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Clinical Studies |
Aging Study Unit, Geriatrics Research, Education, and Clinical Center, Veterans Affairs Medical Center, Palo Alto, California 94304; and the Department of Medicine, Stanford University, Stanford, California 94305
Address all correspondence and requests for reprints to: Robert Marcus, M.D., GRECC 182-B, Veterans Affairs Medical Center, 3801 Miranda Avenue, Palo Alto, California 94304.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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The design of the study was a randomized clinical trial consisting of 12 56-day treatment cycles. Each cycle was initiated by a 12-day period of hormone administration, followed by 44 days of supplemental calcium only. Cycles of hormone administration consisted of 7 daily injections of recombinant GH (20 µg/kg·day) or its placebo, followed by 5 daily injections of salmon CT (100 U/day) or its placebo. The study was performed at the Palo Alto Veterans Affairs medical center.
The patients were 84 healthy women with lumbar spine BMD more than 1 SD below the average value for a healthy 25-yr-old Caucasian woman. BMD was measured at the lumbar spine and proximal femur by dual energy x-ray absorptiometry. Biochemical markers of bone turnover and circulating insulin-like growth factor I were also measured.
GH treatment increased insulin-like growth factor I concentrations from
low values at baseline (112 ± 56 ng/mL) to the young normal range
(
430 ± 125 ng/mL). Groups receiving GH plus CT or GH plus
placebo increased lumbar spine BMD at 2 yr by 2.70 ± 0.81%
(P < 0.01) and 1.72 ± 0.74%
(P < 0.05; intention to treat analysis). No
significant change occurred in women receiving placebo plus CT or
combined placebo. Significant increases in total hip BMD of 1–2% were
observed for the GH plus placebo and placebo plus CT groups, with a
nonsignificant trend in the GH plus CT group. For the femoral
trochanter, significant increases were observed in the GH plus CT and
placebo plus CT groups only. No significant change in femoral neck BMD
was observed in any group.
Women taking replacement estrogen had the same BMD response as those who were estrogen deficient. No significant increase in BMD was observed between 24 and 36 months in the 62 women who returned for a 3 yr measurement. In response to GH, short term increases in resorption and formation markers were observed, but these had decreased before the next treatment cycle. No long term changes in resorption markers were observed, but women in the GH groups showed a sustained rise in circulating osteocalcin over the entire 2-yr protocol.
GH given cyclically with or without CT for 2 yr achieved statistically significant increases in BMD of the lumbar spine and selected areas of the hip in postmenopausal women. These gains were less marked than those achieved with estrogen or bisphosphonates and were associated with a relatively high incidence of adverse experiences. Therefore, it is unlikely that cyclic GH with or without CT will prove clinically useful in the treatment of postmenopausal women with osteoporosis.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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By contrast, evidence that administration of GH actually promotes clinically relevant improvements in bone mass in older individuals has been difficult to obtain. Two independent clinical trials in healthy older men treated with GH for 6 months have reported gains of 1.6% (9) and 0.9% in lumbar spine bone mineral density (BMD) (10), although it may be legitimately argued that skeletal response in these studies was limited by an extremely short treatment duration. In our own experience (4), the results of a 1-yr placebo-controlled clinical trial in healthy older women showed that daily injections of GH maintained, but did not increase, BMD at the proximal femur and had no effect on BMD at the lumbar spine. We concluded that daily administration of GH as monotherapy would probably not prove an effective means to restore bone, but GH might be a useful initiator of bone remodeling if it were given together with an antiresorptive agent to constrain bone loss during the resorption phase.
