Heterotopic ossification (HO) refers to the development of bone tissue in areas other than the skeletal system. The development and maturation of the skeletal system are significantly influenced by macrophage migration inhibitory factor (MIF). The objective of this study was to examine the impact of MIF on the in vitro osteogenic differentiation and mineralization of tendon-derived stem cells (TDSCs), mediated by a positive feedback loop involving ROS/HIF-1α/MIF. TDSCs were isolated and identified from the hind limbs of C57/BL6 mice. The functional and procedural roles of MIF in HO, focusing on the impact of MIF on the differentiation of TDSCs into bone-forming cells were investigated in vitro. Seventy-five mice were randomly assigned to five groups. Gene expression and histological analyses of MIF and its receptors, and determine the expression of osteogenic markers in vivo. The results revealed a positive and concentration-dependent effect of MIF on the osteogenic differentiation of TDSCs. Furthermore, an ROS/HIF-1α/MIF positive loop was detected in the simulated early trauma hypoxic microenvironment, resulting in a 3 to 4 folds increase in MIF expression levels. MIF was also found to enhance double the expression levels of markers associated with bone and cartilage at the site of injury, consequently facilitating the development of HO, which was thought to be associated with the activation of the Wnt/β-catenin pathway. MIF, which mediates the ROS/HIF-1α/MIF positive feedback loop during the hypoxic phase of HO, triggers the Wnt/β-catenin signaling pathway to enhance the osteogenic differentiation and formation of HO in TDSCs.

Heterotopic Ossification with Intrathyroidal Extramedullary Hematopoiesis in Multifocal Papillary Thyroid Carcinoma: Histopathological Findings and Literature Review.

In recent decades, there has been an increase in the identification of thyroid nodules, both benign and malignant, due to the rise in imaging studies and complementary tests. Among thyroid gland tumors, papillary thyroid carcinoma (PTC) stands out as the most prevalent. Degenerative changes, mainly in the form of nodular goiter, have been recorded, occasionally including areas of calcification and, more rarely, ossification; although the latter seldom progresses to calcinosis. Ectopic bone formation, known as osseous metaplasia, is a rare phenomenon in the thyroid gland, even more so when associated with extramedullary hematopoiesis (EMH), characterized by the presence of hematopoietic elements outside the bone marrow. We present the first documented instance in our country of a patient diagnosed with malignant thyroid nodule, specifically PTC, exhibiting areas of heterotopic ossification with EMH on histopathological examination of the surgical specimen. A possible relationship between heterotopic ossification, EMH, and PTC is suggested. Various growth factors such as bone morphogenetic proteins (BMPs), specific BMP subtypes, and associated receptors could play a crucial role in initiating and developing ectopic bone formation in the context of PTC. However, further research is needed to fully elucidate its clinical significance and impact on the therapeutic management of these patients.

Heterotopic Osteotomy for Intrathecal Baclofen Test Dose Administration in a Pediatric Patient With Spinal Fusion: A Technical Note.

Intrathecal baclofen (ITB) pumps are used for the treatment of pediatric movement disorders that are rapidly progressive or do not respond to medical management. An ITB test dose is indicated in patients who have mixed tone, when the family remains unconvinced, or when insurance companies require it. Test doses are typically delivered by lumbar puncture; however, lumbar puncture in patients with heterotopic ossification of the lumbar vertebrae after a previous spinal fusion is not possible. To our knowledge, we present the first technical note describing a heterotopic osteotomy to access the subarachnoid space for a complex ITB test dose in a pediatric patient with a spinal fusion. We present a 14-year-old woman with spastic, dystonic quadriplegic cerebral palsy, neuromuscular scoliosis, and previous T3-pelvis posterior spinal fusion. She continued to have significant dystonia and spasticity despite maximal medical management and was offered ITB therapy. A complex ITB test dose through heterotopic osteotomy was performed with excellent clinical results, and the patient will ultimately receive an ITB pump. Heterotopic ossification following spinal fusion is not a contraindication to an ITB test dose. A heterotopic osteotomy is a feasible surgical approach to administer an ITB test dose in these pediatric patients.

Treatment of Bone Defects and Nonunion via Novel Delivery Mechanisms, Growth Factors, and Stem Cells: A Review.

