Viewing FOP through rosi-colored glasses

Fibrodysplasia ossificans progressiva (FOP) is one of the most disabling conditions known to humankind. Children with FOP succumb to episodes of inflammation-induced ectopic skeletogenesis that transform skeletal muscles and soft connective tissues into an immobilizing second skeleton of heterotopic bone.(1) Removal of heterotopic bone leads to additional episodes of new bone growth.(1) The recent discovery of the mutated gene that causes FOP,(2) an extraordinarily specific mutation in a highly conserved bone morphogenetic protein (BMP) receptor,(2) immediately predicted the mutant receptor and downstream pathway as an ideal target for drug therapy.(3) A recent case report by Gatti and colleagues from the University of Verona approaches the problem from a different perspective.(4) The report claims that rosiglitazone, an anti-inflammatory and antidiabetic agent that alters the fate of marrow stromal cells, “is associated with major clinical improvements in a patient with fibrodysplasia ossificans progressiva (FOP).”(4) Gatti and colleagues describe a 48-year-old woman with FOP characterized by continuous flares that she was partially controlling with prednisone. She took rosiglitazone (initially 4 mg and then 8 mg daily) for 14 months. No new flares were observed during rosiglitazone therapy compared with five episodes observed during the previous year while she was on 20 to 25 mg of prednisone daily. “The steroid dose was progressively lowered to 5 mg daily, the skin became softer, and the articular mobility improved impressively,” according to the authors, who concluded that “rosiglitazone therapy, possibly in association with small doses of prednisone, is associated with important clinical improvements in patients with FOP.”(4) Rosiglitazone is an antidiabetic drug that is useful for the treatment of type 2 diabetes.(5) In addition, it appears to have a potent anti-inflammatory effect as well as an adverse effect on the skeleton.(6,7) Gatti and colleagues postulate that the adverse skeletal effects might be exploited therapeutically in diseases such as FOP.(4) In 2005, major safety concerns emerged about the use of rosiglitazone: Rosiglitazone has adverse cardiovascular side effects, including an increased risk of heart attacks and death from all cardiovascular causes.(8) Rosiglitazone causes osteoporosis and decreased skeletal strength that is reminiscent of aged bone.(6) Pathologic fractures of long bones occur with chronic rosiglitazone use.(7) Rosiglitazone is not approved for use in children. There are concerns about the interpretation of data in the case report by Gatti and colleagues. Specifically: The authors conclude that “rosiglitazone therapy is associated with important clinical improvements in patients with FOP.” However, the data were for drug treatment in a single patient, not in multiple patients, and there were no controls. “Flare-ups of FOP are sporadic and unpredictable, and there is great individual variability in the rate of disease progression. Several large studies on the natural history of FOP have conrmed that it is impossible to predict the occurrence, duration, or severity of an FOP are-up.”(9) Thus the clinical course of a single individual cannot be used to assess therapeutic efcacy. The rarity of FOP and the unpredictable nature of the condition make it extremely difcult to assess any therapeutic intervention, a fact recognized as early as 1918 by Jules Rosenstirn, who noted: The disease was attacked with all sorts of remedies and alternatives for faulty metabolism; every one of them with more or less marked success observed solely by its original author, but pronounced a complete failure by every other follower. In many cases, the symptoms of the disease disappear often spontaneously, so the therapeutic effect (of any treatment) should not be unreservedly endorsed.(10) 4. Exacerbations and remissions are common in FOP and often occur spontaneously. Almost every adult with FOP has experienced a remission while taking a medication that was later proven useless.(9) 5. It is not possible from the data presented to separate the effects, if any, of rosiglitazone from those of chronic prednisone use. Although high-dose, long-term prednisone use is not recommended for the treatment of FOP, its use in animal models is effective in decreasing heterotopic bone.(9) 6. It is possible that the anti-inammatory effect of rosiglitazone could have participated in the quiescence of are-ups noted in this patient. Alternatively, the attributed effect might have been spontaneous and unrelated to the medication or possibly a delayed effect of the chronic prednisone use.(9) Despite concerns associated with chronic rosiglitazone use and the biases inherent in the case report, the observation in this single patient is sufficiently interesting to prompt further investigation in emerging animal models of FOP.(2) Ultimately, these studies must separate the postulated effects of rosiglita-zone from the known effects of prednisone. In vivo testing of rosiglitazone in animal models of FOP is necessary to determine if there may be a physiologic basis for a limited use in FOP, considering its safety profile. FOP is a catastrophic disease with unimaginable human suffering. Affected individuals and their families are vulnerable to hype and are suspicious of inflated claims. In our opinion, rosiglitazone should not be used in FOP patients without investigational review board approval. At present, we favor in vivo studies in emerging animal models of FOP. Extreme caution is necessary until animal testing is completed, and it can be determined whether or not there is a physiologic basis for rosiglitazone use in treating or preventing FOP flare-ups. In summary, the key questions remain: Does rosiglitazone reduce or prevent FOP are-ups? If so, is rosiglitazone safe enough to warrant its chronic use in patients with FOP? The simple answer to both questions is, “Perhaps, but we do not know.” It is prudent to get real answers before viewing FOP through rosi-colored glasses.