4. The Pathologic and Pathophysiologic-Based Treatment of FOP

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We emphasize that this report reflects the authors’ experience an opinions on the various classes of symptom-modifying medications, and is meant only as a guide to this controversial area of therapeutics. Although there are common physical features shared by every person who has FOP, there are differences among individuals that may alter the potential benefits or risks of any medication or class of medications discussed here. The decision to use or withhold a particular medication must ultimately rest with an individual patient and his or her physician.

4-1. Introduction

The ultimate treatment of FOP will likely be based on integrated knowledge of the cellular and molecular pathophysiology of the condition. An abbreviated outline of our current knowledge is presented in Figure 1. Several reviews of treatment in FOP provide general background references (Kaplan et al., 2008; Pignolo et al., 2013; Kaplan et al., 2017) but interested clinicians are guided to these guidelines for the most recent review of symptomatic treatment.

References

Kaplan FS, LeMerrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol 22: 191-205, 2008

Kaplan FS, Pignolo RJ, Al Mukaddam MM, Shore EM. Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP). Expert Opinion on Orphan Drugs 5: 291-294, 2017

Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. In Emerging Concepts in Pediatric Bone Disease. Pediatric Endocrinology Reviews 10 (S-2): 437-448, 2013

4-2. Corticosteroids in FOP

The rational use of corticosteroids early in the course of an FOP flare-up is based primarily on its potent anti-inflammatory effects (Rhen & Cidlowski, 2005; Hapgood et al., 2016) and on emerging knowledge of the importance of inflammatory triggers in FOP flare-ups (Kaplan et al., 2005; Kaplan et al., 2007; Yu et al., 2008; Kaplan et al., 2016).

Widespread favorable anecdotal reports from the FOP community suggest that a brief 4-day course of high-dose corticosteroids, begun within the first 24 hours of a flare-up, may help reduce the intense inflammation and tissue edema seen in the early stages of the disease. In a global assessment of FOP flare-ups involving more than 500 individuals, 198 treatments were reported. Anti-inflammatory agents were the most common. Seventy-five percent used short-term glucocorticoids as a symptomatic treatment for flare-ups at appendicular sites. Fifty-five percent reported that glucocorticoids improved symptoms occasionally whereas 31% reported that they always did. Only 12% reported complete resolution of a flare-up with glucocorticoids. Forty-three percent reported rebound symptoms within 1 to 7 days after completing a course of glucocorticoids (Pignolo et al., 2016). The process of heterotopic ossification (HO) in FOP develops in stages. The very early stage is characterized by intense inflammatory infiltrates (Shore & Kaplan, 2010). Corticosteroids suppress inflammation by multiple mechanisms (Cruz-Topete & Cidlowski, 2015). How long this stage lasts, and the duration of corticosteroid use still needs to be elucidated.

The use of corticosteroids should be restricted to:

The extremely early symptomatic treatment of flare-ups that affect:
▪ Major joints (e.g., hip)
▪ The jaw
▪ The submandibular area
The prevention of flare-ups following major soft tissue injury (severe trauma)
The prevention of flare-ups in emergent, elective, major or minor surgeries such as dental surgery, hypospadias repair, appendectomies, etc. (peri-operative use) as they may decrease the likelihood of HO.

Corticosteroids should not generally be used for the symptomatic treatment of flare-ups involving the neck or trunk due to the long duration and recurring nature of these flare-ups, and the difficulty in assessing the true onset of such flare-ups. On rare occasions, a brief course of corticosteroids may be used to break the cycle of recurrent flare-ups often seen in early childhood or to mitigate intractable pain. However, the utility of this approach is not widely accepted, as flare-ups tend to recur rapidly following cessation of corticosteroid therapy.

Corticosteroids are most effective if used within the first 24 hours of a new flare-up that affects the movement of a major joint, prophylactically following major soft tissue trauma, or peri-operatively as noted above. The dose of corticosteroids is dependent upon body weight.

A typical dose of prednisone for acute flare-ups is 2 mg/kg/day (up to 100 mg), administered as a single daily dose for no more than 4 days (Table 1). In order to have the least suppressive effect on the hypothalamic-pituitary-adrenal axis, the medication should be taken in the morning. However, some patients may tolerate the medication better if divided into twice per day dosing. Equivalent doses of other steroids can also be used. A repeat course may be needed for refractory symptoms and a tapering course may be prescribed over 10 days to 2 weeks maximum if symptoms warrant.

For surgical prophylaxis, solumedrol (1.6 mg/kg; up to 80 mg) should be administered at the time of surgery. If the patient can take oral meds, then prednisone 2mg/kg should be administered once daily on the day of surgery and for 3 days after surgery. In summary, steroids should be administered for a total of four daily doses.

Data from an international prospective, natural history study showed that throughout the 36-month study period, 79.8% of individuals initiated a new medication, of which glucocorticoids represented 32.5% (Pignolo, et al., 2022). Alternatively, high dose intravenous corticosteroid pulse therapy may be considered, but must be performed with an inpatient hospitalization to monitor for potentially dangerous side-effects of hypertension (Sinha & Bagga, 2008; Table 1).

When prednisone is discontinued, a non-steroidal anti-inflammatory medication or COX-2 inhibitor (in conjunction with a leukotriene inhibitor) may be used symptomatically for the duration of the flare-up (Table 1). Corticosteroids should not be used for the long-term chronic treatment of FOP as chronic dependence due to adrenal suppression and other steroid-associated side-effects such as osteoporosis and iatrogenic Cushing’s disease will likely result.

Corticosteroids are an important component in the management of a submandibular flare-up of FOP. Submandibular swelling in patients who have FOP can be a medical emergency and requires intensive precautionary measures to avoid catastrophic clinical deterioration. These measures include early identification of the submandibular flare-up, avoidance of lesional manipulation, airway monitoring, aspiration precautions, nutritional support due to the difficulty in swallowing, and the use of corticosteroids. The potentially dangerous nature of flare-ups in the submandibular region and jaw may dictate a slightly longer use of corticosteroids with an appropriate taper for the duration of the flare-up or until the acute swelling subsides (Janoff et al., 1996).

Flare-ups often result from over-use and soft tissue injuries. Prednisone – 1-2 mgs/kg, (per oral) once daily for 3-4 days is often used in attempt to prevent flare-up after severe soft-tissue injury. Do not use after minor bumps or bruises. Use prednisone prophylactically as directed for dental or surgical procedures.

While patients are encouraged to contact their physician at the earliest sign of a flare-up or following major trauma, many find it comforting to have a supply of prednisone on hand at home in case of an emergency. This “pill in the pocket” approach has been feasible and safe with a monitored reduction in emergency room and hospital visits.

References

Cruz-Topete D, Cidlowski JA. One hormone two actions: anti and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation 22: 20-32, 2015

Hapgood JP, Avenat C, Moliki JM. Glucocorticoid-independent modulation of GF activity: Implications for immunotherapy. Pharmacol Ther 165: 93-113, 2016

Janoff HB, Zasloff MA, Kaplan FS. Submandibular swelling in patients with fibrodysplasia ossificans progressiva. Otolaryngol Head Neck Surg 114: 599-604, 1996

Kaplan FS, Glaser DL, Shore EM, Pignolo RJ, Xu M, Zhang Y, Senitzer D, Forman SJ, Emerson SG. Hematopoietic stem-cell contribution to ectopic skeletogenesis. J Bone Joint Surg Am 89: 347-357, 2007

Kaplan FS, Pignolo RJ, Shore EM. Granting immunity to FOP and catching heterotopic ossification in the Act. Semin Cell Dev Biol 49: 30-36, 2016

Kaplan FS, Shore EM, Gupta R, Billings PC, Glaser DL, Pignolo RJ, Graf D, Kamoun M. Immunological features of fibrodysplasia ossificans progressiva and the dysregulated BMP4 Pathway. Clin Rev Bone & Miner Metab 3: 189-193, 2005 34

Pignolo RJ, Bedford-Gay C, Liljesthröm M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31:650-656, 2016

Pignolo RJ, Baujat G, Brown M, De Cunto C, Hsiao E, Keen R, Al Mukaddam M, Le Quan Sang K, Wilson A, Marino R, Strahs A, Kaplan F. The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study. Genetics in Medicine 24: 2422-2433, 2022

Rhen T & Cidlowski JA. Anti-inflammatory action of glucocorticoids – new mechanisms for old drugs. N Engl J Med 353: 1711-1723, 2005

Shore EM, Kaplan FS. Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol 6: 518-527, 2010

Sinha A, Bagga A. Pulse steroid therapy. Indian J Pediatrics 75: 1057-1066, 2008

van Staa TP, Cooper C, Leufkens HGM, Bishop N. Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 18: 913-918, 2003

Yu PB, Deng DY, Lai CS, Hong CC, Cuny GD, Bouxsein ML, Hong DW, McManus PM, Katagiri T, Sachidanandan C, Nobuhiro K, Fukuda T, Mishina Y, Peterson RT, Bloch KD. BMP type I receptor inhibition reduces heterotopic ossification. Nat Med 14: 1363-1369, 2008

4-3. Cyclo-Oxygenase-2 (COX-2) Inhibitors & NSAIDs in FOP

Selective cyclo-oxygenase-2 (COX-2) inhibitors, non-steroidal anti-inflammatory medications (NSAIDs) and leukotriene receptor antagonists (montelukast) may have a role in the management of FOP symptoms.

The body produces two types of prostaglandins: “physiological” prostaglandins and “inflammatory” prostaglandins. Physiological prostaglandins are normally produced in many of the body’s tissues and serve to protect organs, such as the stomach, from metabolic injury. Inflammatory prostaglandins are produced in response to injury and play a major role in the inflammatory response to tissue injury and repair. Traditional NSAIDs such as aspirin, ibuprofen, and indomethacin inhibit the formation of both physiological and inflammatory prostaglandins. The selective cyclo-oxygenase-2 (COX-2) inhibitors primarily inhibit inflammatory prostaglandins and leave most, but not all, of the physiological prostaglandins relatively intact (Katori & Majima, 2000; Van Ryn & Pairet, 2000).

Inflammatory prostaglandins are potent co-stimulatory molecules along with BMPs in the induction of normotopic and heterotopic bone (Weinreb et al. 1997; Jones et al. 1999; Convente et al., 2015) and are elevated in the urine of patients who have FOP, especially during times of disease flare-up (Levitz et al., 1992). These observations suggest that lowering baseline levels of inflammatory prostaglandins in patients with FOP may raise the threshold for HO even in the presence of promiscuously active ACVR1.

Studies in the orthopaedic literature have shown that lowering inflammatory prostaglandin levels in experimental animals dramatically raise the threshold for trauma-induced HO, thus, making it more difficult for heterotopic bone to form (DiCesare et al. 1991). Preoperative and postoperative treatment with NSAIDs in patients undergoing hip arthroplasty prevents HO (Brunnerkreef et al., 2013; Joice et al., 2018).

