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Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder, characterized by progressive heterotopic ossification (HO) and painful soft-tissue inflammatory flare-ups. This was a post hoc analysis from a phase 2 (NCT03188666) trial in which adults with FOP received intravenous anti-activin A antibody garetosmab 10 mg/kg or placebo every 4 wk over 28 wk (Period 1), followed by a 28-wk open-label treatment and extension (Periods 2 and 3). Here we describe flare-ups, their relationship to new HO lesions, and the impact of garetosmab on flare-ups. Volume of new HO lesions was measured by CT. Patient-reported flare-ups were defined by any 2 of the following: new onset of pain, swelling, joint stiffness, decrease in movement, or perceived presence of HO. Flare-ups were experienced by 71% (17/24) of placebo-treated patients, 59% (10/17) of whom developed a new HO lesion irrespective of flare-up location; 24% of flare-ups location-matched new HO lesions. Twenty-nine new HO lesions occurred in the placebo cohort by week 28, of which 12 (41%) occurred in the same location as new or ongoing flare-ups. A higher volume of newly formed heterotopic bone (week 28) occurred in placebo-treated patients who had experienced a prior flare-up vs those without (median [Q1:Q3] of 16.6 [12.0:31.1] vs 3.2 cm3). Garetosmab was previously shown to decrease patient-reported flare-up frequency in Period 1; here, garetosmab reduced the median (Q1:Q3) duration of patient-reported flares (15.0 [6.0:82.0] vs 48.0 [15.0:1.00] d) and the severity of flare-ups vs placebo. Frequency of corticosteroid use was numerically reduced in those treated with garetosmab (40.0%) vs placebo (58.3%). In this analysis, 71% of placebo-treated adults with FOP experienced flare-ups over 28 wk, which were associated with an increased volume of newly formed heterotopic bone. Garetosmab reduced the severity and duration of flare-ups, with effects sustained during the entire trial., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Single case studies of extraordinary disease resilience may provide therapeutic insight into conditions for which no definitive treatments exist. An otherwise healthy 35-year-old man (patient-R) with the canonical pathogenic ACVR1R206H variant and the classic congenital great toe malformation of fibrodysplasia ossificans progressiva (FOP) had extreme paucity of post-natal heterotopic ossification (HO) and nearly normal mobility. We hypothesized that patient-R lacked a sufficient post-natal inflammatory trigger for HO. A plasma biomarker survey revealed a reduction in total matrix metalloproteinase-9 (MMP-9) compared to healthy controls and individuals with quiescent FOP. Whole exome sequencing identified compound heterozygous variants in MMP-9 (c.59C > T, p.A20V and c.493G > A, p.D165N). Structural analysis of the D165N variant predicted both decreased MMP-9 secretion and activity that were confirmed by enzyme-linked immunosorbent assay and gelatin zymography. Further, human proinflammatory M1-like macrophages expressing either MMP-9 variant produced significantly less Activin A, an obligate ligand for HO in FOP, compared to wildtype controls. Importantly, MMP-9 inhibition by genetic, biologic, or pharmacologic means in multiple FOP mouse models abrogated trauma-induced HO, sequestered Activin A in the extracellular matrix (ECM), and induced regeneration of injured skeletal muscle. Our data suggest that MMP-9 is a druggable node linking inflammation to HO, orchestrates an existential role in the pathogenesis of FOP, and illustrates that a single patient's clinical phenotype can reveal critical molecular mechanisms of disease that unveil novel treatment strategies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder with episodic and progressive heterotopic ossification. Tissue trauma is a major risk factor for flareups, heterotopic ossification (HO), and loss of mobility in patients with FOP. The International Clinical Council on FOP generally recommends avoiding surgery in patients with FOP unless the situation is life-threatening, because soft tissue injury can trigger an FOP flareup. Surprisingly little is known about flareups, HO formation, and loss of mobility after fractures of the normotopic (occurring in the normal place, distinct from heterotopic) skeleton when treated nonoperatively in patients with FOP., Questions/purposes: (1) What proportion of fractures had radiographic evidence of union (defined as radiographic evidence of healing at 6 weeks) or nonunion (defined as the radiographic absence of a bridging callus at 3 years after the fracture)? (2) What proportion of patients had clinical symptoms of an FOP flareup because of the fracture (defined by increased pain or swelling at the fracture site within several days after closed immobilization)? (3) What proportion of patients with fractures had radiographic evidence of HO? (4) What proportion of patients lost movement after a fracture?, Methods: We retrospectively identified 36 patients with FOP from five continents who sustained 48 fractures of the normotopic skeleton from January 2001 to February 2021, who were treated nonoperatively, and who were followed for a minimum of 18 months after the fracture and for as long as 20 years, depending on when they sustained their fracture during the study period. Five patients (seven fractures) were excluded from the analysis to minimize cotreatment bias because these patients were enrolled in palovarotene clinical trials (NCT02190747 and NCT03312634) at the time of their fractures. Thus, we analyzed 31 patients (13 male, 18 female, median age 22 years, range 5 to 57 years) who sustained 41 fractures of the normotopic skeleton that were treated nonoperatively. Patients were analyzed at a median follow-up of 6 years (range 18 months to 20 years), and none was lost to follow-up. Clinical records for each patient were reviewed by the referring physician-author and the following data for each fracture were recorded: biological sex, ACVR1 gene pathogenic variant, age at the time of fracture, fracture mechanism, fracture location, initial treatment modality, prednisone use at the time of the fracture as indicated in the FOP Treatment Guidelines for flare prevention (2 mg/kg once daily for 4 days), patient-reported flareups (episodic inflammatory lesions of muscle and deep soft connective tissue characterized variably by swelling, escalating pain, stiffness, and immobility) after the fracture, follow-up radiographs of the fracture if available, HO formation (yes or no) as a result of the fracture determined at a minimum of 6 weeks after the fracture, and patient-reported loss of motion at least 6 months after and as long as 20 years after the fracture. Postfracture radiographs were available in 76% (31 of 41) of fractures in 25 patients and were independently reviewed by the referring physician-author and senior author for radiographic criteria of fracture healing and HO., Results: Radiographic healing was noted in 97% (30 of 31) of fractures at 6 weeks after the incident fracture. Painless nonunion was noted in one patient who sustained a displaced patellar fracture and HO. In seven percent (three of 41) of fractures, patients reported increased pain or swelling at or near the fracture site within several days after fracture immobilization that likely indicated a site-specific FOP flareup. The same three patients reported a residual loss of motion 1 year after the fracture compared with their prefracture status. HO developed in 10% (three of 31) of the fractures for which follow-up radiographs were available. Patient-reported loss of motion occurred in 10% (four of 41) of fractures. Two of the four patients reported noticeable loss of motion and the other two patients reported that the joint was completely immobile (ankylosis)., Conclusion: Most fractures treated nonoperatively in individuals with FOP healed with few flareups, little or no HO, and preservation of mobility, suggesting an uncoupling of fracture repair and HO, which are two inflammation-induced processes of endochondral ossification. These findings underscore the importance of considering nonoperative treatment for fractures in individuals with FOP. Physicians who treat fractures in patients with FOP should consult with a member of the International Clinical Council listed in the FOP Treatment Guidelines ( https://www.iccfop.org )., Level of Evidence: Level IV, therapeutic study., Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research ® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2023 by the Association of Bone and Joint Surgeons.)

