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Original Studies |
Merck Research Laboratories (M.G.M., K.C., J.C., S.R., D.K., B.J.G.), Rahway, New Jersey 07065-0900; San Diego Endocrine and Medical Clinic (S.W.), San Diego, California 92108; Oregon Osteoporosis Center (M.M.), Portland, Oregon 07213; Rush-Presbyterian St. Lukes Medical Center (T.S.), Chicago, Illinois 60612
Address all correspondence and requests for reprints to: M. Gail Murphy, M.D., Merck Research Laboratories, Building 10, Sentry Parkway, Bluebell, Pennsylvania 19422. E-mail: gail_murphy{at}merck.com
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Abstract |
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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.
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Introduction |
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Human aging is associated with declining serum concentrations of GH and IGF-I (10, 11, 12). This reduction may contribute to the decrease in bone mass that accompanies normal aging (13). Recombinant human GH (rhGH) increases markers of bone turnover, suggesting an overall increase in bone remodeling, in healthy and osteoporotic elderly women and GH-deficient (GHD) adults (14, 15, 16, 17, 18, 19). Increased bone turnover has also been shown in GHD adults treated with rhGH based on histomorphometric measures (20). Although stimulation of skeletal dynamics did not result in increased trabecular bone volume, cortical thickness increased significantly. Whereas GH alone decreased bone mineral density (BMD) in GHD adults after 1 yr of treatment (21), continued treatment with rhGH increased BMD by 18 months in these patients (22). Initial decreases in bone mass after GH administration were ascribed to the hormone’s effect to accelerate both sides of the bone balance equation, formation and resorption, whereas the effect with continued administration was a net anabolic increase in bone density (23).
Despite these effects in GHD individuals, GH administration has not consistently increased bone mass in the elderly (24, 25, 26). In one study, GH given for 6 months increased lumbar spine density by 1.6% in men older than 60 yr of age (24). In another study, administration of GH for 6 months increased bone mineral content by 0.9% in elderly men, although the researchers described the clinical consequence of this increase as unknown (25). Furthermore, administration of rhGH for 12 months to frail elderly men and women resulted in increased bone turnover with no increase (at an average daily dose of 0.003 mg/kg·day or less) or a decrease (at an average daily dose of >0.006 mg/kg·day) in BMD (26).
MK-677 is an orally active nonpeptide spiropiperidine previously demonstrated to be functionally indistinguishable in vitro and in vivo (27) from GH-releasing peptide, a relatively selective GH secretagogue (28, 29, 30). MK-677 enhances the pulsatile release of GH, resulting in sustained elevations in IGF-I, and is well tolerated after oral administration in animals, healthy young men, and older men and women (27, 31, 32, 33). Furthermore, administration of MK-677 to elderly women for 9 weeks increased serum osteocalcin, a marker of bone formation, on the average by 29%, and urinary N-telopeptide cross-links (NTx), a marker of bone resorption, on the average by 25% (34).
Alendronate is a potent nitrogen-containing bisphosphonate (35, 36) that increases bone mass (37, 38) and reduces the incidence of vertebral and other fractures, including those of the hip, in women with postmenopausal osteoporosis (6, 37). Alendronate quickly acts to decrease bone resorption, reaching a plateau effect within 3 months based on a reduction in urinary NTx (39). This decrease in bone resorption is followed by a subsequent secondary reduction in bone formation, which plateaus within 3–6 months, as shown by a reduction in bone formation markers such as osteocalcin and bone-specific alkaline phosphatase (BSAP). This sequence of events is anticipated due to the well established coupling of bone resorption and formation (40). It was hypothesized that combining administration of a net anabolic agent such as a GH secretagogue and a bone resorption inhibitor such as alendronate might allow uncoupling of the indirect suppressive influence of alendronate on bone formation. If administration of MK-677 with alendronate resulted in less suppression of bone formation and similar effects on bone resorption relative to the effects of alendronate alone, combination treatment may increase bone mass beyond that seen with alendronate alone. This would be expected to result in a decreased risk of fractures associated with osteoporosis.
We determined therefore the individual and combined effects of chronic administration of MK-677 and alendronate on IGF-I levels, biochemical markers of bone formation and resorption, and BMD in women with postmenopausal osteoporosis. The percent change from baseline in serum osteocalcin and urinary NTx were the primary and secondary end points of the study, respectively. The percent change from baseline of the femoral neck BMD was the prespecified key BMD end point based on the balance of cortical and trabecular bone at this site.