Aloia et al. (11, 12) explored such an approach by treating small numbers of osteoporotic patients with combined cyclic regimens of GH with salmon calcitonin (CT) and reported modest gains in bone mass. However, several features of those studies may have limited the treatment effect. The nonavailability of recombinant GH necessitated the use of human pituitary-derived hormone of uncertain potency. Limited hormone supply also restricted the size of treatment groups, consequently jeopardizing statistical power. Adequate evaluation of the utility of combined GH-antiresorptive therapy will require the use of recombinant GH in a sufficient number of subjects as well as biochemical confirmation of the efficacy of the administered hormones. We report here the results of a placebo-controlled randomized clinical trial in which 2-month cycles of 7 days of GH followed by 5 days of CT (or their respective placebos) were maintained for 2 yr, with follow-up bone density assessment at 3 yr.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Healthy women more than 60 yr of age were recruited by advertisements from the local community. Women were eligible who satisfied the WHO criterion for osteopenia, i.e. lumbar spine BMD less than 1 SD below the mean value for healthy 25-yr-old women. Volunteers reported to the Aging Study Unit, a clinical investigation ward, for a screening examination that included a health history questionnaire, physical examination, electrocardiogram, and routine multiphasic laboratory profile. In addition, all women undergoing the screening procedure were administered a standard 75-g oral glucose tolerance test. Volunteers were excluded from participation if they had received glucocorticosteroids on a sustained basis, thiazide diuretics, or other medications known to influence mineral metabolism. Volunteers with a blood pressure above 160/100 mm Hg at the screening examination, a history of carpal tunnel syndrome, diabetes mellitus, or a 2-h postchallenge plasma glucose concentration greater than 160 mg/dL were also excluded. Volunteers taking replacement estrogen were permitted to enroll if they had taken a stable dose for 12 months.
Eighty-four women satisfied entrance criteria and provided written
informed consent (Table 1
). The protocol was approved by
the institutional review board of Stanford University.
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Recombinant human GH (rhGH; Nutropin) and its placebo were generously provided by Genentech (South San Francisco, CA) and were administered under IND 34219. Salmon CT (Calcimar), its placebo, and calcium carbonate (CalEl D) were the generous gifts of Rhone-Poulenc Rorer Pharmaceuticals (Fort Washington, PA).
Study design
This 2-yr study consisted of 12 56-day treatment cycles followed by a final bone density examination at 3 yr. Each cycle was initiated by a 12-day period of hormone administration, followed by 44 days of supplemental calcium only. Hormone administration for each cycle consisted of seven daily injections of rhGH (20 µg/kg·day) or its placebo, followed by five daily injections of salmon CT (100 U/day) or its placebo. Thus, four treatment groups were created to which participants were randomly assigned: GH plus CT (n = 17), GH plus placebo (n = 23), placebo plus CT (n = 24), and placebo plus placebo (n = 20). Estrogen use did not differ among groups. Randomization was performed by Robert Coleman (Pharmacy Service, V.A. Medical Center, Palo Alto, CA), who selected a sealed envelope containing the study drug assignment for each participant. Study drugs were administered from masked multidose vials. Subjects were also issued a daily calcium carbonate supplement (500 mg calcium/day), which was taken with breakfast throughout the 2 yr of active treatment and was the only medication administered from days 13–56 of each treatment cycle.
GH, CT, and their respective placebos were dissolved in sterile diluent and self-administered by sc injection at about 2200 h. Subjects were admitted to the Aging Study Unit for baseline measurements and instruction on self-injection. They were issued adequate materials for 4 months of home treatment and came thereafter to the study unit for medication refills and interval measurement of study end points. At each visit, subjects were queried regarding adverse experiences.
Dose adjustment for drug-related side-effects
From previous experience with GH and CT in older women we anticipated that symptoms related to fluid retention (GH) or nausea (CT) might require a reduction in dose. We, therefore, adopted a consistent strategy to deal with these complaints. For participants who experienced fluid retention, we attempted first to control symptoms with 20–40 mg oral furosemide once or twice each week during the hormone cycles only. If that did not suffice, we authorized a 50% reduction in GH dose. For those who experienced nausea during the second 5 days of their treatment cycle, we prescribed diphenhydramine (Benadryl, Parke Davis Inc., Morris Plains, NJ; 25 mg) or prochlorperazine (Compazine, Smith Kline Beecham, Philadelphia, PA; 10 mg) to be taken at the same time. If nausea persisted, we reduced the dose of CT by 50%, and if that did not suffice, we permitted subjects to continue the protocol without taking the second medication.
Study end points
The 24-month changes in BMD (grams per cm2) of the lumbar spine and proximal femur were the primary end points of this study. Secondary end points included changes in biochemical markers of bone turnover and calciotropic hormones.