Compared to the parent class of NSAIDs, the selective COX-2 inhibitors offer the possibility of a lower gastrointestinal risk profile. Also, the half-life of most COX-2 inhibitors is conducive to a once or twice daily dosage regimen, a factor which may help promote patient compliance (Deeks et al. 2002).

However, substantial concerns have been raised about the safety of the COX-2 inhibitors in patients at high risk of cardiovascular and cerebrovascular disease (White et al. 2002; White et al. 2003; Grosser et al. 2017). Although COX-2 activity is necessary for the synthesis of inflammatory prostaglandins, it also controls the synthesis of prostacyclin, a prostaglandin that is essential for the health and patency of blood vessels, especially in the heart and brain.

While concerns have been raised about all COX-2 inhibitors (Fitzgerald, 2004; Topol, 2004), selective COX-2 inhibitors remain a rational choice for patients at low cardiovascular risk who have had serious gastrointestinal events or in patients who are at high risk of serious gastrointestinal events, such as those with FOP who may need to use glucocorticoids intermittently for the treatment of acute flare-ups.

At the present time, the COX-2 inhibitor celecoxib (Celebrex), as well as etoricoxib (Arcoxia) is available in many countries and exhibits reduced gastrointestinal risk compared with other NSAIDs (Feng et al. 2018). Presently, safety and pharmacokinetic data are available for celecoxib in the pediatric population (Stempak et al., 2002). This medication is being used in patients with juvenile idiopathic arthritis. The results of a multicenter pharmacovigilance study in the US, showed a good safety profile of celecoxib compared to nonselective NSAIDs at a minimum 12-month follow-up (Sobel et al. 2014).

Studies on the NSAIDs and selective COX-2 inhibitors integrate important findings from the FOP laboratory on prostaglandin production, mast cell recruitment, and angiogenic factor release with the pathologic findings of severe inflammatory pre-osseous lesions of FOP. As with any condition, the relative risks and benefits of potential therapies must be weighed against the potential risks of the underlying condition being treated (Hochberg, 2003).

With all of the controversy swirling around the selective cox-2 inhibitors, the standard NSAIDs, which inhibit both COX-1 and COX-2 non-selectively, remain an option to consider in the symptomatic management of children and adults with FOP (Table 1). As with the chronic use of all NSAIDs, the risks of serious gastrointestinal side-effects, especially gastrointestinal bleeding, are possible, and special precautions may be warranted in susceptible individuals.

Data from an international prospective natural history study showed that at baseline the most common ongoing medications were non-steroidal anti-inflammatory drugs, used by 28.9 % of individuals (Pignolo et al., 2022).

Finally, although there is no evidence that chronic treatment with COX-2 inhibitors or NSAIDs prevent flare-ups in FOP, COX-2 inhibitors or oral/topical NSAIDS may be helpful for symptomatic management of flare-ups and chronic arthropathy when corticosteroids are not indicated. Topical NSAIDs are discussed in the next section. 36

References

Brunnekreef J, Hoogervorst P, Ploegmakers MJ, Rijnen WH, Schreurs BW. Is etoricoxib effective in preventing heterotopic ossification after primary total hip arthroplasty? International Orthopaedics (SICOT) 37: 583-587, 2013

Convente MR, Wang H, Pignolo RJ, Kaplan FS, Shore EM. The immunological contribution to heterotopic ossification disorders. Curr Osteoporos Rep 13:116-124, 2015

Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomized controlled trials. British Med J (Review) 325(7365): 619, 2002

DiCesare PE, Nimni ME, Pen L, Yazdi M, Cheung DT. Effects of indomethacin on demineralized bone-induced heterotopic ossification in the rat. J Orthop Res 9: 855-861, 1999

Feng X, Tian M, Zhang W, Mei H. Gastrointestinal safety of etoricoxib in osteoarthritis and rheumatoid arthritis: A meta-analysis. PLoS ONE 2018; 13(1): e0190798

Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med 351: 1709-1711, 2004

Grosser T, Ricciotti E, Fitzgerald GA. The cardiovascular pharmacology of non-steroidal anti-inflammatory drugs. Trends Pharmacol Sci 38: 733-748, 2017

Hochberg Mc. COX-2: where are we in 2003? Be strong and resolute: continue to use COX-2 selective inhibitors at recommended dosages in appropriate patients. Arthritis Res Ther 5: 28-31, 2003

Joice M, Vasileiadis GI, Amanatullah DF. Non-steroidal anti-inflammatory drugs for heterotopic ossification prophylaxis after total hip arthroplasty. Bone Joint J 100-B: 915-922, 2018

Jones, MK, Wang H, Peskar BM, Levin E, Itani RM Sarfeh IJ, Tarnawski AS. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nature Med 5: 1418-1423, 1999

Katori M, Majima M. Cyclooxygenase-2: its rich diversity of roles and possible application of its selective inhibitors. Inflammation Res 49: 367-392, 2000

Levitz CL, Cohen RB, Zasloff MA, Kaplan FS. The role of prostaglandins in bone formation. Abstracts from The First International Symposium on Fibrodysplasia Ossificans Progressiva, September 25-26, 1991, Philadelphia, Pennsylvania. Calcif Tissue Int 50: 385-388, 1992

Sobel RE, Lovell DJ, Brunner HI, Weiss JE, Morris PW, et al. for the Pediatric Rheumatology Collaborative Study Group. Safety of celecoxib and nonselective nonsteroidal anti-inflammatory drugs in juvenile idiopathic arthritis: results of the phase 4 registry. Pediatric Rheumatol Online J 12: 29, 2014 37

Stempak D, Gammon J, Klein J, Koren G, Baruchel S. Single-dose and steady-state pharmacokinetics of celecoxib in children. Clin Pharmacol Ther 72: 490-497, 2002

Topol EJ. Failing the public health – rofecoxib, Merck, and the FDA. N Engl J Med 351: 1707-1709, 2004

Van Ryn J, Pairet M. Clinical experience with cyclooxygenase-2 inhibitors. Inflammation Res 48: 247-254, 1999

Weinreb M, Suponitsky I, Keila S. Systemic administration of an anabolic dose of PGE2 in young rats increases the osteogenic capacity of bone marrow. Bone 120: 521-526, 1997

White WB, Faich G, Borer JS, Makuch RW. Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol 92: 411-418, 2003

White WB, Faich G, Whelton A, Maurath C, Ridge NJ, Verburg KM, Geis GS, Lefkowith JB. Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol 89: 425-430, 2002

4-4. Topical Analgesics in FOP

Potential advantages of topical Non-steroidal Anti-inflammatory Agents (NSAIDs) include lower initial rates of systemic absorption, reduced systemic adverse effects (including gastrointestinal toxicity) and directed application to area(s) of pain (Asbill et al., 2014; Branvold & Carvalho, 2014). Several topical agents, available as a gel, spray, or cream, are available for the treatment of musculoskeletal pain. In one study comparing three available topical applications, ketoprofen gel (2.5% w/w), was better than piroxicam gel (0.5% w/w), and slightly better than diclofenac gel (1% w/w) in the treatment of acute soft tissue injury that included a global assessment of treatment response, improvements in stiffness, restriction of mobility, and pain on pressure and movement (Patel and Leswell, 1996). Ketoprofen gel also has a reported "cooling effect". In a head-to-head comparison study, they were each applied three times daily. In clinical studies, topical NSAIDS are typically applied three times daily for acute pain.

In FOP, topical NSAIDs have anecdotally been used for both acute and chronic pain and applied 3-4 times daily. In the use of ketoprofen gel for FOP musculoskeletal complaints, a compounded formulation of 5% gel is commonly the initial dose, with the potential for upward titration to 15-20%. Pediatric use typically does not exceed 10% gel due to the potential for systemic absorption.

Other topical agents include lidocaine patch, gel, cream or spray (available over-the-counter in up to 5% formulations). Topical lidocaine is most appropriate for patients with well localized neuropathic pain. Capsaicin cream, an alkaloid derived from chili peppers and thought to deplete substance P from primary afferent (sensory) neurons may have a theoretical advantage for pain control in FOP; however, clinical experience is very limited and concern over paradoxical effects mandates its very cautious use.

References

Asbill S, Sweitzer SM, Spigener S, Romero-Sandoval A. Compounded pain formulations: what is the evidence? Intl J Pharmaceutical Compounding 18: 278-286, 2014

Branvold A & Carvalho M. Pain management therapy: the benefits of compounded transdermal pain medication. J Gen Practice 2: 1-8, 2014 38

Patel RK, Leswell PF. Comparison of ketoprofen, piroxicam, and diclofenac gels in the treatment of acute soft-tissue injury in general practice. General Practice Study Group. Clin Ther 18:497-507, 1996

4-5. Mast Cell Inhibitors in FOP

Among the most typical features of FOP flare-ups are the intense muscle edema, fibroproliferation, and angiogenesis characteristic of early pre-osseous FOP lesions, and the rapid spread of the lesions into adjacent tissue. A lesion may appear within hours and can reach an alarming size literally overnight. The sudden appearance and rapid spread of an FOP lesion suggests involvement of a repertoire of inflammatory mediators along with an abnormal connective tissue wound response, and points to a potential role for inflammatory mast cells and their mediators in the extension of the disease process.

Mast cells are indigenous cells in the body’s connective tissues and arise from the bone marrow. They circulate in the blood as committed, but not terminally differentiated cells, and migrate into numerous tissues including skeletal muscle where they mature and reside as harmless bystanders until provoked by a traumatic or inflammatory stimulus. Mast cells are found in close proximity to blood vessels and nerves. In normal skeletal muscle, mast cells are sparsely distributed in the connective tissues between the muscle bundles. Mast cells contain granules of potent stored chemicals that induce edema, fibroproliferation and angiogenesis when released into the surrounding tissue. For many years, the role of mast cells was unknown, but it now appears that they play an important role in tissue repair and wound healing (Kaplan, 2002).

When mast cell recruitment and activation go awry, the process can lead to severe inflammatory reactions. This has long been recognized with mast cell activation in the skin and lungs, resulting in the symptoms of hives and asthma, respectively. However, very little is known about mast cells in the deeper tissues of the body such as the skeletal muscles. Mast cells are not easily visible microscopically unless special stains are used to detect them. Mast cells are stimulated by a myriad of external and internal stimuli such as internal immune responses and external tissue injury.

Mast cells contain granules whose sequestered contents include histamine, heparin, angiogenic proteins, and matrix degrading enzymes that allow injured tissue to repair itself. Potent angiogenic proteins released by mast cells include basic fibroblast growth factor, vascular endothelial growth factor, and transforming growth factor beta. Mast cells also release a litany of inflammation-causing molecules including tumor necrosis factor alpha, prostaglandins, and leukotrienes. Upon release from the mast cells, these substances influence a vast array of biological processes including inflammation, immune function, angiogenesis, fibrous tissue formation, extracellular tissue remodeling, and tissue repair (Kaplan, 2002).