Background: The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification (HO). Palovarotene is a selective retinoic acid receptor gamma agonist. Here, we describe the methodology of three studies in the palovarotene clinical development program in FOP and discuss insights that could inform future research, including endpoint suitability and the impact of trial design., Methods: PVO-1A-001 (NCT02322255) was a prospective, protocol-specified, longitudinal FOP natural history study (NHS). PVO-1A-201 (NCT02190747) was a randomized, double-blind, placebo-controlled phase II trial; PVO-1A-202 (NCT02279095) was its open-label extension. Trial designs, including treatment regimens and imaging assessments, were refined between PVO-1A-201 and PVO-‍1A-202, and within PVO-1A-202, based on emerging data as the studies progressed. Palovarotene doses were administered using a flare-up treatment regimen (higher dose for 2/4 weeks, followed by lower dose for 4/≥8 weeks; from flare-up onset), with or without accompanying chronic (daily) treatment. Flare-up and disease progression outcomes were assessed, including incidence and volume of new HO during flare-ups and/or annually, as well as other clinical, patient-reported, and exploratory outcomes. Safety was monitored throughout all studies., Results: Overall, 114 and 58 individuals with FOP were enrolled in the NHS and phase II trials, respectively. Results of the NHS and PVO-1A-201 were published in 2022; complete results of PVO-1A-202 will be publicly available in due course. Together the studies yielded important information on endpoint suitability, including that low-dose whole-body computed tomography was the optimum imaging modality for assessing HO progression annually and that long study durations are needed to detect substantial changes in functional and patient-reported outcomes., Conclusions: A flexible clinical development program is necessary for underexplored rare diseases to overcome the many challenges faced. Here, the NHS provided a longitudinal evaluation of FOP progression and interventional trials were based on emerging data. The studies described informed the design and endpoints implemented in the phase III MOVE trial (NCT03312634) and provide a foundation for future clinical trial development., Trial Registration: NCT02322255 (registered 23/12/2014); NCT02190747 (registered 15/07/2014); NCT02279095 (registered 30/10/2014)., (© 2023. The Author(s).)

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET-CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 ., (© 2023. The Author(s).)

Background: Assessment of cortical bone porosity and geometry by imaging in vivo can provide useful information about bone quality that is independent of bone mineral density (BMD). Ultrashort echo time (UTE) MRI techniques of measuring cortical bone porosity and geometry have been extensively validated in preclinical studies and have recently been shown to detect impaired bone quality in vivo in patients with osteoporosis. However, these techniques rely on laborious image segmentation, which is clinically impractical. Additionally, UTE MRI porosity techniques typically require long scan times or external calibration samples and elaborate physics processing, which limit their translatability. To this end, the UTE MRI-derived Suppression Ratio has been proposed as a simple-to-calculate, reference-free biomarker of porosity which can be acquired in clinically feasible acquisition times., Purpose: To explore whether a deep learning method can automate cortical bone segmentation and the corresponding analysis of cortical bone imaging biomarkers, and to investigate the Suppression Ratio as a fast, simple, and reference-free biomarker of cortical bone porosity., Methods: In this retrospective study, a deep learning 2D U-Net was trained to segment the tibial cortex from 48 individual image sets comprised of 46 slices each, corresponding to 2208 training slices. Network performance was validated through an external test dataset comprised of 28 scans from 3 groups: (1) 10 healthy, young participants, (2) 9 postmenopausal, non-osteoporotic women, and (3) 9 postmenopausal, osteoporotic women. The accuracy of automated porosity and geometry quantifications were assessed with the coefficient of determination and the intraclass correlation coefficient (ICC). Furthermore, automated MRI biomarkers were compared between groups and to dual energy X-ray absorptiometry (DXA)- and peripheral quantitative CT (pQCT)-derived BMD. Additionally, the Suppression Ratio was compared to UTE porosity techniques based on calibration samples., Results: The deep learning model provided accurate labeling (Dice score 0.93, intersection-over-union 0.88) and similar results to manual segmentation in quantifying cortical porosity (R 2  ≥ 0.97, ICC ≥ 0.98) and geometry (R 2  ≥ 0.82, ICC ≥ 0.75) parameters in vivo. Furthermore, the Suppression Ratio was validated compared to established porosity protocols (R 2  ≥ 0.78). Automated parameters detected age- and osteoporosis-related impairments in cortical bone porosity (P ≤ .002) and geometry (P values ranging from <0.001 to 0.08). Finally, automated porosity markers showed strong, inverse Pearson's correlations with BMD measured by pQCT (|R| ≥ 0.88) and DXA (|R| ≥ 0.76) in postmenopausal women, confirming that lower mineral density corresponds to greater porosity., Conclusion: This study demonstrated feasibility of a simple, automated, and ionizing-radiation-free protocol for quantifying cortical bone porosity and geometry in vivo from UTE MRI and deep learning., Competing Interests: Declaration of competing interest B.C.J. No relevant relationships. F.W.W. No relevant relationships. N.K. No relevant relationships. R.D. No relevant relationships. B.D.V. No relevant relationships. H.K.S. No relevant relationships. H.L. No relevant relationships. R.G. No relevant relationships. T.J.C. No relevant relationships. W.R.W. No relevant relationships. N.J.J. No relevant relationships. S.K.I. No relevant relationships. M.a.M. Funding from Ipsen/Clementia, Incyte; funding from Regeneron; honoraria from Excel, Catalyst; support for meetings from Cooley Anemia Foundation, International Clinical. Counsel on Fibrodysplasia Ossificans Progressiva (FOP), International Fibrodysplasia. Ossificans Progressiva Association (IFOPA); advisory board member for Biocryst and IFOPA; member of the International Clinical Council on FOP. P.J.S. No relevant relationships. C.S.R. No relevant relationships., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background Preclinical studies have suggested that solid-state MRI markers of cortical bone porosity, morphologic structure, mineralization, and osteoid density are useful measures of bone health. Purpose To explore whether MRI markers of cortical bone porosity, morphologic structure, mineralization, and osteoid density are affected in postmenopausal osteoporosis (OP) and to examine associations between MRI markers and bone mineral density (BMD) in postmenopausal women. Materials and Methods In this single-center study, postmenopausal women were prospectively recruited from January 2019 to October 2020 into two groups: participants with OP who had not undergone treatment, defined as having any dual-energy x-ray absorptiometry (DXA) T-score of -2.5 or less, and age-matched control participants without OP (hereafter, non-OP). Participants underwent MRI in the midtibia, along with DXA in the hip and spine, and peripheral quantitative CT in the midtibia. Specifically, MRI measures of cortical bone porosity (pore water and total water), osteoid density (bound water [BW]), morphologic structure (cortical bone thickness), and mineralization (phosphorous [P] density [ 31 P] and 31 P-to-BW concentration ratio) were quantified at 3.0 T. MRI measures were compared between OP and non-OP groups and correlations with BMD were assessed. Results Fifteen participants with OP (mean age, 63 years ± 5 [SD]) and 19 participants without OP (mean age, 65 years ± 6) were evaluated. The OP group had elevated pore water (11.6 mol/L vs 9.5 mol/L; P = .007) and total water densities (21.2 mol/L vs 19.7 mol/L; P = .03), and had lower cortical bone thickness (4.8 mm vs 5.6 mm; P < .001) and 31 P density (6.4 mol/L vs 7.5 mol/L; P = .01) than the non-OP group, respectively, although there was no evidence of a difference in BW or 31 P-to-BW concentration ratio. Pore and total water densities were inversely associated with DXA and peripheral quantitative CT BMD ( P < .001), whereas cortical bone thickness and 31 P density were positively associated with DXA and peripheral quantitative CT BMD ( P = .01). BW, 31 P density, and 31 P-to-BW concentration ratio were positively associated with DXA ( P < .05), but not with peripheral quantitative CT. Conclusion Solid-state MRI of cortical bone was able to help detect potential impairments in parameters reflecting porosity, morphologic structure, and mineralization in postmenopausal osteoporosis. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Bae in this issue.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling genetic disorder of progressive heterotopic ossification (HO). The single-arm, open-label, phase 3 MOVE trial (NCT03312634) assessed efficacy and safety of palovarotene, a selective retinoic acid receptor gamma agonist, in patients with FOP. Findings were compared with FOP natural history study (NHS; NCT02322255) participants untreated beyond standard of care. Patients aged ≥4 years received palovarotene once daily (chronic: 5 mg; flare-up: 20 mg for 4 weeks, then 10 mg for ≥8 weeks; weight-adjusted if skeletally immature). The primary endpoint was annualized change in new HO volume versus NHS participants (by low-dose whole-body computed tomography [WBCT]), analyzed using a Bayesian compound Poisson model (BcPM) with square-root transformation. Twelve-month interim analyses met futility criteria; dosing was paused. An independent Data Monitoring Committee recommended trial continuation. Post hoc 18-month interim analyses utilized BcPM with square-root transformation and HO data collapsed to equalize MOVE and NHS visit schedules, BcPM without transformation, and weighted linear mixed-effects (wLME) models, alongside prespecified analysis. Safety was assessed throughout. Eighteen-month interim analyses included 97 MOVE and 101 NHS individuals with post-baseline WBCT. BcPM analyses without transformation showed 99.4% probability of any reduction in new HO with palovarotene versus NHS participants (with transformation: 65.4%). Mean annualized new HO volume was 60% lower in MOVE versus the NHS. wLME results were similar (54% reduction fitted; nominal p = 0.039). All palovarotene-treated patients reported ≥1 adverse event (AE); 97.0% reported ≥1 retinoid-associated AE; 29.3% reported ≥1 serious AE, including premature physeal closure (PPC)/epiphyseal disorder in 21/57 (36.8%) patients aged <14 years. Post hoc computational analyses using WBCT showed decreased vertebral bone mineral density, content, and strength, and increased vertebral fracture risk in palovarotene-treated patients. Thus, post hoc analyses showed evidence for efficacy of palovarotene in reducing new HO in FOP, but high risk of PPC in skeletally immature patients. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, genetic disorder of heterotopic ossification within soft, connective tissues resulting in limited joint function and severe disability. We present results from an international burden of illness survey (NCT04665323) assessing physical, quality of life (QoL), and economic impacts of FOP on patients and family members., Methods: Patient associations in 15 countries invited their members to participate; individuals with FOP and their family members were eligible. The survey was available online, in 11 languages, from 18 January-30 April 2021. Participants responded to assessments measuring joint function, QoL, healthcare service and living adaptation utilization, out-of-pocket costs, employment, and travel., Results: The survey received 463 responses (patients, n = 219; family members, n = 244). For patients, decreased joint function was associated with reduced QoL and greater reliance on living adaptations. Nearly half of primary caregivers experienced a mild to moderate impact on their health/psychological wellbeing. Most primary caregivers and patients (≥18 years) reported that FOP impacted their career decisions., Conclusions: Data from this survey will improve understanding of the impact of FOP on patients and family members, which is important for identifying unmet needs, optimizing care, and improving support for the FOP community.

