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Neuroendocrine Unit (S.G., L.T., K.M., A.K.), and the Adolescent Eating Disorders Unit (D.H.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Steven Grinspoon, M.D., Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: . sgrinspoon{at}partners.org
Abstract
Over 90% of women with anorexia nervosa demonstrate osteopenia, and almost 40% demonstrate osteoporosis at one or more skeletal sites. In addition to estrogen deficiency causing an increase in bone resorption, nutritional effects on the GH–IGI-I axis may contribute to the severe bone loss in this population by decreasing bone formation. We tested the hypothesis that recombinant human IGF-I (rhIGF-I) would increase bone density in women with anorexia nervosa and furthermore assessed the effects of combined rhIGF-I and oral contraceptive administration (OCP) in this population. Sixty osteopenic women with Diagnosis and Statistical Manual of Mental Disorders IV Revised confirmed anorexia nervosa [age (25.2 ± 0.7 yr, range 18–38 yr), body mass index (17.8 ± 0.3 kg/m2 ), spinal bone mineral density T score (-2.1 ± 0.1 SD) were randomized to one of four treatment groups [rhIGF-I (30 µg/kg sc twice daily) and a daily oral contraceptive (Ovcon 35, 35 µg ethinyl estradiol and 0.4 mg norethindrone], rhIGF-I alone (30 µg/kg sc twice daily), oral contraceptive alone, or neither treatment for 9 months. All subjects received calcium 1500 mg/d and a standard multivitamin containing 400 IU of vitamin D. Administration of rhIGF-I was placebo controlled and blinded to subjects. The rhIGF-I was titrated to maintain IGF-I levels within the age-adjusted normal range for each patient and was well tolerated. The effects of rhIGF-I and OCP were analyzed simultaneously among all subjects in a factorial analysis and in an analysis of the four individual treatment groups. Anteroposterior spinal bone density increased significantly in response to rhIGF-I (1.1% ± 0.5% vs. -0.6% ± 0.8%, P = 0.05, all rhIGF-I vs. all placebo treated, respectively, by analysis of covariance). In contrast, OCP did not result in increased bone density (0.8% ± 0.6% vs. -0.4% ± 0.8%, P = 0.21, all OCP vs. all non-OCP treated, respectively, by analysis of covariance). However, bone density increased to the greatest extent in the combined treatment group (rhIGF-I and OCP), compared with control patients receiving no active therapy (1.8% ± 0.8% vs. 0.3% ± 0.6% vs. -0.2% ± 0.8% vs. -1.0% ± 1.3%, rhIGF-I and OCP vs. rhIGF-I alone vs. OCP alone vs. no active therapy, P < 0.05 for rhIGF-I and OCP vs. no active therapy). These data demonstrate that osteopenic women with anorexia nervosa treated with rhIGF-I showed more beneficial changes in bone density, compared with patients not treated with rhIGF-I. Antiresorptive therapy with OCP is not sufficient to improve bone density in undernourished patients, but such therapy may augment the effects of rhIGF-I in a combined treatment strategy. Further long-term studies are needed to investigate the effects of rhIGF-I and combined anabolic/antiresorptive strategies on bone in women with anorexia nervosa.
SIGNIFICANT BONE LOSS occurs among patients with anorexia nervosa (1, 2). Bone density is reduced by more than 2.5 SD at either the hip or spine in 38% of women with anorexia nervosa and by more than 1.0 SD in 92% of such patients (3). Furthermore, bone loss is permanent in a significant number of such women despite weight recovery (4). The potential mechanisms of bone loss in women with anorexia nervosa include nutritionally mediated changes in gonadal steroid concentrations (5) as well as in the GH-IGF-I system, characterized by low IGF-I concentrations (6, 7). A number of studies have now shown an imbalanced state of bone turnover in such patients, characterized by decreased indices of bone formation and increased indices of bone resorption (6, 8). Increased bone resorption has been attributed to estrogen deficiency. However, low-dose estrogen was not shown to have a significant effect on bone density in a randomized study of osteopenic women with anorexia nervosa (9). Similarly, cross-sectional studies do not suggest a protective effect of estrogen use in this adult population (3). Importantly, prior studies have not assessed the effects of anabolic therapy alone or in combination with antiresorptive therapy on bone mass in anorexia nervosa.