The intense inflammatory muscle edema, fibroproliferation, and angiogenesis characteristic of early pre-osseous FOP lesions and the rapid spread of these lesions along muscle planes into adjacent tissue suggested a potential role for mast cells in the FOP process. As little is known about the resident mast cells in skeletal muscle, a comprehensive analysis was undertaken of mast cell distribution in normal skeletal muscle, in uninvolved FOP muscle, in FOP lesions, in inflammatory and genetic muscle diseases, and in experimentally induced animal models of HO (Gannon et al., 2001; Brennan et al., 2017; Convente et al., 2018).

The findings by Gannon et al. (2001) were startling and unexpected. Mobilization and activation of inflammatory mast cells was found at all stages of FOP lesional development. These data documented an important role for mast cells in the pathology of FOP lesions (Gannon et al., 2001):

Tissue injury in FOP patients leads to macrophage, mast cell, and lymphocyte migration into normally appearing skeletal muscle. Mediators released by mast cells stimulate a cycle of inflammatory edema, fibrosis, and angiogenesis which is potentiated at the leading edge of an advancing FOP lesion. Reactive fibroblasts within the muscle tissue produce proteins which lead to further proliferation of mast cells and a self-sustaining escalation of the disease process known as a flare-up. Eventually, transforming growth factor beta, released by mast cells and connective tissue progenitor cells, limits the lymphocytic recruitment and migration and thus the size and extent of the expanding lesion, while endogenous over-activity of ACVR1/ALK2 in the core of the fibroproliferative lesion drives the lesion towards ossification through an endochondral pathway.

The observation of mast cell mobilization in FOP lesions provided a novel and previously unrecognized opportunity to evaluate anti-mast cell therapies in limiting the spread of FOP lesions. In a mouse model of FOP, posttraumatic FOP lesions were evaluated and the proinflammatory cytokine response of TNFα, IL‐1β, and IL‐6 was found to be elevated and prolonged in murine FOP lesions and in murine FOP mast cells. Importantly, depletion of mast cells and macrophages significantly impaired injury‐induced HO in FOP mice (Brennan et al., 2017; Convente et al., 2018).

Mast cells, macrophages, lymphocytes, and their associated inflammatory-mediators may also be reduced with the use of mast cell stabilizers, long-acting non-sedating antihistamines, leukotriene inhibitors, non-steroidal anti-inflammatory medications, c-kit tyrosine kinase inhibitors, and cox-2 inhibitors. Mast cell membrane stabilizers may reduce the release of angiogenic and chemotactic factors, while antihistamines and leukotriene inhibitors may reduce the downstream effects of released mediators (Simmons, 2004). Using an injury-induced, constitutively active transgenic mouse model of FOP mast cell inhibition by cromolyn resulted in a dramatic reduction of HO (Brennan et al., 2017). Cromolyn significantly decreases the total number of mast cells and specifically diminishes the number of degranulating and resting degranulated mast cells in pre-osseous FOP lesions.

The c-kit tyrosine kinase inhibitor imatinib has been shown to induce mast cell apoptosis and decrease HO in an Achilles tendon injury model of HO (Werner et al., 2013) as well as in an injury-induced, constitutively active transgenic mouse model of FOP (Wang et al., 2016). Imatinib has been successfully used to reduce airway hyper-responsiveness and mast cell number in severe asthma (Cahill et al., 2017) and to mitigate severe and unrelenting flare-ups in FOP (Kaplan et al., 2018; Kaplan et al., 2021). Montelukast has also been used anecdotally in FOP, but its systemic efficacy as a mast cell inhibitor in FOP is unknown. The optimal use of these medications and their potential long-term efficacy in FOP is presently unknown.

References

Brennan TA, Lindborg CM, Bergbauer CR, Wang H, Kaplan FS, Pignolo RJ. Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP). Bone 109: 259-266, 2017 40

Cahill KN, Katz HR, Cui J, Lai J, Kazani S, Crosby-Thompson A, Garofalo D, Castro M, Jarjour N, DiMango E, Erzurum S, Trevor JL, Shenoy K, Chinchilli VM, Wechsler ME, Laidlaw TM, Boyce JA, Israel E. KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma. N Engl J Med 376: 1911-1920, 2017

Convente MR, Chakkalakal SA, Yang E, Caron RJ, Zhang D, Kambayashi T, Kaplan FS, Shore EM. Depletion of mast cells and macrophages impairs heterotopic ossification in an Acvr1R206H mouse model of fibrodysplasia ossificans progressiva. J Bone Miner Res 33: 269-282, 2018

Gannon FH, Glaser D, Caron R, Thompson LDR, Shore EM, Kaplan FS. Mast cell involvement in fibrodysplasia ossificans progressiva. Hum Pathol 32: 842-848, 2001

Kaplan AP. Chronic urticaria and angioedema. N Engl J Med 346: 175-179, 2002

Kaplan FS, Andolina JR, Adamson PC, Teachey DT, Finklestein JZ, Ebb DH, Whitehead B, Jacobs B, Siegel DM, Keen R, Hsiao E, Pignolo RJ. Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases. Bone 109: 276-280, 2018

Kaplan FS, Teachey DT, Andolina JR, Siegel DM, Mancilla EE, Hsiao EC, Al Mukaddam M, Rocke DM, Pignolo RJ. Off-on-off-on use of imatinib in three children with fibrodysplasia ossificans progressiva. Bone 2021 Sep;150:116016

Simmons FER. Advances in H1 antihistamines. N Engl J Med 351: 2203-2217, 2004

Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangiavini L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling. J Bone Miner Res 31: 1652-65, 2016

Werner CM, Zimmermann SM, Wurgler-Hauri CC, et al. Use of imatinib in the prevention of heterotopic ossification. HSSJ 9: 166–170, 2013

4-6. Bisphosphonates in FOP

Bisphosphonates are a potent class of medications that have profound effects on bone remodeling and exert their primary effect by decreasing the life span of osteoclasts. Bisphosphonates are thus widely used in adults and children for the treatment of numerous bone diseases where bone resorption exceeds bone formation - disorders such as steroid-induced osteoporosis, idiopathic osteoporosis, osteogenesis imperfecta, Paget’s disease, fibrous dysplasia, and bone cancer (Orcel & Beaudreuil, 2002; Nogginuera et al., 2003; Chen & Sambrook, 2012; Baroncelli & Bertelloni, 2014).

In addition, bisphosphonates have been used experimentally and anecdotally in the symptomatic management of flare-ups in FOP. The first clinically used bisphosphonate, etidronate, when administered at high doses, potently inhibited mineralization of newly formed cartilage and bone protein and had been proposed as a possible treatment for FOP and other disorders of HO. Etidronate had been studied in FOP because of its inhibitory effect on bone mineralization and its potential to impair ossification at high dosages (Brantus & Meunier, 1998). Unfortunately, at high doses for long durations, etidronate caused osteomalacia (soft bones) and impaired ossification of the entire skeletal system, not just the heterotopic bone of the “second skeleton.” Its utility is therefore limited. Etidronate has also been discontinued in the USA. Unlike etidronate, the newer aminobisphosphonates have no appreciable effect on inhibiting mineralization or causing osteomalacia. In 2005, Schuetz and colleagues reported generally beneficial but anecdotal effects of high dose aminobisphosphonates in preventing recurrence of HO in high-risk patients with established HO who were undergoing surgery to excise heterotopic bone. One of the five patients reported had FOP (Schuetz et al., 2005).

The newer aminobisphosphonates have been used anecdotally for many years as an adjunctive symptomatic treatment for refractory flare-ups in FOP. Over the past 15 years, many patients in the FOP community have used pamidronate empirically for the symptomatic relief of refractory flare-ups, especially those that are prolonged or fail to respond to corticosteroids. Approximately three-quarters anecdotally report rapid improvement in the symptoms and signs of a flare-up while one-quarter report no improvement in the symptoms or signs of the flare-up (F. Kaplan, personal observation).

Importantly, there seems to be no protective effect on the occurrence of subsequent flare-ups in any of the patients treated with intravenous aminobisphosphonates. While these anecdotal patient reports are not scientifically valid; they constitute an important set of anecdotal observations that compel further stringent scientific inquiry in controlled clinical studies.

The bisphosphonate protocols used in the adjunctive, symptomatic treatment of FOP flare-ups have varied slightly between the patients (depending on age, body weight, and site of involvement) but in general were similar. The most commonly used protocol is summarized in Section 5 – Classes of Medications (Table 1).

In all patients, serum calcium was monitored prior to treatment to assure that it was in the normal range, as hypocalcemia is a contraindication to the use of intravenous pamidronate or any of the aminobisphosphonates (Rosen & Brown, 2003). All patients had adequate daily oral calcium and vitamin D supplementation during and following treatment. A serum calcium, phosphate, albumin, alkaline phosphatase, 25-Hydroxy vitamin D, BUN, creatinine and complete blood count (CBC) should also be obtained at baseline.

Treatment schedules were based upon published guidelines for children and adolescents with osteogenesis imperfecta as that group constitutes the largest known group of children and adolescents in whom intravenous aminobisphosphonates have been used (Rauch et al., 2002; Falk et al., 2003; Rauch et al., 2003; DiMeglio & Peacock 2006). The treatment of these children has allowed us to extrapolate protocols and safety data for FOP. Zoledronate has been used more recently in adults and children and offers the opportunity for shorter treatment regimens. However, the side-effects in young children are not fully known and the more prolonged exposure to pamidronate is preferred in FOP especially if administered during an acute flare-up (George et al., 2015).

Patients between two and three years of age received pamidronate at a dose of 0.75 mg/kg/day for three consecutive days by slow intravenous infusion over 4-5 hours each day. Patients over the age of three years received Pamidronate at a dose of 1.0 mg/kg/day for three days by slow intravenous infusion over 4-5 hours each day, with a maximal dose of 60 mgs daily. On the first day of the first cycle of treatment, the patient receives half the dose. Lower total doses of pamidronate (½ listed dose on days 2 and 3) and substantially longer durations of infusions (8-10 hours) have been reported anecdotally and have been well-tolerated. The three-day cycle of treatment should be repeated only during refractory flare-ups and no more than 4 times annually.

An alternate approach is to administer intravenous pamidronate about one week apart and assess the patient to see if there is a medical response in between. In many cases, it has been found that two doses are sufficient. Pamidronate should not be used routinely to treat flare-ups. It should be used primarily for the adjunctive treatment of flare-ups where other modes of symptomatic treatment have failed.

Pamidronate should be diluted in normal saline according to the following table (Guidelines courtesy of F.H. Glorieux: Shriner’s Hospital for Children, Montreal):

The maximal concentration of pamidronate should be 0.1 mg/ml. The IV tubing should be flushed at the end of the infusion to ensure full dose delivery.

Side-effects of intravenous pamidronate infusions in FOP patients included flu-like symptoms of fever, chills, and muscle aches. These symptoms can often be lessened by pre-treatment with acetaminophen. One patient developed tetany (uncontrolled muscle contractions due to a low vitamin D level in the blood prior to ameliorative therapy with pamidronate), and one patient developed peripheral phlebitis (inflammation of the vein) at the intravenous infusion site, which required inpatient intravenous antibiotic treatment.