Purpose: We report the first prospective, international, natural history study of the ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP). FOP is characterized by painful, recurrent flare-ups, and disabling, cumulative heterotopic ossification (HO) in soft tissues., Methods: Individuals aged ≤65 years with classical FOP (ACVR1 R206H variant) were assessed at baseline and over 36 months., Results: In total, 114 individuals participated; 33 completed the study (mean follow up: 26.8 months). Median age was 15.0 (range: 4-56) years; 54.4% were male. During the study, 82 (71.9%) individuals reported 229 flare-ups (upper back: 17.9%, hip: 14.8%, shoulder: 10.9%). After 84 days, 14 of 52 (26.9%) imaged flare-ups had new HO at the flare-up site (mean new HO volume: 28.8 × 10 3 mm 3 ). Mean baseline low-dose whole-body computed tomography (excluding head) HO volume was 314.4 × 10 3 mm 3 ; lowest at 2 to <8 years (68.8 × 10 3 mm 3 ) and increasing by age (25-65 years: 575.2 × 10 3 mm 3 ). The mean annualized volume of new HO was 23.6 × 10 3 mm 3 /year; highest at 8 to <15 and 15 to <25 years (21.9 × 10 3 and 41.5 × 10 3 mm 3 /year, respectively) and lowest at 25 to 65 years (4.6 × 10 3 mm 3 /year)., Conclusion: Results from individuals receiving standard care for up to 3 years in this natural history study show the debilitating effect and progressive nature of FOP cross-sectionally and longitudinally, with greatest progression during childhood and early adulthood., Competing Interests: Conflict of Interest R.J.P. is a research investigator at Clementia Pharmaceuticals/Ipsen and Regeneron Pharmaceuticals, Inc and is part of the advisory board as President of the International Clinical Council on Fibrodysplasia Ossificans Progressiva. G.B. is part of the advisory boards of Clementia Pharmaceuticals/Ipsen, FOP European Consortium, and International Clinical Council on FOP and is a speaker at Clementia Pharmaceuticals/Ipsen. M.A.B. is part of the advisory boards of AbbVie, Janssen, Pfizer, UCB Pharma, and Novartis; receives grant support from AbbVie; is a research investigator at AbbVie, Clementia Pharmaceuticals/Ipsen, Janssen, Novartis, Pathios Therapeutics Ltd, and Regeneron Pharmaceuticals, Inc; and is a speaker at AbbVie, United States, Janssen, Novartis, Switzerland, Pfizer, United States, Regeneron Pharmaceuticals, Inc, United States, and UCB Pharma, United Kingdom. C.D.C. is a research investigator at Clementia Pharmaceuticals/Ipsen and is a speaker at Novartis. E.C.H. is part (all voluntary) of the Fibrous Dysplasia Foundation Advisory Board, International Fibrodysplasia Ossificans Progressiva Association (IFOPA), United States Registry Medical Advisory Board, and International Clinical Council on FOP Advisory Board; receives clinical research support from Clementia Pharmaceuticals/Ipsen, France, Neurocrine Biosciences Inc, United States, and Regeneron Pharmaceuticals, Inc; and is a research investigator at Clementia Pharmaceuticals/Ipsen. R.K. is a research investigator at Clementia Pharmaceuticals/Ipsen, Kyowa Kirin, and Regeneron Pharmaceuticals, Inc and is part of the IFOPA Fibrodysplasia Ossificans Progressiva Registry Medical Advisory Board and International Clinical Council on Fibrodysplasia Ossificans Progressiva Advisory Board. M.A.M. receives research support from Clementia Pharmaceuticals/Ipsen and Regeneron Pharmaceuticals, Inc; is a non-paid consultant for BioCryst Pharmaceuticals, Inc, United States, Blueprint Medicines, Daiichi Sankyo, Incyte, and Keros Therapeutics; is part (all voluntary) of the IFOPA Registry Medical Advisory Board, Incyte Advisory Board, and International Clinical Council on FOP Advisory Board; and receives non-restricted educational fund from Excel and Catalyst sponsored by Ipsen. K.-H.L.Q.S. is a coordinator of Ipsen FOP-program and multiple osteochondromas-trial. A.W., R.M., and A.S. are employees of Ipsen. F.S.K. is a research investigator at Clementia/Ipsen and Regeneron Pharmaceuticals, Inc, is part of the IFOPA Medical Advisory Board, is a Founder and immediate past President of the International Clinical Council on FOP, and is the Chair of the Publications Committee of the International Clinical Council. In April 2019, Ipsen acquired Clementia Pharmaceuticals., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Genetic variants are vital in informing clinical phenotypes, aiding physical diagnosis, guiding genetic counseling, understanding the molecular basis of disease, and potentially stimulating drug development. Here we describe two families with an ultrarare ACVR1 gain-of-function pathogenic variant (codon 375, Arginine > Proline; ACVR1 R375P ) responsible for a mild nonclassic fibrodysplasia ossificans progressiva (FOP) phenotype. Both families include people with the ultrarare ACVR1 R375P variant who exhibit features of FOP while other individuals currently do not express any clinical signs of FOP. Thus, the mild ACVR1 R375P variant greatly expands the scope and understanding of this rare disorder., (© 2021 Wiley Periodicals LLC.)

