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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 9 2795-2798
Copyright © 1997 by The Endocrine Society

Original Studies

Reduced Serum Levels of the Growth Hormone-Dependent Insulin-Like Growth Factor Binding Protein and a Negative Bone Balance at the Level of Individual Remodeling Units in Idiopathic Osteoporosis in Men1

Anna G. Johansson, Erik F. Eriksen, Erik Lindh, Bente Langdahl, Werner F. Blum, Anders Lindahl, Östen Ljunggren and Sverker Ljunghall

Department of Internal Medicine (A.G.J., E.L., Ö.L., S.L), University Hospital, S-751 85 Uppsala, Sweden; the University Department of Endocrinology (E.F.E., B.L.), Aarhus Amtssygehus, DK-8000 Aarhus, Denmark; Universitätskinderklinik (W.F.B.), D-7400 Tübingen, Germany; and the Department of Clinical Chemistry (A.L.), Sahlgren’s Hospital, S-413 45 Gothenburg, Sweden

Address all correspondence and requests for reprints to: Dr. Anna G. Johansson, M.D., Ph.D., Department of Internal Medicine, University Hospital, S-751 85 Uppsala, Sweden. E-mail: Anna.Johansson{at}medicin


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Idiopathic osteoporosis in younger individuals could be related to reduced bone formation rather than increased bone resorption, and disturbances in GH or insulin-like growth factor (IGF)-I production could be involved in its pathogenesis. In the present study, men with idiopathic osteoporosis were compared with healthy men, with respect to bone histomorphometry and to serum levels of IGF-I, IGF-II, IGF binding protein (IGFBP)-2 and IGFBP-3, and 24-h urinary excretion of GH. Mean wall thickness was reduced in the patients (48.3 ± 7.2 vs. 61.7 ± 5.4 µm, P < 0.001). Also, resorption depth was decreased, albeit to a lesser degree (54.4 ± 3.8 vs. 60.7 ± 5.3 µm, P < 0.01), thus creating a pronounced negative balance (-6.04 ± 9.8 vs. 0.96 ± 3.2 µm, P < 0.05). In the patients, serum concentrations of IGFBP-3 were reduced, compared with controls, with a 46% lower mean value; whereas levels of IGF-I, IGF-II, IGFBP-2, and GH were similar in the two groups. Thus, there was a significant negative balance caused by a pronounced decrease in wall thickness in men with idiopathic osteoporosis. The finding of low IGFBP-3 levels in these patients is interesting, in view of previous clinical and experimental findings, but its pathophysiological significance remains to be determined.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OSTEOPOROSIS IS characterized by increased fragility caused by a disturbed microarchitecture of the bone tissue and a low bone mass (1). Theoretically, bone loss occurs in response to a negative balance between bone formation and bone resorption, and osteoporosis could thus either be caused by a reduction of the former or an increase of the latter (2). A few studies concerning the pathogenesis of idiopathic osteoporosis in younger men and women have been published, and they suggest that the primary cause of bone loss in these patients is a reduced capacity of bone formation (3, 4).

Insulin-like growth factor (IGF)-I has potent stimulatory effects on synthesis of bone-specific proteins and osteoblastic proliferation in cell and organ cultures in vitro (5, 6). Messenger RNA for IGF-I has been demonstrated in cultures of human osteoblasts (7), and several hormones and growth factors with well-known skeletal effects (e.g. PTH, estrogen, 1,25-dihydroxyvitamin D3, cortisol, PG E2) have been shown to regulate the synthesis of IGF-I in rodent bone tissue (6). Furthermore, the content of IGF-I in cortical bone has been reported to decrease with age (8), which could be related to the high incidence of osteoporosis in older subjects.

