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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 10 3463-3468
Copyright © 1998 by The Endocrine Society

Original Studies

Peak Bone Mass in Young Healthy Men Is Correlated with the Magnitude of Endogenous Growth Hormone Secretion1

Mary Russell-Aulet, Brahm Shapiro, Craig A. Jaffe, Milton D. Gross and Ariel L. Barkan

Department of Internal Medicine, Divisions of Endocrinology and Metabolism and Nuclear Medicine, University of Michigan Health Systems and Department of Veterans Affairs, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Mary Russell-Aulet, Department of Endocrinology and Metabolism, 3920 Taubman Center, Ann Arbor, Michigan 48109-0354.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
GH plays a key role during adolescence in longitudinal bone growth and the attainment of peak bone mass. We explored the hypothesis that in early adulthood, bone mineral accretion and/or maintenance in men with normal GH and bone mineral status are related to the magnitude of endogenous GH secretion. Overnight plasma GH concentrations (sampled every 10 min from 2100–0500 h) were measured in 15 healthy, lean, Caucasian men (age, 24 ± 1 yr; body mass index, 22.6 ± 0.6 kg/m2; mean ± SE). Total body, femur, and lumbar spine bone mineral mass/density were measured by dual energy x-ray absorptiometry. Total body and femoral bone mineral mass correlated with both total nocturnal GH and maximal GH concentrations even when bone mineral mass was adjusted by height (P = 0.005–0.02; r = 0.58–0.74). Neither spinal nor total body bone mineral density (BMD) correlated with GH. Maximum GH correlated with the BMD of all four femoral sites (P = 0.01–0.04; r = 0.55–0.66), whereas total nocturnal GH correlated with only one (trochanter; P = 0.01; r = 0.64) femoral site. Our data support the hypothesis that GH continues to play a role in the accretion and/or maintenance of bone mass in young men. This relationship is more evident in the bone mineral mass achieved than in the BMD.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GH PLAYS a key role in the accretion of bone mass and in longitudinal bone growth during adolescence. Once the epiphyseal growth plates close and maximal height is achieved, the role of GH in the attainment of peak bone mass is less well defined (1).

Several observations point to the possibility that GH might continue to play a role in the attainment or maintenance of peak bone mass in young men. Studies examining bone turnover markers indicate an increase in bone turnover when GH is administered in vivo or in vitro (2, 3, 4). Bone mineral mass (BMC)/bone mineral density (BMD) are decreased in patients with long standing GH deficiency and are increased in patients with acromegaly (5, 6, 7). GH replacement given to hypopituitary patients increased their BMC (8). In healthy men, aged 25–59 yr, insulin-like growth factor-binding protein-3 (IGFBP-3) concentrations correlated with BMD (9). Men with idiopathic osteoporosis have been found to have low insulin-like growth factor I (IGF-I) levels (10). All of these observations point to the possibility that GH may play a role in the normal accretion of bone or in the normal maintenance of bone during early adulthood.

In this study, we explored the hypothesis that bone mineral status is related to the magnitude of endogenous GH secretion in healthy men during early adulthood.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Fifteen Caucasian men were recruited by poster advertisement in the Ann Arbor, MI, area. The study was approved by the institutional review board of the University of Michigan and the Department of Veterans Affairs Medical Research Service, and written informed consent was obtained from the subjects before their participation.

Subjects were 19–30 yr old, with body mass indexes below 26.5 kg/m2. Subjects were screened by laboratory tests, medical history, and physical examination to exclude anyone taking any medications or having medical illnesses known to affect bone metabolism or GH secretion or action, including diabetes mellitus and hematological, liver, and renal impairment. All subjects were nonsmokers and night sleepers. Subjects were admitted overnight to the General Clinical Research Center at the University of Michigan Medical Center. A heparinized saline-filled cannula was placed in a forearm vein, and blood samples were taken every 10 min from 2000–0500 h. Subjects were allowed to consume only water from 1930 h to the end of the study protocol. At 2300 h, lights were turned off for the remainder of the study protocol.

In the analyzed dataset, data from 2100–0500 h were used to allow 1 h of sampling for subjects to adjust to the acute effects of beginning the blood-sampling protocol. Maximum GH was defined as the highest GH concentration measured during this time period. Total nocturnal GH was defined as the area under the curve for each individual (see Fig. 1Go).



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  		Figure 1. Examples of GH profiles and BMC in three subjects: highest, lowest, and intermediate nocturnal GH values. Maximum GH is defined as the highest GH concentration measured. Total nocturnal GH was defined as the area under the GH vs. time curve. BMC is given in grams.