The compassionate use of available medications with unproven efficacy is often in conflict with their clinical evaluation in placebo-controlled clinical trials. For ultra-rare diseases where no approved treatments exist, such as fibrodysplasia ossificans progressiva (FOP), routine clinical trial enrollment for available medications may be difficult to achieve. Therefore adaptive methods of evaluation are often desirable. Off-on-off-on (O4) approaches offer an opportunity to rapidly assess the potential symptomatic efficacy and tolerability of a medication with a limited number of patients and may aid in the design of more focused clinical trials that are amenable to enrollment. Here we report three children with classic FOP who had recalcitrant flare-ups of the back and who had been treated with an O4 regimen of imatinib. In all three children, fewer flare-ups, decreased swelling and improved function with activities of daily living were reported by the parents and treating physician when the children were "on" imatinib than when they were "off" imatinib. The median time to improvement on imatinib was 2-3 weeks. The anecdotal O4 experience with imatinib reported here in three children with FOP who had recalcitrant flare-ups of the back supports the design of a brief placebo controlled trial to assess the potential efficacy of imatinib in reducing the symptoms in children with refractory flare-ups of FOP. A tool to prospectively measure and quantitate flare-up symptoms is presently being developed and validated and will be used for such a study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

BACKGROUND Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of the connective tissue. Over time, patients with FOP experience decreased range of motion in the joints and the formation of a second skeleton, limiting mobility. Patients with FOP are advised to avoid any unwarranted surgery owing to the risk of a heterotopic ossification flare-up. For patients who do require a surgical procedure, a multidisciplinary team is recommended for comprehensive management of the patient's needs. CASE REPORT A 27-year-old woman with FOP underwent a hysterectomy for removal of a suspected necrotic uterine fibroid. To aid in presurgical planning and management, patient-specific 3-dimensional (3D) models of the patient's tracheobronchial tree, thorax, and lumbosacral spine were printed from the patient's preoperative computed tomography (CT) imaging. The patient required awake nasal fiberoptic intubation for general anesthesia and transversus abdominus plane block for regional anesthesia. Other anesthesia modalities, including spinal epidural, were ruled out after visualizing the patient's anatomy using the 3D model. Postoperatively, the patient was started on a multi-modal analgesic regimen and a course of steroids, and early ambulation was encouraged. CONCLUSIONS Patients with FOP are high-risk surgical patients requiring the care of multiple specialties. Advanced visualization methods, including 3D printing, can be used to better understand their anatomy and locations of heterotopic bone ossification that can affect patient positioning. Our patient successfully underwent supracervical hysterectomy and bilateral salpingectomy with no signs of fever or sepsis at follow-up.

There has been evidence that cyclical mechanical stimulation may be osteogenic, thus providing opportunities for nonpharmacological treatment of degenerative bone disease. Here, we applied this technology to a cohort of postmenopausal women with varying bone mineral density (BMD) T-scores at the total hip (-0.524 ± 0.843) and spine (-0.795 ± 1.03) to examine the response to intervention after 1 year of daily treatment with 10 minutes of vibration therapy in a randomized double-blinded trial. The device operates either in an active mode (30 Hz and 0.3 g) or placebo. Primary endpoints were changes in bone stiffness at the distal tibia and marrow adiposity of the vertebrae, based on 3 Tesla high-resolution MRI and spectroscopic imaging, respectively. Secondary outcome variables included distal tibial trabecular microstructural parameters and vertebral deformity determined by MRI, volumetric and areal bone densities derived using peripheral quantitative computed tomography (pQCT) of the tibia, and dual-energy X-ray absorptiometry (DXA)-based BMD of the hip and spine. Device adherence was 83% in the active group (n = 42) and 86% in the placebo group (n = 38) and did not differ between groups (p = .7). The mean 12-month changes in tibial stiffness in the treatment group and placebo group were +1.31 ± 6.05% and -2.55 ± 3.90%, respectively (group difference 3.86%, p = .0096). In the active group, marrow fat fraction significantly decreased after 12 months of intervention (p = .0003), whereas no significant change was observed in the placebo group (p = .7; group difference -1.59%, p = .029). Mean differences of the changes in trabecular bone volume fraction (p = .048) and erosion index (p = .044) were also significant, as was pQCT-derived trabecular volumetric BMD (vBMD; p = .016) at the tibia. The data are commensurate with the hypothesis that vibration therapy is protective against loss in mechanical strength and, further, that the intervention minimizes the shift from the osteoblastic to the adipocytic lineage of mesenchymal stem cells. © 2020 American Society for Bone and Mineral Research (ASBMR)., (© 2020 American Society for Bone and Mineral Research (ASBMR).)

