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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 57:M12-M18 (2002)
© 2002 The Gerontological Society of America

Growth Hormone and Sex Steroid Effects on Bone Metabolism and Bone Mineral Density in Healthy Aged Women and Men

Colleen Christmasa, Kieran G. O'Connora, S. Mitchell Harmanb, Jordan D. Tobinc, Thomas Münzerb, Michele F. Bellantonia, Carol St. Claire, Katharine M. Pabste, John D. Sorkind and Marc R. Blackmane

a Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
b Endocrine, Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
c Applied Physiology, Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
d Metabolism Sections, Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
e Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Marc R. Blackman, Clinical Director and Chief, Laboratory of Clinical Investigation, National Center for Complementary and Alternative Medicine, National Institutes of Health, 8 West Drive, QRTRS 15 B-1, Bethesda, MD 20892 E-mail: blackmam{at}mail.nih.gov.

Decision Editor: John E. Morley, MB, BCh


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
Background. Aging is associated with concomitant declines in activity of the growth hormone (GH) and gonadal steroid axes, and in bone mineral density (BMD), in both sexes. Long-term estrogen replacement slows bone loss and prevents fractures in postmenopausal women, whereas the effects of supplementation of GH or testosterone on bone metabolism and BMD in aged individuals remains uncertain.

Methods. Using a randomized, placebo-controlled, double-blind study design, we investigated the separate and interactive effects of 6 months of administration of recombinant human GH and/or gonadal steroids on bone biochemical markers and BMD in 125 healthy, older (>65 years) women (n = 53) and men (n = 72) with age-related reductions in GH and gonadal steroids.

Results. In women, administration of GH, but not GH + hormone replacement therapy (HRT), increased serum levels of osteocalcin and procollagen peptide (PICP) and increased urinary excretion of deoxypyridinoline (DPD) crosslinks. Urinary calcium excretion decreased after HRT. In men, GH, and to a greater extent GH + T, increased osteocalcin. GH increased serum PICP, and GH + T increased urinary DPD. Urinary calcium excretion was unaffected by hormone treatment in men. In women, administration of HRT and GH + HRT, but not GH, increased BMD at the lumbar spine, femoral neck, and distal radius. In men, GH + T led to a small decrease in BMD at the proximal radius; there were no other significant effects of hormone administration on BMD.

Conclusions. These data suggest that short-term administration of HRT exerts beneficial effects on bone metabolism and BMD in postmenopausal women, which are not significantly altered by the coadministration of GH. In andropausal men, T administration to achieve physiologic levels did not result in significant effects on bone metabolism or BMD, whereas GH + T increased one marker of bone formation and decreased one marker of bone resorption. Given the known biphasic actions of GH on bone and the apparent favorable biochemical effects of GH + T in men, the longer-term effects of GH + T on BMD in aged men remain to be clarified.

THE incidence and prevalence of osteoporosis and fractures increase substantially with age in both women and men (1). The age-related decline in bone mineral density (BMD), which is a strong predictor of fracture risk (2), occurs concomitantly with declines in growth hormone (GH) and gonadal steroid hormone secretion (3)(4)(5)(6). Because both GH and male and female sex steroids are known to have trophic effects on bone tissue, it has been conjectured that declines in these hormones with age may contribute to osteopenia (1)(3)(7)(8)(9)(10)(11)(12)(13).

Young and middle-aged adults with acquired GH deficiency (14)(15)(16)(17)(18) or male hypogonadism (19)(20) exhibit decreased BMD and an increased prevalence of fractures, which can be reversed, at least in part, by appropriate hormone replacement. The menopausal decline in ovarian estrogen and progesterone production accelerates the development of osteoporosis (1). Several short-term studies have revealed that GH supplementation given to elderly "somatopausal" individuals increases biochemical markers of bone formation and turnover but has little or no beneficial effect on BMD (12)(21). Numerous epidemiological and randomized trials have revealed that administration of estrogen or estrogen plus progesterone (hormone replacement therapy [HRT]) to postmenopausal women decreases or delays the losses in BMD (22)(23)(24)(25)(26). In comparison, a biochemical marker of bone formation has been shown to increase (27) and a marker of bone turnover to decrease (28) following short-term administration of testosterone to healthy aged men with low or low-normal testosterone levels, whereas longer-term administration of testosterone improved lumbosacral BMD only in healthy aged men with very low serum testosterone levels (<200 ng/dl) (29).