 
To ascertain whether nocturnal GH sampling indeed reflected total daily GH output, we analyzed data obtained from eight other young men who underwent 24-h (every 10 min) blood sampling. In this group, 80% of the 24-h total GH secretion occurred during the 8 h between 2100–0500 h. Maximum GH levels in all eight men occurred between 2100–0500 h, and total nocturnal and 24-h GH levels correlated well (P = 0.0001; r2 = 0.99). Based on these observations, it was concluded that the nocturnal 8-h profile accurately represented 24-h GH secretory profiles in the study subjects.

Plasma GH concentrations were measured by chemiluminometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) with an intraassay coefficient of variation of 5% and an interassay coefficient of variation of 9%. Plasma estradiol and testosterone were measured by RIA (Diagnostic Products Corp., Los Angeles, CA) with intraassay coefficients of variation of 5% and 6%, respectively. IGFBP-3 was measured by a two-site immunoradiometric assay (Diagnostic Systems Laboratories, Webster, TX) with an intraassay coefficient of variation of 3%. IGF-I was measured in acid-ethanol-extracted samples by an immunoradiometric assay (Diagnostic Systems Laboratories) with an intraassay coefficient of variation of 3%.

Estradiol, testosterone, IGF-I, and IGFBP-3 were measured in a plasma sample obtained by pooling aliquots obtained between 2000–2100 h. All GH samples from each subject were measured in the same assay. Similarly, samples for testosterone, estradiol, IGF-I, and IGFBP-3 from all individuals were measured in a single assay for each analyte. All samples were assayed in duplicate.

Total body, left femoral neck, and anterior-posterior lumbar spine (L2–L4) dual energy x-ray absorptiometry (Lunar IQ, analysis software version 4.1, Lunar Corp., Madison, WI) scans were performed to determine BMC (grams) and BMD (grams per cm2) where BMD equals BMC divided by the projected bone area. Four sites were measured on the femoral scan: total femur, femoral neck, trochanter, and Ward’s triangle. Measurements of fat and lean body mass were obtained from the total body scan.

Statistics

Results are reported as the mean ± SE. Because the data were not normally distributed, Spearman rank correlation was used to assess simple linear relationships using SAS for Windows, version 6.12. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The demographic, anthropomorphic, hormonal, and bone mineral characteristics of the subjects are shown in Tables 1Go and 2Go.


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  		Table 1. Demographic and hormonal characteristics of 15 study participants

 

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  		Table 2. Bone mineral parameters in 15 study participants

 
Relationships of bone mineral parameters to age and body composition

Although height did not correlate with any BMD measure, height did correlate positively with BMC of total body, femoral neck, and spine (P = 0.02–0.05; r = 0.51–0.59). Therefore, height-adjusted BMC was calculated for each subject [BMC (grams)/height (meters)]. Neither age nor BMI correlated with any bone mineral parameter, except for trochanter BMD, which negatively correlated with age (P = 0.03; r = -0.55). Weight positively correlated with total body BMC (P = 0.02; r = 0.59), but not with any other bone mineral parameter, including height-adjusted BMCs. Body fat, whether expressed as absolute mass or percentage of total body mass, did not correlate with any bone mineral parameter. In contrast, lean mass correlated positively with total body (P = 0.002; r = 0.73), femoral neck (P = 0.01; r = 0.61), Ward’s triangle (P = 0.05; r = 0.51), and total femur (P = 0.03; r = 0.55) BMC. However, only the correlation with total body mineral mass remained significant when measurements were adjusted for height (P = 0.009; r = 0.64). Lean mass did not correlate with any BMD measurement.

Relationships of testosterone, estradiol, IGF-I, and IGFBP-3 with bone mineral parameters, age, and body composition

Plasma levels of testosterone, estradiol, IGF-I, or IGFBP-3 did not correlate with any measurement of bone mineral parameters, age, height, weight, BMI, percent body fat, fat mass, or lean body mass.

Relationships of GH with age, body composition, and other hormones

GH parameters did not correlate with either age or height. Both maximum and total nocturnal GH levels were negatively correlated with percent body fat (P = 0.03; r = -0.56 and P = 0.05; r = -0.52); however, there were no correlations with body weight, BMI, fat mass, or lean mass.

There were no relationships between GH parameters and testosterone, estradiol, IGF-I, or IGFBP-3. Maximal and total nocturnal GH were highly correlated with each other (P = 0.0001; r = 0.90).