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder of extraskeletal bone formation, but could appropriately be viewed as a seminal disorder of osteochondrogenesis. Many, if not most, of the musculoskeletal features of FOP are related to dysregulated chondrogenesis including abnormal articular cartilage formation, abnormal diarthrodial joint specification, growth plate dysplasia, osteochondroma formation, heterotopic endochondral ossification (HEO), and precocious arthropathy. In FOP, causative activating mutations of Activin receptor A type I (ACVR1), a bone morphogenetic protein (BMP) type I receptor, are responsible for the osteochondrodysplasia that impacts developmental phenotypes as well as postnatal features of this illustrative disorder. Here, we highlight the myriad developmental and postnatal effects on osteochondrogenesis that emanate directly from mutant ACVR1 and dysregulated bone morphogenetic protein (BMP) signaling in FOP., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Genetic contributors to cardiac arrhythmias are often found in cardiovascular conduction pathways and ion channel proteins. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disease of massive heterotopic ossification caused by a highly recurrent R206H mutation in ACVR1/ALK2. This mutation causes abnormal activation of the bone morphogenetic protein (BMP) pathway in response to Activin A. Prior studies suggested increased risks of cardiopulmonary complications in FOP. We examined participants in a Natural History Study (NHS) of FOP (ClinicalTrials.gov #NCT02322255) to better understand their cardiovascular status., Methods: The NHS is an ongoing 3 year international multi-center longitudinal study of 114 patients (ages 4-56 years) with genetically confirmed ACVR1/ALK2 R206H FOP. Patients were clinically assessed at baseline and 12 months. Electrocardiograms (ECGs) were reviewed in a central ECG laboratory. Conduction abnormalities were compared against clinical data collected in the NHS, and echocardiograms collected from NHS and non-NHS patients., Results: Conduction abnormalities were present in 45.3% of baseline ECGs, with the majority of abnormalities classified as nonspecific intraventricular conduction delay (37.7%). More specifically, 22.2% of patients > 18 years old had conduction abnormalities, which was significantly higher than a prior published study of a healthy population (5.9%; n = 3978) (p < 0.00001). Patients with FOP < 18 years old also had a high prevalence of conduction abnormalities (62.3%). The 12-month follow up data was similar to baseline results. Conduction abnormalities did not correlate with chest wall deformities, scoliosis, pulmonary function test results, or increased Cumulative Analog Joint Involvement Scale scores. Echocardiograms from 22 patients with FOP revealed 8 with structural cardiac abnormalities, only 1 of which correlated with a conduction abnormality., Conclusions: We found that patients with FOP may have subclinical conduction abnormalities manifesting on ECG, independent of heterotopic ossification. Although clinically significant heart disease is not typically associated with FOP, and the clinical implications for cardiovascular risk remain unclear, knowledge about ECG and echocardiogram changes is important for clinical care and research trials in patients with FOP. Further studies on how ACVR1/ALK2 R206H affects cardiac health will help elucidate the underlying mechanism.

A global, patient-reported registry has been established to characterize the course of disease and track clinical outcomes in patients with fibrodysplasia ossificans progressiva (FOP), an ultra-rare genetic condition of progressive heterotopic ossification (HO) that results in ankylosis of joints and renders most affected individuals immobile by the second decade of life. Here, we present baseline phenotypes on 299 patients (median age 21 years; range 0.1 to 78 years) from 54 countries based on aggregate data from the International FOP Association (IFOPA) Global Registry (the "FOP Registry"). The mean current age of the patients is 23.7 years (range, 0.1 to 78 years). Baseline characteristics are presented for FOP diagnosis, HO, flare-ups and precedent events, system-based prevalent symptomatology, encounters with medical and dental care providers, Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale scores, physical function, as well as the use of aids, assistive devices, and adaptations. Correlations of PROMIS Global Health scores with HO burden and physical function are calculated. Associations of joint mobility with PROMIS Global Health scores, physical function, and use of aids, assistive devices, and adaptations are summarized. Overall, the FOP Registry database contains a broad sample of the global FOP patient population, providing a useful tool for expanding knowledge of FOP, designing clinical trials and facilitating evidence-based decisions about the optimal monitoring and management of affected individuals., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Clinical trials for orphan diseases are critical for developing effective therapies. One such condition, fibrodysplasia ossificans progressiva (FOP; MIM#135100), is characterized by progressive heterotopic ossification (HO) that leads to severe disability. Individuals with FOP are extremely sensitive to even minor traumatic events. There has been substantial recent interest in clinical trials for novel and urgently-needed treatments for FOP. The International Clinical Council on FOP (ICC) was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for individuals who suffer from FOP. The Clinical Trials Committee of the ICC developed a focused list of key considerations that encompass the specific and unique needs of the FOP community - considerations that are endorsed by the entire ICC. These considerations complement established protocols for developing and executing robust clinical trials by providing a foundation for helping to ensure the safety of subjects with FOP in clinical research trials., (© 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Fibrodysplasia Ossificans Progressiva (FOP; OMIM#135100) is an ultra-rare, severely disabling genetic disease characterized by congenital malformation of the great toes and progressive heterotopic ossification (HO) in muscles, tendons, ligaments, fascia, and aponeuroses often preceded by painful, recurrent soft tissue swelling (flare-ups). The formation of HO leads to progressive disability, severe functional limitations in joint mobility, and to a shortened life-span. In this prospective natural history study, we describe the baseline, cross-sectional disease phenotype of 114 individuals with FOP., Methods: All subjects underwent protocol-specified baseline assessments to determine their disease status. Cross-sectional analyses were performed using linear regression in which functional evaluations (Cumulative Analogue Joint Involvement Scale [CAJIS] and the FOP-Physical Function Questionnaire [FOP-PFQ]) and the burden of HO as measured by low-dose whole body CT (volume of HO and number of body regions with HO) were assessed., Results: Findings from 114 subjects (age range 4 to 56 years) were evaluated. While subject age was significantly (p < 0.0001) correlated with increased CAJIS (r = 0.66) and FOP-PFQ scores (r = 0.41), the estimated mean increases per year (based on cross-sectional average changes over time) were small (0.47 units and 1.2%, respectively). There was also a significant (p < 0.0001) correlation between baseline age and HO volume (r = 0.56), with an estimated mean increase of 25,574 mm 3 /year. There were significant (p < 0.0001) correlations between the objective assessment of HO volume and clinical assessments of CAJIS (r = 0.57) and FOP-PFQ (r = 0.52)., Conclusions: Based on the cross-sectional analysis of the baseline data, functional and physical disability as assessed by CAJIS and the FOP-PFQ increased over time. Although longitudinal data are not yet available, the cross-sectional analyses suggest that CAJIS and FOP-PFQ are not sensitive to detect substantial progression over a 1- to 2-year period. Future evaluation of longitudinal data will test this hypothesis. The statistically significant correlations between HO volume and the functional endpoints, and the estimated average annual increase in total HO volume, suggest that the formation of new HO will be measurable over the relative short-term course of a clinical trial, and represents an endpoint that is clinically meaningful to patients., Trial Registration: This study ( NCT02322255 ) was first posted on 23 December, 2014.