Serum levels of IGF-I, a nutritionally regulated bone trophic hormone, are low in patients with anorexia nervosa, correlate with indices of bone formation and body mass index, and increase in association with weight gain (6, 7, 10). Administration of recombinant human IGF-I (rhIGF-I) at 30 µg/kg sc twice daily over 6 d increased markers of collagen formation without increasing indices of bone resorption during acute fasting in healthy control subjects (11). Similarly, short-term studies of low-dose physiologic IGF-I in women with anorexia nervosa demonstrate a potent effect of IGF-I to selectively increase indices of bone formation (6).
We tested the hypothesis that administration of physiologic rhIGF-I would increase bone density in women with anorexia nervosa. Furthermore, we compared the relative effect of rhIGF-I and oral contraceptive administration with that of single active therapy with rhIGF-I alone or oral contraceptive administration (OCP) alone and a control population receiving neither rhIGF-I nor OCP. We hypothesized that combined anabolic (rhIGF-I) and antiresorptive (OCP) therapy might increase bone density to a greater extent relative to control than either agent alone. The aim of the study was to restore low IGF-I levels within the physiologic range, based on prior studies demonstrating the effects of short-term rhIGF-I on bone turnover in acute and chronic undernutrition (6, 11).
Our data demonstrate that osteopenic women with anorexia nervosa treated with rhIGF-I showed more beneficial changes in bone density, compared with placebo-treated patients. Administration of rhIGF-I over 9 months of treatment is well tolerated in this population. Furthermore, anteroposterior (AP) spinal bone density increased to the greatest extent in patients receiving combined rhIGF-I and OCP. At the current time, no effective therapies exist to increase bone density in the large population of osteoporotic or osteopenic women with anorexia nervosa. Our data suggest a novel paradigm using combined anabolic and antiresorptive therapy to reverse the nutritionally induced changes in bone density in patients with anorexia nervosa. Further studies are needed to investigate the effects of rhIGF-I and other combined anabolic/antiresorptive strategies on bone in women with anorexia nervosa.
Research Design and Methods
Sixty women with DSM-IV-confirmed anorexia nervosa were recruited into a longitudinal treatment study for bone loss. All subjects satisfied the Diagnosis and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM IV-TR) criteria for the diagnosis of anorexia nervosa, weighed less than 85% of ideal body weight and were amenorrheic for at least 3 months before the study (12, 13). No patient had received estrogen, related hormones known to affect bone density, or turnover within 6 months of the study. None of the patients had previously received bisphosphonate therapy. Screening thyroid function, FSH, and PRL levels were normal in all patients. Subjects with World Health Organization defined osteopenia (T score -1.0 or less) at the AP spine were eligible for the current study. Screening bone density in a subset of the subjects was previously reported (3). In addition, serial changes in regional body composition with spontaneous weight recovery were also reported in a subset of the patients (14). The protocol was approved by the Subcommittee on Human Studies of the Massachusetts General Hospital, and informed consent was obtained from all patients. A Data Safety Monitoring Board met every 6 months to review adverse events associated with the study.