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Subjects and Methods |
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Two-hundred and ninety-two women (mean age, 72.1 yr; range, 64–85 yr) were selected for participation at 10 study centers. To be eligible for the study, subjects had to be postmenopausal (without menses for at least 4 yr), with a femoral neck BMD at least 2.0 SD below the mean peak value for healthy young women (<0.695 g/cm2 as measured by Hologic, Inc., Waltham, MA; model 1000W, 2000, or 4500), but no more than 3.0 SD below the age-specific mean. Other than osteoporosis, the patients were in good health. Patients with any fracture attributed to osteoporosis or any disease or drug therapy (including any GH, bisphosphonate, fluoride, glucocorticoid, or estrogen therapy within the past 6 months or bisphosphonate treatment at any time) potentially affecting bone metabolism were excluded. The following were additional exclusion criteria: abnormal renal function, elevated fasting glucose, a history of cancer or major upper gastrointestinal mucosal erosive disease, or low 25-hydroxyvitamin D levels. The women were recruited by direct mailings or telephone contacts and advertisements in the media. Ethical review committee approval was obtained at each participating site, and written informed consent was obtained from each subject.
Study design
This was a multicenter, randomized, double blind,
placebocontrolled, parallel group, 6-month study with planned
extensions from 6–12 and 12–18 months. After a 2-week, single blind
placebo/calcium carbonate (OSCAL 500, Marion Merrell Dow, Kansas City,
MO) run-in period, 292 women were randomly assigned in a 3:3:1:1 ratio
to 1 of 4 daily treatment groups (Table 1
). The 4 treatment groups from months
0–12 were MK-677 (25 mg) plus alendronate (10 mg);
alendronate (10 mg); MK-677 (25 mg); and double dummy
placebo. Patients who received MK-677 or placebo through
month 12 received MK-677 (25 mg) plus alendronate (10 mg)
from months 12–18 while retaining the study blind (Table 1). Patients
in the other two groups continued their assigned therapy.
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Biochemical analyses
Urine (fasting second morning voided specimen) chemistry values (N-telopeptide cross-links and creatinine), special serum bone biochemistry assessments (osteocalcin and bone-specific alkaline phosphatase), and hormones (including IGF-I) were obtained at baseline (after 2-week placebo run-in, before study drug) and at months 1, 3, 6, 9, and 12 of treatment. The primary comparison of biochemical markers of bone turnover was after 12 months of treatment, allowing comparison among the four original treatment groups (i.e. combination, alendronate, MK-677, or placebo).
Serum IGF-I was measured by a competitive binding RIA after acid-ethanol extraction (Endocrine Sciences, Inc., Tarzana, CA). At a mean serum concentration of approximately 36.6–40.5 nmol/L, the within- and between-assay coefficients of variation (CVs) were 5.9% and 8.2%, respectively.
Osteocalcin was measured using an immunoradiometric assay (CIS International, Pacific Biometrics, Seattle, WA) with interassay CVs of 4.3% and 5.5% at serum concentrations of 1.5 and 3.4 nmol/L, respectively. BSAP was measured using an immunoradiometric assay (Tandem-R Ostase, Hybritech, Inc., San Diego, CA) with an interassay CV of 7.4%. The manufacturer reports these values in mass units; this is the standard unit of expression in medical literature for BSAP. NTx were measured using the Osteomark assay from Ostex International, Inc. (Seattle, WA), with an interassay CV of 4.0% and are reported after correction for creatinine [NTx/Cr, nanomoles of bone collagen equivalent (BCE) per mmol creatinine].
