Microarchitecture of Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva: An HR-pQCT Case Series.

Esmée Botman,Bert Van Rietbergen,Caroline E Wyers,Bernd P Teunissen,Melissa S A M Bevers,Elisabeth M W Eekhoff,Pieter G Raijmakers,Jan Coen Netelenbos,Joop P Van Den Bergh

doi:10.3389/fcell.2021.627784

Abstract

It is challenging to study heterotopic ossification (HO) in patients with fibrodysplasia ossificans progressiva (FOP) due to the contraindication of invasive techniques (i.e., bone biopsies), which can trigger flare-ups. The aim of this case study was to assess mature HO at the microarchitectural level non-invasively with high-resolution peripheral quantitative computed tomography (HR-pQCT). Depending on the patient’s mobility, HR-pQCT scans were acquired of peripherally located HO and standard distal radius and tibia regions in two FOP patients, a 33-year-old woman and a 23-year-old man, with the classical mutation (p.R206H). HO was located around the halluces, the ankles, and in the Achilles tendon. Standard HR-pQCT analyses were performed of the distal radius, tibia, and HO to quantify bone mineral density (BMD) and bone microarchitecture. Micro-finite element analysis was used to estimate failure load (FL). The outcomes were compared between HO and neighboring skeletal bone and with an age- and gender-matched normative dataset from literature. The bone parameters of the radius were within the interquartile range (IQR) of normative data. In contrast, in the tibiae of both patients, total and trabecular BMD were below the IQR, as were trabecular bone volume fraction, number, and thickness, cortical thickness, and FL. Trabecular separation and heterogeneity were above the IQR. Isolated HO in the Achilles tendon had a lower total, trabecular, and cortical BMD, trabecular bone volume fraction, and cortical thickness than the normative tibia data. Trabecular microarchitecture was within the IQR, and FL was approximately 10% higher than that of the neighboring tibia after accounting for areal differences. Other scanned HO could only be qualitatively assessed, which revealed coalescence with the neighboring skeletal bone, development of a neo-cortex, and partial replacement of the original skeletal cortex with trabeculae. To conclude, isolated HO seemed microarchitecturally more comparable to reference tibia data than the peripheral skeleton of the FOP patients. HO and skeleton also appear to be able to become one entity when contiguous.

Highlights

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease that is characterized by the formation of heterotopic ossification (HO) in ligaments, tendons, and muscles (Rogers and Geho, 1979; Cohen et al, 1993; Kaplan et al, 2008)
High-resolution peripheral quantitative computed tomography (HR-pQCT) scans could not be acquired of the halluces and left ankle of patient 2 as he was not able to position his foot in plantar flexion due to ankle ankylosis
HO around the halluces and ankle of the patients was merged with the neighboring skeletal bone, and it appeared that a neo-cortex was formed, surrounding the HO where it fused with the skeletal bone

Summary

Introduction

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease that is characterized by the formation of heterotopic ossification (HO) in ligaments, tendons, and muscles (Rogers and Geho, 1979; Cohen et al, 1993; Kaplan et al, 2008). The formation of HO is often preceded by a clinical flare-up whose clinical signs are, among others, pain, redness, and swelling (Kaplan et al, 2008; Pignolo et al, 2016). The histology of these flare-ups developing into HO has previously been studied through biopsies that were obtained for other purposes, mainly to exclude malignancies in non-diagnosed FOP patients (Kaplan et al, 1993; Gannon et al, 1998). The fibroproliferative tissue develops into cartilage before it develops into endochondral bone (Kaplan et al, 1993; Gannon et al, 1998; Pignolo et al, 2011)

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