Much information has been adduced to demonstrate the complex interrelationships between the GH and gonadal steroid axes (30)(31)(32)(33). In the current study, we investigated the effects of administration of GH and gonadal steroids, alone and in combination, on biochemical markers of bone metabolism and BMD in a group of healthy older women and men with age-related declines in GH and gonadal steroids.


   Methods
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 Methods
Results
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Subjects
A total of 125 subjects (53 women and 72 men) 65 years of age and older (range 65–88 years) were recruited from the community by mailed advertisements. Subjects were recruited during a period of 5 years, without regard to, and with even distribution by, season. All were healthy by screening history and physical examination, routine blood studies (including automated complete blood count with differential, routine electrolytes and chemistries, and thyroid-stimulating hormone level), urinalysis, and resting and graded treadmill electrocardiogram. All subjects had serum insulin-like growth factor (IGF)-I levels 1 standard deviation (SD) or more below the mean for healthy adults aged 20 to 35 years (230 ng/ml = 30 nmol/l). No woman had taken any estrogen or progestogen for at least 3 months prior to study. All men were andropausal and had serum testosterone levels at least 1 SD below the mean for healthy men aged 20 to 39 years (470 ng/dl = 16.3 nmol/l). No man had received exogenous testosterone prior to participation in the study. The body mass index (BMI = kg/m2) values ranged from 19.7 to 32.5. No subject had diabetes mellitus, symptomatic coronary artery disease, clinical depression, or untreated thyroid disease. Study participants were nonsmokers, consumed <2 oz alcohol per day, and took no medications known to interfere with the GH/IGF-I or gonadal steroid axes, bone metabolism, or any other outcome measure. The study was approved by the combined Institutional Review Board of the Johns Hopkins Bayview Medical Center/Intramural Research Program, National Institute on Aging. Written informed consent was obtained from all subjects.

After successful completion of screening, subjects were assigned by random draw to receive recombinant human GH plus placebo sex steroid ("GH" group), sex steroid plus placebo GH ("HRT" group for women, "T" group for men), GH plus sex steroid(s) ("GH + HRT" for women, "GH + T" for men), or placebo GH plus placebo sex steroid(s) ("placebo" group).

Study Protocol
At baseline, all subjects were admitted to the General Clinical Research Center (GCRC) at the Johns Hopkins Bayview Medical Center at 8 AM on day 1. Height and weight were measured using a standing stadiometer. BMD was determined using dual-energy x-ray absorptiometry (DEXA) (Model DPX-L; Lunar Radiation, Madison, WI).

At 8 AM on the morning of day 2, after an overnight fast, blood was collected for measurements of IGF-I, estradiol in women and testosterone in men, and osteocalcin and procollagen-I peptide. Urine was collected for 2 hours for determination of deoxypyridinoline excretion. Urine was collected for 24 hours between days 2 and 3 for determination of urinary calcium and creatinine excretion. Subjects were discharged after the urine collection was completed.

At 26 weeks, all subjects were readmitted to the GCRC for a repeat of the baseline evaluation. The week-26 levels of IGF-I, and estradiol in women, were measured in blood obtained 24 h after the last GH injection. The week-26 T level was measured in serum samples obtained 1 week after the final T injection.

Laboratory Assays
Serum IGF-I was measured at weeks 0 and 26 by radioimmunoassay (RIA) after acid-ethanol extraction (Endocrine Sciences Laboratories, Calabasas Hills, CA) (34). Sensitivity of the IGF-I assay was 30 µg/ml, and intra- and interassay coefficients of variance (CVs) were 5.4% and 7.3%, respectively.