Bone nonunion following a fracture represents a significant global healthcare challenge, with an overall incidence ranging between 2 and 10% of all fractures. The management of nonunion is not only financially prohibitive but often necessitates invasive surgical interventions. This comprehensive manuscript aims to provide an extensive review of the published literature involving growth factors, stem cells, and novel delivery mechanisms for the treatment of fracture nonunion. Key growth factors involved in bone healing have been extensively studied, including bone morphogenic protein (BMP), vascular endothelial growth factor (VEGF), and platelet-derived growth factor. This review includes both preclinical and clinical studies that evaluated the role of growth factors in acute and chronic nonunion. Overall, these studies revealed promising bridging and fracture union rates but also elucidated complications such as heterotopic ossification and inferior mechanical properties associated with chronic nonunion. Stem cells, particularly mesenchymal stem cells (MSCs), are an extensively studied topic in the treatment of nonunion. A literature search identified articles that demonstrated improved healing responses, osteogenic capacity, and vascularization of fractures due to the presence of MSCs. Furthermore, this review addresses novel mechanisms and materials being researched to deliver these growth factors and stem cells to nonunion sites, including natural/synthetic polymers and bioceramics. The specific mechanisms explored in this review include BMP-induced osteoblast differentiation, VEGF-mediated angiogenesis, and the role of MSCs in multilineage differentiation and paracrine signaling. While these therapeutic modalities exhibit substantial preclinical promise in treating fracture nonunion, there remains a need for further research, particularly in chronic nonunion and large animal models. This paper seeks to identify such translational hurdles which must be addressed in order to progress the aforementioned treatments from the lab to the clinical setting.

CD1530, selective RARγ agonist, facilitates Achilles tendon healing by modulating the healing environment including less chondrification in a mouse model.

Heterotopic ossification (HO) in Achilles tendon often arises due to endochondral ossification during the healing process following trauma. Retinoic acid receptor γ (RARγ) plays a critical role in this phenomenon. This study aims to elucidate the therapeutic effects of CD1530, an RARγ selective agonist, along with the contributing cells, in Achilles tendon healing, utilizing a cell lineage tracing system. Local injection of CD1530 facilitated histological tendon healing by inhibiting chondrification in a mouse Achilles rupture model. Resident Scleraxis (Scx)+ cells in Achilles tendon were not found to be actively involved in HO or tendon healing following injury. Instead, these processes were primarily driven by tendon stem/progenitor cells (TSPC)-like cells. Furthermore, an in vitro assay revealed that CD1530 attenuated inflammation in injured Achilles tendon-derived tendon fibroblasts (iATF) and inhibited the chondrogenesis of iATF. This dual effect suggests the potential of CD1530 in effectively modulating the healing environment during tendon healing. Together, the present study demonstrated that the local administration of CD1530 accelerated tendon healing by modulating the healing environment, including reducing chondrification via targeting TSPC-like cells in a mouse Achilles tendon rupture model. These results suggest that CD1530 may have the potential to be a novel tendon therapy that offers benefits via the inhibition of chondrogenesis.

The Use Of External Beam Radiation Therapy For Heterotopic Ossification Prophylaxis After Surgical Fixation Of Acetabular Fractures: A Randomized Controlled Trial.

To determine the effect of external beam radiation (XRT) on preventing severe heterotopic ossification (HO) after acetabular surgery. Design: Randomized controlled trial. Two level I academic trauma centers. Patients with an acetabular fracture (OTA/AO type 62) surgically treated through a posterior or combined anterior and posterior approach.Outcome Measures and Comparisons: Radiographic HO was determined using Brooker Classification at the last follow-up. The primary outcome was severe HO (Brooker class III-IV). The secondary outcome was any HO (Brooker class I-IV). The incidence of radiographic HO was compared between patients that did and did not undergo postoperative XRT. The results were analyzed in both an intention-to-treat (randomized to XRT) and as-treated (received XRT) basis. Severe HO occurred in 3 of 54 (6%) patients randomized to XRT and 9 of 50 (18%) patients randomized to no XRT (odds ratio (OR) 0.24, 95% confidence interval (CI) 0.05 to 0.94; p=0.05). Any HO occurred in 10 (19%) patients assigned to XRT and 17 (34%) patients in the no XRT control group (OR 0.39; 95% CI 0.13 to 1.05; p =0.07). The findings of this dual-center randomized controlled trial suggest that XRT after acetabular surgery significantly reduced the odds of severe HO compared to patients that did not receive XRT. These results can help guide shared decision-making between surgeons and patients regarding the use of XRT for HO prophylaxis. Level I, therapeutic.

