Oral administration of the growth hormone secretagogue MK-677 increases markers of bone turnover in healthy and functionally impaired elderly adults

Growth hormone (GH) stimulates osteoblasts in vitro and increases bone turn over and stimulates osteoblast activity when given to elderly subjects. Pro bably a major effect of GH on bone is mediated through stimulation of eithe r circulating or locally produced insulin-like growth factor I (IGF-I). We determined the effect of chronic administration of the GH secretagogue, MK- 677, on serum IGF-I and markers of bone turnover in 187 elderly adults (65 years or older) enrolled in three randomized, double-blind, placebo-control led clinical studies lasting 2-9 creeks. Urine was collected for determinat ion of N-telopeptide cross-links (NTXs), a marker of bone resorption, and b lood was collected for determination of serum osteocalcin and bone-specific alkaline phosphatase (BSAP), as bone formation markers, and serum IGF-I le vels pre- and post-treatment. Dose response data were Initially obtained in healthy elderly subjects who received oral doses of 10 mg or 25 mg of Mk-6 77 or placebo for 2 weeks (n = 10-12/group). Treatment with 10 mg and 25 mg of MK-677 for 2,weeks increased mean urine NTXs 10% and 17%, respectively (p < 0.05 vs. placebo, Additionally, 50 healthy elderly subjects received e ither placebo in = 20) for 4 weeks or 25 mg of MK-677 (n = 30) daily for 2 weeks followed by 50 mg daily for 2 weeks. MK-677 increased mean serum oste ocalcin by 8% (p < 0.05 vs. placebo). In both studies, MK-677 increased ser um IGF-I levels significantly (55-94%). Subsequently, the biological effect s of MK-677 were studied in 105 elderly subjects who met objective criteria for functional impairment. Subjects were randomized to receive oral doses of placebo for 9 weeks or either 5, 10, or 25 mg of MK-677 daily for an ini tial 2 weeks followed by 25 mg of MK-677 daily for the nest 7 weeks (n = 63 on MK-677 and rt = 28 on placebo completed 9 weeks of therapy), Treatment with MK-677 (all Mk-677 groups combined) for 9 weeks increased mean serum o steocalcin by 29.4% and BSAP by 10.4% (p < 0.001 vs. placebo) and mean urin ary NTS excretion by 22.6% (p < 0.05 vs. placebo), The change from baseline serum osteocalcin correlated with the change from baseline serum IGF-I in the MK-677 group (r = 0.37; p < 0.01), In conclusion, once daily dosing wit h MK-677, an orally active GH secretagogue, stimulates bone turnover in eld erly subjects based on elevations in biochemical markers of bone resorption and formation.