A published case report documents the development of iatrogenic osteopetrosis in a child treated with 60 mgs of intravenous pamidronate every three weeks for two years. The child did not have FOP and the cumulative doses reported far exceeded any published recommendations for the use of pamidronate in skeletal diseases (Whyte et al., 2003).

Several important rare but serious complications the bisphosphonates are necessary to note - osteonecrosis of the jaw (ONJ) and low-energy atypical femoral fractures. The following references contain detailed reviews of these rare but serious complications (Bilezikian, 2006; Black et al., 2010; Khosla et al., 2007; Shane et al., 2010; Vargas-Franco et al., 2018). Patients considering bisphosphonates should have a dental exam prior to initiation whenever possible.

Bisphosphonates have a long half-life and can reside in the skeleton for many years after the infusion. In women of child-bearing potential, the risk of bisphosphonate exposure on the fetus with future pregnancies is unknown.

A recent study showed that osteoclast inhibition does not affect HO enhanced by the FOP-related mutation (Kawao et al., 2016), so any effect of aminobisphosphonates on HO, if any, are not due to anti-osteoclastic activity, but through other less-explored mechanisms. Clearly, if the aminobisphosphonates are truly beneficial in the treatment of FOP flare-ups, there must be a mechanism of action that is very brief and substantially different from that of osteoclast inhibition from which the medication derives its beneficial effects in the normotopic skeleton.

One intriguing line of investigation concerns the role of inflammatory cells in triggering HO. Kan and colleagues showed that systemically delivered bisphosphonates powerfully and specifically inhibited monocytes and led to substantial inhibition of trauma-induced HO in a BMP4-transgenic mouse model of HO (Kan et al., 2009).

Intravenous aminobisphosphonates have also been shown to modulate macrophages and various lymphocyte subpopulations in the circulation and may be responsible for its dose-related side-effects of causing flu-like symptoms. We cannot yet rule-out the possibility that aminobisphosphonates may affect early lymphocytic and monocytic infiltration into skeletal muscle seen in FOP lesions. It is also likely that the aminobisphosphonates directly inhibit the metabolic activity of monocytes and macrophages that play such key roles in the response of the innate immune system in FOP (Convente et al., 2018).

Several studies provide some additional clues. These studies document the potent antiangiogenic effects of the aminobisphosphonates by decreasing serum vascular endothelial growth factor (VEGF) levels and basic fibroblast growth factor (bFGF) levels in cancer patients with bone metastasis (Santini et al., 2002; Wood et al., 2002). Compelling evidence has emerged that aminobisphosphonates inhibit endothelial cell adhesion, migration and survival through suppression of multiple prenylation- dependent signaling pathways (Hasmim et al., 2007). Other independent studies have shown that aminobisphosphonates have potent anti-angiogenic properties by inhibiting endothelial cell differentiation (Yamada et al., 2009). Taken together, these data strongly suggest that the aminobisphosphonates may be potent anti-angiogenic agents.

Other possible mechanisms by which the aminobisphosphonates might affect FOP lesions include a direct inhibition on the proliferation of a rapidly dividing population of cells. Such an effect was noted in studies investigating the effects of aminobisphosphonates on cancer cells in vitro (Tassone et al., 2000; Green, 2003). It is possible that pamidronate and zoledronate may affect one or more cell types in an early FOP lesion. Another study showed (Idris et al., 2008) that aminobisphosphonates cause osteoblast apoptosis and inhibit bone nodule formation in vitro, thus suggesting that aminobisphosphonates may have a direct effect on inhibiting osteoblastic ability, especially in early bone nodules, as in FOP.

It remains unclear whether bisphosphonates have effects on flare-ups, though anecdotally they seem to decrease the flare symptoms in some patients. As with all medications, the risks and benefits need to be assessed carefully. Only rigorous controlled investigations in vitro and in vivo, as well as placebo– controlled clinical trials will be able to definitively decipher these possibilities and provide a solid rational basis for determining whether or not one or more of the aminobisphosphonates may have a beneficial role in the treatment of FOP.

Most importantly, intravenous aminobisphosphonates are indicated for the prevention and treatment of steroid-associated bone loss, or osteoporosis of the native skeleton, both of which are common problem in FOP patients (Nogginuera et al., 2003; Staa et al., 2003; Chen & Sambrook, 2012; Baroncelli & Bertelloni, 2014; Buckley & Humphrey, 2018). Dentists should be made aware of any prior bisphosphonate use.

Of note, denosumab, a monoclonal antibody to RANK ligand, is a potent anti-resorptive drug approved for the treatment of osteoporosis and certain cancers. As far as we are aware, denosumab has not been used in patients with FOP. Recent reports of increased risks of spinal compression fractures with discontinuation of denosumab, as well as increased risk of hypocalcemia in patients with impaired renal function, lead to the recommendation not to use denosumab in FOP at this time.

References

Baroncelli GI, Bertelloni S. The use of bisphosphonates in pediatrics. Horm Res Paediatr 82: 290-302, 2014

Bilezikian JP. Osteonecrosis of the jaw – do bisphosphonates pose a risk? N Engl J Med 355: 2278-2281, 2006

Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, Bucci-Rechtweg, Cauley J, Leung PC, Boonen S, Santora A, de Papp A, Bauer DC. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med 362: 1761-1771, 2010

Brantus JF, Meunier PJ. Effects of intravenous etidronate and oral corticosteroids in fibrodysplasia ossificans progressiva. Clin Orthop 346: 117-120, 1998

Buckley L, Humphrey MB. Glucocorticoid-Induced Osteoporosis. New Engl J Med 379: 2547-2556, 2018

Chen JS, Sambrook PN. Antiresorptive therapies for osteoporosis: a clinical overview. Nat Rev Endocrinol 8: 81–91, 2012

Convente MR, Chakkalakal SA, Yang E, Caron RJ, Zhang D, Kambayashi T, Kaplan FS, Shore EM. Depletion of Mast cells and macrophages impairs heterotopic ossification in an ACVR1 (R206H) mouse model of fibrodysplasia ossificans progressiva. J Bone Miner Res 33: 269-282, 2018

DiMeglio LA, Peacock M. Two-year clinical trial of oral alendronate versus intravenous pamidronate in children with osteogenesis imperfecta. J Bone Miner Res 21: 132-140, 2006

Falk MJ, Heeger S, Lynch KA, DeCaro KR, Bohach D, Gibson KS, Warman ML. Intravenous bisphosphonate therapy in children with osteogenesis imperfecta. Pediatrics 111: 573-578, 2003

George S, Weber DR, Kaplan P, Hummel K, Monk HM, Levine MA. Short-term safety of zoledronic acid in young patients with bone disorders: an extensive institutional experience. J Clin Endocrinol Metab 100: 4163-4171, 2015

Green JR. Antitumor effects of bisphosphonates. Cancer 97 (supplement): 840-847, 2003

Hasmim M, Bieler G, Rüegg C. Zoledronate inhibits endothelial cell adhesion, migration and survival through the suppression of multiple, prenylation-dependent signaling pathways. J Throm Haemost 5: 166- 173, 2007

Idris AI, Rojas J, Greig IR, Van’t Hof RJ, Ralston SH. Aminobisphosphonates cause osteoblast apoptosis and inhibit bone nodule formation in vitro. Calcif Tissue Int 82: 191-201, 2008

Kan L, Liu Y, McGuire TL, Berger DM, Awatramani RB, Dymecki SM Kessler JA. Dysregulation of local stem/progenitor cells as a common cellular mechanism for heterotopic ossification. Stem Cells 27: 150- 156, 2009

Kawao N, Yano M, Tamura Y, Okumoto K, Okada K, Kaji H. Role of osteoclasts in heterotopic ossification enhanced by fibrodysplasia ossificans progressiva-related activin-like kinase 2 mutation in mice. J Bone Miner Metab 34: 517-525, 2016

Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Shum L, Silverman SL, Van Poznak CH, Watts N, Woo SB, Shane E. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of The American Society for Bone and Mineral Research. J Bone Miner Res 22: 1479-1491, 2007

Nogginuera A, Ros JB, Pavia C, Alcover E, Valls C, Villaronga M, Gonzalez E. Bisphosphonates, a new treatment for glucocorticoid-induced osteoporosis in children. J Pediatr Endocrinol Metab 16: 529-536, 2003

Orcel P, Beaudreuil J. Bisphosphonates in bone disease other than osteoporosis. Joint Bone Spine 69: 19- 27, 2002

Rauch F, Plotkin H, Zeitlin L, Glorieux FH. Bone mass, size, and density in children and adolescents with osteogenesis imperfecta: effect of intravenous pamidronate therapy. J Bone Miner Res 18: 610-614, 2003

Rauch F, Travers R, Plotkin H, Glorieux FH. The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta. J Clin Invest 110: 1293-1299, 2002

Rosen CJ, Brown S. Severe hypocalcemia after intravenous bisphosphonate therapy in occult vitamin D deficiency. N Engl J Med 348: 1503-1504, 2003

Santini D, Vincenzi B, Avvisati G, Dicuonzo G, Battistoni F, Gavasci M, Salerno A, Denaro V, Tonini G. Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 8: 1080-1084, 2002

Schuetz P, Mueller B, Christ-Crain M, Dick W, Haas H. Amino-bisphosphonates in heterotopic ossification: first experience in five consecutive cases. Spinal Cord 43: 604-610, 2005

Shane E. Evolving data about subtrochanteric fractures and bisphosphonates. N Engl J Med 362: 1825- 1827, 2010

Staa TPV, Cooper C, Leufkens HGM, Bishop N. Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 18: 913-918, 2003

Tassone P, Forciniti, S, Galea E, Morrone G, Turco MC, Martinelli V, Tagliaferri P, Venuta S. Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines. Leukemia 14: 841-844, 2000

Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S. Bisphosphonate-induced osteopetrosis. N Engl J Med 349: 457-463, 2003

Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L, Foidart JM, Castronovo V, Green JR. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Therap 302: 1055-1061, 2002

Yamada J, Tsuno NH, Kitayama J, Tsuchiya T, Yoneyama S, Asakage M, Okaji Y, Nishikawa T, Tanaka J, Takahashi K, Nagawa H. Anti-angiogenic property of zoledronic acid by inhibition of endothelial progenitor cell differentiation. J Surg Res 151: 115-120, 2009

Vargas-Franco JW, Castaneda B, Rédiní F, Gómez DF, Heymann D, Lézot F. Paradoxical side effects of bisphosphonates on the skeleton: What do we know and what can we do? J Cell Physiol 233: 5696-5715, 2018

4-7. Off-Label Use of Potent Medications for Managing Inflammation in FOP

Clinical trials for rare diseases commonly focus on one target and one potential therapeutic at a time. However, the exigencies of clinical care in a real-world setting require flexibility in managing symptomatic disease, especially when no other alternatives are available. Approved medicines for one condition may have potential off-target effects for another and thereby be suitable for off-label use on a compassionate basis. Early anecdotal experience with such medications may suggest useful parameters for monitoring meaningful endpoints in future clinical trials.