Is partial excision of the radial head safe and effective in all-arthroscopic treatment of terrible triad fractures?

Our study aimed to evaluate the clinical and radiologic results of all-arthroscopic treatment of terrible triad injuries followed-up for a minimum of 5 years and investigate how arthroscopic partial excision for radial head fractures affects the results at the final follow-up. We retrospectively reviewed consecutive patients with terrible triad injuries who underwent all-arthroscopic treatment between January 2011 and June 2018. In group I, we performed conservative or arthroscopic fixation of stable radial head fractures, while in group II, arthroscopic partial excision of unstable radial head fractures involving <30%-50% of the articular surface area was performed. Clinical outcomes were measured by visual analog scale score and assessment of instability, range of motion (ROM), and Mayo Elbow Performance Score. Radiological outcomes were evaluated using x-rays, and the integrity of the repaired lateral collateral ligament complex was confirmed through magnetic resonance imaging. Thirty-two patients with an average age of 49.5±16.2 years met the inclusion criteria and were followed-up for a mean of 82.7±22.2 months. Twenty patients were assigned to group I and 12 patients to group II. Clinical outcomes showed no significant differences between the two groups at the final follow-up (P>0.05). On radiological evaluation, more heterotopic ossifications were found in the radial head excision group (group II, 66.7% versus group I, 35%, P=0.02); however, there was no significant difference in ROM between the two groups (P>0.05). In all-arthroscopic treatment of terrible triad injuries, arthroscopic partial excision of the radial head did not seem to have a significant impact on elbow joint stability. Level of evidence: III.

Challenges and Long-Term Outcomes of Cementless Total Hip Arthroplasty in Patients Under 30: A 24-Year Follow-Up Study with a Minimum 8-Year Follow-Up, Focused on Developmental Dysplasia of the Hip.

Background: Total hip arthroplasty (THA) is a well-established and effective treatment for advanced osteoarthritis (OA) of the hip joint. While commonly performed in older patients, THA is increasingly used in younger individuals, especially in cases of secondary coxarthrosis. Technological advances have led to the development of specialized implants, which allow surgeons to address severe post-inflammatory or dysplastic deformities. Younger patients undergoing THA, often in their 20s or 30s, present higher functional expectations. Despite limited long-term studies, research indicates a higher rate of revision surgeries in this age group compared to older populations, making these procedures a unique challenge. Methods: This retrospective study analyzed 5263 primary total hip arthroplasties (THAs) performed at our center between May 1985 and December 2016. After excluding cemented and hybrid implants, as well as patients lost to follow-up or with other etiologies, 101 uncemented THA procedures in 92 patients aged 30 years or younger were included. The majority (64.4%) were due to dysplastic coxarthrosis (DDH), while avascular necrosis (26.7%) and juvenile rheumatoid arthritis (8.9%) accounted for the rest. The average patient age was 25.6 years, with a mean follow-up period of over 24 years. Surgical technique involved the anterolateral approach, with implants placed in the true acetabular region. Implants included Munich/Plasmacup, Mittelmeier, and P-M designs. Implant survival was estimated using the Kaplan-Meier estimator to determine the probability of implant longevity over the follow-up period. Outcomes were assessed using Merle d'Aubigné and Postel scores, modified by Charnley, alongside radiographic evaluations based on the Crowe, De Lee, and Gruen classifications. Results: Preoperatively radiological assessment of all hips was classified as grade IV according to the Kellgren-Lawrence scale. Over an average follow-up of 24 years, final outcomes using the modified Merle d'Aubigné and Postel (MAP) classification were excellent in 24%, good in 37%, satisfactory in 8%, and poor in 32% of cases. Results compared between DDH group and control group indicate significantly more poor results for the DDH group compared to the control group (p-value < 0.05). All poor outcomes were associated with prosthesis loosening, primarily involving P-M and Mittelmeier acetabular components. Complications included intraoperative fractures in five cases, peripheral nerve dysfunction in six cases, and heterotopic ossification in eight cases. Postoperative pain scores on the VAS scale improved from 6.8 to 1.7. The Kaplan-Meier estimator indicated 10-year survival rates of 85.2% for the entire prosthesis, with 69.8% survival at 15 years and 54.5% at 20 years. For each period the bio-functionality according to Kaplan-Meier estimator was in favor of the control group. Conclusions: Cementless THA in patients aged 30 or younger has demonstrated itself to be an efficacious treatment for hip osteoarthritis, yielding favorable bio-functional outcomes in both short- and long-term follow-up. Nevertheless, THA performed in the context of developmental dysplasia of the hip (DDH) carries a significantly elevated risk of postoperative complications, most notably aseptic loosening, which critically undermines implant survival rates. Given the young demographic and the anticipated prolonged functional lifespan of the prosthesis, there is an increased propensity for loosening over time, necessitating vigilant and sustained postoperative surveillance.