Clinical data suggest that GH secretion is important for maintenance of bone mass in adults. A well-known effect of GH is to increase the circulating levels of IGF-I. Bone mineral density (BMD) was reduced, compared with normal subjects, and the circulating levels of IGF-I were significantly correlated to BMD in adult patients with GH deficiency (9, 10), and the GH-dependent IGF binding protein (IGFBP)-3 was an important determinant of BMD in healthy men (11). Recently, it was suggested that variation in GH secretion could explain racial differences in BMD (12).

We have previously described that a group of men with idiopathic osteoporosis had lower plasma levels of IGF-I than did healthy controls (13). In the present study, our aims were to further evaluate the IGF system and to characterize the bone disease at the level of individual remodeling units in men with idiopathic osteoporosis.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients and healthy controls

Altogether, 28 men with idiopathic osteoporosis, 45 ± 10 yr old (mean ± SD; range 29–62), who had been referred to the osteoporosis unit, were included in the study. A total of 16 patients had suffered from vertebral compression fractures, and 3 patients suffered from hip fractures. Only 1 patient had suffered from both vertebral and hip fractures. Out of 8 patients with multiple rib fractures, 5 had had vertebral fractures, whereas 2 had had hip, hand, or pelvic fractures. Radiological evidence of osteopenia (striation or reduced attenuation of vertebral bodies and suspected, but not conclusive, vertebral fractures) was the cause of investigation in a total of 7 patients. BMD of the spine was 0.892 ± 0.156 g/cm2 (t-score -2.9 ± 1.3) and of the neck, 0.818 ± 0.115 g/cm2 (t-score -2.2 ± 1.0), measured by dual-energy x-ray absorptiometry (DPX-L, Lunar Radiation Incorporation, Madison, WI).

The diagnosis of idiopathic osteoporosis was established, as previously described (13), by exclusion of secondary causes; i.e. all patients with alcoholism, hypogonadism, thyroid or parathyroid disturbances, malabsorption, pituitary disease, renal or hepatic disease, or prior treatment with glucocorticoids were excluded. Mean body weight of the patients was 77 ± 11 kg (range 51–96 kg) and body height was 178 ± 7.8 cm (range 159–192), giving a mean body mass index of 24.4 ± 2.9 kg/m2. The patients were otherwise healthy. Bone biopsies were performed, as part of the clinical investigation, to exclude mineralization defects. Mean age at the time of diagnosis was 42 ± 11 yr (range 23–61 yr).

For the serum and urine analyses, sampling was performed after overnight fasting in patients and in 19 healthy controls, 45 ± 9 yr old, who were recruited from the hospital staff. For the analysis of urinary GH, both patients and controls collected urine for 24 h at leisure in their homes. For the bone histomorphometric comparisons, 11 healthy men, 31 ± 10 yr old (P < 0.05, compared with 43 ± 9 yr, which was the mean age of the patients who participated in the histomorphometric part of the study) served as controls.

The study was approved by the Ethical Committee at the Faculty of Medicine, University of Uppsala, Sweden.

Laboratory methods

IGF-I levels in serum were measured by RIA, with a polyclonal rabbit anti-IGF-I antiserum, after reduction of IGFBP concentrations by acid-ethanol. To minimize the interference of any remaining IGFBPs, a tracer with reduced affinity for IGFBPs was used (125I-des-(1, 2, 3)-IGF-I). Intra- and interassay variations were 3.1 and 10.0%, respectively. IGF-II and IGFBP-2 concentrations in serum were determined by RIA, as previously described (14, 15), with intra- and interassay variations of 3.6 and 12.2%, respectively, for IGF-II measurements and 3.7 and 9.6%, respectively, for IGFBP-2 measurements. IGFBP-3 levels in serum were measured by RIA, using a commercially available kit (Diagnostic Systems Laboratories Inc., Webster, TX), with intra- and interassay variations of 4.9% and 7.2%, respectively.