BMD measurements and radiographic assessment
BMDs of the femoral neck, hip, lumbar spine, and total body were measured by dual energy x-ray absorptiometry using Hologic, Inc., model 1000W, 2000, or 4500. BMD was determined twice (femoral neck and lumbar spine) or once (total body) at baseline and after 3, 6, 9, 12, and 18 months of treatment. The primary comparison among treatments for BMD was after 18 months of treatment to allow for the maximal duration of treatment with MK-677/alendronate and alendronate alone. A common, standardized procedure for patient positioning and utilization of software was incorporated into the QA manual procedures provided by the central QA center. The baseline scan was evaluated before follow-up hip scan. Patient positioning was duplicated as closely as possible, and identical scan parameters were used. As the scan was acquired, the identical starting point and femur positioning used at baseline were verified. If the match of baseline and follow-up acquisitions was not optimal, then the patient was repositioned or rescanned. Internal dual energy x-ray absorptiometry calibration was maintained at each center, and calibration across centers was performed using Hologic, Inc., spine and linearity phantoms. Hologic, Inc., Medical Data Management Services was responsible for handling all aspects of quality assurance for BMD measurements, including assessment of consistency of acquisition, analysis, and data management at the study sites without knowledge of treatment assignment. Lateral thoracic and lumbar spine radiographs were evaluated at each center for the presence of prevalent or incident vertebral fractures at baseline and after 12 and 18 months of treatment. Radiographic fractures were defined as an x-ray report from an expert reader noting one or more definite fractures or as a 20% or more decrease in the height of a vertebral body and at least a 4-mm decrease in vertebral height.
Assessment of treatment safety
Patients were questioned about intercurrent health problems at each visit. Standard clinical evaluations and laboratory analyses, including hematological and chemistry values, were performed at least every 6 weeks during the first 9 months of treatment and every 3 months thereafter. Physical examinations were performed at baseline and after 12 and 18 months of treatment. Radiographs were obtained during the study if needed to assess a clinical syndrome consistent with fracture. All adverse events (including clinical reports of fracture) were recorded by the physician investigator, who rated each event as to whether it appeared causally related to the study drug. Study drug referred collectively to any combination of MK-677/MK-677 placebo, alendronate/alendronate placebo, and calcium supplement.
Statistical methods
The biochemical markers included osteocalcin (primary end point), urine NTx (secondary end point), and BSAP. Data were transformed to ln (fraction of baseline) for the analysis and backtransformed to percent change from baseline for presentation. The analysis included the effects of the four treatments on femoral neck BMD (prespecified key BMD end point) as well as lumbar spine, total hip, and total body BMD. The percent change from baseline was analyzed.
The percent change from baseline was analyzed with ANOVA with factors for the effect of center, treatment, and treatment by center interaction. If the P value from the F test for the interaction effect was greater than 0.1, the interaction term was dropped from the ANOVA model before assessment of the treatment effect. Also before assessment of the treatment effect, appropriate diagnostic tests were performed to ensure that the data conformed to the statistical assumptions of common variance and normality of distribution. Patients who completed 18 months of the study and had valid BMD measurements at baseline and month 18 were included in the analysis of the change from baseline BMD to month 18. A per protocol approach was taken, which excluded data from patients with serious protocol deviations and made no attempt to replace missing values. The per protocol analysis was specified because it provided the best evaluation of the scientific model underlying the protocol. Comparisons were accomplished using the t test computed with the least square means (LSMEANS) and root mean squared error provided by SAS PROC GLM. Data are reported as the mean ± SE. There was 80% power (I = 0.05, by two-tailed test) with a sample size of 60 patients in the MK-677/alendronate treatment group and 60 patients in the alendronate alone treatment group to detect between group differences from baseline in osteocalcin, NTx, femoral neck BMD, and lumbar spine BMD of 17, 9, 2.4, and 2.0 percentage points, respectively.
Accounting for patients in the analysis
Four patients were excluded from the 18-month analysis of BMD data due to new-onset concurrent therapy including thyroid, estrogen, and steroid therapy. Patients who completed 12 months of the study and had bone turnover marker measurements at baseline and month 12 were included in the analysis of the change from baseline to month 12. Four patients were excluded from the latter analysis due to extended periods off study drug (failure to take >75% of doses, as prespecified in the data analysis plan), and seven patients were excluded due to new-onset concurrent therapy or missing biochemical marker data at the 12 month point. All patients with available data were included in the safety analysis.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. There were no
significant differences for subject demographics, IGF-I, bone turnover
markers, or BMD baseline values among the treatment groups.
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IGF-I (up to 12 months)
IGF-I levels were used as a surrogate for monitoring the GH
secretory stimulus of MK-677. MK-677
administered with or without alendronate for 12 months increased IGF-I
levels to approximately 20.9 nmol/L (i.e. increased from
baseline by approximately 40%; P < 0.05
vs. placebo; Fig. 1 and Table 3). As expected, alendronate alone had no effect on serum IGF-I levels,
nor did alendronate influence the stimulatory effect of
MK-677 on serum IGF-I (Table 3). There appeared to be a slight
attenuation of the increase in IGF-I over the 12-month experimental
period (Fig. 1).
