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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

The present study was performed to investigate the role of insulin-like growth factor I (IGF-I), IGF-binding protein-2 (IGFBP-2), and IGFBP-3 in age-dependent bone loss in postmenopausal Japanese women. One hundred and sixty-five Japanese women aged 43–88 years (mean age, 62) were enrolled in the cross-sectional study. Bone mineral density (BMD) was measured at the lumbar spine, femoral neck, and midradius by dual-energy X-ray absorptiometry or single-photon absorptiometry. Serum levels of IGF-I, IGFBP-2, and IGFBP-3 were measured by radioimmunoassay. BMD at all sites as well as serum levels of IGF-I and IGFBP-3 declined with age, while the serum IGFBP-2 level increased with age. Serum IGFBP-3 and −2 levels were positively and negatively correlated with the serum IGF-I level, respectively. Serum IGF-I and IGFBP-3 levels showed positive correlationship with BMD at any site, particularly at the midradius, while the serum IGFBP-2 level showed negative correlation with BMD. Multiple regression analyses showed age-independent positive correlation between the serum IGF-I level and BMD at all sites as well as age-independent positive correlation between the serum IGFBP-3 level and midradius BMD. The relationship between susceptibility to osteoporotic spinal fracture and serum IGF-I, IGFBP-3, or −2 levels was examined by decade to exclude the influence of aging. Serum levels of IGF-I and IGFBP-3 were significantly lower in subjects with spinal fractures than those without fractures at any decade. No significant difference of serum IGFBP-2 level was observed between subjects with and without fractures. The present findings suggest that IGF-I and IGFBP-3 are important to maintaining bone mass quantitatively as well as qualitatively, and that the determination of serum IGF-I and IGFBP-3 levels could be clinically useful to predict the severity of osteoporosis, particularly the risk of bone fracture associated with osteoporosis.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Osteoporosis is a serious disease affecting a large number of older people throughout the world. The endpoint of its treatment is the prevention of bone fractures associated with osteoporosis, particularly hip and spinal fractures. Recent development of the methods measuring bone mineral density (BMD) and biochemical bone markers has prompted us to establish the fracture threshold1–4 and to estimate the severity of osteoporosis as well as to predict the rate of bone loss,5,6 although the consensus is still pending about predicting the risk of osteoporotic fractures from these measurements. In bone, insulin-like growth factor I (IGF-I) is synthesized in osteoblasts and is an important local regulator of bone formation acting in paracrine and/or autocrine fashions.7 Insulin-like growth factor binding proteins (IGFBPs) are also produced in osteoblasts and modulate biological actions of IGF indirectly by their binding to IGF.7 In addition, IGFBPs per se may directly affect bone and cartilage metabolism.8–10 However, circulating IGF-I, mainly produced in the liver by growth hormone (GH)- and nutrition-dependent fashions, acts in an endocrine manner as well, which activates bone remodeling and exerts anabolic effects on the bone tissue.11–13

Indeed, there has been recent evidence that the GH–IGF-I axis plays an important role in the maintenance of bone mass in adults as well as longitudinal growth of bone in childhood.14–17 In circulation, IGF-I is bound to various IGFBPs and a major part of bound IGF-I is connected to IGFBP-3.18 The serum IGFBP-3 level is considered to be positively regulated by GH and/or IGF-I,19–21 whereas IGFBP-2 is reported to inhibit IGF-I action.8 Although there have been several lines of evidence about the relationship between BMD and serum levels of IGF-I or IGFBP-3,14,17,21–25 the significance of circulating IGF-I and IGFBPs in the regulation of bone metabolism remains uncertain.

The present study was performed to clarify the possible role of IGF-I and IGFBPs in endocrine regulation of bone mass in postmenopausal women and to evaluate further whether serum levels of IGF-I and IGFBPs could be useful markers to estimate the severity of osteoporosis and predict the risk of osteoporotic fractures.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Subjects

Subjects were 165 Japanese postmenopausal women aged 43–88 years (mean, 62) who visited our out-patient clinic for metabolic bone diseases, including osteoporosis, to see if they might suffer from osteoporosis. This study was approved by the Institutional Review Board of our institution. Subjects agreed to participate in this study and gave informed consent. All women had been without spontaneous menses for more than 1 year. Their serum estradiol levels were all <20 pg/ml. Nobody had hepatic or renal dysfunction or nutritional derangements which might cause changes in bone metabolism. All subjects were free of drugs known to influence bone and calcium metabolism until the time of the present study.

Radiography

Lateral X-rays of the thoracic and lumbar spine were taken. The anterior, central, and posterior heights of each of the 13 vertebral bodies from Th4 to L4 were measured using an electronic caliper. Spinal fracture was diagnosed to be present if at least one of three height measurements taken from along the length of the same vertebrae had decreased by more than 20% as compared with the height of the nearest uncompressed vertebral body. From this riteria, 62 women were diagnosed as having spinal fracture (24 and 38 women with single fracture and multiple fractures, respectively). None had a history of serious trauma.