BMD assessment
BMD was measured by dual energy x-ray absorptiometry (QDR1000W, Hologic, Waltham, MA) on entry and again at 12 and 24 months. In addition, 1 yr after termination of active treatment, subjects were invited to undergo a final BMD assessment. In our laboratory, coefficients of variation for replicate measurements at the lumbar spine and proximal femur approximate 1.5% for older women. To minimize precision error, subjects underwent duplicate measurements at each time point. After completion of the first scan, they climbed down from the densitometer table and were then completely repositioned. Reported data represent average values from duplicate scans. Quality control measures during the course of this study include daily scanning of anthropomorphic phantoms (Hologic). During the period when this study was conducted, our laboratory participated in the Postmenopausal Estrogen/Progestin Interventions Trial. As part of the Postmenopausal Estrogen/Progestin Interventions Trial quality control program, daily phantom scan results were forwarded to a central facility and consistently passed scrutiny for machine drift and other anomalies.
Bone turnover assessment
Biochemical markers were measured in 2-h urine specimens that were obtained after an overnight fast and after discarding the first voided morning specimen. Collections were made at entry and periodically throughout the study. The effects of study drugs on bone turnover were evaluated over the course of a single treatment cycle (cycle 1) and also chronically over the 2 yr of active treatment. During cycle 1, biochemical measurements were made at baseline and again after 1 and 3 weeks. Subsequent measurements were taken specifically to determine the residual effects on bone turnover of previous treatment cycles and were made before initiating cycles 3, 7, and 13 (4, 12, and 24 months). All samples for any given participant were processed in single assay runs.
Biochemical analyses
Assays were carried out using methods reported previously from our laboratory (13, 14). Serum concentrations of IGF-I and IGF-binding protein-3 were measured by immunoradiometric assays (DSL, Diagnostic Systems Laboratories, Webster, TX). Osteocalcin was measured by RIA (DSL). Total urinary pyridinolines were measured by competitive enzyme immunoassay (Metra Biosystems, Mountain View, CA). Type I collagen C-terminal propeptide (CICP) was measured by sandwich immunoassay (Metra Biosystems). Type I collagen-specific sequence (CrossLaps) was measured by enzyme-linked immunosorbent assay (Osteometer, DSL). Intact PTH was measured by immunoradiometric assay (Allegro, Nichols Laboratories, San Juan Capistrano, CA).
Data analysis
Randomized treatment assignments were maintained double blind until completion of the study, although not all subjects had completed their 1-yr postprotocol (yr 3) bone density assessment when they were informed of their treatment assignment. Attempts were made to obtain follow-up measurements on subjects who withdrew from active treatment. Data were stored on a personal computer and analyzed using the StatView IV software package (Abacus Concepts, Berkeley, CA).
Analytical methods included routine descriptive statistics and ANOVA. Comparisons of treatment effects over time were made by two-way repeated measures ANOVA, using Scheffe’s test for post-hoc analysis. Data were first analyzed using an intention to treat strategy, with secondary analyses for subjects who had taken more than 80% of their assigned study medication throughout the 2 yr of the study. Results are presented as the mean ± SD unless otherwise noted.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Of the original study cohort of 84 women, 72 (86%) completed the 24-month protocol, of whom 56 (78%) took more than 80% of the assigned study medication. Sixty-two women returned at 36 months for a follow-up bone density assessment after 12 months off treatment. Nonadherence to the 80% treatment standard was greatest in the placebo plus CT group (n = 7) and least in the placebo plus placebo group (n = 3). Twelve women withdrew entirely from the study. Of these, 9 had been assigned to GH (GH plus CT, n = 5; GH plus placebo, n = 4). The most common side-effect of medication was nausea (n = 15), which, except for 1 case, was confined to women receiving CT. In 10 instances, nausea was controlled by reducing the CT dose by half. The next most common side-effect, peripheral edema, was largely confined to women receiving GH (n = 9). Of these, only 4 women were not adequately controlled with furosemide, necessitating a reduction in GH dose. Other adverse experiences were infrequent and equally distributed among treatment groups. Serious adverse experiences include single instances of hyperthyroidism, polymyalgia rheumatica, cholecystitis, myocardial infarction, carotid artery surgery, lung cancer, and parotid tumor and 2 instances of herpes zoster neuritis. These 9 subjects were removed from study drugs.
No significant differences were observed between the baseline
characteristics of the original study cohort and those of the 72 women
who completed the protocol (Table 1
).
Effects of treatment on circulating IGF-I
At baseline, IGF-I concentrations for the entire group (mean ± SD, 112 ± 56.1 ng/mL) reflected the characteristically low values for women of this age. During the first intervention cycle, serum IGF-I concentrations increased substantially by 1 week (P < 0.0005) in both GH groups (GH plus CT, 440 ± 123; GH plus placebo, 416 ± 127 ng/mL) and dropped to baseline levels by 3 weeks (123 ± 48 and 144 ± 66 ng/mL, respectively). Subsequent determinations, made just before beginning a new cycle, remained at baseline levels throughout the 2-yr experiment. No changes were observed in IGF-I at any time in women in the non-GH groups.