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Serum osteocalcin and BSAP levels were used as surrogates for
monitoring the effect of MK-677 and alendronate, alone and
in combination, on bone formation. MK-677 administered for
12 months (Fig. 2) increased osteocalcin
to approximately 5.7 nmol/L (i.e. increased from baseline by
approximately 22%; P < 0.001 vs. placebo;
Fig. 2 and Table 3
). MK-677 administered for 12 months
(Fig. 2) increased BSAP to approximately 16 µg/L (i.e.
increased from baseline by approximately 17%; P <
0.05 vs. baseline, but NS vs. placebo; Fig. 2 and
Table 3). There appeared to be a slight attenuation of the increase in
osteocalcin and BSAP over the 12-month administration of
MK-677 alone (Fig. 2).
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and
Table 3). MK-677 plus alendronate significantly decreased
osteocalcin and BSAP, respectively, to approximately 2.9 nmol/L and 8.5
µg/L (i.e. decreased from baseline by approximately 40%
and 32%; P < 0.05 vs. placebo; Fig. 2 and
Table 3). As noted in Fig. 2, serum osteocalcin and BSAP decreased
significantly throughout the first year with alendronate in the
presence or absence of MK-677. Of note, the suppression in
osteocalcin and BSAP was less in the group that received combination
treatment compared with the group receiving alendronate (-40.2%
vs. -53.9% for osteocalcin and -32.7% vs.
-40.7 for BSAP; P < 0.05; Fig. 2A). The nadir of
response was reached within 6–12 months of administration of
alendronate alone. The time course of change from baseline for markers
of bone formation was not different whether alendronate was given with
or without MK-677.
Urinary NTx/Cr levels were used as a surrogate for monitoring the
effect of MK-677 and alendronate, alone and in
combination, on bone resorption. MK-677 administered for
12 months (Fig. 2) increased NTX to approximately 65 nmol BCE/mmol Cr
(i.e. increased from baseline by approximately 41%;
P < 0.05 vs. placebo; Fig. 2 and Table 3).
There appeared to be a slight attenuation of the increase in NTX over
the 12-month administration of MK-677 alone (Fig. 2).
As expected, alendronate alone significantly decreased NTx to
approximately 17 nmol BCE/mmol Cr (i.e. decreased from
baseline by approximately 61%; P < 0.05
vs. placebo; Fig. 2 and Table 3). MK-677 plus
alendronate significantly decreased NTx to approximately 21 nmol
BCE/mmol Cr (i.e. decreased from baseline by approximately
52%; P < 0.05 vs. placebo; Fig. 2 and
Table 3). As noted in Fig. 2, NTX decreased significantly throughout
the first year with alendronate in the presence or absence of
MK-677. Administration of MK-677 and
alendronate slightly reduced the effect of alendronate on urinary
NTx/Cr, a marker of bone resorption (-51% vs. -62%,
P < 0.05; Fig. 2C). Of note, the magnitude of effect
of combination therapy relative to alendronate alone on bone formation
was greater than the effect on bone resorption (Fig. 2, A and C). The
nadir of the response was reached within 3 months of administration of
alendronate alone. The time course of change from baseline for NTx was
not different whether alendronate was given with or without
MK-677.
BMD (up to 18 months)
Administration of alendronate with or without MK-677
increased BMD at the hip (including femoral neck), lumbar spine, and
total body (Fig. 3 and Tables 4 and 5).
Administration of MK-677 plus alendronate increased
femoral neck BMD more than that seen with administration of alendronate
alone (at 18 months, 4.2% vs. 2.5% for
MK-677/alendronate and alendronate, respectively;
P < 0.05). The incremental benefit in femoral neck BMD
with alendronate in the presence of MK-677 was noted as
early as 6 months and was maintained at 12 and 18 months despite a
waning of the initial increase seen in IGF-I (Fig. 1). Increases
occurred in other proximal femur subregions also, although none reached
statistical significance in terms of the comparison of the combination
to alendronate alone; the increase in femoral neck BMD was not
accompanied by loss at another site. However, MK-677 plus
alendronate had no additional effect on the increase in BMD of the
total hip, lumbar spine, and total body compared with that seen with
alendronate alone (Table 5 and Fig. 3). Indeed, the increase in total
body BMD was numerically less in the group that received combination
treatment compared with the group receiving alendronate (Fig. 3D).