GH levels in urine were measured with an immunometric assay for urinary GH (BioMerieux, Marcy L’Etoile, France) in samples collected over a 24-h period. The detection limit was 1.3 µU/L of GH, and the total coefficient of variation was less than 8% at mean 8.8 µU/L (n = 75), 5.6% at mean 45.8 µU/L (n = 80), and 7.4% at mean 98.3 µU/L (n = 63). The assay was calibrated against the first international standard from WHO (80:2.6 U/mg). The linearity was tested with a serial dilution procedure of a urine sample. The dilution curve was parallel to the standard curve, thus excluding unspecific cross-reactivity. All samples were run as duplicates, and values were expressed as µU/day.

Transiliac bone biopsy specimens were obtained after in vivo double-tetracycline labeling. The cylindrical bone samples were fixed and embedded, and dynamic quantitative bone histomorphometry was performed, as previously described (16), in bone biopsies from 11 of the patients and 11 healthy controls. Bone biopsies were performed early in the diagnostic investigation of the patients. As a consequence, the time between onset of clinical evidence of osteoporosis and the performance of bone biopsies was only 1 ± 1 yr (range 0–4).

Statistical methods

Student’s unpaired t test was used to compare the groups, and multiple regression analyses were performed to evaluate age-dependent differences between patients and controls. A P-value less than 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Mean values and ranges of histomorphometric variables are shown in Tables 1Go and 2Go. The men with idiopathic osteoporosis had clearly reduced balance, because bone formation (wall thickness) was more reduced than bone resorption (preosteoblastic erosion depth). Because the patients were somewhat older than the controls, multiple regression analyses were performed to test significance of age and study group for the variation in the histomorphometric indices. There was no significant contribution of age to the variation in either balance or wall thickness, indicating that the differences between the study groups were independent of age. The correlation between study group and preosteoblastic resorption depth did not reach significance if the explanatory equation also included age, i.e. the difference between the study groups in resorption depth was biased by age.


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  		Table 1. Resorptive indices measured by bone histomorphometry of tetracycline-labeled bone biopsies from 11 men with idiopathic osteoporosis and from 11 healthy men

 

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  		Table 2. Indices of formation, balance, and activation of remodeling measured by bone histomorphometry of tetracycline-labeled bone biopsies from 11 men with idiopathic osteoporosis and from 11 healthy men

 
There was a significant positive correlation between mean wall thickness and preosteoblastic erosion depth in the controls (r = 0.82, P < 0.01) but not in the men with idiopathic osteoporosis, where the correlation tended to be negative (r = -0.56, P = 0.07; Fig. 1Go).



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  		Figure 1. Relationship between preosteoblastic resorption depth and mean wall thickness, measured by bone histomorphometry, in healthy men (top) and in men with idiopathic osteoporosis (bottom).

 
Mean values and ranges of serum and urinary variables in the patients and the controls are shown in Table 3Go. The serum levels of IGFBP-3 were clearly lower in the men with idiopathic osteoporosis. There were no significant differences between the patients and the controls in the serum concentrations of IGF-I, IGF-II, IGFBP-2, or in the 24-h urinary excretion of GH (Table 3Go).


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  		Table 3. Serum levels of IGF-I and -II, IGFBP-2 and -3, and 24-h urinary excretion of GH (U-GH) in men with idiopathic osteoporosis and in healthy, age-matched men

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Idiopathic osteoporosis in men is diagnosed by careful exclusion of known causes of osteopenia, such as alcoholism, glucocorticoid treatment, endocrine or neoplastic disease, and osteomalacia (17). In the present study, male patients with idiopathic osteoporosis had clearly negative balance between formation and resorption at the level of individual remodeling units. This, in turn, was dependent on reduced bone formation with a decrease in wall thickness, whereas neither resorptive indices, nor activation frequency, nor mineralization rate were significantly deviant from that of the controls. The lack of a positive correlation between resorption depth and wall thickness in the men with osteoporosis suggests that there is an insufficient coupling from bone resorption to bone formation in these patients. Because the IGF system has been implicated in the coupling between bone resorption and bone formation, it is of great interest that the serum concentrations of IGFBP-3 were reduced in the men with idiopathic osteoporosis. However, there were no significant linear correlations between histomorphometric indices and IGFBP-3 levels, and therefore, we can only speculate that the two observations are connected. Nevertheless, IGFBP-3 is the only variable besides strictly bone-related indices that deviate from what is seen in healthy men. Furthermore, Reed and co-workers (4) were able to demonstrate linear correlations between serum levels of IGF-I and histomorphometric indices of bone formation in men and women with idiopathic osteoporosis. In view of recent clinical and experimental indications of the significance of IGF-I and GH in bone metabolism (8, 9, 10, 11), it is tempting, therefore, to link reduced bone formation with a disturbed IGF system.