Recently, there has been growing interest in a number of off-label medications that may have benefits for managing FOP. Many of these medications modulate the immune system. These medications do not have detailed outcome results for blocking of heterotopic ossification. At this time, the use of off-label medications is recommended only for patients with refractory, severe flares that have not responded to standard-of-care therapies, and in which there are no additional contraindications or medication interactions.

The ICC has published statement on the use of off-label medications for the management of FOP. These can be found on the ICC website (ICCFOP.org).

Imatinib for FOP:

In FOP often relentless flare-ups, ongoing discomfort and progressive loss of axial mobility of early childhood pose a special challenge in the symptomatic management of FOP. Presently, there are no adequate solutions for this problem. Research studies have identified multiple potential targets for therapy in FOP, and novel drug candidates are being developed for testing in clinical trials. A complementary approach seeks to identify approved drugs that could be re-purposed against defined targets in FOP.

One such drug is imatinib mesylate, a tyrosine kinase inhibitor originally developed for use in patients with chronic myeloid leukemia (CML). Imatinib has the desirable effect of attacking multiple targets involved in the early hypoxic and inflammatory stages of FOP flare-ups, including HIF1-α, PDGFRα, c-KIT, and multiple MAP kinases (Cahill et al., 2017; Galli, 2017). Notably, imatinib is effective in the treatment of systemic mast cell disease and inhibits multiple inflammatory proteins implicated in the formation of HO. Thus, imatinib has potential impact on major therapeutic targets of FOP.

Based on compelling biologic rationale, strong preclinical data, and a favorable safety profile, imatinib has been prescribed on an off-label basis in a non-trial setting in seven children with continuous FOP flare-ups, predominantly in the axial regions which were not responsive to standard-of-care regimens (Wang et al., 2016; Kaplan et al., 2018). All seven children failed to demonstrate any durable symptomatic response to the standard medications used to manage symptoms of FOP such as corticosteroids, non-steroidal anti- inflammatory agents, cromolyn or intravenous bisphosphonates.

All seven children were referred to a pediatric hematologist-oncologist or a pediatric rheumatologist for consideration of imatinib therapy after detailed consultation with the parents on the relative risks and benefits of off-label use of imatinib for FOP. Parents were informed that imatinib use was on an off-label basis and was not part of a clinical research study. The parents were also informed that progress would be monitored clinically, and that radiographs would not be performed routinely.

Anecdotal reports in these cases document that the medication was well-tolerated with an overall reported decrease in the intensity of flare-ups in the six children who took the medication. Moreover, the parents of all six children who were able to take imatinib on a daily basis noted subjective decreases in flare-up intensity after several weeks of use (Kaplan et al., 2018).

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. Kaplan et al. (2021) reported 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 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 (Kaplan et al., 2021).

Presently, there is no definitive evidence that imatinib prevents or ameliorates flare-ups in FOP. However, early clinical observations support the implementation of clinical trials of imatinib in children with uncontrolled FOP flare-ups (Kaplan et al., 2018; Kaplan et al., 2021).

Tofacitinib for FOP:

Since flares of FOP are associated with inflammation, it was hypothesized that JAK inhibitors can control active FOP due to blocking multiple inflammatory signaling pathways (Nikishina et al., 2023). The authors reported their observations on the safety and efficacy of tofacitinib in 13 patients with FOP refractory to standard of care treatment. Thirteen genetically confirmed FOP patients (seven boys and six girls from 2-20 years) were treated with tofacitinib 5 mg twice a day. All patients initially failed treatment with NSAIDs, corticosteroids, and bisphosphonates. Patients were evaluated for 12 months before the beginning of their treatment with tofacitinib and continued for at least12 months during their tofacitinib treatment period.

During the trial, the median frequency of flares decreased from 10 during 12 months before the baseline to 0 in the following 12 months and 0 in 24 months of treatment. Twelve patients had no deteriorations of the CAJIS index during the study; in one patient the CAJIS index deteriorated by 1 point. Improvement in the range of motion in the large joints was noted in 31% of patients. NSAID, oral and intravenous corticosteroids were successfully decreased from 100%; 61.5%, and 15.4% (baseline) to 46.2%, 7.7%, and

0% (12 months) and 22.2%, 0%, and 0% (24 months). Patients tolerated the drug well. No severe adverse events were registered. The authors concluded that Tofacitinib was a well-tolerated option that may decrease FOP flares and that further studies of the therapeutic potential of JAK-kinase inhibitors in FOP patients are needed (Nikishina et al., 2023).

Of note, JAK-kinase inhibitors can lead to renal and hepatic toxicity. There is concern about tofacitinib leading to an increased risk of deep vein thromboses or pulmonary emboli, as well as certain types of cancer, heart-related events, and death. The FDA has issued a black box warning detailing these concerns (Sept 1, 2021)

https://www.fda.gov/drugs/fda-drug-safety-podcasts/fda-requires-warnings-about-increased-risk-serious- heart-related-events-cancer-blood-clots-and-death

Anti-IL1 therapies for FOP (anakinra, canakinumab):

Multiple studies suggest that IL-1 is a major regulator of inflammation (Barruet et al., 2018; Matsuo et al., 2019; Matsuo et al., 2021; Lounev et al., 2024). This interest has led to the off-label trials of anti-IL1 therapies such as anakinra (which targets the IL1 receptor) and canakinumab (which blocks IL-1beta) for treating the inflammatory components of FOP. Initial reports of a patient in Israel showed promising results with controlling flares. A subsequent case series of four patients receiving longer-term anti-IL1 drugs was recently published, showing a significant decrease in flare activity (Haviv et al., 2024). When therapy was discontinued briefly in one patient, the FOP flares returned; this was subsequently suppressed by restarting anti-IL1 therapy.

Canakinumab is of particular interest because it is given every 4-8 weeks. Anakinra, which is a daily medication, has been associated with injection site pain in both FOP and non-FOP patients. Both of these medications are immune suppressants, and so may increase the risk of serious infections. Long term use of up to 6 years in cryopyrin associated periodic syndrome (CAPS) and other inflammatory conditions have shown good safety and tolerability (Walker et al., 2021). However, the efficacy of reducing new HO formation in FOP and long term safety for use in FOP remains unclear.

Other anti-inflammatory medications:

There has been no compelling anecdotal data to support the use of other anti-inflammatory medications, including methotrexate, rituximab, TNF-α inhibitors, or rapamycin. Therefore, the use of these medications for the primary management of FOP is not indicated.

Statement Regarding Off Label Medications for the Management of FOP from the International Clinical Council on FOP (ICC; May 2024)

The International Clinical Council (ICC) on FOP is aware of several recent publications describing the off- label use of potent medications for managing inflammation in FOP. These potential treatments include the use of anakinra (Haviv et al., 2019), canakinumab (Haviv et al., 2019; 2024), tofacitinib (Nikishina et al., 2023), and imatinib (Kaplan et al., 2018; Kaplan et al., 2021). These reports appear to show some benefits, particularly with managing FOP flares and flare pain.

In addition, there are recent reports of medications such as minocycline (Lounev et al., 2024), momelotinib (Oh et al., 2020), and pacritinib (Oh et al., 2023) that have activity in animal models of FOP or that may directly target ACVR1 activity. There are no clinical data regarding the risks or benefits of these therapies for managing patients with FOP.

These off-label and investigational medications have very limited data. We have no or limited data on:

whether the benefit is only for reducing flares (which is what has been reported for all of these medications);
whether there is any benefit for function or reducing heterotopic ossification in FOP;
the long-term safety of these medications in patients with FOP; and
what happens when a patient stops the medication.

We also have very little or no systematic data for the safety of these medications in children with FOP, even though many of these medications have been used in children with non-FOP conditions.

These preliminary studies support the need for larger, well controlled, human clinical trials to determine the safety and efficacy of these medications in FOP.

Until those studies are completed, the ICC recommends considering these medications only for situations where all three minimal key criteria are met:

FOP flares are considered severe and intractable, or where there is unusually severe or rapid progression of the disease, and
Once standard of care therapies (ICCFOP.org) have been exhausted, and
The clinical team feels that the medications could be used safely (i.e. no other contra-indications, no underlying problems with infection, no immunocompromised situations, no medication interactions, etc.) and according to the age at which these drugs may have been authorized.

The ICC brings particular attention to medications that have known severe interactions with palovarotene. This includes all tetracycline-like drugs such as minocycline or doxycycline. Taking these medications with palovarotene or other retinoids can cause pseudotumor cerebri, a dangerous condition of high pressure inside the skull that can damage the brain and nervous system.

Due to the risk profiles of all these medications, the ICC does NOT recommend the use of off-label medications as a preventive.

If you wish to consider these medications for you or your child, please discuss the pros and cons in detail with your doctors and FOP clinicians. Medication interactions and individual risks vary and can be severe. These risks must be discussed at the individual patient level.

Social media claims of safety or efficacy are not the same as an open medical discussion of potential risks and benefits. The ICC believes in individual choice. Whether someone takes a potential therapy, or feels that a therapy works, is an individual judgment that must be made with all available risks and benefits clearly presented.

The ICC also recommends review of active clinical trials before making decisions regarding off-label use of these medications. Taking any of these off-label or investigational medications may disqualify you or your child from participation in formal clinical trials. In addition, clinical trials are monitored closely for safety and efficacy, and information from those clinical trials can help the FOP community advance different therapeutic options and support future drug approvals. Information from off-label use of a medication outside of a clinical study is not sufficient for drug approval.

If you choose to use these medications, or any other medications that are not considered standard-of-care for patients with FOP, it should be done with close monitoring in collaboration with your FOP clinical team. If you are in a clinical trial, you must discuss any potential changes to your therapy before starting a new medication. Off-label medications are often not allowed during your participation in a clinical trial.