Increases in femoral neck and lumbar spine BMD were not dependent on
the patient’s baseline IGF-I level. Furthermore, neither percent
change from baseline in femoral neck nor lumbar spine BMD were
correlated with percent change from baseline in IGF-I levels as
examined across all treatment groups. Administration of
MK-677 alone for 12 months did not increase BMD at any
site significantly compared with that in the group receiving placebo
for 12 months when examined at either the 12 month point or at month
18, when both groups had alendronate added. In fact, the group
receiving MK-677 alone may have experienced a trend toward
a net decrease, relative to placebo (P = 0.07), in
total body BMD over 12 months (Fig. 3D).
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Administration of MK-677 and alendronate, alone
or in combination, was generally well tolerated based on a review of
patient discontinuations and serious adverse events. A total of 25 of
292 patients (8.6%) discontinued the study due to clinical or
laboratory adverse events that were judged to be related to study
treatment (Table 6). No deaths or hip
fractures occurred. Only 1 patient (combination group) had a vertebral
compression fracture of L1 and T12 identified radiographically. During
the study period, 17 patients experienced a clinical syndrome of
fracture reported as adverse experiences (6, 9, 2, and 0 in the
combination, alendronate alone, MK-677 alone, and placebo
groups, respectively). The majority of fractures were associated with a
fall, and none resulted in patient discontinuation.
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Elevations in serum glucose or PRL resulted in discontinuation in three patients each (all received MK-677). Modest increases in serum PRL (within the physiological range) and in fasting blood glucose were noted in patients who received MK-677, consistent with earlier experience with MK-677 (32, 41). Clinically significant increases in serum transaminase values (>3 times the upper limit of normal) resulted in study discontinuation in two patients (both received MK-677). Serum alkaline phosphatase and calcium decreased as expected in groups treated with alendronate. There were no other significant differences among treatment groups in laboratory values.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In contrast to the largely antiresorptive agents currently available to treat osteoporosis, which over the long term suppress bone turnover, GH and MK-677 have a stimulatory effect on bone remodeling. In a previous study (32), administration of 25 mg MK-677 daily for 9 weeks produced mean increases in IGF-I levels of 68%, in serum osteocalcin of 29%, in BSAP of 10%, and in urinary NTx of 25% in elderly men and women. In the current study, administration of 25 mg MK-677 once daily for 12 months to osteoporotic postmenopausal women achieved similar mean increases in serum osteocalcin (22%), BSAP (17%), and urinary NTx (41%). The increases in IGF-I were evident through month 12, supporting a persistent GH secretory response. However, there was a decline from peak values at 1 month (average 80% increase in IGF-I levels) to an average increase of 45% at month 12 (the last time point at which IGF-I data are available). Nevertheless, the indices of bone turnover did not wane during this period. We observed a similar pattern of IGF-I changes over 12 months of treatment in another study of MK-677 in elderly patients (Merck Research Laboratories, data on file). It is not clear whether a slow decrease in IGF-I levels would continue beyond 12 months. This pattern of IGF-I change over time may represent the GH/IGF-I axis slowly establishing a new equilibrium. It is unknown whether the GH secretagogue or GH receptors may down-regulate, or somatostatin receptors or secretion may increase with chronic MK-677 exposure. Nevertheless, the relative stability of the biochemical marker response to MK-677 over months 6–12 suggests that the attenuation of the IGF-I increase does not influence the skeletal response to a major extent, and thus one may still draw conclusions over the entire course of the study.
MK-677 alone increased BMD relative to baseline at the femoral neck, but at no other site, after 12 months of treatment, and even this effect at the femoral neck was not significantly different from the change during placebo treatment. The effect of MK-677 alone could not be ascertained beyond 12 months because of the study design in these osteoporotic study participants. Total body BMD tended to decrease during treatment with MK-677 alone over the initial 12 months of the trial. This could reflect the findings previously reported with rhGH, where BMD was reduced during the initial year of therapy (23). However, in that trial, subsequent continued dosing with rhGH increased BMD, an effect that could not be assessed in the current trial. That total body BMD manifested the apparent decrease might be reflective of the greater influence of GH on cortical bone, which comprises 80% of total body bone mineral.
