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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 1 200-206
Copyright © 2000 by The Endocrine Society

Original Studies

The Relationship between Bone Turnover and Body Weight, Serum Insulin-Like Growth Factor (IGF) I, and Serum IGF-Binding Protein Levels in Patients with Anorexia Nervosa1

Mari Hotta, Izumi Fukuda, Kanji Sato, Naomi Hizuka, Tamotsu Shibasaki and Kazue Takano

Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women’s Medical University School of Medicine, 8–1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666; and Department of Physiology, Nippon Medical School (T.S.), 1–1-5 Sendagi, Bunkyo-ku, 113-8602, Japan

Address all correspondence and requests for reprints to: Mari Hotta, M.D., Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women’s Medical University School of Medicine, 8–1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail: BZI00174{at}niftyserve.or.jp


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Malnutrition is one of the risk factors for bone loss in patients with anorexia nervosa (AN). To clarify the effects of nutritional status on bone metabolism, we examined the relationship between serum levels of nutritional indicators [insulin-like growth factor I (IGF-I), IGF-binding protein-2 (IGFBP-2), and IGFBP-3] and markers for bone metabolism [serum osteocalcin and urinary excretion of C-terminal telopeptide of collagen type I (CrossLaps)] in 45 AN out-patients, including 8 severely malnourished patients who required hospitalization and iv hyperalimentation (IVH).

Compared to healthy subjects, serum IGF-I and IGFBP-3 were lower, whereas IGFBP-2 was higher in out-patients who had a body mass index (BMI) less than 16.5 kg/m2. In these patients, urinary excretion of CrossLaps, a marker of bone resorption, was higher, whereas serum osteocalcin, a marker of bone formation, was lower than those in control subjects. All of these parameters were normal in patients whose BMI ranged from 16.5–18.5 kg/m2. Serum levels of osteocalcin correlated positively with BMI (r = 0.512; P < 0.0001), IGF-I (r = 0.558; P < 0.0001), and IGFBP-3 (r = 0.369; P < 0.001) in AN out-patients. In the 8 severely malnourished AN patients, serum levels of IGF-I and osteocalcin significantly increased 3 and 7 days, respectively, after the start of a 5-week IVH therapy regimen and reached normal levels within 5 weeks, accompanied by still elevated urinary excretion of CrossLaps.

The present study demonstrates that an improvement in nutritional status in AN patients during IVH therapy rapidly increases the serum IGF-I levels, followed by a progressive increase in osteocalcin, suggesting immediate start of bone formation. However, increased bone resorption appears to continue for at least 5 weeks.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ANOREXIA NERVOSA (AN) consists of a decrease in caloric intake, weight loss, amenorrhea, and behavioral changes. In addition, several studies have revealed that the disorder is frequently accompanied by osteoporosis (1, 2, 3, 4, 5). Body weight history is the most important predictor of the occurrence of osteoporosis (1, 2, 3, 4, 5). AN patients show both a reduction in serum osteocalcin and an increase in urinary excretion of bone resorption markers such as CrossLaps, deoxypyridinoline, and N-telopeptide (5, 6). We recently demonstrated that the annual increase in bone mineral density (BMD) evaluated by dual x-ray absorptiometry significantly correlates with the body mass index (BMI) (5). The critical BMI for a positive increase in the BMD is 16.4 ± 0.3 kg/m2 (mean ± SE), and indexes of bone formation as well as bone resorption are normalized in AN patients when their BMI becomes greater than 16.5 kg/m2 (5). Therefore, abnormalities in bone metabolism appear to be highly dependent upon the degree of emaciation in AN patients.