In the present study, serum levels of IGF-I were similar in men with idiopathic osteoporosis and healthy age-matched controls. However, in the study by Reed et al. (4), low serum levels of IGF-I were seen in young men and women with idiopathic osteoporosis and deficient bone formation. Serum concentrations of IGFBP-3 were not measured, and the reduction of IGF-I was mainly seen in the patients below the age of 36 yr. Considering the age range of the patients in the present study, the findings of Reed et al. and the present study, therefore, need not be contradictory. In a previous study, we have reported on reduced levels of circulating IGF-I in men with idiopathic osteoporosis (13). However, in that study, the total amount of IGF-I was measured in plasma without prior extraction of IGFBPs. Because IGFBPs interfere with the RIA for IGF-I, a reduction in IGFBP levels could partially explain the previously reported results. IGFBP-3 levels significantly contributed to the variation in BMD in healthy men (11), and in a large group of patients with osteoporosis, both IGF-I and IGFBP-3 concentrations in serum were lower than in control subjects (18). Together with the present finding of reduced IGFBP-3 levels in serum in men with idiopathic osteoporosis, these findings suggest a defective regulation of the serum levels IGF-I and IGFBP-3 in idiopathic osteoporosis. Nevertheless, the pathophysiological role of these observations remains to be determined.

In our patient group, low values of IGFBP-3 were not related to any other gross abnormality of GH secretion, and according to the diagnostic criteria, they did not have any other hormonal deficiency. An impaired peripheral response to GH, of unknown character, can not be ruled out. Apart from disturbances in the regulation of IGFBP-3 synthesis, also increased proteolysis and/or disturbed complex formation in the circulation with increased clearance could result in reduced serum levels of IGFBP-3 (19). A divergent pattern in IGF-I and IGFBP-3 levels is rarely seen but has been reported in some circumstances. For example, 24-h infusion with PTH(1–38) in healthy women resulted in unchanged serum levels of IGF-I and IGF-II, whereas IGFBP-3 concentrations increased (20). Finally, it can not be excluded that the low serum levels of IGFBP-3 in male idiopathic osteoporosis are a consequence, and not a cause, of disease.

In summary, bone histomorphometry revealed a significant negative balance, caused by a pronounced decrease in wall thickness, in men with idiopathic osteoporosis. They also had lower serum levels of IGFBP-3 than healthy age-matched men. There are also previous reports on low serum levels of IGF-I and IGFBP-3 in osteoporosis, but yet we lack evidence that a disturbed IGF system is part of the pathogenesis in idiopathic osteoporosis.


   Footnotes
 
1 This study was supported by the Swedish Medical Research Council and Pharmacia AB, Stockholm, Sweden. Back

Received September 5, 1996.