As expected from previous studies of alendronate, a significant decrease in markers of bone resorption and formation was seen with alendronate alone over the initial 3–6 months, which tended to plateau thereafter (39). Treatment with the combination of MK-677 and alendronate attenuated the magnitude of the effect of alendronate on bone formation and resorption markers, but did not change the shape of the curves. Interestingly, the relative impact of MK-677 on the indices of resorption and formation were fairly comparable, although one might have predicted perhaps a greater attenuation of the effect on formation.
The underlying hypothesis of this study was that the combination of MK-677 and alendronate would result in less suppression of the bone formation rate by exploiting the anabolic effect of GH on bone and thereby would increase bone mass at all sites more than that seen with alendronate alone. It was considered especially important to test this concept, as a previous trial of the bisphosphonate pamidronate plus GH actually suggested the GH treatment abrogated any benefit due to pamidronate on BMD (42). Clearly, a uniform benefit in BMD across sites was not seen with MK-677 plus alendronate. Possible reasons why this did not occur include the relatively moderate potency of MK-677 to increase bone formation when given alone or in the presence of alendronate. Although MK-677 alone resulted in significant increases in osteocalcin and BSAP, these increases were less than those previously seen with rhGH (18, 19). Nonetheless, typical clinical adverse experiences associated with GH treatment were evident in the current trial, suggesting that an adequate GH effect was present (as supported by IGF-I increases). Combination treatment resulted in 26% less suppression of markers of bone formation (-40% vs. -54% for alendronate) and 15% less suppression in markers of bone resorption (-52% vs. -61% for alendronate). Despite mitigation of alendronate’s effect on bone formation by MK-677, BMD increases were only seen at the femoral neck and not at other sites. This could be due to the relative contributions of bone formation and resorption to BMD changes at the different sites as well as differences in mechanical effects on skeletal dynamics at various sites and the interaction of GH and such mechanical influences. At the femoral neck, stimulation of periosteal bone formation, the presumed action of GH/IGF (9) should have the greatest impact and would be most detectable. In summary, the uncoupling of bone formation and resorption rates when alendronate was administered in the presence of MK-677 was modest and 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 further increases in bone mass at other sites is a concern in light of the potential side effects of enhanced GH secretion. These results are similar to those seen in previous studies of combination GH with bisphosphonate or calcitonin treatment (42, 43, 44). In these studies, combination treatment with GH suggested a more beneficial balance on bone turnover, without evidence of an improved response of BMD.
The use of GH in elderly patients is limited due to the frequent occurrence of adverse effects, such as carbohydrate intolerance or fluid retention (15, 18). Although it was anticipated that MK-677 might reduce the incidence of these adverse effects by producing a more physiological pattern of GH release, adverse effects did occur; 25 patients (8.2%) discontinued the study due to a drug-related adverse experience, including 2 patients with hypertension, 2 with fluid retention, and 3 patients who became hyperglycemic. These changes reversed after discontinuation of treatment. Otherwise, MK-677 was generally well tolerated. Women receiving alendronate reported no unexpected side effects.
Whether addition of rhGH or MK-677 to an antiresorptive agent (e.g. estrogen or a bisphosphonate) in patients who manifest an extremely low bone mass or who experience a plateau in the BMD response to an antiresorptive agent might accrue positive skeletal benefit was not tested in our study. However, treatment duration and sample size in our study were sufficient to evaluate whether combination therapy would result in greater increases in bone mass compared with the antiresorptive agent alone from the initiation of such therapy. Furthermore, the dose of MK-677 used in this study in elderly patients was appropriate based on earlier short-term dose-response studies and the observed GH-related adverse event profile in patients receiving MK-677. The dose selection was based on a study of daily administration of 2, 5, 10, and 25 mg MK-677 to elderly subjects (33). In this study, 25 mg MK-677 resulted in a greater increase in IGF-I than did 10 mg MK-677. Tolerability was generally similar at the 10- and 25-mg doses, although MK-677 had a slight effect on fasting serum glucose at the 25-mg, but not at the 10-mg, daily dose level. Dose selection was also based on a study in which 25 and 50 mg MK-677 were given once daily to elderly subjects. In the latter study, administration of 50 mg MK-677 once daily for 2 weeks did not result in a greater increase in IGF-I than that seen after 2 weeks of 25 mg MK-677 once daily (Merck Research Laboratories, data on file). Therefore, daily administration of 25 mg MK-677 was chosen for further long-term study in elderly patients. The pattern of GHrelated adverse events in this study supports the conclusion that a daily dose of 25 mg MK-677 is probably maximal in these elderly osteoporotic women. Although this dose did not lead to supraphysiological IGF-I levels, achieving such levels has been shown in many studies, especially in the elderly, to be associated with intolerable adverse effects with rhGH (13, 15, 24).