BMD and biochemical measurements

BMD of the lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry (DEXA) (QDR-2000, Hologic Inc., Waltham, MA, U.S.A.). BMD of the lumbar spine (L2–L4) was measured separately and expressed as the mean. Because spinal compression fractures may cause aberrations in BMD, the data from those spines found to have fractures were excluded. Bone mineral content (BMC), bone width, and BMD (defined as BMC/BW) were measured at the distal one-third of the radius using single-photon absorptiometry (SPA) (Bone Mineral Analyzer Type 278O, Norland Co., Fort Atkinson, WI, U.S.A.). The same operator tested all the women during the study to eliminate operator discrepancies. The coefficients of variation (precision) of measurements of lumbar spine, femoral neck, and midradius by our methods were 0.9, 1.7, and 1.9%, respectively. Z score means deviation from the normal age- and sex-matched mean in standard deviation.

After overnight fasting, serum was collected. Serum was promptly separated and stored at −20°C until assay. Serum IGF-I levels were measured by radioimmunoassay (RIA) after acid-ethanol extraction.26,27 Serum IGFBP-3 and −2 levels were also measured by RIA.19 The intact forms of IGFBP-2 and −3 were mostly measured by each assay. Intra-assay and interassay variations of these measurements were 3–4% and 7–8%, respectively.

Statistical analysis

Data were expressed as the mean ± SEM. Statistical significance was determined using Student's t-test. p values <0.05 were considered significant. The regression analysis was performed using the statistical computer program Statview (Abacus Concepts, Inc., Berkely, CA, U.S.A.). Simple regression analysis was used to assess the linear relationship between study parameters, and then Pearson's correlation coefficients were calculated. In some cases, multiple regression analyses were also employed.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Serum levels of IGF-I and IGFBPs with aging

Serum levels of IGF-I and IGFBP-3 decreased with aging (r = −0.491, p < 0.0001 and r = −0.409, p < 0.0001 by single regression analysis, respectively). In contrast, the serum IGFBP-2 level increased with aging (r = 0.460, p < 0.0001 by single regression analysis). Regression analysis revealed that the serum IGFBP-3 level was positively correlated with the serum IGF-I level (r = 0.643, p < 0.0001), while the serum IGFBP-2 level was negatively correlated with the serum IGF-I and IGFBP-3 levels (r = −0.555, p < 0.0001 and r = −0.433, p < 0.0001, respectively).

Role of IGF-I and IGFBPs in age-dependent decrease in BMD

Figure 1 showed age-dependent changes in BMD of the lumbar spine, femoral neck, and midradius in postmenopausal women. BMD at all sites declined with age. We next examined whether IGF-I and IGFBPs would be involved in age-dependent decrease in BMD. As shown in Figs. 2 and 3, serum levels of IGF-I and IGFBP-3 were positively correlated with BMD of the lumbar spine, femoral neck, and midradius. The highest correlation was observed between midradius BMD and serum levels of IGF-I or IGFBP-3. In contrast, the serum IGFBP-2 level was negatively correlated with BMD at all sites (Fig. 4). Since BMD as well as serum levels of IGF-I and IGFBPs were influenced by age and/or body size, the relationship between BMD and serum levels of IGF-I and IGFBPs was re-evaluated after the influence of age and body size was minimized. As shown in Fig. 5, the Z score of lumbar spine BMD (standard deviation of average BMD at each age) was again positively correlated with serum levels of IGF-I as well as IGFBP-3 and negatively correlated with the serum IGFBP-2 level. The highest correlation was observed between Z score and serum IGFBP-3 level. Moreover, BMD/height, the most convenient index of body size adjustment,28 was also positively correlated with serum levels of IGF-I as well as IGFBP-3 and negatively correlated with the serum IGFBP-2 level (Fig. 6). The highest correlation was observed between BMD/height and serum IGF-I level.

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Figure FIG. 1. Age-dependent changes in BMD of the lumbar spine, femoral neck, and midradius.

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Figure FIG. 2. Relationship between serum IGF-I level and BMD at various sites.

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Figure FIG. 3. Relationship between serum IGFBP-3 level and BMD at various sites.

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Figure FIG. 4. Relationship between serum IGFBP-2 level and BMD at various sites.

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Figure FIG. 5. Relationship between Z score of the lumbar spine BMD and serum levels of IGF-I or IGFBPs. Z score means the standard deviation of average BMD at each age.

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Figure FIG. 6. Relationship between lumbar spine BMD/height and serum levels of IGF-I or IGFBPs. BMD/height was employed as an index of BMD adjusted by body size.