References

Barruet E, Morales BM, Cain CJ, Ton AN, Wentworth KL, Chan TV, Moody TA, Haks MC, Ottenhoff TH, Hellman J, Nakamura MC, Hsiao EC. NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification. JCI Insight 2018 Nov 15;3(22). pii: 122958

Galli SJ. Mast Cells and KIT as Potential Therapeutic Targets in Severe Asthma. N Engl J Med 376: 1983- 1984, 2017

Haviv R, Moshe V, De Benedetti F, Prencipe G, Rabinowicz N, Uziel Y. Is fibrodysplasia ossificans progressiva an interleukin-1 driven auto-inflammatory syndrome? Pediatr Rheumatol Online J 2019 Dec 21:17 (1):84

Haviv R, Zeitlin L, Moshe V, Ziv A, Rabinowicz N, De Benedetti F, Prencipe G, Matteo V, De Cunto CL, Hsiao EC, Uziel Y. Long term use of interleukin-1 inhibitors reduce flare activity in patients with fibrodysplasia ossificans progressiva. Rheumatology (Oxford). 2024 May 11:keae255

Lounev V, Groppe JC, Brewer N, Wentworth KL, Smith V, Xu M, Schomburg L, Bhargava P, Al Mukaddam M, Hsiao EC, Shore EM, Pignolo RJ, Kaplan FS. Matrix metalloproteinase-9 deficiency confers resilience in fibrodysplasia ossificans progressiva in a man and mice. J Bone Miner Res 39: 382-398, 2024

Matsuo K, Chavez RD, Barruet E, Hsiao EC. Inflammation in fibrodysplasia ossificans progressiva and other forms of heterotopic ossification. Curr Osteoporos Rep 17: 387-394, 2019

Matsuo K, Lepinski A, Chavez RD, Barruet E, Pereira A, Moody TA, Ton AN, Sharma A, Hellman J, Tomoda K, Nakamura MC, Hsiao EC. ACVR1R206H extends inflammatory responses in human induced pluripotent stem cell-derived macrophages. Bone 2021 Dec;153:116129

Nikishina IP, Arsenyeva SV, Matkava VG, Arefieva AN, Kaleda MI, Smirnov AV, Blank LM, Kostik MM. Successful experience of tofacitinib treatment in patients with Fibrodysplasia Ossificans Progressiva.

Pediatr Rheumatol Online J 2023 Aug 29;21(1):92

Oh ST, Mesa RA, Harrison CN, Bose P, Gerds AT, Gupta V, Scott BL, Kiladjian JJ, Lucchesi A, Kong T, Buckley SA, Tyavanagimatt S, Harder BG, Roman-Torres K, Smith J, Craig AR, Mascarenhas J, Verstovsek S. Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. Blood Adv 7: 5835-5842, 2023

Oh ST, Talpaz M, Gerds AT, Gupta V, Verstovsek S, Mesa R, Miller CB, Rivera CE, Fleischman AG, Goel S, Heaney ML, O'Connell C, Arcasoy MO, Zhang Y, Kawashima J, Ganz T, Kowalski M, Brachmann CB. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv 4: 4282-4291, 2020

Walker UA, Tilson HH, Hawkins PN, Poll TV, Noviello S, Levy J, Vritzali E, Hoffman HM, Kuemmerle- Deschner JB; CACZ885D2401 Study Investigators. Long-term safety and effectiveness of canakinumab therapy in patients with cryopyrin-associated periodic syndrome: results from the β-Confident Registry.

RMD Open 2021 May;7(2):e001663

Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangivani L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling. J Bone Miner Res 31: 1652-1665, 2016

4-8. Muscle Relaxants in FOP

Early FOP flare-ups are associated with intense mast cell, macrophage, and lymphocytic infiltration into skeletal muscle and are often accompanied by intense inflammatory changes within regions of locally damaged or necrotic skeletal muscle. Areas of relatively healthy skeletal muscle bordering the lesion are thus subject to metabolic changes that would lead to muscle spasm and fiber shortening.

The judicious short-term use of muscle relaxants such as cyclobenzaprine (Flexeril), metaxalone (Skelaxin), or baclofen (Liorisal) may help to decrease muscle spasm and maintain more functional activity even in the setting of an evolving FOP lesion (Glaser & Kaplan, 2005). This is especially true for painful flare-ups involving the limbs. The chronic use of muscle relaxants between episodes of flare-ups is not advised due to multiple drug interactions and central nervous system (depressant) effects. Careful attention to dosing schedules is important, as certain muscle relaxants (such as baclofen) need to be tapered slowly to avoid side-effects and others (such as cyclobenzaprine) can only be used for short periods of time up to 2-3 weeks.

References

Glaser DL, Kaplan FS. Treatment considerations for the management of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 243-250, 2005

4-9. Chemotherapy Agents & Radiation Therapy in FOP

The definitive diagnosis of FOP is often delayed due to the rarity of the condition and the failure to associate the tumor-like soft tissue swellings with the congenital malformations of the great toes. As a result, many children with FOP are misdiagnosed as having a wide range of benign or malignant conditions. It is not surprising, therefore, that many children with FOP have been treated with unnecessary chemotherapy, dangerous surgical excisions, and damaging radiotherapy before the definitive diagnosis of FOP has been made. It would be important to note retrospectively if radiation therapy or any of the chemotherapy agents had been helpful in altering the natural history of the condition.

There has been no convincing anecdotal evidence that either radiation therapy or any of the standard chemotherapy agents such as actinomycin, adriamycin, cyclosphosphamide, doxorubicin, ifosfamide, vinblastine, vincristine or any others were helpful for patients with FOP. In fact, many of these medications caused harmful long-term side-effects. The use of these approaches is, therefore, contraindicated in the treatment of FOP (Glaser & Kaplan, 2005; Kaplan et al., 2008).

References

Glaser DL, Kaplan FS. Treatment considerations for the management of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 243-250. 2005

Kaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby R, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva (FOP). Best Practice & Research – Clinical Rheumatology 22: 191-205, 2008

4-10. Bone Marrow Transplantation in FOP

Bone marrow derived stem cells have been implicated in the ectopic bone formation of FOP (reviewed in Kaplan et al., 2007). The replacement of these stem cells by bone marrow transplantation has been suggested as a possible cure for FOP. However, the definitive contribution of bone marrow derived stem cells to the formation of heterotopic bone has remained obscure. Careful clinical observations were made of an FOP patient who underwent bone marrow transplantation twenty-five years earlier for the treatment of intercurrent aplastic anemia. Replacement of the FOP patient’s bone marrow with normal donor bone marrow cured his fatal bone marrow condition but was not sufficient to prevent further HO and progression of his FOP. However, acute immunoablation and chronic immunosuppression quenched the activity of his FOP (Kaplan et al., 2007).

In complementary transplantation studies in mice, blood cells derived from the bone marrow contributed to the early inflammatory and to the late marrow repopulating stages of BMP4-induced bone formation, but were not present in the fibroproliferative, chondrogenic or osteogenic stages of the FOP-like lesions (Kaplan et al., 2007).

Taken together, these findings demonstrated that bone marrow transplantation did not cure FOP in this patient, most likely because the hematopoietic cells from the bone marrow were not the source of cells that formed the FOP lesions. However, it is critical to note that normal bone marrow-derived cells were capable of stimulating HO in a genetically susceptible individual (Kaplan et al., 2007). Recent genetic experiments and bone marrow transplantation studies in FOP mouse models substantiate this finding (Chakkalakal et al., 2016; Dey et al., 2016), although a non-hematopoietically derived population of resident tissue macrophages remains a possible trigger.

These findings are of immense research interest and vital clinical importance, and they exemplify powerfully how much can be learned by careful observation in an individual patient. They also illustrate the importance of the immune system in triggering FOP flare-ups. At present, however, the general use of potent immunosuppressive medications is not advocated in the routine management of FOP and would likely be extremely dangerous and possibly life-threatening if it were applied broadly to the FOP community. At the present time, (and until further studies are performed in appropriate animal models), this international consortium recommends against the use of chronic immunosuppressive medications in the management of FOP.

References

Chakkalakal SA, Uchibe K, Convente MR, Zhang D, Economides AN, Kaplan FS, Pacifici M, Iwamoto M, Shore EM. Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1 (R206H) fibrodysplasia ossificans progressiva (FOP) mutation. J Bone Miner Res 31: 1666-1675, 2016

Dey D, Bagarova J, Hatsell SJ, Armstrong KA, Huang L, Ermann J, Vonner AJ, Shen Y, Mohedas AH, Lee A, Eekhoff EM, van Schie A, Demay MB, Keller C, Wagers AJ, Economides AN, Yu PB. Two tissue- resident progenitor lineages drive distinct phenotypes of heterotopic ossification. Sci Transl Med 2016 Nov 23;8(366):366ra163

4-11. Miscellaneous Agents & Approaches in FOP

The chronic use of antiangiogenic agents, calcium binders, colchicine, fluoroquinolone antibiotics, mineralization inhibitors, PPAR-gamma agonists, TNF-α inhibitors and warfarin have been described anecdotally or reported with either unsatisfactory or equivocal results (Moore et al., 1986; Bocciardi & Ravazzolo, 2010; Gatti et al., 2010; Kaplan et al., 2010).

Maxillofacial surgery has been reported in one patient with FOP and was beneficial for the patient from a quality-of-life standpoint despite recurrence of HO. There is 100% risk of recurrence of HO after jaw surgery which should be highly discouraged and remain a management choice of last resort (Eekhoff et al., 2017).

While there has been one case report of successful surgical excision of heterotopic bone in a patient with FOP, such an approach is not recommended, as the literature is littered with casualties following similar adventures (Benetos et al., 2006).

References

Benetos IS, Mavrogenis AF, Themistocleous GS, Kanellopoulos AD, Papagelopoulos PJ, Soucacos PN. Optimal treatment of fibrodysplasia ossificans progressiva with surgical excision of heterotopic bone, indomethacin, and irradiation. J Surg Orthop Adv 15: 99-104, 2006

Bocciardi R, Ravazzolo R. Is there a biological basis for treatment of fibrodysplasia ossificans progressiva with rosiglitazone? Potential benefits and undesired effects. PPAR Res 2010;2010:541927

Eekhoff EMW, Netelenbos JC, de Graaf P, Hoebink M, Bravenboer N, Micha D, Pals G, de Vries TJ, Lammertsma AA, Raijmakers PG, van Es RJ. Flare-Up After Maxillofacial Surgery in a Patient with Fibrodysplasia Ossificans Progressiva: An [18F]-NaF PET/CT Study and a Systematic Review. JBMR Plus 2: 55-58, 2017

Gatti D, Viapiana O, Rossini M, Silvano A. Rosiglitazone therapy is associated with major clinical improvements in a patient with fibrodysplasia ossificans progressiva. J Bone Miner Res 25: 1460-1462, 2010

Kaplan FS, Pignolo RJ, Shore EM. Viewing FOP through rosi-colored glasses. J Bone Miner Res 25: 2295-2296, 2010

Moore, SE, Jump A, Smiley JD. Effect of warfarin sodium therapy on excretion of 4-carboxy-L-glutamic acid in scleroderma, dermatomyositis, and myositis ossificans progressiva. Arthritis Rheum 29: 344-351, 1986

4-12. Supportive Treatment in FOP

There is presently one approved medical treatment for FOP, but only in certain jurisdictions. Management is mainly supportive. High-dose glucocorticoids have limited use but are most effective in the management of the early inflammatory flare-ups affecting major joints of the appendicular skeleton and jaw, especially when used immediately after the onset of a flare-up. Oral and topical non-steroidal anti-inflammatory medications, cyclo-oxygenase-2 inhibitors, mast cell stabilizers, leukotriene inhibitors and occasional intravenous aminobisphosphonates are reported by patients to manage chronic pain, arthritic symptoms or ongoing disease progression (Kaplan et al., 2008; Pignolo et al., 2013). These are discussed in the prior sections.