Failed radial head arthroplasty treated by removal of the implant.

In patients with a failed radial head arthroplasty (RHA), simple removal of the implant is an option. However, there is little information in the literature about the outcome of this procedure. The aim of this study was to review the mid-term clinical and radiological results, and the rate of complications and removal of the implant, in patients whose initial RHA was undertaken acutely for trauma involving the elbow. A total of 11 patients in whom removal of a RHA without reimplantation was undertaken as a revision procedure were reviewed at a mean follow-up of 8.4 years (6 to 11). The range of motion (ROM) and stability of the elbow were recorded. Pain was assessed using a visual analogue scale (VAS). The functional outcome was assessed using the Mayo Elbow Performance Score (MEPS), the Oxford Elbow Score (OES), and the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH). Radiological examination included the assessment of heterotopic ossification (HO), implant loosening, capitellar erosion, overlengthening, and osteoarthritis. Complications and the rate of further surgery were also recorded. The indications for removal of the implant were stiffness in five patients, aseptic loosening in five, and pain attributed to the RHA in three. The mean time interval between RHA for trauma to removal was ten months (7 to 21). Preoperatively, three patients had overlengthening of the implant, three had capitellar erosion, six had HO, and four had radiological evidence of loosening. At the final follow-up, the mean the flexion-extension arc improved significantly by 38.2° (95% CI 20 to 59; p = 0.002) and the mean arc of prono-supination improved significantly by 20° (95% CI 0 to 72.5; p = 0.035). The mean pain VAS score improved significantly by 3.5 (95% CI 2 to 5.5; p = 0.004). The mean MEPS improved significantly by 27.5 (95% CI 17.5 to 42.5; p = 0.002). The mean OES improved significantly by 9 (95% CI 2.5 to 14; p = 0.012), and the mean DASH score improved significantly by 23.5 (95% CI 7.5 to 31.6; p = 0.012). Ten patients (91%) had HO and osteoarthritis. Two patients underwent further surgery due to stiffness and pain, respectively. Simple removal of the implant at revision surgery following a failed RHA introduced following trauma provides satisfactory mid-term results with an acceptable risk of complications. Osteoarthritis, instability, and radioulnar impingement were not problems in this series.

Surgical Treatment and Outcomes of Trans-Ulnar Basal Coronoid Fracture-Dislocations