Serum levels of estradiol (E2, for women) and total testosterone (T, for men) were measured at weeks 0 and 26 by routine RIA in the Endocrinology Research Laboratory of the Intramural Research Program, NIA, using commercial kits (Diagnostic Products Corporation, Los Angeles, CA). All measurements were performed in duplicate. The sensitivity of the E2 assay was 20 pg/ml (73 pmol/l) with intraassay CVs of 8.3%, 2.5%, and 5.3%, respectively, at mean E2 concentrations of 48, 119, and 187 pg/ml (176, 437, and 686 pmol/l) and interassay CVs of 8.9%, 6.0%, and 6.8%, respectively, at mean E2 levels of 29, 99, and 186 pg/ml (106, 363, and 683 pmol/l). The sensitivity of the T assay was 10 ng/dl (0.35 nmol/l), with intraassay CVs of 11.7%, 6.7%, 1.5%, and 3.1% at mean T concentrations of 60, 300, 597, and 998 ng/dl (2.1, 10.4, 20.7, and 34.6 nmol/l), respectively, and interassay CVs of 9.5%, 5.8%, 5.7%, and 1.4% at mean T concentrations of 74, 293, 704, and 1032 ng/dl (2.6, 10.2, 24.4, and 35.8 nmol/l), respectively.

Bone biochemical markers were measured at weeks 0 and 26 in the GCRC Core Laboratory at Johns Hopkins Bayview Medical Center. Serum osteocalcin was measured by IRMA (Nichols Institute Diagnostics, San Juan Capistrano, CA) with a sensitivity of 0.06 ng/ml, an intraassay CV of 3.0%, and an interassay CV of 6.7%. Serum concentrations of the carboxyterminal propeptide of Type 1 procollagen peptide (PICP) were measured by RIA (Incstar Co., Stillwater, MN) with a sensitivity of 1.2 ng/ml, an intraassay CV of 2.2%, and an interassay CV of 4.8%. Urinary excretion of deoxypyridinoline crosslinks (DPD) was quantified by enzyme-linked immunosorbent assay (ELISA) (Metra Biosystems Inc., Palo Alto, CA) with a sensitivity of 1 nM, an intraassay CV of 8.1%, and an interassay CV of 7.9%. Urinary creatinine (Cr) excretion was determined on a 24-hour collection specimen by the Jaffe rate method employing a Beckman creatinine analyzer 2 (Beckman Instruments, Fullerton, CA) with a linear range of 0.2 to 25 mg/dl, an intraassay CV of 1.1%, and an interassay CV of 1.6%. Urinary excretion of calcium (UCal) was measured using standard assays. Both DPD and UCal were expressed as a ratio to Cr excretion.

Measurements of Bone Density
Bone mineral density at the right femoral neck and trochanter, the AP lumbar spine (L2–L4), the right proximal (at the junction of the first and second thirds) and distal radius, and of the total body were determined by DEXA scanning at weeks 0 and 26. Scans were analyzed by two observers with both intra- and interobserver CVs of <2%.

Because of concern for reliability of AP scans in elderly subjects prone to deformity, arthritis, vascular calcification, and compression fracture, the AP spine DEXAs were given further review. To determine the reliability of the scans, the spine DEXA data were reviewed by two independent analysts who were blind to treatment groups. In all instances, both reviewers concurred as to whether skeletal deformity (e.g., severe scoliosis or multiple compression fractures) existed and whether or not the scan could be used for analysis. Four women and 5 men had AP scans that were felt to be unreadable by this method, and their spine BMD data were not used in the final analyses. Scans of the AP lumbar spine with a BMD >=2 SD above the mean BMD for each gender were also selected for review; however, no additional scans were identified by this method as being possibly unreliable.

Administration of Hormones
On the day of discharge from the GCRC, women received the first of six 1-month supplies of Estraderm (Novartis Pharmaceutical Corp., East Hanover, NJ) 100 µg or placebo patches, plus Provera (Pharmacia Corp., Peapack, NJ) 10 mg or placebo tablets. Subsequently, women applied a new active or placebo patch twice per week and took Provera 10 mg/d or placebo progestogen for the last 10 days of each 28-day cycle. Testosterone was administered by the GCRC nurses as an intramuscular injection of 100 mg testosterone enanthate in oil every 2 weeks. Men in the placebo group received the same volume of a sterile saline T placebo by intramuscular injection. Men and women were also given their first s.c. injections of recombinant human GH (0.02 mg/kg s.c.) or saline GH placebo at the time of discharge from the GCRC, under direct supervision of the study nurses. All subjects self-administered GH or placebo GH injections three times per week (Monday, Wednesday, and Friday) in the evening, approximately 1 hour before bedtime.