Effects of treatment on BMD
Lumbar spine (L2–L4). Percent changes from baseline in L2–L4
BMD are shown in Table 2 and Fig. 1.
Using intention to treat analysis, nonsignificant trends toward
increased BMD were observed at 12 months in all groups except for
placebo plus placebo. By 24 months, significant increases were seen
compared to baseline values in the combined GH plus CT (2.70 ±
0.81%; P < 0.01) and GH plus placebo (1.72 ±
0.74%; P < 0.05) groups. Both changes differed
significantly (P < 0.05) from the nonsignificant trend
toward bone loss observed in the placebo group. No significant change
occurred in women receiving placebo plus CT. No substantial difference
in results occurred when the analysis was restricted to subjects who
had taken more than 80% of their assigned study drug, except that the
positive trend in the placebo plus CT group (1.09 ± 0.70%) now
achieved significance (P < 0.05). Estrogen status did
not influence these results. In estrogen-replete women, the increases
in lumbar spine BMD at 24 months were 2.2% and 2.3% in the GH/CT and
GH/placebo groups, whereas in women not receiving estrogen, the
increases were 2.6% and 1.9%, respectively.
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and Table 2. By intention to
treat analysis, 12-month trends for the total hip achieved significance
by 24 months, with a significant increase compared to baseline values
of 1.27 ± 0.53% for the placebo/CT group, but a continued
nonsignificant trend in the GH groups. Using the more than 80%
adherence criterion, the change in hip BMD for the GH/placebo group
became significant, but for the placebo plus CT group, there was no
longer a significant change. No significant change in femoral neck BMD
was observed at any time in any group. For the trochanter, 24 month
increases in BMD were significant for the GH/CT and placebo/CT groups
only (Fig. 2). Once again, estrogen status did not alter these
results.
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. In our laboratory, the coefficient of variation
(SD ÷ mean value) for replicate measurements was 1.5% at
both spine and hip; thus, a difference of 2 x 
2 times that
amount, i.e. a 4.2% change in BMD, would be required to
establish a significant gain or loss with 95% confidence for an
individual woman. Using that 4.2% criterion at the lumbar spine, all
active treatment groups resulted in a significantly (P
< 0.05) lower prevalence of women who lost bone and a significantly
higher prevalence of women who gained bone, although significant
differences among the active treatment groups were not observed.
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Effects of treatment on bone turnover
Short term response to a single treatment cycle (Table 3). No baseline differences in bone turnover
markers were observed. In response to study drugs, trends toward
increased urinary excretion of total pyridinolines and CrossLaps were
observed after 1 week in both groups assigned to GH. Significance was
achieved in the GH plus CT group, but not in the GH plus placebo group.
This response appeared to diminish and lost significance by 3 weeks. No
significant rise in resorption markers occurred in groups that did not
receive GH. A trend at 1 week toward increased circulating osteocalcin
achieved significance in both GH groups, and this also decreased by 3
weeks. A significant, albeit transient, rise in CICP was also observed
in the GH groups at 1 week.
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).
Sustained and significant elevations in circulating osteocalcin were
observed in both GH groups throughout the 2-yr protocol. A significant
rise in the osteocalcin concentration was observed only at 24 months
for the placebo plus CT group. Sustained increases in CICP or in either
resorption marker were not observed in any treatment group, except for
a transient increase in pyridinolines in the GH plus CT group that
reverted to pretreatment levels by 4–12 months. |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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2%). These increases were associated
with sustained increases in osteocalcin, a marker of bone formation,
but not in other bone turnover indexes. Any therapeutic response to GH or CT must be considered in light of the substantial propensity of these agents to produce side-effects. In this trial, 16 subjects were required to reduce the dose of study drug or terminated their participation. The variety of side-effects typified those previously described for these study drugs. Women receiving CT reported nausea, whereas those receiving GH experienced symptoms of fluid retention. Despite this relatively high incidence of adverse experiences, however, we do note that cyclic GH was overall better tolerated than we reported previously for daily GH (4).
