GH increases bone turnover and stimulates osteoblast activity. We hypothesized that administration of
MK-677, an orally active GH
secretagogue, together with
alendronate, a potent inhibitor of
bone resorption, would maintain a higher bone formation rate relative to that seen with
alendronate alone, thereby generating greater enhancement of bone mineral density (BMD) in women with
postmenopausal osteoporosis. We determined the individual and combined effects of
MK-677 and
alendronate administration on
insulin-like growth factor I levels and
biochemical markers of bone formation (
osteocalcin and bone-specific
alkaline phosphatase) and resorption [urinary
N-telopeptide cross-links (NTx)] for 12 months and BMD for 18 months. In a multicenter, randomized, double blind, placebo-controlled, 18-month study, 292 women (64-85 yr old) with low femoral neck BMD were randomly assigned in a 3:3:1:1 ratio to 1 of 4 daily treatment groups for 12 months:
MK-677 (25 mg) plus
alendronate (10 mg);
alendronate (10 mg);
MK-677 (25 mg); or a double dummy placebo. Patients who received
MK-677 alone or placebo through 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, with or without
alendronate, increased
insulin-like growth factor I levels from baseline (39% and 45%; P < 0.05 vs. placebo).
MK-677 increased
osteocalcin 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 formation compared with
alendronate alone based on mean relative changes in serum
osteocalcin (-40% vs. -54%; P < 0.05, combination vs.
alendronate) and reduced the effect of
alendronate on resorption (NTx) as well (-52% vs. -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, similar enhancement was not seen with
MK-677 plus
alendronate in BMD of the lumbar spine, total hip, or total body compared with
alendronate alone. GH-mediated side effects were noted in the groups receiving
MK-677, although adverse events resulting in discontinuation from the study were relatively infrequent. In conclusion, the
anabolic effect of GH, as produced through the GH
secretagogue MK-677, attenuated the indirect suppressive effect of
alendronate 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 concern when weighed against the potential side effects of enhanced GH secretion.