Trans-ulnar fracture-dislocations of the elbow are complex injuries that can be difficult to classify and treat. Trans-ulnar basal coronoid injuries, in which the coronoid is not attached to either the olecranon or the metaphysis, present substantial challenges to achieve anatomic reduction and stable internal fixation. The purpose of this study was to analyze the outcome of surgical treatment of trans-ulnar basal coronoid fracture-dislocations. Between 2002 and 2019, 32 consecutive trans-ulnar basal coronoid fracture-dislocations underwent open reduction and internal fixation (ORIF) at our institution. Four elbows were lost to follow-up within the first 6 months after surgery and were excluded. Among the 28 elbows remaining, there were 13 females and 15 males with a mean age of 56 (range 28-78) years at the time of injury. The mean clinical and radiographic follow-up times were 37 months and 29 months, respectively. Radiographs were reviewed to determine rates of union, Hastings and Graham heterotopic ossification (HO) grade, and Broberg and Morrey arthritis grade. Union occurred in 25 elbows. Union could not be determined for 1 elbow at most recent follow-up and the remaining 2 elbows developed nonunion of the coronoid. Complications occurred in 10 elbows (36%): deep infection (4), ulnar neuropathy (2), elbow contracture (2), and nonunion (2). There were reoperations in 11 elbows (39%): irrigation and débridement with hardware removal (4), hardware removal (2), ulnar nerve transposition (2), contracture release with HO removal (2), and revision ORIF with iliac crest autograft (1). At most recent follow-up, the mean flexion-extension arc was 106° (range 10-150°), and the mean pronation-supination arc was 137° (range 0-170°). The mean Quick Disabilities of Arm, Shoulder, and Hand score was 11 (range 0-39) points with a mean Single Assessment Numeric Evaluation-Elbow score of 81 (range 55-100) points. At final radiographic follow-up, 16 elbows (57%) had HO (8 class I and 8 class II), and 20 elbows (71%) had arthritis (8 grade 1, 6 grade 2, and 6 grade 3). Trans-ulnar basal coronoid fracture dislocations are severe injuries associated with high rates of reoperation, heterotopic ossification, and post-traumatic arthritis. However, the majority of elbows achieve union, a functional range of motion, and reasonable patient reported outcome measures. Over the study period, surgeons were more likely to utilize multiple deep approaches and separate fixation of the coronoid (either with lag screws or anteromedial plates) to ensure anatomic reduction.

Interleukin-6 Does Not Contribute to Neurogenic Heterotopic Ossification Pathogenesis

Interleukin-6 Does Not Contribute to Neurogenic Heterotopic Ossification Pathogenesis

Influence of Femoral Stem Geometry on Total Hip Replacement: A Comparison of Clinical Outcomes of a Straight and an Anatomical Uncemented Stem.

Background/Objectives: There are many aspects that may influence clinical outcomes in a total hip arthroplasty (THA). The influence of femoral stem on the clinical outcome of THA is probably underestimated in the literature. Our work aims to analyze how uncemented stem geometry (straight or anatomical) in THA might affect outcomes in clinical and radiographic terms. Methods: Over a period of 36 months, in a prospective-observational manner, we collected the results of THA secondary to osteoarthritis (OA) that met the inclusion criteria with the only variable being the straight or anatomical stem design in a single manufacturer. A total of 84 patients were selected and divided into two groups: group A, treated with straight stem (44 patients), and group B, treated with anatomical stem (40 patients). The assessment clinical tools were Harris Hip Score (HHS), Visual Analogue Scale (VAS), and Short Form Health Survey-36 (SF-36). Follow-up controls were at 6 months (T0), 12 months (T1), 24 months (T2), and 36 months (T3). Results: No statistically significant differences emerged between the two groups under analysis with VAS, SF-36, and HHS. At follow-up controls, eight patients (group A) and four patients (group B) showed anterior thigh pain. At T1, there were radiographic signs of aseptic loosening in two cases (group A) and one case (group B). In group A there were two cases of iatrogenic fracture, two cases of dislocation, one case of infection, and two cases of heterotopic ossification. Conclusions: The anatomical stem compared to the straight stem showed lower complication rates outcomes; the anatomical uncemented stem could be considered as a preferred first choice in THA compared to the straight stem.

Considerations of growth factor and material use in bone tissue engineering using biodegradable scaffolds in vitro and in vivo

Bone tissue engineering aims to harness materials to develop functional bone tissue to heal ‘critical-sized’ bone defects. This study examined a robust, coated poly(caprolactone) trimethacrylate (PCL-TMA) 3D-printable scaffold designed to augment bone formation. Following optimisation of the coatings, three bioactive coatings were examined, i) elastin-like polypeptide (ELP), ii) poly(ethyl acrylate) (PEA), fibronectin (FN) and bone morphogenetic protein-2 (BMP-2) applied sequentially (PEA/FN/BMP-2) and iii) both ELP and PEA/FN/BMP-2 coatings applied concurrently. The scaffold material was robust and showed biodegradability. The coatings demonstrated a significant (p < 0.05) osteogenic response in vitro in alkaline phosphatase gene upregulation and alkaline phosphatase production. The PCL-TMA scaffold and coatings supported angiogenesis and displayed excellent biocompatibility following evaluation on the chorioallantoic membrane assay. No significant (p < 0.05) heterotopic bone formed on the scaffolds within a murine subcutaneous implantation model, compared to the positive control of BMP-2 loaded collagen sponge following examination by micro-computed tomography or histology. The current studies demonstrate a range of innovative coated scaffold constructs with in vitro efficacy and clearly illustrate the importance of an appropriate in vivo environment to validate in vitro functionality prior to scale up and preclinical application.