Serum insulin-like growth factor I (IGF-I), IGF-binding protein-2 (IGFBP-2), and IGFBP-3 levels represent useful nutritional indicators in both normal subjects and malnourished patients (7, 8, 9, 10, 11, 12). In AN patients, serum IGF-I and IGFBP-3 are both lower, whereas serum IGFBP-2 is higher, than those in normal subjects (13, 14, 15, 16), and BMI correlates positively with free IGF-I and negatively with IGFBP-2 (17). However, the relationship between bone metabolism and nutritional state in AN patients is unclear because bone turnover markers and nutritional indicators have not been investigated simultaneously in the same patients. To investigate the effects of various nutritional states on bone metabolism, we studied the relationship between markers of bone formation (serum osteocalcin) and resorption (urinary CrossLaps excretion) and nutritional indicators, including serum IGF-I, IGFBP-2, and IGFBP-3, in 45 AN patients and followed these parameters longitudinally in 8 severely malnourished AN patients who underwent iv hyperalimentation (IVH) therapy for 5 weeks.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The present study included 45 amenorrheic Japanese patients (aged 17–33 yr) who met the criteria for AN outlined in the Diagnostic and Statistical Manual IV (18) as well as the criteria determined by the survey committee for eating disorders of the Japanese Ministry of Health and Welfare (Table 1Go). Their BMIs ranged from 9.9–22.9 kg/m2. Thirty-eight of the patients had restricting AN, and the remaining 7 had binge-eating/purging AN. All patients were under the care of Dr. Mari Hotta at Tokyo Women’s Medical University (Tokyo, Japan). None of the patients had been treated with estrogen, vitamin D, or calcium before the study.


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  		Table 1. The diagnostic criteria for anorexia nervosa as determined by the Survey Committee for Eating Disorders of the Japanese Ministry of Health and Welfare (1990)

 
To investigate the correlation between bone metabolic markers and nutritional indicators in out-patients, we analyzed 92 serum and urine samples obtained from the 45 amenorrheic AN patients when their body weight changed from 1 of 5 categories of BMI to another, as determined below, or their condition became bulimic phase. Samples were collected twice from 43 patients and 3 times from 2 patients. Moreover, we used 15 samples obtained from 12 patients who had recovered from this disorder, and 10 samples from 10 healthy women aged between 24–30 yr. Serum and urine samples were collected between 0800–1000 h on the same day for each patient and were stored at -80 C until use. Urine samples were obtained at the second morning voiding. Because changes in BMD are correlated with BMI in AN patients (5), the 45 patients were divided into 5 groups according to their BMI: 1) BMI lower than 12.5 kg/m2, 2) BMI between 12.5–14.5 kg/m2, 3) BMI between 14.5–16.5 kg/m2, 4) BMI between 16.5–18.5 kg/m2, and 5) BMI higher than 18.5 kg/m2. The 7 patients were consuming a diet of over 3000 Cal/day during their bulimic phase without purging in the process of recovery, and their BMI values ranged from 15.4–22.7 kg/m2 (mean ± SEM, 19.7 ± 0.7). The recovered AN patients had restored their body weight to 85% or more of their ideal body weight and had resumed regular menses within 1 month of the study. BMI values of the recovered AN patients ranged from 18.6–24.3 kg/m2 (mean ± SEM, 19.8 ± 0.5). BMI values of the control subjects ranged from 19.1–22.0 kg/m2 (mean ± SEM, 20.4 ± 0.5).

Eight of the 45 AN patients (aged 17.4–28.8 yr; BMI, 9.9–14.0 kg/m2 at the start of therapy) had an oral intake of food of no more than an estimated 500 Cal/day and consequently required hospitalization and IVH therapy to prevent further deterioration of their nutritional states. To study levels of bone metabolic markers during acute improvement in nutritional state, the levels of serum osteocalcin, IGF-I, IGFBP-2, IGFBP-3, and urinary CrossLaps excretion were measured at the start of IVH, on the third day of therapy, and once every week thereafter for 5 weeks.