Baseline assessment
At the baseline visit, weight and height were measured, bone density of the total body, one-third distal radius, total hip, femoral neck, AP, and lateral lumbar spine were determined by dual-energy x-ray absorptiometry, IGF-I, procollagen carboxyl-terminal propeptide (PICP), 25 hydroxy vitamin D (25-OHD), PTH, and calcium levels were determined. Twenty-four-hour urinary calcium excretion and N-telopeptide (NTX) excretion were also determined. Caloric intake, fat, carbohydrate, calcium, and vitamin D intake were determined from analysis of food records, and a urine pregnancy test was performed. After the baseline assessment, subjects were randomized to rhIGF-I (30 µg/kg sc twice daily, Genentech, Inc., San Francisco, CA) and OCP (Ovcon 35, once a day, containing 35 µg ethinyl estradiol and norethindrone 0.4 mg, Bristol-Myers Squibb Co. Inc., Princeton, NJ) (group I, n = 14), rhIGF-I alone (30 µg/kg sc twice daily) and no OCP (group II, n = 16), rhIGF-I placebo and OCP (Ovcon 35, once a day) (group III, n = 15), or rhIGF-I placebo and no OCP (group IV, n = 15). All subjects received calcium at 1500 mg/d and a standard multivitamin containing 400 IU of vitamin D. Placebo was prepared by the Massachusetts General Hospital pharmacy and was identical in color and consistency to active drug. The administration of rhIGF-I was blinded to the patient but not to investigator or study personnel to permit safety monitoring and dose reduction as needed to keep IGF-I levels within the age-appropriate normal range. OCP administration was not blinded to either patient or investigator, given the expected withdrawal bleeding. The randomization schema was prepared using a permuted block algorithm.
Subsequent study visits
Subjects were assessed for safety at 1 wk by telephone and returned for safety monitoring and assessment of IGF-I levels at 2 wk and then monthly after study initiation. A urine pregnancy test was performed at each visit. Weight was measured at each visit. Serum IGF-I was determined in real time at each visit, and a dose reduction of 25% was performed for patients with an IGF-I level above the normal age-adjusted range for the assay. Dose adjustment was further made based on measured weight at each visit to maintain a dose of 30 µg/kg sc twice daily. Repeat bone density, hormone, and dietary measurements were made at 9 months. Urinary measurements were made at 3, 6, and 9 months. Blood glucose was determined immediately before and 30, 60, 90, and 120 min after the first injection of rhIGF-I or placebo at the baseline, 3-, 6-, and 9-month visits. Subjects kept an injection log and returned unused or empty vials. In addition, patients recorded menses and OCP pills taken in a separate log.
One patient in the rhIGF-I alone group (group II) was discontinued for local skin irritation associated with injections. Two patients in the combined rhIGF-I and OCP group (group I) and one patient in the placebo group (group IV) dropped out after randomization but before study drug administration because of unwillingness to participate in the protocol. One patient in the rhIGF-I alone group (group II) refused further participation after the baseline visit. Two additional patients, each in the IGF-I alone group (group II), were unable to complete the study because severe underlying disease prevented their return for study visits.
Data analysis
Baseline clinical variables were compared among the groups by t test. The primary end point was the change in lumbar spine bone density over 9 months. For urinary excretion of NTX and calcium, measurements at 3, 6, and 9 months were averaged to reduce variability, and the change in time from baseline over the course of the study was determined. The primary analysis was performed using a 2 x 2 factorial design, whereby the effects of IGF vs. placebo injections and OCP vs. no OCP were determined simultaneously across the entire group of patients, using analysis of covariance (ANCOVA), controlling for baseline levels. To test for an interaction between rhIGF-I and OCP, we used ANCOVA with an interaction term. In a secondary analysis, we investigated the change in each individual treatment group (rhIGF-I and OCP, rhIGF-I alone, or OCP alone), compared with the control group using a t test. Paired t tests were also performed within treatment groups. The study was designed as an intent-to-treat analysis. Partial follow-up data from two patients in the placebo-treated group were rejected as extreme outliers using the Dixon criterion.
Materials and methods
Height was determined by stadiometer. Weight was determined on a calibrated scale to the nearest 0.1 kg. Bone density and body composition was performed by dual-energy x-ray absorptiometry (Hologic 4500, Hologic, Inc. Waltham, MA). The precision of this technique is less than 1.5% for the lumbar spine, 1%, for total body fat mass, and 3% for total body lean mass. PRL, FSH, and TSH were determined at screening by previously reported methods. Glucose was determined by fingerstick (Accucheck III meter, Boehringer Mannheim, Indianapolis, IN). Ionized calcium and urinary calcium excretion were determined by previously reported methods. IGF-I was assessed at each visit in real time for safety monitoring by RIA after alcohol extraction with an intraassay coefficient of variation of 2.4–3.0% (Nichols Institute Diagnostics, San Juan Capistrano, CA). Caloric intake was determined by food records and analyzed for total caloric, protein, and fat intake (Minnesota Data Nutrition Systems, Minneapolis, MN). PTH was determined by immunoradiometric assay with an intraassay coefficient of variation of 1.8–3.4% (Nichols Institute Diagnostics). Twenty-five-OHD was determined by RIA with an intraassay coefficient of variation of 9.6–13.4% (DiaSorin, Inc., Stillwater, MN). PICP was determined by RIA with an intraassay coefficient of variation of 2.1–3.2% (DiaSorin, Inc.). Urinary excretion of NTX was determined by ELISA with an intraassay coefficient of variation of 5.0–8.6% (Ostex International, Inc., Seattle, WA) and adjusted for urinary creatinine excretion.