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Multiple regression analyses were also employed to explore further whether age-independent correlation would exist between BMD and serum levels of IGF-I or IGFBP-3 (Tables 1 and 2). Age was a greater predictor of BMD than serum levels of IGF-I and IGFBP-3. However, the serum IGF-I level was still positively correlated with BMD at all sites, even if age was taken into account. In addition, although a significant correlationship was not observed between serum IGFBP-3 level and BMD of the lumbar spine or femoral neck, the serum IGFBP-3 level was also still positively correlated with midradius BMD. Moreover, even if age and body mass index were held constant, the serum IGF-I level was still significantly correlated with BMD of all sites, and the serum IGFBP-3 level was significantly correlated with midradius BMD (data not shown).

Table Table 1. Multiple Regression of BMD at Various Sites Against IGF-I and Age
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Table Table 2. Multiple Regression of BMD at Various Sites Against IGFBP-3 and Age
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Relationship between severity of osteoporosis and serum levels of IGF-I or IGFBPs

BMD does not always reflect bone strength in the strict sense, although BMD is considered to account for about 75–85% of the variance in ultimate strength of bone tissue.25 We next analyzed the relationship between susceptibility to osteoporotic spinal fractures and serum levels of IGF-I or IGFBPs. The subjects were classified by decade to exclude the influence of aging. As shown in Fig. 7, serum levels of IGF-I and IGFBP-3 were significantly lower in subjects with spinal fractures, compared with those without fractures at any decade, while serum IGFBP-2 level was not significantly different between these two groups. No significant differences of serum IGF-I and IGFBP-3 levels were observed between subjects with single fracture and those with multiple fractures (data not shown).

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Figure FIG. 7. Differences in serum levels of IGF-I and IGFBPs between subjects with and without spinal fractures by decade. The subjects were classified by decade to exclude the influence of aging. NS, no significant difference.

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Sensitivity-specificity analysis of fracture risk was performed to examine whether serum levels of IGF-I and IGFBP-3 are clinically important predictors of fracture risk. A serum IGF-I level of 110 ng/ml provided a specificity of 81% with a sensitivity of 76%, and a serum IGFBP-3 level of 2.1 μg/ml provided a specificity of 81% with a sensitivity of 81%, while a serum IGFBP-2 level of 470 ng/ml provided a specificity of 32% with a sensitivity of 31%. The present findings suggested that serum levels of IGF-I and IGFBP-3 would be clinically important predictors of fracture risk.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

It is known that the GH secretion rate as well as serum levels of IGF-I and IGFBP-3 decrease with aging.14 Although IGF-I in serum is largely derived from the liver synthesis and closely related to the secreted GH amount, except in the case of poor nutritional state,11 the controversy exists about whether the serum IGFBP-3 level is dependent on IGF-I or on GH itself.19–21,30,31 The present study revealed that the serum IGFBP-3 level was highly correlated to the serum IGF-I level. Although it still remains uncertain whether the IGFBP-3 level is directly stimulated by either GH alone, IGF-I alone, or both, the attenuation of the GH-IGF-I axis with age would be responsible for the reduction in the IGFBP-3 level. The present data, therefore, suggested an age-dependent attenuation of the GH-IGF-I–IGFBP-3 axis in postmenopausal women. However, the present study also revealed that the serum IGFBP-2 level increased with age and was negatively correlated to serum levels of IGF-I and IGFBP-3. Since the serum IGFBP-2 level is known to increase under the conditions where the amount of IGFBP-3 is insufficient to bind available IGFs,14,32,33 IGFBP-2 serves as an additional IGF carrier, when the IGFBP-3 level is inadequate. Alternatively, the serum IGFBP-2 level might be negatively regulated by the GH-IGF-I–IGFBP-3 axis.

The present study revealed that serum levels of IGF-I and IGFBP-3 were positively correlated with BMD at any site, in agreement with previous reports.13,14 Since the BMD and GH-IGF-I–IGFBP-3 axes are both affected by age, the question of whether the age-dependent decline in the GH-IGF-I–IGFBP-3 axis is associated with the age-related loss of bone mass is crucial but remains unsolved. In the present study, we clearly demonstrated that Z score, an index of bone mass adjusted by age, gender, and race, is positively correlated with serum levels of IGF-I and IGFBP-3. Moreover, multiple regression analyses revealed age- and body mass index–independent positive correlation between serum IGF-I level and BMD at all sites as well as age-independent positive correlation between serum IGFBP-3 level and midradius BMD. Attention should be paid to the body size of the subjects, since BMD data measured by DEXA and single photon absorptiometry (SPA) are influenced by body size, and the GH-IGF-I–IGFBP-3 axis is also affected by obesity and body mass index. Therefore, we calculated the BMD/height in each of the subjects, which was reported to be the most convenient index of body size adjustment,28 and found the positive correlationship of BMD/height with serum levels of IGF-I and IGFBP-3. The present findings, therefore, indicate that the GH-IGF-I–IGFBP-3 axis plays an important role in the maintenance of bone mass in postmenopausal women and also suggest that the age-dependent decrease in serum levels of IGF-I and IGFBP-3 is at least in part involved in age-dependent bone loss. However, further studies are necessary to establish to what extent IGF-I and IGFBP-3 contribute to the regulation of BMD.