Biochemical and endocrinological study

Bone turnover was assessed by measuring levels of both a fragment (1–43) of osteocalcin and intact osteocalcin in serum (19) as well as CrossLaps excretion in urine (20). CrossLaps is an eight-amino acid fragment derived from the C-terminal telopeptide of collagen type I. Levels of these markers were measured using enzyme-linked immunosorbent assays (Osteometer Bio Tech A/S, Rodover, Denmark). The urinary excretion of CrossLaps was corrected for creatinine (Cr) and expressed as micrograms per mmol Cr. Serum levels of IGF-I and IGFBP-3 were measured using immunoradiometric assays (Daiichi Pharmaceutical Co. Ltd., Radioisotope Laboratories, Tokyo, Japan). Serum IGFBP-2 measurements were performed using a RIA kit (Diagnostics Systems Laboratories, Inc., Webster, TX). The serum levels of 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D [1,25-(OH)2D] were measured by a competitive protein binding assay and RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA), respectively. The serum levels of estradiol were estimated by RIA (Diagnostic Products, Los Angels, CA).

IVH procedure

IVH solutions (PN Twin-1, -2, and –3, Morishita Co., Osaka, Japan) were continuously infused for 24 h. The starting nonnitrogenous calorie intake was 480 Cal/day (PN Twin 1). On the third day of IVH, calorie intake was increased to 720 Cal (PN Twin 2), and then to 1000 Cal (PN Twin 3) on the seventh day. The PN Twin-1, -2, and -3 solutions contained 200, 300, and 400 mL 10.36% amino acid solution, respectively. Each pack contained 51–52 mEq Na+, 30 mEq K+, 50 mEq Cl-, 34–46 mEq acetate, 6 mEq Mg2+, 8 mEq Ca2+, 8 mmol phosphate, and 20 µmol Zn. Multivitamin supplements containing 200 IU vitamin D3 were administered parenterally every day. Although the oral intake of food was permitted, patients gained no more than an estimated 500 Cal/day in this manner during the first 2 weeks.

Statistical analysis

For nonparametric data, Spearman’s ranked correlations (r) were determined between bone metabolic marker levels and BMI or nutritional indicators. Differences in bone metabolic marker levels among the out-patient groups were analyzed for significance for each variable using Mann-Whitney’s U test. A Wilcoxon signed rank test was used to determine significant differences between bone metabolic marker levels or nutritional indicators measured during IVH and those measured before IVH.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Changes in bone metabolic markers and nutritional indicators in each group of out-patients

As shown in Table 2Go, in the three patient groups (F, G, and H) with BMIs below 16.5 kg/m2, serum osteocalcin levels were significantly lower, and urinary CrossLaps excretion was higher than those in the control group (A). The serum osteocalcin level was the lowest (9.4 ± 1.2 ng/mL) and urinary excretion of CrossLaps was the highest (733 ± 75 m/mmol Cr) in patients whose BMI was below 12.5 kg/m2 (group H). As BMI increased in these groups, serum osteocalcin increased, whereas urinary CrossLaps excretion decreased. Serum osteocalcin further increased to 16.2 ± 1.8 µg/L, and urinary excretion of CrossLaps decreased to 251 ± 28 µg/mmol Cr in patients with BMI ranging from 16.5–18.5 kg/m2 (group E). Neither parameter in group E differed significantly from control values (group A). In contrast, both parameters were significantly higher than control values in patients with a BMI greater than 18.5 kg/m2 (group D), bulimic phase patients (group C), and recovered AN patients (group B).


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  		Table 2. Bone turnover markers and nutritional indicators in control, recovered AN patients, bulimic phase AN patients without purging, and AN out-patients

 
As BMI decreased to below 16.5 kg/m2, the serum levels of IGF-I and IGFBP-3 decreased in a BMI-dependent manner. In contrast, serum IGFBP-2 increased reciprocally in a BMI-dependent manner. Mean serum levels of IGF-I, IGFBP-2, and IGFBP-3 were normal in patients with BMI ranging from 16.5–18.5 kg/m2. Furthermore, serum levels of IGF-I and osteocalcin were significantly higher in bulimic phase AN patients than in the controls.

