Oral Administration of the Growth Hormone Secretagogue MK-677 Increases Markers of Bone Turnover in Healthy and Functionally Impaired Elderly Adults

Abstract

Growth hormone (GH) stimulates osteoblasts in vitro and increases bone turnover and stimulates osteoblast activity when given to elderly subjects. Probably a major effect of GH on bone is mediated through stimulation of either 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-controlled clinical studies lasting 2-9 weeks. Urine was collected for determination of N-telopeptide cross-links (NTXs), a marker of bone resorption, and blood was collected for determination of serum osteocalcin and bone-specific alkaline phosphatase (BSAP), as bone formation markers, and serum IGF-I levels 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-677 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 either placebo (n = 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 osteocalcin by 8% (p < 0.05 vs. placebo). In both studies, MK-677 increased serum IGF-I levels significantly (55-94%). Subsequently, the biological effects 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 initial 2 weeks followed by 25 mg of MK-677 daily for the next 7 weeks (n = 63 on MK-677 and n = 28 on placebo completed 9 weeks of therapy). Treatment with MK-677 (all MK-677 groups combined) for 9 weeks increased mean serum osteocalcin by 29.4% and BSAP by 10.4% (p < 0.001 vs. placebo) and mean urinary NTX 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 with MK-677, an orally active GH secretagogue, stimulates bone turnover in elderly subjects based on elevations in biochemical markers of bone resorption and

Association of Plasma Des-acyl Ghrelin Levels with CKD

“…DG has been reported to be the "inactive" degradation product of AG but recent studies suggest that DG may itself have pleiotropic biologic activities, including opposing actions to AG (38)(39)(40)(41)(42)(43). In normal individuals, DG and AG levels decrease in parallel on feeding, but the ratio of DG/AG remains constant (22).…”

Molecular Endocrinology and Physiology of the Aging Central Nervous System

“…Chronic activation of the GHS-R by the small molecule agonist MK-0677 sustained rejuvenation of the GH/IGF-I axis in elderly subjects (25,38,(277)(278)(279)(280). This is accompanied by increased lean body mass and increased bone mass (38, [281][282][283]. In addition to beneficial effects on peripheral tissues, restoring young adult levels of GH and IGF-I is anticipated to be neuroprotective (213,284).…”

Immune Enhancing Effect of a Growth Hormone Secretagogue

“…It is an analog of MK677, which was in clinical trials (11,16). It was dissolved in water and given to the mice daily by gavage.…”

“…Indeed, encouraging results from preclinical and clinical studies have indicated that GHS are efficacious in facilitating muscle development and mobilization in dogs whose hind legs were surgically immobilized (15). In a controlled clinical trial of elderly individuals, it improved the well being of the treated group (16). Markers of bone turnover were elevated in the 12-wk trial of these elderly people, suggesting that GHS will strengthen bones in the elderly.…”