Research to develop treatments for FOP has focused on targeted inhibition of the ACVR1 receptor, ACVR1 ligands, BMP pathway signaling, the pre-osseous chondrogenic anlagen of HO, and inflammatory triggers of disease activity, and offers hope for the future.

References

Kaplan FS, LeMerrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol 22: 191-205, 2008

4-13. Definitive Therapeutic Targets in FOP

“With so much being discovered about how the BMPs act, it might be possible to develop drugs that would block some part of the BMP pathway and therefore prevent the progression of what is a horrible, nightmare disease.”

- Brigid Hogan (Roush, 1996)

The ultimate goal of FOP research is the development of treatments that will prevent, halt, or even reverse the progression of the condition. The prevention and treatment of HO in FOP, as in any of the more common forms of HO, will ultimately be based on at least one of four approaches: disrupting the inductive signaling pathways, suppressing the inflammatory triggers, altering the relevant osteoprogenitor cells in the target tissues, and/or modifying the tissue environment so that it is less conducive to heterotopic osteogenesis (Reviewed in Wentworth et al., 2019; Pignolo & Kaplan, 2020).

The identification of the recurrent heterozygous missense point mutation that causes FOP in all classically affected individuals provides a specific pharmaceutical target and a rational point of intervention in a critical signaling pathway. The discovery of the FOP gene identifies ACVR1 as a susceptible pharmaceutical target for the treatment of FOP (Shore et al., 2006). Plausible therapeutic strategies to inhibiting BMP signaling in FOP include inhibitory RNA technology (Kaplan et al., 2012), monoclonal antibodies directed against ACVR1 (Kaplan et al., 2017), small molecule selective signal transduction inhibitors (STIs) of ACVR1 (Hong et al., 2009; Kaplan et al., 2017; Williams et al., 2021), small molecule signal transduction inhibitors against inflammatory triggers and osteoprogenitor cells (Kaplan et al., 2018), retinoic acid receptor gamma (RARγ) agonists (Shimono et al., 2011; Chakkalakal et al., 2016; Kaplan & Shore, 2011), anti-Activin A antibodies (Hatsell et al., 2015; Hino et al., 2016; Kaplan et al., 2016; Vanhoutte et al., 2020) and inhibition of HIF1-α/ mTOR signaling (Wang et al., 2016; Hino et al., 2017; Maekawa et al., 2020), senotherapeutic agents (Wang et al., 2022), and gene therapy (Eekhoff et al., 2022). Information about clinical trials on FOP can be found at: http://www.clinicaltrials.gov

Two recent studies show that anti-ACVR1 antibodies can exacerbate heterotopic ossification in FOP mice. This property resulted from anti-ACVR1 antibody mediated dimerization of mutant ACVR1. Conversely, wild-type ACVR1 was inhibited by anti-ACVR1 antibodies. These data raise serious safety and efficacy concerns and indicate that bivalent anti-ACVR1 antibodies should not be considered as therapeutics for FOP (Aykul et al., 2022; Lees-Shepard et al., 2022). In contrast, a recent study from Japan showed that a blocking monoclonal antibody could prevent HO in a mouse model of FOP (Katagiri et al., 2023) leading to the conclusion that antibody specificity may be critically important therapeutically.

Muscle injury in FOP was shown to results in senescent cell accumulation, and senescence promotes tissue reprogramming toward a chondrogenic fate in FOP muscle but not wild-type muscle. Pharmacologic clearance of senescent cells and reduction in the senescence associated secretory phenotype (SASP) ameliorates HO in mouse models of FOP. Thus, senolytic drugs provide proof-of-principle as a future therapeutic strategy in FOP (Wang et al., 2022).

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 (Hsiao et al., 2018). While there is risk, there is also much benefit and hope (Kaplan et al., 2020).

It is still too early to determine which one of these approaches or combinations of approaches will be most effective, and all are being studied intensively in preclinical and/or clinical studies (www.clinicaltrials.gov; https://www.ifopa.org/ongoing_clinical_trials_in_fop). Much of the present worldwide collaborative research effort in FOP is focused on this area of research, and detailed accounts of the work and progress can be found in the Twenty Ninth Annual Report of the FOP Collaborative Research Project (Kaplan, Al Mukaddam, Shore et al., 2024), as well as in recent reviews.

References

Aykul S, Huang L, Wang L, Das NM, Reisman S, Ray Y, Zhang Q, Rothman N, Nannuru KC, Kamat V, Brydges S, Troncone L, Johnsen L, Yu PB, Fazio S, Lees-Shepard J, Schutz K, Murphy AJ, Economides AN, Idone V, Hatsell SJ. Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1. J Clin Invest 2022 Jun 15;132(12):e153792

Eekhoff EMW, de Ruiter RD, Smilde BJ, Schoenmaker T, de Vries TJ, Netelenbos C, Hsiao EC, Scott C, Haga N, Grunwald Z, De Cunto CL, di Rocco M, Delai PLR, Diecidue RJ, Madhuri V, Cho TJ, Morhart R, Friedman CS, Zasloff M, Pals G, Shim JH, Gao G, Kaplan F, Pignolo RJ, Micha D. Gene Therapy for Fibrodysplasia Ossificans Progressiva: Feasibility and Obstacles. Hum Gene Ther 33:782-788, 2022

Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, D’Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN. ACVR1(R206H) receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med 7(303)ra137, 2015

Hino K, Horigome K, Nishio M, Komura S, Nagata S, Zhao C, Jin Y, Kawakami K, Yamada Y, Ohta A, Toguchida J, Ikeya M. Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva. J Clin Invest 127: 3339-3352, 2017

Hino K, Ikeya M, Horigome K, Matsumoto Y, Ebise H, Nishio M, Sekiguchi K, Shibata M, Nagata S, Matsuda S, Toguchida J. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc Natl Acad Sci USA 112: 15438-15443, 2015

Hong CC, Yu PB. Application of small molecules BMP inhibitors in physiology and disease. Cytokines Growth Factor Rev 20: 409-418, 2009

Hsiao EC, Di Rocco M, Cali A, Zasloff M, Al Mukaddam M, Pignolo RJ, Grunwald Z, Netelenbos C, Keen R, Baujat G, Brown MA, Cho TJ, De Cunto C, Delai P, Haga N, Morhart R, Scott C, Zhang K, Diecidue RJ, Friedman CS, Kaplan FS, Eekhoff EMW. Special considerations for clinical trials in fibrodysplasia ossificans progressiva (FOP). Br J Clin Pharmacol 85: 1199-1207, 2019

Kaplan FS, Al Mukaddam M, Shore EM. Twenty-Ninth Annual Report of the fibrodysplasia ossificans progressiva (FOP) collaborative research project. IFOPA Website & ICC Website (www.ifopa.org; www.iccfop.org), 2024

Kaplan FS, Al Mukaddam M, Baujat G. Cali A, Cho-T-J, DeCunto C, Delai P, Diecidue RJ DiRocco M, Friedman C, Grunwald Z, Haga N, Hsiao EC, Keen R, Morhart R, Netelenbos JC, Scott C, Zasloff MA, Zhang K, Eekhoff EMW, Pignolo RJ. Editorial - The twilight zone: benefit, risk & hope in clinical trials for FOP. ICCFOP.org; IFOPA.org. December 3, 2020

Kaplan J, Kaplan FS, Shore EM. Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele–specific targeting. Gene Therapy 19: 786-790, 2012

Kaplan FS, Pignolo RJ, Shore EM. Granting immunity to FOP and catching heterotopic ossification in the Act. Semin Cell Dev Biol 49: 30-36, 2016

Kaplan FS, Shore EM. Derailing heterotopic ossification and RARing to go. Nat Med 17: 420-421, 2011

Katagiri T, Tsukamoto S, Kuratani M, Tsuji S, Nakamura K, Ohte S, Kawaguchi Y, Takaishi K. A blocking monoclonal antibody reveals dimerization of intracellular domains of ALK2 associated with genetic disorders. Nat Commun 2023 May 25;14(1): 2960

Lees-Shepard JB, Stoessel SJ, Chandler JT, Bouchard K, Bento P, Apuzzo LN, Devarakonda PM, Hunter JW, Goldhamer DJ. An anti-ACVR1 antibody exacerbates heterotopic ossification by fibro-adipogenic progenitors in fibrodysplasia ossificans progressiva mice. J Clin Invest 2022 Jun 15;132(12):e153795

Maekawa H, Kawai S, Nishio M, Nagata S, Jin Y, Yoshitomi H, Matsuda S, Toguchida J. Prophylactic treatment of rapamycin ameliorates naturally developing and episode -induced heterotopic ossification in mice expressing human mutant ACVR1. Orphanet J Rare Dis 2020 May 24;15(1):122

Pignolo RJ, Kaplan FS. Druggable targets, clinical trial design and proposed pharmacological management in fibrodysplasia ossificans progressiva. Expert Opinion on Orphan Drugs p. 1-9, 2020

Shimono K, Tung W-e, Macolino C, Chi A, Didizian JH, Mundy C, Chandraratna RA, Mishina Y, Enomoto-Iwamoto M, Pacifici M, Iwamoto M. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. Nat Med 17: 454-460, 2011

Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho T-J, Choi IH, Connor JM, Delai P, Glaser DL, Le Merrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genetics 38: 525-527, 2006

Vanhoutte F, Liang S, Ruddy M, Zhao A, Drewery T, Wang Y, DelGizzi R, Forleo-Neto E, Rajadhyaksha M, Herman G, Davis JD. Pharmacokinetics and pharmacodynamics of Garetosmab (Anti-Activin A): Results from a first-in-human phase 1 study. J Clin Pharmacol 2020 Jun 18

Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangiavini L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling. J Bone Miner Res 31: 1652-65, 2016

Wang H, Zhang Q, Kaplan FS, Pignolo RJ. Clearance of Senescent Cells from Injured Muscle Abrogates Heterotopic Ossification in Mouse Models of Fibrodysplasia Ossificans Progressiva. J Bone Miner Res 37: 95-107, 2022

Wentworth KL, Masharani U, Hsiao EC. Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol 85: 1180-1187, 2019

Williams EP, Bagarova J, Kerr G, Xia DD, Place ES, Dey D, Shen Y, Bocobo GA, Mohedas AH, Huang X, Sanderson PE, Lee A, Zheng W, Economides AN, Smith JC, Yu PB, Bullock AN. Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva. JCI Insight 2021 Mar 11:95042

Yang YS, Kim JM, Xie J, Chaugule S, Lin C, Ma H, Hsiao E, Hong J, Chun H, Shore EM, Kaplan FS, Gao G, Shim JH. Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery. Nat Commun 2022 Oct 19;13(1):6175

4-14. Clinical Trial Results in FOP

This section of The Guidelines briefly outlines the peer reviewed, published results of registered clinical trials (clinicaltrials.gov) in FOP. Interested readers are directed to the full manuscripts.

Palovarotene

A placebo-controlled, double-blind trial (NCT02190747) Phase II study evaluated palovarotene, an orally bioavailable selective retinoic acid receptor gamma agonist, for prevention of HO in patients with FOP.