Prospective observational studies indicate that every SD in
BMD below age-predicted mean levels confers a 2- to 3-fold increase in
long term fracture risk (15). As the SD in BMD at most
skeletal sites is about 12% of the mean value, a 2% rise in BMD (0.16
SD) would be predicted to reduce fracture incidence by
about 16%. By contrast, 0.625 mg/day conjugated estrogens increased
spine and hip density by 5% and 2.5% over 3 yr in postmenopausal
women (16), a response associated with a 50% reduction in fracture
risk when used long term (17), whereas the bisphosphonates, etidronate
and alendronate, increased spine BMD by 8% (18, 19), and the latter
decreased vertebral and hip fractures by 50% over a 3-yr interval
(20). As these agents appear to be more effective, less associated with
adverse experiences, and less expensive than GH, it does not appear
that cyclic GH will be the basis of a clinically useful therapy for
osteoporosis.
Despite encouraging results in vitro, administration of GH to humans has not led to important gains in bone mass, whether given on a daily or cyclic basis. The reason for these disappointing results probably lies in the fact that GH acts on adult bone to initiate new remodeling activity, resulting in a stimulation of both bone resorption and bone formation. As remodeling efficiency, the degree to which resorbed bone is replaced, declines with age (21), it is not clear that any increase in bone mass would occur with a treatment whose sole effect was to initiate new remodeling cycles. That any gains were observed suggests that some direct osteoblastic activation by GH or its surrogate, IGF-I, had occurred. It is interesting to note that significant bone loss was not observed at any site in the placebo group. We attribute this result to the calcium supplement that was administered throughout this trial.
In this trial, evidence of increased bone resorption 1 week after rhGH achieved statistical significance for the carboxyl-terminal telopeptide (CrossLaps), but showed only a nonsignificant trend for pyridinolines. We attribute this response to the fact that some women in each group were receiving estrogen replacement therapy, which we have previously shown blunts the biochemical responses to rhGH (4). We also did not observe suppression of resorption activity in groups receiving CT at any time. However, this result was predictable, given the fact that the 3 week specimens were collected more than a week after CT had been stopped, and all subsequent measurements were made before the next cycle of hormone treatment.
The premise underlying this study was that constraining GH-dependent bone resorption might permit augmented expression of its anabolic effects. Possible reasons why this did not occur include inappropriate dose or timing of the study drugs. However, the dose of CT was identical to that which has shown clinical efficacy (22), whereas GH was given in amounts sufficient to increase serum IGF-I concentrations to the normal "young" range. In our previous studies (4, 14), we have shown this dose of GH to provide a full effect with respect to increasing bone remodeling activity without an unacceptable burden of adverse experiences. It is possible that daily administration of CT or another antiresorptive drug throughout the study would have permitted a greater response. We have previously observed that some short term physiological responses to GH are blunted in women who receive estrogen replacement therapy (4). It was, therefore, unexpected that the BMD responses in this study were not evidently affected by estrogen status. We currently have no explanation for this finding.
In the United States, currently approved drugs for osteoporosis consist solely of agents that act primarily, if not exclusively, to inhibit the production or actions of osteoclasts. The major effect of these drugs is to reduce the magnitude of a transient deficit in bone called the remodeling space. For larger gains in bone mass to be achieved, it will be necessary to develop medications that are truly anabolic, that is agents showing direct stimulation of osteoblast number or function. Fluoride salts have clearly shown this type of activity (23, 24, 25), although argument persists regarding the quality of fluoride-treated bone (23). PTH or PTH analogs represent another group of agents with potent anabolic actions on the skeleton, and clinical trials of some of these are currently in progress. For reasons discussed above, neither daily nor cyclic administration of GH appears to offer a clinically useful approach to the treatment of osteoporosis. However, other strategies involving the somatotropic axis warrant further evaluation. Administration of GHRH or GHRH analogs may permit a more physiological, pulsatile release of endogenous GH, which might conceivably provide a superior skeletal response. Even more interesting is recent evidence that IGF-I is skeletally anabolic. Ebeling et al. (26) and our own group (13) have both reported that low doses of recombinant IGF-I substantially increase bone formation activity and only slightly increase bone resorption activity in older women. These results suggest the rationale for a clinical trial of IGF-I in osteoporotic postmenopausal women.
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Acknowledgments |
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Footnotes |
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Received November 5, 1996.
Revised January 3, 1997.
Accepted January 13, 1997.
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References |
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and 
,
Groups sharing these symbols differed significantly (P <
0.05).