A significant and positive correlation was found between serum osteocalcin and BMI (r = 0.512; P < 0.0001), serum IGF-I (r = 0.558; P < 0.0001), and IGFBP-3 (r = 0.369; P < 0.001; Fig. 1Go, A–C) in AN outpatients. In contrast, a negative correlation was observed between serum levels of osteocalcin and IGFBP-2 (r = -0.472; P < 0.001; Fig. 1DGo) in AN out-patients. The relationship between serum osteocalcin and osteo-anabolic growth factors is presented in Fig. 2Go. A significant correlation was observed between urinary excretion of CrossLaps and BMI (r = -0.451; P < 0.0001). When the ratio of urinary excretion of CrossLaps to serum osteocalcin as an index for the ratio of bone resorption to bone formation was calculated, a highly significant correlation was observed between BMI and ratio of urinary excretion of CrossLaps to serum osteocalcin (r = -0.730; P < 0.0001; Fig. 3Go).



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  		Figure 1. Relationship between serum osteocalcin and BMI (A), serum IGF-I (B), IGFBP-3 (C), or IGFBP-2 (D) in AN out-patients.

 


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  		Figure 2. Relationship among osteocalcin, serum IGF-I, and IGFBP-3 in AN out-patients.

 


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  		Figure 3. Relationship between the ratio of urinary excretion of CrossLaps to serum osteocalcin and BMI in AN out-patients. Ninety-two serum and urine samples were obtained from the 45 amenorrheic AN patients when their BMI or conditions changed. Samples were collected twice from 43 patients and 3 times from 2 patients. Each line connects the data obtained from the same patient.

 
Changes in BMI, bone metabolic marker levels, and nutritional indicators in in-patients undergoing IVH therapy

After 5 weeks of IVH therapy, the BMI of the eight treated patients increased from 12.6 ± 0.3 (mean ± SE) to 14.8 ± 0.6 kg/m2 (Fig. 4Go). The mean serum IGF-I and IGFBP-3 levels at the start of treatment were significantly lowered to 79.6 ± 19.1 ng/mL (control, 254.3 ± 18.4) and 1.79 ± 0.37 µg/mL (control, 3.61 ± 0.13), respectively, whereas the mean serum IGFBP-2 level was significantly elevated to 1.50 ± 0.31 µg/mL (control, 0.43 ± 0.05). By 3 days after the start of IVH therapy, the serum IGF-I level had rapidly and significantly increased to 118.6 ± 16.5 ng/mL despite the lack of a significant increase in BMI and had become normalized after 3 weeks of IVH therapy. The mean serum IGFBP-2 level significantly decreased to1.06 ± 0.17 µg/mL, and the mean serum IGFBP-3 level markedly increased to 2.53 ± 0.23 µg/mL after 2 weeks of IVH therapy when the mean BMI of these patients had significantly increased to 13.54 ± 0.48 kg/m2. The serum levels of IGFBPs were also normalized during IVH therapy.



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  		Figure 4. Changes in nutritional indicators, BMI, and bone turnover marker levels in 8 anorexia nervosa patients during 5 weeks of IVH therapy. The upper panel represents BMI ({blacksquare}) and serum IGF-I (•), IGFBP-2 ({square}), and IGFBP-3 ({circ}). The lower panel represents serum osteocalcin ({blacksquare}) and urinary CrossLaps (•). Data are expressed as the mean ± SE. *, P < 0.05 vs. values at the start of treatment.