Aims: To examine the prevalence/determinants of fracture in the T1D Exchange Clinic Registry., Research Design/methods: Adults (≥18 years) with T1D duration ≥5 years, diagnosed before age 45 years completed a fracture questionnaire. Additional characteristics were collected from registry data. Only fractures reported as occurring after T1D diagnosis were included. Characteristics were compared between those with and without fractures., Results: Respondents included 756 adults (mean age 39 ± 16 years, 28% ≥50 years, 63% female, 90% non-Hispanic White, diabetes duration 24 ± 14 years); 48% reported ≥1 fracture since diagnosis. Of the 659 reported fractures, 24% involved metatarsal/toe, 21% metacarpal/fingers, 14% fibula/tibia, 5% hip/pelvis/femur and 3% vertebrae. Those with fracture were more likely to be older (43 ± 16 vs. 36 ± 14 years), have longer T1D duration (28 ± 14 vs. 20 ± 12 years), been diagnosed with T1D before age 20 years (79% vs. 71%) compared to those without fracture (all p-values < 0.01)., Conclusions: Data from this national sample suggest fractures in adults with T1D are common at young age and frequently involve peripheral sites. Age, longer diabetes duration, and T1D diagnosis prior to peak bone mass accrual are notable risk factors. Further research is needed to examine the impact of these determinants on fracture risk in T1D., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We evaluated fall frequency and factors affecting falls among middle-aged and older adults with type 1 diabetes (T1D) from T1D Exchange Registry. Twenty-nine percent of T1D participants reported falls within the past 12 months. Severe hypoglycemia, diabetic peripheral neuropathy, and depression were associated with falls in adults with T1D., Purpose: Fall is an important risk factor for osteoporotic fracture; we evaluated fall frequency and factors affecting falls among middle-aged and older adults with type 1 diabetes (T1D)., Methods: Participants aged ≥ 55 years with T1D completed an email-based questionnaire on falls in the prior 12 months. Demographic, clinical, and fall-related information were gathered from the questionnaire; HbA1c was recorded from medical record data extraction., Results: Four hundred and thirty five adults with T1D completed the fall questionnaire (mean age 64 ± 7 years, 57% females, and 97% were non-Hispanic whites). The mean diabetes duration was 36 years with mean HbA1c of 7.3%. Among the 435 participants, 126 reported at least one fall in the prior 12 months (29%). The fall frequency values in adults (55-64 years) with T1D and older adults (> 65 years) were 26 and 32%, respectively (p = 0.16). There was no significant difference in frequency of fall between female and male participants (31 vs. 26%, p = 0.33). Of 126 participants who had a fall, 44% had injuries due to fall, 24% required medical attention, and 13 participants reported fracture (10%). Severe hypoglycemia (odds ratio (OR) 3.6), diabetic peripheral neuropathy (OR 2.2), and depression (OR 1.7) were associated with falls in adults with T1D. Forty-one percent of participants were fearful of falls., Conclusions: This is the first study on prevalence and risk factors for falls suggesting that falls are common in T1D and severe hypoglycemia is a unique diabetes-related factor associated with threefold higher risk for falls.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare autosomal dominant genetic disorder of heterotopic ossification (HO) characterized by skeletal anomalies and episodic soft tissue swelling (flare-ups) that can transform into heterotopic bone. The progressive development of heterotopic bone and progressive arthropathy leads to significant limitation of mobility. This paper will review various imaging modalities used in evaluating episodic soft tissue swelling (flare-ups), heterotopic bone and skeletal anomalies. Different imaging modalities are required at different stages of the disease. Ultrasound and MRI can be useful for evaluating edema in early stages of a flare-up; MRI being superior to ultrasonography. Plain radiographs and computed tomography (CT) can evaluate heterotopic bone in later stages of HO, but CT scan is better at evaluating presence and the volume of heterotopic bone. Functional imaging demonstrates increased activity at sites of flare-ups, their utility in determining disease progression need to be further evaluated. Cost, radiation exposure, availability of various imaging modalities and the ability of FOP patients to fit in the scanner are all considerations when requesting radiographic tests in a patient with FOP. Future studies are required to determine if early radiographic findings can determine disease progression and response to treatment in this disorder., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The worldwide prevalence and risk factors for kidney stones in patients with fibrodysplasia ossificans progressiva (FOP) are unknown. We conducted a survey of 383 patient-members of the International Fibrodysplasia Ossificans Progressiva Association, comprising the entire global membership of the international FOP community. Two hundred seven patients from 31 nations and 6 continents (54%) responded. Nineteen of 207 respondents had kidney stones, revealing a worldwide prevalence of 9.2%. In a confirmatory follow-up study of subjects participating in a longitudinal FOP natural history study, 9 of 114 individuals reported a history of kidney stones (7.9%). In both study populations patients with kidney stones were found to be more functionally impaired compared to those without nephrolithiasis. The prevalence of kidney stones in the adult FOP population of the Unites States was 15.8% (9/57 individuals) compared to a sex- and age-weighted prevalence of 4.5% (p=4×10 -5 ) in the general population. Although geographical variation exists, patients with FOP have an approximately three-fold greater prevalence of kidney stones than the general population. This unusually high prevalence may be due to high bone turnover from chronic immobilization, or to unknown mechanistic effects of the activating FOP mutation in activin A receptor, type I/activin-like kinase-2 (ACVR1/ALK2), increasing the disease burden and morbidity in this already disabling condition., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Fibrodysplasia Ossificans Progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification for which there is presently no definitive treatment. Several recent studies in genetic mouse models of FOP support involvement of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathophysiology of FOP and propose the repurposed use of rapamycin, an