Although these findings were not statistically significant, they supported further evaluation of palovarotene for prevention of HO in FOP in larger studies (Pignolo, Baujat et al., 2022).

In a publication in The Journal of Bone & Mineral Research, Palovarotene, an RARγ receptor agonist, was reported to reduce new heterotopic ossification (HO) in an Open-Label, Phase 3 Trial (Pignolo, Hsiao et al., 2022). The single-arm, open-label, phase 3 MOVE trial (NCT03312634) assessed efficacy and safety of palovarotene in patients with FOP. Findings were compared with FOP natural history study

(NHS; NCT02322255) participants untreated beyond standard of care. The primary endpoint was annualized change in new HO volume versus NHS participants (by low-dose whole-body computed tomography [WBCT]). Twelve-month interim analyses met futility criteria. Post hoc 18-month interim analyses showed 99.4% probability of any reduction in new HO with palovarotene versus NHS participants. Annualized new HO volume was 60% lower in MOVE versus the NHS. 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 modest efficacy of palovarotene in reducing new HO in FOP, but high risk of PPC in skeletally immature patients (Pignolo, Hsiao et al., 2023).

Palovarotene was approved for FOP by the U.S. Food & Drug Administration (FDA) on August 16, 2023, for use in boys older than 10 years of age and girls older than 8 years of age (when 90% of their height has been achieved, based on national averages). It should be noted that palovarotene is not expected to change flare activity, as the primary molecular target is the formation of new heterotopic ossification. Furthermore, palovarotene should not be taken with certain medications due to the risks of interactions, including tetracyclines (such as tetracycline, doxycycline, minocycline, etc.) or medications that are strong inducers of Cyp3A4.

The International Clinical Council on FOP (ICC) issued the following official statement in August 2023:

Statement Regarding Palovarotene from the International Clinical Council (ICC) on FOP

The International Clinical Council (ICC) on FOP is aware of the recent decisions by the United States Food and Drug Administration (FDA), the European Medicines Agency, and Health Canada on the use of palovarotene for the treatment of fibrodysplasia ossificans progressiva (FOP). The ICC has no direct influence on these regulatory decisions, as we believe it is important that the review and regulatory processes play out in accordance with established scientific and legal principles.

On August 16th, 2023, the US FDA announced the approval of palovarotene for the treatment of FOP. Palovarotene has been evaluated by other regulatory agencies, including approval by Health Canada in January 2022, and rejection by the European Medicines Agency (EMA) in June 2023.

The FDA advisory committee in June 2023 made a non-unanimous positive recommendation, with notable concerns regarding the benefit/risk balance, significant risks of side effects, and reliance on post-hoc analyses of the data.

FOP is a devastating genetic disease where progressive abnormal bone formation (heterotopic ossification, HO) leads to loss of mobility, independence, and quality of life. To date, only symptomatic treatments are available. Palovarotene is a small molecule in the retinoid class and represents the first drug approved specifically for decreasing new HO formation in patients with FOP.

The ICC has reviewed the data publicly presented to the FDA advisory committee in June 2023, as well as reviewed the publications of the Natural History Study (Pignolo, et al. Genet. Med 2022) and the Phase III MOVE Trial (Pignolo et al., J Bone Mineral Res 2023). The primary analysis of the data raised significant concerns about the efficacy of palovarotene in blocking new HO formation, and in fact met the futility criteria for stopping the trial due to these concerns.

Examination of the data after unblinding revealed deficiencies in the planned analysis method. Multiple subsequent post-hoc analyses, performed both by Ipsen and the FDA, suggested that palovarotene likely reduced new HO formation by 50-60%. The Phase III MOVE trial also showed that palovarotene had significant side effects, including the risk of early growth plate closure in younger patients with FOP and complications related to the retinoid class of medications (skin rash, dry skin and eyes, possible bone loss, etc.).

The members of the ICC strongly support the continued development of therapies for treating the devastating consequences of FOP.

Palovarotene represents a first step in that direction, with approval in the USA, Canada, and UAE. However, the ICC also feels that there are significant limitations to the existing data – specifically the necessarily short-term results of a clinical trial for a drug that is expected to be used lifelong; the still unanswered questions regarding the exact efficacy of reduction of HO bone formation; the unclear impact on long-term functional outcomes; and the potential for significant side effects and bone toxicity especially in children.

Therefore, the ICC recommends:

If a patient with FOP considers palovarotene, the potential benefits and risks, as detailed in the package insert, by the MOVE trial publication, and in subsequent publications, must be discussed in detail with the patient and the patient’s medical team.
Additional risks should be explicitly discussed, including potential effects on bone health (loss of bone mass), skin/mucosal dryness and complications, potential for eye complications, and the risk of fetal malformations in pregnancy. The ICC supports continued close long-term follow-up of these potential complications.
A long term, detailed study of the safety and efficacy of palovarotene should be pursued, such as through a registry or formalized long-term study.
Standard-of-care therapies, as recommended by the FOP Treatment Guidelines (available at ICCFOP.org), should still be used in combination with palovarotene as appropriate, and with guidance from the patient’s medical team.
Worldwide affordable access to palovarotene should be facilitated, including ensuring reasonable cost for therapy.
Careful monitoring of patients to prevent pregnancy while on palovarotene should be required, due to the known teratogenicity of the retinoid class of medications.
Careful education of potential drug interactions, including with antibiotics like tetracycline or doxycycline, should be required.
Patients should not use non-pharmaceutical grade palovarotene.

The ICC continues to support open discussions and data sharing in all clinical trials and studies as potential therapies for FOP are examined.

While the majority of ICC members believe that palovarotene may have benefits for the care of patients with FOP, a number of ICC members had serious concerns about its approval and use. These concerns include the high risk of growth plate effects in young children with FOP, leading to a potential consideration that palovarotene should never be used in growing children. In addition, the long-term risks of treatment with palovarotene remain unknown, and could result in significant secondary complications that have yet to be identified. Furthermore, the use of palovarotene may impact a patient’s ability to take certain medications or participate in clinical trials.

The FOP treatment guidelines at ICCFOP.org will be updated with additional information once palovarotene is available commercially in the jurisdictions where it has been approved. In addition, the ICC is planning a future review manuscript regarding palovarotene.”

Garetosmab

In a publication in Nature Medicine, intravenous garetosmab, an inhibitor of activin A, was reported to reduce heterotopic ossification and flare-ups in adults with FOP in a small multi-center, randomized, double-blind, placebo-controlled phase 2 trial [LUMINA-1 (NCT03188666) Di Rocco et al., 2023].

Patients were randomized to garetosmab or placebo. In Period-1, there was a trend for garetosmab to decrease HO versus placebo (24.6%), primarily driven by near complete prevention of new lesions. Flare- ups were significantly reduced. For placebo patients transitioning to garetosmab in Period-2, no patients developed new HO lesions. Garetosmab was associated with more adverse events than placebo: mild recurrent epistaxis, madarosis, and skin/soft tissue infections. Overall, the adverse events AEs were predominantly mild in severity. Five deaths (5/44; 11.4%) occurred either in Period-2 or the open-label extension. The deaths were associated with baseline disease severity in some, preexisting comorbidities in others and occurred following 8-16 doses (median: 15) of garetosmab in the open label/follow-up periods. Garetosmab reduced flare-ups and prevented new HO lesions in FOP patients. Although the reported side effects were mild to moderate, there was an unexpectedly high number of deaths for a small study. Five deaths (5 of 44; 11.4%) occurred in the open-label period. Although these were considered unlikely to be related to garetosmab, causality cannot be ruled out (Di Rocco et al., 2023).

References

Pignolo RJ, Baujat G, Hsiao EC, Keen R, Wilson A, Packman J, Strahs AL, Grogan DR, Kaplan FS. Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, Placebo- Controlled, Double-Blind Phase 2 Trial. J Bone Miner Res 37: 1891-1902, 2022

Pignolo RJ, Hsiao EC, Al Mukaddam M, Baujat G, Berglund SK, Brown MA, Cheung AM, De Cunto C, Delai P, Haga N, Kannu P, Keen R, Le Quan Sang KH, Mancilla EE, Marino R, Strahs A, Kaplan FS. Reduction of New Heterotopic Ossification (HO) in the Open-Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP). J Bone Miner Res 38: 381-394, 2023

Di Rocco M, Forleo-Neto E, Pignolo RJ, Keen R, Orcel P, Funck-Brentano T, Roux C, Kolta S, Madeo A, Bubbear JS, Tabarkiewicz J, Szczepanek M, Bachiller-Corral J, Cheung AM, Dahir KM, Botman E, Raijmakers PG, Al Mukaddam M, Tile L, Portal-Celhay C, Sarkar N, Hou P, Musser BJ, Boyapati A, Mohammadi K, Mellis SJ, Rankin AJ, Economides AN, Trotter DG, Herman GA, O’Meara SJ, DelGizzi R, Weinreich DM, Yancopoulos GD, Eekhoff EMW, Kaplan FS. Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial. Nat Med 29: 2615-2624, 2023

Featured

GUIDELINES HOME

INTRODUCTION

1. ABSTRACT

2. EXECUTIVE SUMMARY OF KEY PRACTICE POINTS

3. THE CLINICAL AND BASIC SCIENCE BACKGROUND OF FOP

4. THE PATHOLOGIC AND PATHOPHYSIOLOGIC-BASED TREATMENT OF FOP

5. SPECIAL MEDICAL CONSIDERATIONS IN FOP

6. CURRENT TREATMENT CONSIDERATIONS

7. CLASSES OF MEDICATIONS

8. EMERGENCY GUIDELINES FOR FIRST RESPONDERS, PHYSICIANS & DENTISTS

9. CONCLUSIONS

10. ACKNOWLEDGMENTS

11. DISCLOSURES

12. AUTHORS’ CONTACT INFORMATION

Civiane Chung

4. The Pathologic and Pathophysiologic-Based Treatment of FOP

4-1. Introduction

References

4-2. Corticosteroids in FOP

References

4-3. Cyclo-Oxygenase-2 (COX-2) Inhibitors & NSAIDs in FOP

References

4-4. Topical Analgesics in FOP

References

4-5. Mast Cell Inhibitors in FOP

References

4-6. Bisphosphonates in FOP

References

4-7. Off-Label Use of Potent Medications for Managing Inflammation in FOP

Imatinib for FOP:

Tofacitinib for FOP:

Anti-IL1 therapies for FOP (anakinra, canakinumab):

Other anti-inflammatory medications:

References

4-8. Muscle Relaxants in FOP

References

4-9. Chemotherapy Agents & Radiation Therapy in FOP

References

4-10. Bone Marrow Transplantation in FOP

References

4-11. Miscellaneous Agents & Approaches in FOP

References

4-12. Supportive Treatment in FOP

References

4-13. Definitive Therapeutic Targets in FOP

References

4-14. Clinical Trial Results in FOP

Palovarotene

Garetosmab

References

3. The Clinical and Basic Science Background of FOP

5. Special Medical Considerations in FOP

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