Statistical Analysis
Data were analyzed with SAS statistical software version 6.12 (SAS Institute Inc., Cary, NC). All data are expressed as the mean values ± SEM.

Gender differences at baseline were assessed by the unpaired Student t test. Significance of changes in markers of bone metabolism, urine calcium excretion, and BMD after 26 weeks of hormone administration versus placebo were calculated by ANCOVA adjusted for age, hormone concentration at baseline, and treatment group. The ANCOVA was performed using the General Linear Models Procedure to control for unequal group size. A p value of <=.05 was considered significant.


   Results
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Discussion
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Baseline Characteristics of the Study Population
The study population was comprised of 53 women and 72 men aged 65 to 88 years (mean 72.2 ± 0.4 years). There were no significant differences in mean values for age or serum PICP levels. Mean values for weight, BMI, IGF-I, and all BMD measurements were higher in men than in women, whereas values for osteocalcin, DPD/Cr, and UCa/Cr were higher in women than in men (Table 1 ). There were no significant within-sex-group differences in any of the measured variables in either women or men, except for lower values for distal radial BMD in men randomized to receive GH (p < .02) and T (p < .002) versus placebo (Table 1 ).


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  		Table 1. Baseline Characteristics of Subjects in Each Treatment Group

 
Effects of Hormone or Placebo Intervention on Serum Levels of IGF-I or Sex Steroids
In women treated with GH alone or with GH + HRT, IGF-I levels rose from 107 ± 11 to 191 ± 13 µg/l (p <= .001) and from 132 ± 12 to 166 ± 17 µg/l (p <= .05), respectively, with a significantly greater response in women on GH alone (p <= .05). In men, administration of GH alone or GH + T increased IGF-I levels from 147 ± 12 to 250 ± 24 µg/l (p = .0001) and from 117 ± 10 to 219 ± 12 µg/l (p = .0001), respectively, with no significant difference in IGF-I response between the treatment groups. Neither placebo nor sex steroid administration significantly changed IGF-I levels in either sex (data not shown). After GH administration, IGF-I levels were higher in men versus women (187 ± 10 vs 142 ± 9 µg/l; p <= .01).

In women, administration of HRT or GH + HRT increased serum E2 levels similarly, from <=7.3 to 31 ± 5.5 pmol/l (p <= .005) and 34 ± 5.1 pmol/l (p <= .0001), respectively. In men, administration of T or GH + T increased serum T levels similarly, from 15.3 ± 0.8 nmol/l to 20.2 ± 1.6 nmol/l (437 ± 28 ng/dl to 577 ± 46 ng/dl; p <= .005) and from 14.6 ± 1.2 nmol/l to 18.1 ± 0.9 nmol/l (417 ± 34 ng/dl to 517 ± 26 ng/dl; p <= .0005), respectively. Neither placebo nor GH treatment significantly changed sex steroid levels in women or men (data not shown).

Changes in Bone Biochemical Measures After Hormone Interventions
The effects of 26 weeks of hormone administration on bone biochemical measurements are shown in Table 2 . In women, GH increased osteocalcin by just over 50% (p < .001), whereas neither HRT nor GH + HRT changed osteocalcin significantly. The addition of HRT to GH appeared to inhibit the GH effect on osteocalcin (p < .05). Administration of HRT produced a small (13%) increase in serum PICP (p < .05), whereas other hormone interventions did not significantly affect it. The urinary excretion of DPD increased by nearly 50% after GH (p < .0001). There were no significant effects of HRT or GH + HRT on DPD. The addition of HRT to GH appeared to eliminate the GH effect on DPD (p < .05). There was a 27% decrease in urinary calcium excretion after HRT (p < .05). The addition of GH to HRT did not significantly alter the effect of HRT to decrease urinary calcium excretion.


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  		Table 2. Effects of Hormone Administration on Bone Biochemical Measurements in Healthy Elderly Women and Men: Change in Measured Value from Week 0 to Week 26

 
In men, GH and GH + T increased osteocalcin by 70% and 74%, respectively (p < .0001). The effect of GH + T was greater than that of T (p < .0001). Serum PICP increased 15% after GH (p = .02). The effect of GH + T did not differ significantly from that of either GH or T. Urinary DPD excretion more than doubled after GH + T (p < .04) and increased to a lesser extent (56%, NS) after GH alone. The effect of GH + T was greater than that of T (p < .001). Urinary calcium excretion did not change significantly in any treatment group.