Fibrodysplasia ossificans progressiva: a comprehensive review

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder that causes heterotopic ossification of soft tissues, leading to abnormal bone growth in muscles, tendons, and ligaments. First identified in the 17th century, FOP was classified in 1968 and is linked to a mutation in the Activin A receptor type I gene (ACVR1) which affects bone morphogenetic protein (BMP). The autosomal dominant condition FOP has the potential to lead to aberrant bone development. At birth, FOP individuals appear normal, except for characteristic malformations of the great toes. FOP patients develop painful, inflammatory soft tissue swellings during the first decade of life, often precipitated by soft tissue injury. Minor trauma can trigger new flare-ups and leads to progressive heterotopic ossification. Most FOP sufferers are wheelchair-bound by their third decade and needs lifelong assistance with daily living tasks. Bone morphogenetic proteins (BMPs) are bound by the transmembrane kinase receptor ALK2, which is encoded by the (ACVR1/ALK2 gene). FOPs induce heterotopic bone formation in skeletal muscle and can be caused by mutations in the activin A receptor type I (ACVR1) and activin-like kinase 2 (ALK2) gene. Clinical therapy focuses on preventing and controlling inflammation, with ongoing research focusing on specific therapies targeting receptor activity, aberrant pathways, or cellular components influencing bone neo-formation.

Denervation‑induced NRG3 aggravates muscle heterotopic ossification via the ErbB4/PI3K/Akt signaling pathway.

Peripheral nerve injury exacerbates progression of muscle heterotopic ossification (HO) and induces changes in expression of local cytokines in muscle tissue. The objective of the present study was to assess the impact of peripheral nerve injury on muscle HO development and the mechanism of cytokine modulation. A mouse model of gastrocnemius muscle HO was established and the sciatic nerve cut to simulate peripheral nerve injury. To evaluate the underlying factors contributing to the exacerbation of muscle HO resulting from denervation, fresh muscle tissue was collected and micro‑computed tomography, histochemical staining, RNA‑sequencing, reverse transcription‑quantitative PCR, Western blot, muscle tissue chip array were performed to analyze the molecular mechanisms. Sciatic nerve injury exacerbated HO in the gastrocnemius muscle of mice. Moreover the osteogenic differentiation of nerve‑injured muscle tissue‑derived fibro‑adipogenic progenitors (FAPs) increased in vitro. The expression of neuregulin 3 (NRG3) was demonstrated to be increased after nerve injury by muscle tissue chip array. Subsequent transcriptome sequencing analysis of muscle tissue revealed an enrichment of the PI3K/Akt pathway following nerve injury and an inhibitor of the PI3K/Akt pathway reduced the osteogenic differentiation of FAPs. Mechanistically, in vitro, peripheral nerve injury increased secretion of NRG3, which, following binding to ErbB4 on the cell surface of FAPs, promoted expression of osteogenesis‑associated genes via the PI3K/Akt signaling pathway, thus contributing to osteogenic differentiation of FAPs. In vivo, inhibition of the PI3K/Akt pathway effectively protected against muscle HO induced by peripheral nerve injury in mice. The present study demonstrated that the regulatory roles of NRG3 and the PI3K/Akt pathway in peripheral nerve injury exacerbated muscle HO and highlights a potential therapeutic intervention for treatment of peripheral nerve injury‑induced muscle HO.

