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We used multiple linear regression models to determine the independent impact of total and intact IGFBP-3 (in quartiles) and PAPP-A2 (% total IGF-I) on 25(OH)D levels. Dependent variables were predefined as 25(OH)D. After adjusting for age, sex, race, sun exposure index, BMI, season of blood draw, and waist-to-hip ratio, a positive linear association was observed between 25(OH)D and both total IGFBP-3 and intact IGFBP-3. However, only intact IGFBP-3 remained significant after adjustment for multiple variables, with a dose-response curve indicating that for every 1 unit increase in intact IGFBP-3, there is a.9 ng/mL increase in 25(OH)D (3.8 nmol/L) (Table 2). In addition, 25(OH)D levels were also significantly lower in those with higher PAPP-A2 (% total IGF-I), although the dose-response curve was only linear for total IGFBP-3. PAPP-A2 (% total IGF-I) and total IGFBP-3 were inversely correlated with each other (Pearson r = −0.48; p = 0.001). Our findings suggest that intact IGFBP-3 and PAPP-A2 (% total IGF-I) independently predict 25(OH)D levels, and that intact IGFBP-3 has a higher statistical association with 25(OH)D than PAPP-A2. This is novel and possibly clinically important, considering PAPP-A2 levels are easily measured and PAPP-A2 levels are directly proportional to the percentage of free IGF-I, a metabolically active form that impacts many of the biological actions of IGF-I in the body, including bone accrual. Thus, if intact IGFBP-3 is more closely correlated with 25(OH)D than PAPP-A2 (% total IGF-I) in free IGF-I levels, a high intact IGFBP-3 level could be indicative of lower 25(OH)D levels in free IGF-I.
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