Type VI Osteogenesis imperfecta: effect of plasma transfusion on bone metabolism

Background: Type VI Osteogenesis Imperfecta (OI) is caused by homozygous or compound heterozygous null mutations in SERPINF1 gene, coding for pigment-epithelium derived factor (PEDF). Null SERPINF1 mutant patients appear healthy at birth and free from fractures until after 6 months of age, suggesting a protective effect of circulating maternal PEDF during fetal development. Moreover, unaffected asymptomatic heterozygotes parents, have PEDF circulating levels of about 1 mu g/mL, lower than normal concentrations and sufficient for a normal bone metabolism/development. This study aims to evaluate efficacy and safety of plasma administration and provide a minimum amount of PEDF similar to the levels found in heterozygotes in patients affected by type VI OI. Materials and methods: Ten patients (5-18 yrs old) were eligible for the study. Pharmaceutical grade plasma (Plasmasafe) (12-15 mL/Kg) was administered e.v. every month for 6 months. At baseline, before each plasma transfusion, and 6 months after the last plasma transfusion, PEDF, bone metabolic markers (Ca, P, 25-OH Vitamin D, PTH, bone ALP, osteocalcin, P1NP, DKK1, sclerostin, b CTX), iron and ferritin were determined. PEDF, DKK1, Sclerostin and P1NP were repeated 1, 2 and 7 days after first plasma administration to see the effective bloodstream increase and evaluate the short-term response. Results: Of the initial 10 patients, only 4 completed the study. PEDF (5 patients) showed an increase from <0.045 mu g/mL before infusion to 1,357 +/- 0.27 mu g/mL at day 1, returning to <0.045 mu g/mL from day 2 and thereafter. We found a significant decrease in DKK1 (p=0.05) and a non-significant increase in P1NP levels the day after the first transfusion, with a rapid return to previous levels. Biochemical markers of bone turnover and BMD did not show significant changes during the study. Conclusions: Plasma infusion at doses and intervals used in our study produced only a slight and not lasting increase in PEDF circulating levels, not useful to modify bone metabolic markers and BMD. The slight decrease in DKK1 could be an acute effect due to the administration of PEDF, confirming the relationship between PEDF and the Wnt/beta-catenin signaling pathway.