Changes in BMD After Intervention
The effects of hormone administration on BMD at several sites are summarized in Table 3 . In women, HRT administration increased BMD at the lumbar spine (8.9%), femoral neck (1.2%), and distal radius (3.3%) (all p < .05). Treatment with GH did not significantly affect BMD at any site. The combination of GH + HRT produced a small (0.8%) increase in total BMD versus placebo (p < .05) and also versus GH alone (p < .05), which was not significantly different from that seen with HRT alone.


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  		Table 3. Effects of Hormone Administration on Change in BMD in Healthy Elderly Women

 
In men, except for a small but significant decrease in BMD at the proximal radius after GH + T (p < .05), there were no other significant treatment effects (data not shown).


   Discussion
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 Abstract
 Methods
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 Discussion
References
 
In the current study, we evaluated the separate and interactive effects of 6 months of administration of GH and sex steroid(s) on biochemical markers of bone metabolism and BMD in a group of healthy older women and men. We found that administration of GH increased IGF-I levels in women and, to a greater extent, in men. In women, coadministration of GH + HRT lessened the stimulatory effect of GH on IGF-I. There were no effects of T on IGF-I levels in men, nor of GH on sex steroid levels in either sex. Administration of GH, HRT, or T increased levels of IGF-I, E2, and T, respectively, to the levels found in healthy young individuals.

Our finding that administration of HRT, given as transdermal estradiol plus progestin for 6 months, significantly attenuated the GH-mediated increase in IGF-I levels contrasts with the prior report of similar increases in IGF-I in women with Turner syndrome treated with GH or GH plus E2 (35). We previously observed unchanged serum IGF-I levels after 6 weeks of administration of transdermal estradiol plus progestin, in doses similar to those used in the present study (36), and decreased serum IGF-I levels after administration of oral estrogen for a similar period (37), in healthy younger and older postmenopausal women. Whether discrepancies in the above-noted effects of HRT on IGF-I result from differences in the dose, route and duration of estrogen administration, concomitant use of progestin, or other factors remains to be elucidated.

Our observations that in healthy elderly women GH administration for 6 months increased circulating osteocalcin levels (an important marker of bone formation) and urinary excretion of DPD crosslinks (a marker of bone resorption) without changing BMD significantly are consistent with prior reports related to the effects of GH administration given for similar time periods to GH-deficient non-elderly women (38) or healthy postmenopausal women (21)(39). However, the effects of GH administration on biochemical markers of bone metabolism and BMD in GH-deficient patients have been reported to be biphasic; GH treatment increases bone biochemical markers in the first 3 to 6 months with little or no effect on BMD, whereas treatment for more than 12 to 18 months is associated with significant increases in BMD and with little or no measurable changes in bone biochemical markers (15)(17)(38)(40)(41)(42)(43). Some studies have demonstrated changes in blood and urine markers of bone metabolism as early as 7 days after GH administration in healthy elderly people (44).

In the current study, short-term HRT administration decreased urinary calcium excretion, a marker of bone turnover, and increased BMD at the spine, femoral neck, and distal radius, consistent with the known short- and long-term bone antiresorptive effects of estrogens or estrogens plus progestins in estrogen-deficient young (45)(46) and middle-aged (22)(26)(47) or older (23)(25)(48)(49) women.

Coadministration of HRT and GH attenuated the effects of GH alone on osteocalcin and urinary deoxypyridinoline, but not the effect of HRT on urinary calcium, and led to a small but significant increase in total BMD while lessening the effects of HRT on regional BMD. Similar results were demonstrated in a small prospective, blind trial of 27 healthy elderly women randomized to 6 months' treatment with either GH or placebo. In the latter study, women who received GH but no concurrent estrogen exhibited dramatic increase in markers of bone turnover, whereas those taking GH and concurrent estrogen did not show this effect (39). Similarly, in young women with Turner's syndrome, treatment with GH in combination with oxandrolone resulted in growth acceleration similar to that occurring with the normal pubertal growth spurt, but the addition of estrogen significantly reduced this effect (50).