Comparison of PET/CT versus CT only in the assessment of new heterotopic ossification bone lesions in patients with fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder characterized by the deposition of bone in soft tissues, known as heterotopic ossification (HO). This post hoc analysis compared the performance of two imaging modalities for the detection and volumetric measurement of new HO lesions. LUMINA-1, a phase 2, randomized, double-blind study (NCT03188666), evaluated the safety and efficacy of garetosmab, an anti-activin A antibody, versus placebo in adult patients with FOP. From baseline through to week 28, 18F-labeled sodium fluoride positron emission tomography (PET)/X-ray computed tomography (CT) and CT-only scans prospectively acquired during the initial placebo-controlled period of the study were independently reviewed by two sets of fixed blinded readers plus an adjudicator for the presence and volume of new HO lesions. The number of patients with new lesions was 14/44 (31.8 %) and 12/44 (27.3 %) as detected by PET/CT and CT only, respectively. The aggregate number/volume of new lesions were very similar both for the placebo and the garetosmab group between PET/CT (27/245.0 cm3 and 3/21.3 cm3, respectively) and CT only (37/261.8 cm3 and 1/0.1 cm3, respectively). The mean (standard deviation) number of new lesions per patient by PET/CT through week 28 was 0.68 (1.57) versus 0.86 (1.95) as detected by CT only. Through week 28, the mean (standard deviation) volume of new lesions per patient detected by PET/CT was 6.05 (14.88) cm3 versus 5.94 (21.13) cm3 by CT only. Moderate agreement between PET/CT and CT-only detection was observed when identifying patients with new lesions, with a kappa coefficient of 0.46 (standard error, 0.146; 95 % confidence interval, 0.17–0.74). CT-only imaging showed similar performance to PET/CT in the detection and characterization of new HO lesions. CT-only imaging therefore is a viable option for the assessment of therapies on new HO in patients with FOP.

18F]NaF PET/CT as a Marker for Fibrodysplasia Ossificans Progressiva: From Molecular Mechanisms to Clinical Applications in Bone Disorders.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic bone disorder characterized by episodic flare-ups in connective tissue, which are frequently followed by the formation of heterotopic ossification. The absence of available plasma-soluble biomarkers for flare-ups or heterotopic bone formation poses severe challenges to the monitoring of disease activity to measure or predict disease progression. Recently, 18-fluor-sodium fluoride positron emission tomography/computed tomography ([18F]NaF PET/CT) was introduced as a potential marker for ossifying FOP activity. This review discusses the pharmacokinetics of [18F]NaF in relation to the pathophysiology of FOP, and its use as a marker of local bone metabolism in a variety of bone-related disorders. In addition, the review specifically addresses the applicability of [18F]NaF PET/CT imaging in FOP as a monitoring modality.

Severe heterotopic ossification after total hip arthroplasty in male patients under 70years of age: effectiveness of prophylactic protocol.

This study aims to evaluate the incidence of clinically significant heterotopic ossification (HO) in primary total hip arthroplasty (THA), comparing outcomes with and without the adoption of an HO prophylactic protocol in male patients under 70years of age. The prophylactic protocol involved the administration of 50mg of Indomethacin twice daily for 3 weeks. HO presence was classified according to the Brooker classification system, considering "severe" clinically significant HO (Brooker grade 3 and 4). Two hundred and seventy-nine patients were included in our study, and an overall HO rate of 68.2% versus a rate of 61.5% was found respectively in patients not subjected and subjected to prophylactic protocol, without significant difference (PR 0.062). However, patients not subjected to the HO prophylactic protocol exhibited a severe HO rate of 22.4% compared to 7.7% in the prophylactic group, with a statistically significant difference (P = 0.008). Our study demonstrated that prophylactic protocol adoption is significantly associated with lower rate of severe HO in male patients under 70years of age. Currently, there are no orthopedic guidelines for the prevention and management of HO after THA, but in the absence of contraindications, the adoption of a prophylactic protocol for HO should always be considered in high-risk patients.

