Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women

GH increases bone turnover and stimulates osteoblast activity. We hypothesi zed that administration of MK-677, an orally active GH secretagogue, togeth er with alendronate, a potent inhibitor of bone bone resorption, would main tain a higher bone formation rate relative to that seen with alendronate al one, thereby generating greater enhancement of bone mineral density (BMD) i n women with postmenopausal osteoporosis. We determined the individual and combined effects of MK-677 and alendronate administration on insulin-like g rowth factor I levels and biochemical markers of bone formation (osteocalci n and bone-specific alkaline phosphatase) and resorption [urinary N-telopep tide cross-links (NTx)] for 12 months and BMD for 18 months. In a multicenter, randomized, double blind, placebo-controlled, 18-month st udy, 292 women (64-85 yr old) with low femoral neck BMD were randomly assig ned in a 3:3:1:1 ratio to 1 of 4 daily treatment groups for 12 months: MK-6 77 (25 mg) plus alendronate (10 mg); alendronate (10 mg); MK-677 (25 mg); o r a double dummy placebo. Patients who received MK-677 alone or placebo thr ough month 12 received MK-677 (25 mg) plus alendronate (10 mg) from months 12-18. All other patients remained on their assigned therapy. All patients received 500 mg/day calcium. The primary results, except for BMD, are provided for month 12. MK-677, wit h or without alendronate, increased insulin-like growth factor I levels fro m baseline (39% and 45%; P < 0.05 vs, placebo). MK-677 increased osteocalci n and urinary NTx by 22% and 41%, on the average, respectively (P < 0.05 vs . placebo). MK-677 and alendronate mitigated the reduction in bone formatio n compared with alendronate alone based on mean relative changes in serum o steocalcin (-40% vs. -54%; P < 0.05, combination vs. alendronate) and reduc ed the effect of alendronate on resorption (NTx) as well (-52% us. -61%; P < 0.05, combination vs. alendronate). MK-677 plus alendronate increased BMD at the femoral neck (4.2% vs. 2.5% for alendronate; P < 0.05). However, si milar enhancement was not seen with MK-677 plus alendronate in BMD of the l umbar spine, total hip, or total body compared with alendronate alone. GH-m ediated side effects were noted in the groups receiving MK-677, although ad verse events resulting in discontinuation from the study were relatively in frequent. In conclusion, the anabolic effect of GH, as produced through the GH secretagogue MK-677, attenuated the indirect suppressive effect of alen dronate on bone formation, but did not translate into significant increases in BMD at sites other than the femoral neck. Although the femoral neck is an important site for fracture prevention, the lack of enhancement in bone mass at other sites compared with that seen with alendronate alone is a con cern when weighed against the potential side effects of enhanced GH secreti on.