Our observations that in healthy older men 6 months of GH administration increased circulating osteocalcin and PICP levels without changing BMD significantly are consistent with prior reports related to the effects of GH administration, given for similar time periods, to GH deficient non-elderly (15)(16)(38)(40)(41) or healthy elderly men (12)(21). GH treatment exerts temporally biphasic effects on bone metabolic markers and BMD in GH-deficient men, as in women (15)(16)(38)(41). Whether longer-term administration of GH to healthy older women and men would elicit comparable biphasic effects on bone metabolism and BMD remains to be determined.

In our study, healthy andropausal men treated with testosterone alone exhibited no significant alterations in bone biochemical markers or in BMD. Possible explanations for our negative findings may include the relatively high baseline T levels in our subjects, the comparatively low dose of testosterone we employed, and the relatively short duration of hormone administration. Snyder and colleagues (29) recently reported that 3 years of testosterone treatment given to healthy elderly men with baseline T levels <200 ng/dl (6.94 nmol/l), but not to comparably healthy men with minimally reduced T levels, significantly increased BMD values in the lumbar spine but not the hip, suggesting that only significantly hypogonadal men are likely to be responsive to androgen administration. There were too few men in our study with basal T levels <200 ng/dl (6.94 nmol/l) to evaluate the latter possibility. To avoid possible adverse effects of T, we applied a low dose of only 100 mg every 2 weeks, which is half the dose used in prior studies of elderly andropausal (27)(28)(51) and non-elderly hypogonadal (52)(53)(54)(55) men. For example, in a study by Tenover (28), testosterone enanthate was administered i.m. at a dose of 100 mg every week to elderly men with low or borderline low serum T levels. This dose reduced urinary hydroxyproline excretion after 3 months of therapy. In two other important studies in elderly men, the dose of testosterone administered was 200 mg i.m. every 2 weeks, and this resulted in significant improvements in grip strength (27)(51). In one of these studies, serum osteocalcin levels rose after 3 months of testosterone administration (27), whereas in the other, osteocalcin levels were unchanged after 12 months (51). Finally, the duration of therapy may be insufficient, particularly given the lower T dosage we employed. In studies by Katznelson (52) and others (14)(29)(56) in hypogonadal men, significant changes in BMD were demonstrated only after 12 to 18 months of T administration.

We found that coadministration of GH + T did not significantly alter the effect of GH to increase osteocalcin, whereas it eliminated the GH stimulatory effects on PICP levels, the latter because of apparently opposing effects of GH to stimulate and T to inhibit PICP. In addition, combination treatment, but not administration of GH or T alone, increased urinary deoxypyridinoline excretion and led to a small but significant decrease in BMD at the proximal radius. Whether these findings resulted from an interactive effect of the relatively high dose of GH and low dose of T remains to be determined. To our knowledge, there are no prior controlled studies describing the effects on bone metabolism or bone density of concomitant administration of GH + T given to healthy older men with age-related declines in testosterone.

In summary, short-term HRT improves bone metabolism and BMD in women at clinically important sites, and this effect is not significantly altered by the addition of GH. The doses and duration of T employed in this study did not result in any measurable effects on bone metabolism or BMD in men. Given the known bimodal action of GH on bone and the apparent favorable biochemical effects of GH + T in men, longer duration trials of combined hormone administration and efforts to define the characteristics of responders appear warranted.


   Acknowledgments
 
This work was supported in part by National Institutes of Health Research Grant RO-1 AG11005 (to MRB) and General Clinical Research Center Grant MO-1-RR-02719, from the National Center for Research Resources, National Institutes of Health, Bethesda, MD 20892.

We thank Drs. M. Janette Busby-Whitehead, Thomas E. Stevens, Jocelyn J. Jayme, Tracey A. Roy, and the nursing staff of the General Clinical Research Center (GCRC) for their invaluable assistance in the conduct of patient studies; Dr. Neal Fedarko and the GCRC Core Laboratory staff for their expert performance of the bone biochemical measurements; Genentech, Inc., and Novartis Pharmaceuticals for their generous provision, respectively, of recombinant human GH and transdermal estradiol; and Drs. Neal Fedarko and Jeff Metter for their careful review of the manuscript.

Received August 6, 2001

Accepted August 27, 2001


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