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 of 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.
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Acknowledgments |
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Footnotes |
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2 Present address: Northwestern Center for Clinical Research,
Chicago, Illinois 60611.
3 The MK-677 Study Group consisted of: University
Ambulatory Research Unit (Richmond, VA): Robert W. Downs, Jr., M.D.;
Ann Miller; Beth Israel Deaconess Medical Center (Boston, MA): Susan
Greenspan, M.D.; Dyanna DeMarco; University of California (San
Francisco, CA): Steven Harris, M.D.; Kay Bolla; Oregon Osteoporosis
Center (Portland, OR): Michael McClung, M.D.; Ana Balske, M.D.; Pam
Workman; Tampa Medical Group (Tampa, FL): Harris McIlwain, M.D.;
Marilyn Deaton; Research for Health (Houston, TX): Clark McKeever,
M.D.; Amy Scales; Rush Medical Center (Chicago, IL): Thomas Schnitzer,
M.D.; Joel Block, M.D.; Susan Fowler; Roger Williams Medical Center
(Providence, RI): Joseph R. Tucci, M.D.; Susan Studley; The San Diego
Endocrine and Medical Clinic (San Diego, CA): Stuart Weiss, M.D.; Eva
Gripp; The Colorado Center for Bone Research PC (Lakewood, CO): Paul
Miller, M.D., Carol Wasnok.
Received May 1, 2000.
Revised November 6, 2000.
Accepted November 6, 2000.
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  R. G. SMITH, Y. SUN, H. JIANG, R. ALBARRAN-ZECKLER, and N. TIMCHENKO Ghrelin Receptor (GHS-R1A) Agonists Show Potential as Interventive Agents during Aging Ann. N.Y. Acad. Sci., November 1, 2007; 1119(1): 147 - 164. [Abstract] [Full Text] [PDF]
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 Y. Sun, J. M. Garcia, and R. G. Smith Ghrelin and Growth Hormone Secretagogue Receptor Expression in Mice during Aging Endocrinology, March 1, 2007; 148(3): 1323 - 1329. [Abstract] [Full Text] [PDF]
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 H. Jiang, L. Betancourt, and R. G. Smith Ghrelin Amplifies Dopamine Signaling by Cross Talk Involving Formation of Growth Hormone Secretagogue Receptor/Dopamine Receptor Subtype 1 Heterodimers Mol. Endocrinol., August 1, 2006; 20(8): 1772 - 1785. [Abstract] [Full Text] [PDF]
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B. Holst, E. Brandt, A. Bach, A. Heding, and T. W. Schwartz Nonpeptide and Peptide Growth Hormone Secretagogues Act Both as Ghrelin Receptor Agonist and as Positive or Negative Allosteric Modulators of Ghrelin Signaling Mol. Endocrinol., September 1, 2005; 19(9): 2400 - 2411. [Abstract] [Full Text] [PDF]
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 R. G. Smith Development of Growth Hormone Secretagogues Endocr. Rev., May 1, 2005; 26(3): 346 - 360. [Abstract] [Full Text] [PDF]
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R. G. Smith, L. Betancourt, and Y. Sun Molecular Endocrinology and Physiology of the Aging Central Nervous System Endocr. Rev., April 1, 2005; 26(2): 203 - 250. [Abstract] [Full Text] [PDF]
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A. J. van der Lely, M. Tschop, M. L. Heiman, and E. Ghigo Biological, Physiological, Pathophysiological, and Pharmacological Aspects of Ghrelin Endocr. Rev., June 1, 2004; 25(3): 426 - 457. [Abstract] [Full Text] [PDF]
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 Y. Sun, S. Ahmed, and R. G. Smith Deletion of Ghrelin Impairs neither Growth nor Appetite Mol. Cell. Biol., November 15, 2003; 23(22): 7973 - 7981. [Abstract] [Full Text] [PDF]
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N. M. Thompson, J. S Davies, A. Mode, P. A. Houston, and T. Wells Pattern-Dependent Suppression of Growth Hormone (GH) Pulsatility by Ghrelin and GH-Releasing Peptide-6 in Moderately GH-Deficient Rats Endocrinology, November 1, 2003; 144(11): 4859 - 4867. [Abstract] [Full Text] [PDF]
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