Accepted May 2, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Consensus Development Conference. 1993 Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. 94:646–649.[CrossRef][Medline]
  2. Eriksen EF. 1986 Normal and pathological remodeling of human trabecular bone: three dimensional reconstruction of the remodeling sequence in normals and in metabolic bone disease. Endocr Rev. 7:379–408.[Abstract/Free Full Text]
  3. Khosla S, Lufkin EG, Hodgson SF, Fitzpatrick LA, Melton LJ. 1994 Epidemiology and clinical features of osteoporosis in young individuals. Bone. 15:551–555.[Medline]
  4. Reed BY, Zerwekh JE, Sakhaee K, Breslau NA, Gottschalk F, Pak CYC. 1995 Serum IGF 1 is low and correlated with osteoblastic surface in idiopathic osteoporosis. J Bone Miner Res. 10:1218–1224.[Medline]
  5. Hock JM, Centrella M, Canalis E. 1988 Insulin-like growth factor I has independent effects on bone matrix formation and cell replication. Endocrinology. 122:254–260.[Abstract/Free Full Text]
  6. Schmid C. 1993 IGFs: function and clinical importance. 2. The regulation of osteoblast function by hormones and cytokines with special reference to insulin-like growth factors and their binding proteins. J Intern Med. 234:535–542.[Medline]
  7. Okazaki R, Conover CA, Harris SA, Spelsberg TC, Riggs BL. 1995 Normal human osteoblast-like cells consistently express genes for insulin-like growth factors I and II but transformed human osteoblast cell lines do not. J Bone Miner Res. 10:788–795.[Medline]
  8. Nicolas V, Prewett A, Bettica P, et al. 1994 Age-related decreases in insulin-like growth factor-I and transforming growth factor-ß in femoral cortical bone from both men and women: implications for bone loss with aging. J Clin Endocrinol Metab. 78:1011–1016.[Abstract]
  9. Johansson AG, Burman P, Westermark K, Ljunghall S. 1992 The bone mineral density in acquired growth hormone deficiency correlates with circulating levels of insulin-like growth factor I. J Intern Med. 232:447–452.[Medline]
  10. Holmes SJ, Economou G, Whitehouse RW, Adams JE, Shalet SM. 1994 Reduced bone mineral density in patients with adult onset growth hormone deficiency. J Clin Endocrinol Metab. 78:669–674.[Abstract]
  11. 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 bone mineral density in healthy men. J Bone Miner Res. 9:915–921.[Medline]
  12. 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]
  13. Ljunghall S, Johansson AG, Burman P, Kämpe O, Lindh E, Karlsson FA. 1992 Low plasma levels of insulin-like growth factor I (IGF-I) in male patients with idiopathic osteoporosis. J Intern Med. 232:59–64.[Medline]
  14. Blum WF, Ranke MB, Bierich JR. 1988 A specific radioimmunoassay for insulin-like growth factor II: the interference of IGF binding proteins can be blocked by excess of IGF-I. Acta Endocrinol (Copenh). 118:374–380.[Abstract/Free Full Text]
  15. Blum WF, Horn N, Kratzsch J, et al. 1993 Clinical studies of IGFBP-2 by radioimmunoassay. Growth Regul. 3:100–104.[Medline]
  16. Eriksen EF, Melsen F, Mosekilde L. 1984 Reconstruction of the formative site in iliac trabecular bone: a kinetic model for bone resorption in 20 normal individuals. Metab Bone Dis Relat Res. 5:235–242.[CrossRef][Medline]
  17. Jackson JA, Kleerekoper M. 1990 Osteoporosis in men: diagnosis, pathophysiology, and prevention. Medicine. 69:137–152.[Medline]
  18. Wüster C, Blum WF, Schlemilch S, Ranke MB, Ziegler R. 1993 Decreased serum levels of insulin-like growth factors and IGF binding protein 3 in osteoporosis. J Intern Med. 234:249–255.[Medline]
  19. Lewitt MS, Saunders H, Phuyal JL, Baxter RC. 1994 Complex formation by human insulin-like growth factor-binding protein-3 and human acid-labile subunit in growth hormone-deficient rats. Endocrinology. 134:2404–2409.[Abstract/Free Full Text]
  20. Johansson AG, Baylink DJ, af Ekenstam E, Lindh E, Mohan S, Ljunghall S. 1994 Circulating levels of insulin-like growth factor-I and -II, and IGF-binding protein-3 in inflammation and after parathyroid hormone infusion. Bone Miner. 24:25–31.[Medline]



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