Results
Baseline clinical characteristics
Baseline clinical and bone density data are shown in Tables 1
and 2 . As a group, the subjects were young age (25.2 ± 0.7 yr, range 18–38 yr), low weight (17.8 ± 0.3 kg/m2 ) and significantly osteopenic (AP T score -2.1 ± 0.1 SD). Bone density, body composition, bone turnover indices, and dietary calcium and vitamin D intake were not different among groups at baseline in the factorial analysis. Age was slightly but significantly lower and IGF-I levels higher at baseline among the subjects randomized to receive rhIGF-I.
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IGF-I levels increased significantly over the course of treatment by approximately 200 ng/ml (Fig. 1). Dose reductions were required in 28% of the patients receiving IGF-I. The mean IGF-I level was within the normal range over the course of treatment in all subjects. There were no differences in the OCP vs. non-OCP-treated patients receiving rhIGF-I.
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). In contrast, no effect of OCP on bone density was observed at any site (Table 1). Lean body mass (2.2 ± 0.4 kg vs. 1.1 ± 0.4 kg, P = 0.05) increased significantly in response to rhIGF-I but not OCP (Table 1). Among all the subjects, the change in lean body mass and AP spinal bone density were significantly correlated (r = 0.43, P < 0.001). Neither weight nor caloric intake increased in response to rhIGF-I or OCP in the factorial analysis.
In the four-group analysis, AP spinal bone density increased significantly in the combined treatment group (rhIGF-I and OCP), compared with the placebo-treated, non-OCP-treated control group (+1.8% ± 0.8% vs. -1.0% ± 1.3%) over 9 months (Table 2 and Fig. 2). Bone density did not increase at other sites in response to rhIGF-I or combined rhIGF-I and OCP (Tables 1 and 2). The within-group change in bone density was positive only among the combined treatment group (P = 0.03). Caloric intake decreased slightly in the OCP-alone-treated group, compared with the nontreated control group in the four-group model.
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Serum ionized calcium, urinary calcium, PTH, and 25-OHD did not change significantly among the treatment groups. PICP (10 ± 14 ng/ml vs. -24 ± 15 ng/ml, P = 0.04) and urinary calcium excretion increased (62 ± 14 mg/d vs. 13 ± 14 mg/d, P = 0.02) in response to rhIGF-I, compared with placebo (Table 1, Fig. 3), whereas NTX decreased in response to OCP (-26 ± 6 vs. 1 ± 5 nmol BCE/mmol creatinine, OCP vs. no OCP, P = 0.004, Table 1, Fig. 4).
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The rhIGF-I was well tolerated. Transient, mild irritation at the injection site (erythema and itchiness) was reported by two patients in the rhIGF-I- and OCP-treated group. Significant erythema was noted at the injection site in one patient in the rhIGF-I alone group, resulting in discontinuation from the study. Nadir blood glucose remained above 50 mg/dl after rhIGF-I injection in all patients, and hypoglycemic symptoms were not reported acutely after rhIGF-I injection or at any time throughout the study. Two patients, each in the rhIGF-I alone group, reported mild joint stiffness in association with increased IGF-I levels before dose reduction. Symptoms resolved with normalization of IGF-I levels. One patient in the rhIGF-I alone group reported transient gastric upset after rhIGF-I injection in the setting of normal IGF-I levels. Transient breast tenderness was reported by four patients in the study, one in each treatment group. No other adverse effects related to OCP were reported.