 
Serum osteocalcin was markedly lower (6.2 ± 0.7 µg/L) than control levels at the start of IVH therapy, increased significantly to 8.3 ± 1.1 µg/L after 1 week, and reached the control level (13.8 ± 1.1 µg/L) after 3 weeks of IVH therapy. A significant and positive correlation was found between serum osteocalcin and serum IGF-I (r = 0.389; P < 0.05). Urinary CrossLaps excretion was elevated to 723 ± 117 µg/mmol Cr (control, 176 ± 25) at the start of IVH therapy and had slightly, but not significantly, increased to 999 ± 177 µg/mmol Cr within 2 weeks of IVH therapy. It then gradually decreased, but still remained higher than control levels after 5 weeks of IVH therapy, when serum levels of IGF-I, IGFBP-2, IGFBP-3, and osteocalcin were normalized. The mean level of urinary CrossLaps excretion after 5 weeks of IVH therapy was 485 ± 65 µg/mmol Cr, which was not significantly different from that of out-patients with BMI between 14.5–16.5 kg/m2 (Table 2Go). Although vitamin D3 was infused at a daily dose of 200 IU for 5 weeks, serum levels of 25OHD were marginally, but not significantly, increased (Table 3Go). There was no significant increase in serum 1,25-(OH)2D concentrations. The levels of estradiol were less than the sensitivity of the assay (10 pg/mL) during IVH therapy (Table 3Go).


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  		Table 3. The serum levels of 25OHD, 1,25-(OH)2D, and estradiol at the start and during IVH in eight severely malnourished AN patients

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
IGFs and IGFBPs are believed to have a defining role in bone remodeling (21). IGF-I as an anabolic growth factor acts on osteoblasts and preosteoblasts, resulting in potent stimulation of osteocalcin synthesis (22) and collagen synthesis (21, 23) as well as of osteoclastogenesis indirectly via osteoblast activity (24). Higher IGF-I levels are associated with greater BMD in elderly women (25). IGFBP-3 augments the biological activity of IGF-I on osteoblasts and is presumed to synergistically enhance bone formation (21, 26, 27, 28). In contrast, IGFBP-2 inhibits the proliferation of fetal rat calvariae and its collagen synthesis (29). The present study clearly demonstrated that serum IGF-I, IGFBP-2, and IGFBP-3 are closely related to bone formation in AN out-patients, indicating consistency with the results of previous reports (21, 22, 23, 24, 25, 26, 27, 28). In addition, we found rapid increases in serum IGF-I and osteocalcin levels in AN in-patients undergoing IVH therapy. Therefore, it is highly likely that the rapid increase in serum osteocalcin levels in IVH therapy was primarily due to systemic and/or local production of bone IGF-I. Although 1,25-(OH)2D is known to affect osteoblasts as well as osteoclasts (30), the serum 1,25-(OH)2D levels of eight severely malnourished patients did not change significantly during IVH therapy in the present study. These findings are consistent with the results of a previous report that the lowered serum osteocalcin levels of children with kwashiorkor are improved independently of the serum level of 1,25-(OH)2D during nutritional rehabilitation (31). Therefore, vitamin D does not appear to play the major role in the increase in osteocalcin production during IVH therapy. On the other hand, the precise mechanism of enhanced bone resorption in AN patients with BMI lower than 16.5 kg/m2 remains unclear. As bone resorption markers are increased in postmenopausal women who have low concentrations of estrogen (32), estrogen deficiency may be related to the increase in bone resorption marker in AN patients. Furthermore, tumor necrosis factor-{alpha} (TNF{alpha}) may play a role in the increase in bone resorption markers, because TNF{alpha} is known to be a potent inducer of bone resorption, and plasma concentrations of TNF{alpha} are elevated in patients with anorexia nervosa (33).

Several trials have analyzed the effect of recombinant human (rh) IGF-I on bone formation in AN patients or osteoporotic patients due to various causes (6, 28, 34, 35, 36). In one study in AN patients, the administration of rhIGF-I at a dose of 100 µg/kg BW twice a day for 6 days increased bone metabolic markers of bone formation as well as bone resorption, whereas the injection of rhIGF-I at a dose of 30 µg/kg BW·day stimulated only bone formation marker production (6). In AN patients treated with 30 µg/kg BW·day rhIGF-I, the mean serum levels of IGF-I increased to approximately 500 ng/mL, whereas the serum levels of IGFBP-3 did not change (6). IGFBP-3 binds IGF-I and affords the body protection against the most potentially harmful side-effect of rhIGF-I, hypoglycemia. Indeed, in the above study, AN patients with decreased serum levels of IGFBP-3 (28) received continuous infusion of 5% glucose and half-normal saline that was begun simultaneously with the first injection of rhIGF-I to prevent hypoglycemia (6). The changes in bone metabolic markers in the present patients who underwent IVH appear to be similar to the effects of low dose rhIGF-I administration. In contrast to rhIGF-I administration (6, 28, 37), the present study has demonstrated that IVH therapy increases serum IGFBP-3 levels and decreases the IGFBP-2 levels. IGFBP-3 with IGF-I enhances bone formation (27) and reduces side-effects (28).