Relationships of GH with BMD

Maximum GH positively correlated with all four femoral BMD measurements (Table 3Go). Total nocturnal GH also positively correlated with trochanter BMD. Positive trends were found between total nocturnal GH and BMDs of the femoral neck (P = 0.06; r = 0.50), total femur (P = 0.05; r = 0.51), and Ward’s triangle (P = 0.07; r = 0.48), which did not reach statistical significance. Neither spine nor total body BMD showed any correlation with total nocturnal or maximum GH.


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  		Table 3. Spearman rank correlation coefficients between bone mineral parameters and GH measurements

 
Relationship of GH with BMC

BMC of the total body and of all four measurement sites in the femur correlated positively with GH parameters (Table 3Go and Fig. 2Go). These relationships remained significant even when bone mass was adjusted for height. Spinal BMC was not related to GH parameters.



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  		Figure 2. Relationships between maximum GH and bone mineral parameters in the total body and femoral neck. Spearman rank correlation coefficients are reported. BMC is given in grams. BMD is given as grams per cm2.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, we have demonstrated that the BMC of total body and the femur positively correlated with the magnitude of nocturnal spontaneous GH secretion in young healthy men. There are many factors known to affect BMD and BMC. The subjects in this study were selected to be a homogeneous group of young men with a lean physique and normal hormonal and health profiles. Thus, potential contributions of age and body composition were kept to a minimum, allowing the effects of GH secretion to be examined selectively. Within this well defined group of individuals, neither BMI nor age consistently correlated with any bone mineral measurement.

We examined two relatively simple measures of GH secretion: 8-h total nocturnal GH and maximum GH. Both measures of GH secretion were found to correlate with BMC of the total body and hip, even when BMC was adjusted for height. BMD of the hip correlated with maximal GH secretion. In contrast, BMC and BMD of the spine (which has a high proportion of trabecular bone) did not correlate with GH parameters, suggesting that the interaction between GH and bone may be most evident at cortical sites. This finding is consistent with Bavenboer et al. (11), who found that 12 months of GH administration to young GH-deficient men resulted in increased cortical thickness, but no change in trabecular bone volume, as measured in bone biopsies. In addition, Kotzmann et al. (7) found that patients with acromegaly had increased BMD at the femur, but similar BMD at the lumbar spine compared to normal controls.

Our finding that GH is more highly associated with BMC than with BMD is also in agreement with data reported by Johannsson et al. (8), who found a significant increase in total body BMC, but not in total body BMD, when GH-deficient adults were treated with GH for 24 months. In the same study, the incremental increases in BMC were more marked than the increases in BMD at the femoral neck.

We found that plasma IGF-I concentrations were not related to BMC or BMD, suggesting that the relationship of GH and bone mass may not be mediated by systemic IGF-I concentrations. Our findings do not, however, exclude the possibility that GH-mediated bone accretion may be via autocrine/paracrine action of locally produced IGF-I at the level of the bone. Testosterone and estradiol were not related to any bone mineral parameter. Whereas clinical and biochemical hypogonadism may contribute to the decrement in bone mass/density, there may be a threshold effect, such that variations in plasma testosterone and estradiol concentrations within the normal range may not demonstrate an obvious dose-response relationship.

A limitation of this study is its cross-sectional nature. BMC at the time of this study may reflect earlier pubertal levels of GH secretion. In a longitudinal study of adolescent boys, Martha et al. (12) found that parameters of GH secretion varied much less with respect to intraindividual compared to interindividual values. Thus, relative differences in the magnitude of GH secretion parameters among the subjects in our study may have been preserved over time and reflected their individual GH milieu during puberty.

The findings of this study are also limited to young, lean, Caucasian men. GH secretory profiles have been shown to differ between young men and women (13) and between lean and obese individuals (14). Similarly, African-American men have higher GH levels and bone density than Caucasian men (15). Thus, additional studies may be needed to investigate the relations between parameters of GH secretion and bone physiology in other populations.

The relationship between GH and bone may change throughout adulthood. GH may be important in bone accretion before the end of the third decade of life. However, the relationship between GH and bone in middle-aged and elderly populations has yet to be definitively determined (1).

In summary, our data support the hypothesis that the magnitude of GH secretion continues to play a role in the accretion and/or maintenance of bone mass in normal, young, lean, Caucasian men and that this relationship is more evident with respect to BMC than BMD. Physiological (e.g. nutrition and exercise) and, if necessary, pharmacological interventions to optimize GH secretion during puberty and early adulthood may be important for the achievement of maximal bone mass to prevent osteoporosis and fractures during subsequent years.


