ossificans progressiva (FOP) is among the most disabling conditions known to

ossificans progressiva (FOP) is among the most disabling conditions known to humankind. stromal cells “is definitely associated with major medical improvements in a patient with fibrodysplasia ossificans progressiva (FOP).”(4) Gatti and colleagues describe a 48-year-old female with FOP characterized by continuous flares that she was partially controlling with prednisone. She required rosiglitazone (in the beginning Wortmannin 4 mg and then 8 mg daily) for 14 weeks. No fresh flares were observed during rosiglitazone therapy compared with five episodes observed during the earlier yr 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 probably in association with small doses of prednisone is definitely associated with important medical improvements in individuals with FOP.”(4) Rosiglitazone is an antidiabetic Cav1.2 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 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 offers adverse cardiovascular side effects including an increased risk of heart attacks and death from all cardiovascular causes.(8) Rosiglitazone Wortmannin 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 Wortmannin 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 Wortmannin 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 tests of rosiglitazone in pet types of FOP is essential to see whether there could be a physiologic basis for a restricted.