inhibitor of mTORC1 signaling in clinical trials for the management of FOP. Here we report two patients with the classic FOP mutation who received rapamycin-one for four months on a compassionate basis for treatment of acute flare-ups of the neck and back that were refractory to corticosteroid therapy-and the other for 18years for chronic immunosuppression following liver transplantation for intercurrent cytomegalovirus infection. In both patients, FOP progressed despite the use of rapamycin. This report highlights the real-world use of rapamycin in two FOP patients and provides insight into the use of rapamycin in clinical trials for the management of FOP., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling genetic disorder characterized by episodic soft tissue swelling (flare-ups) that leads to progressive heterotopic ossification and restricted joint mobility., Methods: Here we present the first longitudinal patient-reported mobility assessment (PRMA) in FOP based on a simple evaluation tool. At initial presentation and follow-up (1-11year span; median: 6 year span), 64 patients (36 females; 28 males) with classic FOP completed a questionnaire designed to rapidly assess mobility at 15 sites (three axial; six upper limb, and six lower limb). In order to validate this instrument, twenty-one of 64 patients (33%) underwent a cumulative analogue joint involvement scale (CAJIS) evaluation by two physicians within six months of their second self-assessment., Results: We found that: 1) mobility changes were episodic and regional, occurring first in the neck and trunk, followed by the upper limbs and finally the lower limbs; 2) interval improvements in mobility did occur, most notably in the lower limbs (18%), and less so in the upper limbs (12%) and trunk (3%), and 3) patient-reported mobility assessments correlate highly (R 2 =0.81) with physician-reported CAJIS evaluations., Conclusion: This is the first longitudinal PRMA in FOP and provides a simple and valid tool that can be used in the design and evaluation of clinical trials in this progressively disabling disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Flare-ups of the hips are among the most feared and disabling complications of fibrodysplasia ossificans progressiva (FOP) and are poorly understood. In order to better understand the nature of hip flare-ups in FOP, we evaluated 25 consecutive individuals with classic FOP (14 males, 11 females; 3-56years old, median age, 17years old) who presented with acute unilateral hip pain., Results: All 25 individuals were suspected of having a flare-up of the hip based on clinical history and a favorable response to a four day course of high-dose oral prednisone. Ten individuals (40%) experienced rebound symptoms of pain and/or stiffness within seven days after discontinuation of prednisone and all ten subsequently developed heterotopic ossification (HO) or decreased mobility of the affected hip. None of the 14 individuals who experienced sustained relief of symptoms following a course of oral prednisone experienced HO or decreased mobility. Incidental radiographic findings at the time of presentation were multifactoral and included osteochondromas of the proximal femur (18/25; 72%), degenerative arthritis (17/25; 68%), developmental hip dysplasia (15/25; 60%), previously existing heterotopic ossification (12/25; 48%), intra-articular synovial osteochondromatosis (8/25; 32%) or traumatic fractures through pre-existing heterotopic bone (1/25; 4%)., Conclusions: Developmental joint pathology may confound clinical evaluation of hip pain in FOP. The most useful modality for suspecting an ossification-prone flare-up of the hip was lack of sustained response to a brief course of oral prednisone. Evaluation of soft tissue edema by ultrasound or magnetic resonance imaging showed promise in identifying ossification-prone flare-ups and warrants further analysis in prospective studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Fibrodysplasia ossificans progressiva (FOP) is a catastrophic genetic disorder of progressive heterotopic ossification (HO). Assessment of functional mobility in FOP will be essential to support clinical trials of investigational agents., Results: Of necessity, we developed a simple, rapidly-administered, cumulative analogue joint involvement scale (CAJIS) for FOP based on assessments in 144 individuals worldwide with classic FOP., Conclusions: CAJIS scores correlated with patient age, activities of daily living, and ambulatory function with excellent inter-rater variability. We show here that the CAJIS score provides an accurate and reproducible snapshot of total body and regional mobility burden in FOP., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Context: Severe deficiencies of testosterone (T) and GH are associated with low bone mineral density (BMD) and increased fracture risk. Replacement of T in hypogonadal men improves several bone parameters. Replacement of GH in GH-deficient men improves BMD., Objective: Our objective was to determine whether T and GH treatment together improves the structural and mechanical parameters of bone more than T alone in men with hypopituitarism., Design and Subjects: This randomized, prospective, 2-year study included 32 men with severe deficiencies of T and GH due to panhypopituitarism., Intervention: Subjects were randomized to receive T alone (n = 15) or T and GH (n = 17) for 2 years., Main Outcome Measures: We evaluated magnetic resonance microimaging-derived structural (bone volume fraction [BVF] and trabecular thickness) and mechanical (axial stiffness [AS], a measure of bone strength) properties of the distal tibia at baseline and after 1 and 2 years of treatment., Results: Treatment with T and GH did not affect BVF, thickness, or AS differently from T alone. T treatment in all subjects for 2 years increased trabecular BVF by 9.6% (P < .0001), trabecular thickness by 2.6% (P < .001), and trabecular AS by 9.8% (P < .001). In contrast, testosterone treatment in all subjects significantly increased cortical thickness by 2.4% (P < .01) but decreased cortical BVF by -4.7% (P < .01) and cortical AS by -6.9% (P < .01)., Conclusion: Combined T and GH treatment of men with hypopituitarism for 2 years did not improve the measured structural or mechanical parameters of the distal tibia more than T alone. However, testosterone significantly increased the structural and mechanical properties of trabecular bone but decreased most of these properties of cortical bone, illustrating the potential importance of assessing trabecular and cortical bone separately in future studies of the effect of testosterone on bone.