7635 Severe Osteoporosis in a Patient with Heterotopic Calcification: A Case Report

Abstract Disclosure: D. Salih Bacha: None. L.Z. Khan: None. Background: While osteoporosis and heterotopic ossification (HO) are distinct conditions affecting bone health, their coexistence poses intriguing clinical challenges. Osteoporosis, characterized by increased bone fragility, typically results from various factors such as aging, steroid use, or malabsorption. HO is a condition where bone forms abnormally in soft tissues. Risk factors that predispose to HO include male sex, spinal cord injury, trauma, surgery, and genetic factors. Treatment of HO is typically surgical resection and NSAIDs. Initial evidence supported the use of bisphosphonates for preventing ectopic bone formation post-trauma, but recent data failed to show significant benefit in HO prevention. This case presents a patient with unique challenges of both HO and bone fragility with multiple severe vertebral fractures. Case: A 44-year-old male patient had a major motor vehicle accident necessitating multiple recurrent abdominal surgeries. During one exploratory laparotomy, diffuse mesenteric calcifications were noted, indicative of HO. A baseline Dual X-ray Absorptiometry (DXA) scan revealed bone density of 1.003 g/cm2 and 0.788 g/cm2 at the spine and femoral neck, respectively, concerning for osteopenia. He was started on zoledronic acid in preparation for upcoming intestinal transplant. Few months after the transplant, he was started on daily tacrolimus and hydrocortisone for immunosuppression. Within months, he experienced sudden back pain while riding an elevator, and was found to have acute fractures in T8 and T9 vertebrae. A repeat DXA scan showed a further decline in bone density to 0.909 g/cm2 and 0.748 g/cm2 at the spine and femoral neck, respectively. Within a year, additional fractures occurred in the thoracic and lumbar spine (T10, T11, T12, L1, L2, L3, and L4), requiring multiple kyphoplasty interventions. Over time, worsening kyphosis, back pain, and height loss occurred, significantly affecting the patient's quality of life. He continued receiving yearly zoledronic acid infusions and underwent regular DXA scans, which revealed mild improvement in his bone density. Currently, there are no established guidelines specifying the optimal duration for bisphosphonate treatment in such cases. Therefore, our individualized treatment plan involves a tentative 10-year course of bisphosphonate treatment with yearly assessment of bone mineral density. Conclusion: Although the patient had some risk factors for osteoporosis, including daily steroid and tacrolimus use, the severity and frequency of his fractures suggested a potential synergy between osteoporosis and HO, where the formation of heterotopic calcifications may have been exacerbating his bone loss. The coexistence of osteoporosis and HO in this patient underscores the need for individualized care and establishment of treatment guidelines in patients with multiple bone disorders. Presentation: 6/3/2024

Use of Dual Mobility Cups Reduce Dislocation Risk After Internal Fixation for Acetabular Fracture Concomitant With Total Hip Arthroplasty in Patients Who are Over 60 Years Old

Treatment of complex acetabular fractures in patients over 60 remains challenging. Functional treatments for these fractures have yielded disappointing outcomes. Internal fixation may fail facing this porotic bone, and postoperative non weight bearing may expose the patient to decubitus complications. Our hypothesis was that use of a dual mobility cup (DMC) reduces dislocation risk after concomitant internal fixation and total hip arthroplasty (THA) for acetabular fracture in patients who are over 60 years old. A retrospective, observational non comparative and continuous study was conducted from January 2015 to September 2022. Patients aged over 60 years who had displaced acetabular fractures, treated surgically via concomitant internal fixation and THA, utilizing a DMC exclusively through the Kocher-Langenbeck approach and a minimum follow-up was of one year, were included. There were 45 patients (45 hips) who had an average age of 71 (range, 60 to 88) who were included (75.5% men). The main mechanisms of injury were the motor vehicle accidents (in 21 cases (46,7%)). Bi-column fractures were prevalent (46.6%). The analysis of complications included intraoperatively nerve palsy, postoperatively dislocations, deep infections, periprosthetic fractures and loosening. Clinical assessment included the Harris hip score (HHS) and the level of return to previous activities. Radiological evaluation assessed fracture union, periprosthetic osteolysis, graft integration, the presence of leg length discrepancy (LLD) and heterotopic ossification. There was one case of dislocation (2.2%) requiring reoperation for replacement of the prosthetic neck, and one patient (2.2%) experienced early THA infection, successfully treated with surgical lavage and antibiotics. Functional outcomes showed a mean HHS of 88 (range, 69 to 99) and 84% of patients resumed their previous activities. Radiological follow-up revealed no loosening. This study has shown that the use of DMC in concomitant THA with Open Reduction and Internal Fixation (ORIF) for acetabular facture in patient over age 60 years achieved a low dislocation rate with favorable clinical and radiological outcomes and a low complication rate.