   Acknowledgments
 
We thank the nurses and staff of the University of Michigan General Clinical Research Center for their skillful clinical assistance during this study. We thank the nuclear medicine service at the Ann Arbor Department of Veterans Affairs Medical Center for their professional clinical and technical support. We also thank all of the participants of this study for their patience, willingness, and dedication.


   Footnotes
 
1 This work was supported by NIH Grants RO1–38449 (to A.L.B.) and MO1-RR-00042 (to the General Clinical Research Center) and by the Department of Veterans Affairs Medical Research Service. Back

Received April 22, 1998.

Revised June 23, 1998.

Accepted July 1, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Ohlsson C, Bengtsson B, Isaksson OGP, Andreassen TT, Slootweg MC. 1998 Growth hormone and bone. Endocr Rev. 19:55–79.[Abstract/Free Full Text]
  2. Brixen K, Nielsen HK, Mosekilde L, Flyvbjerg A. 1990 A short course of recombinant human growth hormone treatment stimulates osteoblasts and activates bone remodeling in normal human volunteer. J Bone Miner Res. 5:609–618.[Medline]
  3. Stracke H, Schulz A, Moeller D, Rossol S, Schatz H. 1984 Effect of growth hormone on osteoblasts and demonstration of somatomedin-C/IGF I in bone organ culture. Acta Endocrinol (Copenh). 107:16–24.[Abstract/Free Full Text]
  4. Marcus R, Butterfield G, Holloway L, et al. 1990 Effects of short term administration of recombinant human growth hormone to elderly people. J Clin Endocrinol Metab. 70:519–527.[Abstract]
  5. DeBoer H, Blok GJ, Van Lingen A, Teule GJJ, Lips P, Van der Veen EA. 1994 Consequences of childhood-onset growth hormone deficiency for adult bone mass. J Bone Miner Res. 9:1319–1326.[Medline]
  6. Kaufman JM, Taelman P, Vermeulen A, Vandeweghe M. 1992 Bone mineral status in growth hormone-deficient males with isolated and multiple pituitary deficiencies of childhood onset. J Clin Endocrinol Metab. 74:118–123.[Abstract]
  7. Kotzmann H, Bernecker P, Hubsch P, et al. 1993 Bone mineral density and parameters of bone metabolism in patients with acromegaly. J Bone Miner Res. 8:459–465.[Medline]
  8. Johannsson G, Rosen T, Bosaeus I, Sjostrom L, Bengtsson B. 1996 Two years of growth hormone (GH) treatment increases bone mineral content and density in hypopituitary patients with adult-onset GH deficiency. J Clin Endocrinol Metab. 81:2865–2873.[Abstract]
  9. Johansson AG, Forslund A, Hambraeus L, Blum WF, Ljunghall S. 1994 Growth hormone-dependent insulin-like growth factor binding protein is a major determinant of BMD in healthy men. J Bone Miner Res. 9:915–921.[Medline]
  10. Ljunghall S, Johansson AG, Burman P, Kampe O, Lindh E, Karlsson FA. 1992 Low plasma levels of insulin-like growth factor 1 (IGF-I) in male patients with idiopathic osteoporosis. J Intern Med. 232:59–64.[Medline]
  11. Bravenboer N, Holzmann P, De Boer H, Roos JC, Van Der Veen EA, Lips P. 1997 The effect of growth hormone(GH) on histomorphometric indices of bone structure and bone turnover in GH-deficient men. J Clin Endocrinol Metab. 82:1818–1822.[Abstract/Free Full Text]
  12. Martha PM, Rogol AD, Veldhuis JD, Blizzard RM. 1996 A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. III. The neuroendocrine growth hormone axis during late prepuberty. J Clin Endocrinol Metab. 81:4068–4074.[Abstract/Free Full Text]
  13. Ho KY, Evans WS, Blizzard RM, et al. 1987 Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab. 64:51–58.[Abstract]
  14. Veldhuis JD, Liem AY, South S, et al. 1995 Differential impact of age, sex steroid hormones, and obesity on basal vs. pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay. J Clin Endocrinol Metab. 80:3209–3222.[Abstract]
  15. Wright NM, Renault J, Willi S, et al. 1995 Greater secretion of growth hormone in black than in white men: possible factor in greater bone mineral density–a clinical research center study. J Clin Endocrinol Metab. 80:2291–2297.[Abstract]



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