EFFECTS OF SHORT-TERM RECOMBINANT HUMAN INSULIN-LIKE GROWTH-FACTOR-I ADMINISTRATION ON BONE TURNOVER IN OSTEOPENIC WOMEN WITH ANOREXIA-NERVOSA

Significant osteoporosis affects over half of all women with anorexia nervosa (AN). The mechanisms of bone loss in this condition are not kn own, and estrogen administration alone has not been shown to prevent b one loss. Insulin-like growth factor I (IGF-I), a nutritionally depend ent bone trophic hormone, is known to stimulate osteoblast function an d collagen synthesis in vivo and in vitro. We hypothesized that short term administration of recombinant human IGF-I (rhIGF-I) would increas e bone turnover in young women with AN. We studied 23 women, aged 18-2 9 yr (mean +/- SD, 23 +/- 4 yr) with AN. Spinal bone density was signi ficantly reduced compared to that in age-matched controls (0.85 +/- 0. 11 vs. 1.19 +/- 0.12 g/cm(2) by dual energy x-ray absorptiometry; P < 0.001) and was below the normal mean in 54% of the women. Patients wer e randomized to receive rhIGF-I (100 or 30 mu g/kg) or placebo sc twic e a day for 6 days. Bone turnover was assessed at baseline and after 3 and 6 days of treatment using two markers of bone formation [osteocal cin (OC) and type I procollagen carboxyl-terminal propeptide (PICP)] a nd three specific markers of bone resorption [pyridinoline (PYRX), deo xypyridinoline (DPYRX), and N-telopeptide (NTX)]. Serum OC was reduced significantly (P < 0.001) in women with AN compared to normal premeno pausal women (5.4 +/- 3.8 vs. 8.6 +/- 4.5 ng/mL) and correlated with p ercent fat mass (r = 0.60; P < 0.01) and body mass index (r = 0.50; P < 0.05). Markers of bone resorption were elevated significantly compar ed to normal levels [DPYRX, 18.2 +/- 7.0 vs. 11.4 +/- 5.2 nmol/mmol cr eatinine, (P < 0.001); NTX, 53.5 +/- 22.5 vs. 36.5 +/- 14.6 nmol BCE/m mol creatinine (P < 0.01)]. IGF-I levels were relatively low at baseli ne compared to those in age-matched controls (203 +/- 93 vs. 262 +/- 8 4 ng/mL; P < 0.01) and increased to 673 +/- 268 ng/mL [P < 0.05; 100 m u g/kg twice daily (BID)] and 545 +/- 255 ng/mL (P < 0.05; 30 mu g/kg BID). During short term administration of rhIGF-I at a dose of 100 mu g/kg BID, there was a significant (P < 0.05) increase in markers of bo ne formation, as assessed by both PICP (147 +/- 33 to 303 +/- 187 ng/m L) and OC (5.3 +/- 3.8 to 10.9 +/- 7.4 ng/mL). There was also a signif icant (P < 0.05) increase in markers of bone resorption as assessed by PYRX (51.0 +/- 16.6 to 87.1 +/- 8.2 nmol/mmol creatinine) and DPYRX ( 17.3 +/- 4.5 to 26.3 +/- 3.7 nmol/mmol creatinine). The group randomiz ed to receive short term administration of rhIGF-I at a dose of 30 mu g/kg BID demonstrated a significant (P < 0.05) increase in PICP (110.9 +/- 47.0 to 134.8 +/- 43.2 ng/mL) and an insignificant increase in OC levels (4.5 +/- 3.2 to 6.8 +/- 5.9 ng/mL). However, markers of bone r esorption were unchanged during rhIGF-I administration at this dose. S erum PTH and serum and urinary calcium were unchanged in both treatmen t groups compared to placebo levels. These data demonstrate that young women with anorexia nervosa have decreased markers of bone formation and increased bone resorption. This is the first demonstration that sh ort term rhIGF-I administration increases markers of bone turnover in severely osteopenic women with AN. The effects of short term rhIGF-I o n bone turnover are dose dependent. At a dose of 100 mu g BID, rhIGF-I administration significantly stimulated both markers of bone formatio n and bone resorption. At a dose of rhIGF-I of 30 mu g BID, there was an increase in one marker of bone formation, PICP, without a change in markers of bone resorption. Further studies are required to determine whether chronic administration of rhIGF-I can affect bone mass in you ng women with profound osteopenia due to anorexia nervosa.