Analog Method for Radiographic Assessment of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva

Abstract

Rationale and Objectives Severe progressive multi-focal heterotopic ossification (HO) is a rare occurrence seen predominantly in patients who have fibrodysplasia ossificans progressiva (FOP) and is difficult to quantitate due to patient-, disease-, logistical-, and radiation-related issues. The purpose of this study was to develop and validate a scoring system based on plain radiographs for quantitative assessment of HO lesions in FOP patients. Materials and Methods IRB approval was obtained from the University of Pennsylvania and all data comply with HIPAA regulations. The University of Pennsylvania Institutional Animal Care and Use Committee (IACUC) approved the use of mice in this study. First, we used a mouse model of FOP-like HO to validate a semi-quantitative analogue scale for estimating relative heterotopic bone volume. Second, we used this validated scale to estimate the relative amount of HO from a retrospective analysis of plain radiographs from 63 patients with classic FOP. Finally, the scale was applied to a retrospective analysis of CT images from three FOP patients. Results In the FOP-mouse model, the observed rating on the analogue scale is highly correlated to heterotopic bone volumes measured by micro-computed tomography (R2 = 0.89). The scoring system that was applied to radiographs of FOP patients captured the clinical range of HO typically present at all axial and appendicular sites. Analysis of CT scans of FOP patients found that observed radiograph ratings were highly correlated with HO volume (R2 = 0.80). Conclusion The scoring system described here could enable practical, quantitative assessment of HO in clinical trials to evaluate new treatment modalities, especially for FOP. Clinical Relevance The development of the six-point analogue scale described here provides and validates a much-needed, reproducible and quantifiable method for describing and assessing heterotopic ossification in FOP patients. This scale has the potential to be a key descriptor that can inform FOP patients and clinicians about disease progression and response of heterotopic ossification lesions to interventions and treatments.

18F-Sodium Fluoride PET as a Diagnostic Modality for Metabolic, Autoimmune, and Osteogenic Bone Disorders: Cellular Mechanisms and Clinical Applications

“…Plain radiographs are cheap and readily available, but they cannot detect lesions undergoing early inflammatory stage and are limited in calculating the volume of heterotopic bone. CT scans allow volumetric measurements but are also of limited value in detecting subtle edema associated with early stages of flare-ups [ 97 , 98 ]. 18 F-NaF-PET has been shown to be capable of detecting the flare-ups and predicting the location of heterotopic ossification in early disease progress before it is detectable by CT scan alone [ 99 , 100 ].…”

Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial

“…(28) Although the volume of new HO at weeks 6 and 12 was similar in the palovarotene 5/2.5 mg and palovarotene 10/5 mg groups, these results were likely influenced by flare-up location. For example, hip flare-ups are considered to be among the most long-lasting and functionally disabling flare-ups experienced by patients with FOP, (18) and may be accompanied by large amounts of HO; three of the four flare-ups that were associated with new HO in the palovarotene 10/5 mg group were located at the hip, compared with none in the palovarotene 5/2.5 mg group and two of three in the placebo group.…”

“…Responders were defined as those with no or minimal new HO at the flare‐up body region, as indicated by a HO score ≤3 on a scale from 0 to 6 (lower score indicates less HO; Table S 3 ). ( 18 ) Secondary endpoints included the same assessment at week 12, the volume of new HO at the flare‐up body region (assessed by low‐dose computed tomography [CT] scan) at weeks 6 and 12, and presence of soft tissue swelling/edema at the flare‐up body region (assessed by magnetic resonance imaging [MRI] or ultrasound in patients unable to undergo MRI).…”

“…The proportion of patients with no or minimal HO (primary endpoint) was hypothesized to be 20% with placebo and 80% with successful palovarotene treatment, based on patient survey data and nonclinical data, respectively. ( 18 ) Assuming that a higher dose results in increased efficacy, the power to detect a significant trend over the dose range (Cochran‐Armitage test of trend; α = 0.05) was tested in six scenarios, based on hypothesized efficacy, with chosen sample sizes pooled across Cohort 1 and Cohort 2: placebo: n = 10; palovarotene 5/2.5 mg: n = 9; palovarotene 10/5 mg: n = 21 (Table S 5 ).…”

Ultrasonography Monitoring of Trauma-Induced Heterotopic Ossification: Guidance for Rehabilitation Procedures

“…A recent study proposed an analog scoring method ( 26 ) for radiographic classification and evaluation of HO based on normotopic reference bone. Its results showed high correlation ( R 2 = 0.89) between the scores of the analog scale and the heterotopic bone volumes measured by micro-CT, i.e., higher score means larger size of HO.…”