The results of the present study are the first to show that IVH therapy in severely malnourished AN patients significantly increases serum levels of osteocalcin within 1 week of IVH therapy after an increase in serum IGF-I despite a lack of significant change in body weight. This suggests that bone formation marker production increases in an extremely rapid manner in response to serum IGF-I. In contrast to a rapid increase in and complete normalization of serum levels of osteocalcin and nutritional parameters, 5-week IVH therapy was unable to suppress the enhanced urinary excretion of CrossLaps to the control level. Given that the bone-remodeling period ranges from 100 days in cortical bone to 200 days in cancellous bone (38), it is reasonable that increased bone resorption persisted for more than 5 weeks.

The caloric intake required in AN patients to increase serum IGF-I to levels that prevent a decrease in bone formation is an important issue to be clarified. Serum IGF-I generally correlates with energy intake and nitrogen balance (39). According to studies of nutritional regulation of IGF-I in normal men (39, 40), fasting for 5 days reduces serum IGF-I levels to 36% of prefast values and refeeding a diet of more than 18 Cal/kg BW·day containing 1.0g/kg BW·day protein can raise serum IGF-I levels. A protein-deficient diet with adequate energy (35 Cal and 0.2 g protein/kg BW·day) and a normal diet (35 Cal and 1.35 g protein/kg BW·day) raise serum IGF-I levels to almost 50% and 70% of the basal prefast values by the fifth day, respectively, suggesting that energy intake is relatively important in the regulation of serum IGF-I. Moreover, refeeding an essential amino acid-rich diet causes a larger increase in serum IGF-I than a nonessential amino acid-rich diet (41). In our present study, the nonnitrogenous calorie intake of the starting IVH solution was 480 Cal/day. On the third day of IVH, calorie intake was increased to 720 Cal and then to 1000 Cal on the seventh day. These patients had an oral intake calorie of no more than an estimated 500 Cal/day during the first 2 weeks. The serum IGF-I levels rapidly and significantly increased on the third day of IVH therapy and were normalized after 3 weeks of IVH therapy, when serum osteocalcin reached the control level. Therefore, the IVH solution in our study that contained 1000 Cal and essential amino acids was sufficient to increase serum levels of IGF-I to the normal range in AN patients whose food intake of calories was less than 500 Cal. Such nutritional improvement should continue for a prolonged period of 100–200 days until increased bone resorption subsides to the control level.

As a matter of course, it is difficult for AN patients to accept weight gain, because they have disturbance in perception of body weight or shape and an intense fear of gaining weight. However, in addition to psychotherapy, AN patients should be given precise and detailed information about osteoporosis in an effort to educate them about the impaired quality of life that may be induced as one of the most severe complications of AN.


   Acknowledgments
 
We thank Dr. Norihiro Suzuki of Fuji Rebio Co. (Tokyo, Japan) for his assistance in providing the osteocalcin and CrossLaps assays, Dr. Katsunori Shimada in STATZ Co. (Shinjuku, Tokyo, Japan) for biostatistical advice, and Ms. Kishiko Nakajima and Ms. Mihoko Fujii for their technical assistance.


   Footnotes
 
1 This work was supported in part by a grant for anorexia nervosa research from the Japanese Ministry of Health and Welfare. Back

Received June 4, 1999.

Revised September 15, 1999.

Revised October 7, 1999.

Accepted October 12, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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