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

Posted Feb 28, 2017 Updated Apr 10, 2023
By Chamith S. Rajapakse PhD , Carter Lindborg PhD , Haitao Wang PhD , Benjamin T. Newman BSc , Elizabeth A. Kobe , Gregory Chang MD , Eileen M. Shore PhD , Frederick S. Kaplan MD , Robert J. Pignolo MD PhD
8 min read

Rationale and Objectives

Severe progressive multifocal heterotopic ossification (HO) is a rare occurrence seen predominantly in patients who have fibrodysplasia ossificans progressiva (FOP) and is difficult to quantitate owing 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 patients with FOP.

Materials and Methods

Institutional review board approval was obtained from the University of Pennsylvania, and all data comply with Health Insurance Portability and Accountability Act regulations. The University of Pennsylvania Institutional Animal Care and Use Committee approved the use of mice in this study. First, we used a mouse model of FOP-like HO to validate a semiquantitative analog 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 computed tomographic images from three patients with FOP.

Results

In the FOP-mouse model, the observed rating on the analog scale is highly correlated to heterotopic bone volumes measured by microcomputed tomography ( R 2 = 0.89). The scoring system that was applied to radiographs of patients with FOP captured the clinical range of HO typically present at all axial and appendicular sites. Analysis of computed tomographic scans of patients with FOP found that observed radiograph ratings were highly correlated with HO volume ( R 2 = 0.80).

Conclusions

The scoring system described here could enable practical, quantitative assessment of HO in clinical trials to evaluate new treatment modalities, especially for FOP. The development of the six-point analog scale described here provides and validates a much-needed, reproducible, and quantifiable method for describing and assessing HO in patients with FOP. This scale has the potential to be a key descriptor that can inform patients with FOP and clinicians about disease progression and response of HO lesions to interventions and treatments.

Introduction

Fibrodysplasia ossificans progressiva (FOP) (Mendelian Inheritance in Man #135100) is a severely disabling heritable disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) that forms qualitatively normal bone at extraskeletal sites . During the first decade of life, affected children experience episodic exacerbations of painful soft tissue swellings (flare-ups), often precipitated by soft tissue injury, intramuscular injections, viral infection, muscular stretching, falls, or muscular fatigue . These flare-ups transform skeletal muscles, tendons, ligaments, fascia, and aponeuroses into heterotopic bone, rendering movement restricted or impossible. Classic FOP is caused by a recurrent activating mutation (c.617G>A; R206H) in the gene encoding activin A receptor type I/activin-like kinase 2 ( ACVR1/ALK2 ), a bone morphogenetic protein type I receptor . At present, there is no definitive treatment, but emerging drug development offers the possibility of beneficial interventions .

Although multiple classification systems grade the severity of focal HO , none is applicable to progressive multifocal HO, nor does any adequately measure volumetric bone by plain radiographs. A simple method for quantifying extraskeletal bone formation would be useful to assess the effectiveness of evolving treatments, especially for FOP, where rigid immobility because of progressive multifocal HO often precludes serial quantitative computed tomographic (CT) scans at major urban medical centers.

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Table 1

Analog Scale to Measure HO on Plain Radiographs in Patients with FOP \*

0 No HO 1 Single or multiple spicules (punctate) or islands (non-contiguous) of HO 2 Coalescing islands or reticular complexes of heterotopic bone 3 Single contiguous HO having longest dimension ≤one-half of the diameter of the reference normotopic bone \\ in any projection 4 Single contiguous HO with longest dimension >one-half but ≤1 of the diameter of the reference normotopic bone \\ in any projection 5 Single contiguous HO with longest dimension >1 but ≤2 of the diameter of reference normotopic bone \* in any projection 6 Single contiguous HO with longest dimension >2 diameters of reference normotopic bone \\ in any projection

HO, heterotopic ossification.

Ankle, tibial shaft; back or chest, height of cervical vertebral body nearest to HO midpoint; Distal lower extremity, tibial shaft; Distal upper extremity, radial shaft; Foot, metatarsal; Hip or proximal lower extremity, width of femoral neck; Jaw or chin, width of hyoid; Knee, femoral shaft; Neck, height of cervical vertebral body nearest to HO midpoint (lateral projection); Proximal upper extremity, humeral shaft; TMJ, height of cervical vertebral body nearest to HO midpoint.

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Materials and Methods

Animals and Injury-induced HO Model

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Microcomputed Tomography

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Patients

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Assessment of Radiographs

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Clinical CT Imaging and HO Volume Analysis

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HO Scoring System

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Statistics

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Results

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Figure 1, High correlation between microcomputed tomography-quantified bone volume and heterotopic ossification (HO) scores on the analog scale ( n = 34) in a mouse model of HO. R 2 , coefficient of determination.

Figure 2, Two-dimensional renderings of reconstructed microcomputed tomographic images in an inducible heterotopic ossification (HO) mouse model of fibrodysplasia ossificans progressiva (FOP). Shown are representative images of HO corresponding to the indicated analog scores 0–6, as defined in Table 1 . Insets for scores 3 and 4 show magnified views of the longest contiguous ectopic bone (↔) corresponding to the indicated grade.

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Figure 3, Grading of radiographic lesions of heterotopic ossification in patients with fibrodysplasia ossificans progressiva by the analog scoring system. Shown are representative images from plain X-rays corresponding to the indicated analog scores 2–6, as defined in Table 1 .

Table 2

Localization and Grading of Radiographic HO Lesions

HO Grade Totals by Location 1 2 3 4 5 6 Neck 2 21 23 Back or chest 1 1 47 49 Shoulders 3 5 4 49 61 Elbows 2 8 10 Wrists 0 Hips 1 3 8 27 39 Knees 1 12 13 Distal lower extremities (incl. ankles or feet) 2 3 1 7 13 Totals by grade 0 4 5 9 19 171 208

HO, heterotopic ossification.

Figure 4, Distribution of radiographic heterotopic ossification lesions by score on the analog scale in patients with fibrodysplasia ossificans progressiva.

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Figure 5, Correlation between bone volumes measured by computed tomographic image analysis with heterotopic ossification scores on the analog scale ( n = 20). R 2 , coefficient of determination.

Figure 6, Examples of heterotopic ossification (HO) grading in three-dimensional reconstructions of computed tomographic images by the analog scoring system in patients with fibrodysplasia ossificans progressiva. HO lesions are displayed with the indicated analog scores 1–6. Each image is from a different patient with FOP (a, b, c) .

Figure 7, Anterior and posterior three-dimensional (3D) reconstructions of computed tomographic (CT) images obtained from a patient with fibrodysplasia ossificans progressiva and heterotopic ossification lesions highlighted in red. 3D reconstructions of CT images can aid in identifying lower grade lesions and in determining how lesions connect to and impact skeletal structure on a systemic level. (Color version of figure is available online.)

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Discussion

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Figure 8, Example of intra-articular synovial osteochondromatosis and osteochondromas of the hip. These radiographic lesions should not be graded on the heterotopic ossification scale.

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Acknowledgments

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References

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Academic Radiology, Volume 24, Issue 3
Journals General Radiology
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