Whole-body Computed Tomography Versus Dual Energy X‑ray Absorptiometry for Assessing Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva

Sarah E Warner, Frederick S Kaplan, Robert J Pignolo, Stacy E Smith, Edward C Hsiao, Carmen De Cunto, Maja Di Rocco, Kathleen Harnett, Donna Grogan, Harry K Genant, Sarah E Warner, Frederick S Kaplan, Robert J Pignolo, Stacy E Smith, Edward C Hsiao, Carmen De Cunto, Maja Di Rocco, Kathleen Harnett, Donna Grogan, Harry K Genant

Abstract

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder that leads to heterotopic ossification (HO), resulting in progressive restriction of physical function. In this study, low-dose, whole-body computed tomography (WBCT) and dual energy X-ray absorptiometry (DXA) were evaluated to determine the preferred method for assessing total body burden of HO in patients with FOP. This was a non-interventional, two-part natural history study in patients with FOP (NCT02322255; date of registration: December 2014). In Part A (described here), WBCT and DXA scans were individually assessed for HO presence and severity across 15 anatomical regions. All images were independently reviewed by an expert imaging panel. Ten adult patients were enrolled across four sites. The sensitivity to HO presence and severity varied considerably between the two imaging modalities, with WBCT demonstrating HO in more body regions than DXA (76/138 [55%] versus 47/113 [42%]) evaluable regions). Inability to evaluate HO presence, due to overlapping body regions (positional ambiguity), occurred less frequently by WBCT than by DXA (mean number of non-evaluable regions per scan 1.2 [standard deviation: 1.5] versus 2.4 [1.4]). Based on the increased sensitivity and decreased positional ambiguity of low-dose WBCT versus DXA in measuring HO in patients with FOP, low-dose WBCT was chosen as the preferred imaging for measuring HO. Therefore, low-dose WBCT was carried forward to Part B of the natural history study, which evaluated disease progression over 36 months in a larger population of patients with FOP.

Keywords: Dual energy X-ray absorptiometry; Fibrodysplasia ossificans progressiva; Heterotopic ossification; Whole-body computed tomography.

Conflict of interest statement

SEW: Employee of PAREXEL International (dba Calyx); FSK: Research investigator: Ipsen, Regeneron; Advisory board: IFOPA Medical Advisory Board; Founder and Immediate Past-President of the International Clinical Council (ICC) on FOP; Chair of the Publications Committee of the ICC; RJP: Research investigator: Ipsen, Regeneron; Advisory board: President of the International Clinical Council on FOP; Chair of the Publications Committee for the IFOPA Registry Medical Advisory Board; SES: None declared; ECH: Advisory board (all voluntary): Fibrous Dysplasia Foundation, IFOPA Registry Medical Advisory Board, International Clinical Council on FOP; Research support: International FOP Association, Ipsen, National Institutes of Health, Radiant Hope Foundation; Prior research support: Regeneron, Neurocrine Biosciences Inc; Research investigator: Ipsen; CDC: Research investigator: Ipsen; MDR: Advisory board: Ipsen; Research investigator: Ipsen, Regeneron; HKG: Consultant for Agnovos, Amgen, AstraZeneca, Bioclinica, BioMarin, Ipsen, Medimmune, Medtronic, Radius and Regeneron; KH, DG: Employees of Ipsen.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Body regions assessed for the presence of HO. Figure depicts the anatomical regions assessed for HO: (1) the right shoulder (shoulder through mid-humerus); (2) the left shoulder (shoulder through mid-humerus); (3) the right elbow (mid-humerus through mid-radius/ulna; (4) the left elbow (mid-humerus through mid-radius/ulna); (5) right distal upper extremity (mid-radius/ulna including entire hand); (6) left distal upper extremity (mid-radius/ulna including entire hand); (7) right hip (entire hip, including iliac crest and femoral head through mid-femur; (8) left hip (entire hip, including iliac crest and femoral head through mid-femur); (9) right knee (mid-femur through mid-tibia); (10) left knee (mid-femur through mid-tibia); (11) right distal lower extremity (mid-tibia [or distal], including whole foot); (12) left distal lower extremity (mid-tibia [or distal], including whole foot); (13) upper spine/chest (thoracic spine); (14) lower spine/abdomen (lumbar spine); (15) head and neck (for WBCT, the head was not included). DXA dual energy X-ray absorptiometry, HO heterotopic ossification, WBCT whole-body computed tomography
Fig. 2
Fig. 2
Representative 3-mm axial slices from a CT scan showing HO segmentations. Images were taken from the same 37-year-old male, with a Baseline CAJIS score of 24 at enrollment. Axial slices depict HO (each lesion segmented with a different color) located in: a upper body regions (representing regions 1, 2 and 13 from diagram in Fig. 1); b anterior to the left hip (region 8); c left and right hips (regions 7 and 8); d/e the right upper leg (region 9); f the left upper leg (region 10); and g the distal lower legs (regions 11 and 12). CAJIS Cumulative Analogue Joint Involvement Scale for FOP, CT computed tomography, HO heterotopic ossification
Fig. 3
Fig. 3
Representative a DXA and b 3D reconstructed WBCT scan (for demonstration only). Images were taken from the same 33-year-old male, with a Baseline CAJIS score of 18 at enrollment. The 3D reconstructed WBCT scan images were not used in the assessment or quantification of new HO in the analyses presented here, but are provided to demonstrate the amount of HO in a patient with FOP and to provide a similar view to the DXA images. 3D three-dimensional, CAJIS Cumulative Analogue Joint Score, DXA dual energy X-ray absorptiometry, FOP fibrodysplasia ossificans progressiva, WBCT whole-body computed tomography
Fig. 4
Fig. 4
Overlapping anatomy precludes HO evaluation using a DXA or b CT scout scans. Image a was taken from an 18-year-old male, with a Baseline CAJIS score of 14 at enrollment. Image b was taken from a 34-year-old female, with a Baseline CAJIS score of 12 at enrollment. CT computed tomography; DXA dual energy X-ray absorptiometry, HO heterotopic ossification

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