Although serum levels of IGF-I and IGFBP-3 were positively correlated with BMD at any site, their correlationships with midradius BMD seemed to be more prominent than those with BMD of the lumbar spine and femoral neck. Multiple regression analyses revealed that the serum IGFBP-3 level was significantly correlated with BMD at the midradius but not with BMD at the lumbar spine and femoral neck, once age was taken into account. Since more than 90% of midradius consists of cortical bone, our results suggest that IGF-I and IGFBP-3 play a more important role in endocrine regulation of cortical bone metabolism compared with that of trabecular bone metabolism.

In the present study, the serum IGFBP-2 level showed a negative correlation with BMD. Since IGFBP-2 has been shown to inhibit IGF-I receptor binding and action,8 IGFBP-2 might be involved in endocrine regulation of bone metabolism. However, we cannot rule out the possibility that this negative correlation only reflects negative and strong correlation between serum IGFBP-2 and IGF-I or IGFBP-3 levels.

In the similar direction to IGFBP-2, the serum level of IGFBP-4, which is known to inhibit IGF action in vitro,34,35 is reported to be higher in elderly women with osteoporotic fractures, compared with those without fractures.36 In contrast, IGFBP-3 has been reported to either potentiate or inhibit the effects of IGF-I on bone in vitro, depending on the experimental conditions.37,38 In an in vivo animal study, however, IGFBP-3 potentiates the anabolic actions of IGF-I on bone when administered in combination,39 which is consistent with our present findings in humans. In vitro IGFBP-3 is processed and exposed at the cell surface where IGFBP-3 may potentiate the activity of IGF-I at the receptor level.40–42 Moreover, there has been evidence recently about the existence of receptors for IGFBP-3 and the direct effect of IGFBP-3 on cell proliferation.43,44 It is, therefore, possible that IGFBP-3 may also directly influence skeletal metabolism in a manner independent of IGF-I.

The endpoint of treatment for osteoporosis is the prevention of bone fractures attributed to it. It is, therefore, of great importance to predict the risk of osteoporotic fracture. From this point of view, we and others tried to establish the threshold of osteoporotic fractures of hip and spine.1–4 However, it became evident that there is no absolute threshold of BMD for predicting bone fractures which shows sufficiently high sensitivity and specificity.

Measurements of biochemical bone markers such as osteocalcin, pyridinoline, and deoxypyridinoline are helpful to predict the rate of bone loss, but it is still difficult to predict the risk of osteoporotic fractures from these measurements.5,6 The most meaningful evidence from the present study is that serum levels of both IGF-I and IGFBP-3 were clearly lower in subjects with spinal fractures compared with those without fractures at any decade. These findings suggest that the GH-IGF-I–IGFBP-3 axis plays some important role in maintaining bone mass quantitatively as well as qualitatively, and that serum levels of IGF-I and IGFBP-3 are useful markers for predicting the risk of osteoporotic fractures. However, subjects enrolled in the present study may not represent the general population. Consequently, assessment of larger numbers of patients from the general population and population studies are necessary to determine whether measurements of serum IGF-I and IGFBP-3 levels would be clinically useful as screening tools to predict the severity of osteoporosis and the risk of osteoporotic fractures.

Both IGF-I and IGFBP-3 are synthesized locally in bone and may be released into the blood stream. Nevertheless, circulating IGF-I and IGFBP-3 are considered to be derived from the liver, since the reduced number of hepatocytes caused marked decreases in serum IGF-I and IGFBP-3 levels.11 Furthermore, serum IGF-I and IGFBP-3 levels are dependent on pituitary GH, since GH-deficient patients showed extremely low levels of IGF-I and IGFBP-3 in serum.31 It cannot be ruled out, however, that the proportion of liver and other tissues including bone in generating IGF-I and IGFBP-3 may be changed in some pathological situations.

In conclusion, the endocrine axis of GH-IGF-I–IGFBP-3 seems to be of important in maintaining the bone mass in quantitatively as well as qualitatively favorable conditions. Circulating IGF-I and IGFBP-3 play an endocrine role in the regulation of bone metabolism. Serum levels of IGF-I and IGFBP-3 are candidates of clinically useful markers to predict the severity of osteoporosis.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
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