EFFECTS OF RHIGF-I ADMINISTRATION ON BONE TURNOVER DURING SHORT-TERM FASTING

Insulin-like growth factor-I (IGF-I) is a nutritionally dependent bone trophic hormone which stimulates osteoblast function and collagen synthesis in vivo and in vitro, We hypothesized that in the fasting state, IGF-I levels would decline significantly and would establish a model in which we could investigate the effects of IGF-I administration on bone turnover, We therefore studied 14 normal women ages 19-33 (mean, 24+/-4 [SD] years) during a complete 10-d fast, After 4 d of fasting, subjects were randomized to receive rhIGF-I or placebo subcutaneously twice a day for 6 d, Bone turnover was assessed using specie markers of formation (osteocalcin and type I procollagen carboxyl-terminal propeptide [PICP]) and resorption (pyridinoline, deoxypyridinoline, type I collagen crosslinked N-telopeptide [N-telopeptide] and hydroxyproline), Serum levels of PICP and osteocalcin decreased from 143+/-52 to 60+/-28 ng/ml (P = 0.001) and from 7.6+/-5.4 to 4.2+/-3.1 ng/ml (P = 0.001) respectively with 4 d of fasting, Urinary excretion of pyridinoline and deoxypyridinoline decreased from 96+/-63 to 47+/-38 nmol/mmol creatinine (P < 0.05) and from 28+/-17 to 14+/-11 nmol/mmol creatinine (P ( 0.05) respectively, Mean IGF-I levels decreased from 310+/-81 to 186+/-78 ng/ml (P = 0.001), In the second part of the experimental protocol, serum osteocalcin and PICP levels increased 5- and 3-fold, respectively with rhIGF-I administration and were significantly elevated compared with the placebo group at the end of treatment (20.9+/-17.3 vs, 5.9+/-6.4 ng/ml for osteocalcin [P < 0.05] and 188+/-45 vs, 110+/-37 ng/ml for PICP [P < 0.05]), In contrast, all four markers of bone resorption, including urinary pyridinoline, deoxypyridinoline, N-telopeptide and hydroxyproline were unchanged with rhIGF-I administration. This report is the first to demonstrate that bone turnover falls rapidly with acute caloric deprivation in normal women, RhIGF-I administration uncouples bone formation in this setting by significantly increasing bone formation, but not resorption, These data suggest a novel use of rhIGF-I to selectively stimulate bone formation in states of undernutrition and low bone turnover.