Discussion
Anorexia nervosa is a common condition, affecting a significant percentage of adolescent and college-aged females (15, 16). Bone loss is a significant problem for the great majority of women with anorexia nervosa. We have previously shown that 92% and 38%, respectively, of women with anorexia nervosa demonstrate osteopenia and osteoporosis (3). Bone loss in young women with anorexia nervosa may predispose to increased fractures (1). The mechanisms of bone loss in anorexia nervosa are unclear and may relate to gonadal steroid deficiency and/or other factors related directly to the poor nutritional status of such patients (5). Decreased bone formation indices have been shown in association with increased resorption indices in patients with anorexia nervosa (6, 10). Low weight and decreased IGF-I are associated with reduced bone formation indices, suggesting a potential mechanism whereby chronic undernutrition may contribute to the severe bone loss and abnormal pattern of bone turnover in this population (6, 10). We therefore investigated the effects of low-dose rhIGF-I to increase bone density in patients with anorexia nervosa. We also investigated the effects of OCP and combined rhIGF-I and OCP in this population. These data demonstrate that osteopenic women with anorexia nervosa treated with rhIGF-I showed more beneficial changes in bone density, compared with patients not treated with rhIGF-I. Furthermore, bone density increased to the greatest extent in the combined treatment group (rhIGF-I and OCP), compared with control. In contrast, OCP alone did not result in increased bone density.
One mechanism by which low weight may contribute to low bone density in patients with anorexia nervosa is through an effect on IGF-I. IGF-I is a nutritionally dependent hormone with significant anabolic effects on bone. IGF-I is known to stimulate collagen synthesis, through an effect on the type II IGF-I receptor on the osteoblast (17, 18, 19, 20, 21). In severe undernutrition, patients develop acquired resistance to the action of GH, with resultant decrease in IGF-I and a diminished trophic effect of IGF-I on collagen formation (10).
We have previously shown that the effects of acute undernutrition on bone are in part reversed by short-term rhIGF-I administration. In healthy control subjects, fasting over 4 d was associated with decreased IGF-I levels and decreased bone turnover indices. Administration of rhIGF-I during continued fasting resulted in increased bone turnover, with stimulation of bone resorption and formation indices at supraphysiologic doses of 100 µg/kg sc twice daily and selective stimulation of formation indices at a dose of 30 µg/kg sc twice daily (11). Similarly, rhIGF-I administration at a total daily dose of 60 µg/kg over 6 d was shown to selectively increase markers of bone formation, without increasing markers of bone resorption, in osteopenic women with anorexia nervosa (6). We therefore hypothesized that long-term administration of rhIGF-I at this dose might increase bone density through a trophic effect on bone and collagen formation in relatively IGF-I-deficient, low-weight patients with anorexia nervosa. Our goal was to increase IGF-I levels within the normal physiologic range, rather than to use IGF-I as a pharmacological therapy with resulting IGF-I excess.
In a factorial analysis, rhIGF-I was shown to result in a modest increase in bone density in the AP spine in association with increased PICP. These data suggest an anabolic action of rhIGF-I on bone. In addition, rhIGF-I increased lean body mass but not weight. Furthermore, the change in lean body mass in response to rhIGF-I was correlated with the change in AP spinal bone density. In a multivariate model, the change in lean body mass rather than rhIGF-I treatment assignment was significant, suggesting that the effects of rhIGF-I on bone density may be due to anabolic effects on body composition in this population.
The effect of rhIGF-I to increase bone density, although significant, was relatively small, given the severe degree of bone loss in this population and the known effects of recovery on bone density in anorexia nervosa. For example, Zipfel et al. (22) recently demonstrated an increase in bone mineral density of 12% over 3.6 yr in fully recovered anorexia nervosa patients (annualized rate of increase equal to 3.3%). In our study, the change seen because of rhIGF-I was assessed over a relatively short treatment duration of only 9 months and occurred in the setting of severe ongoing bone loss, as seen by the almost 1% decline in bone density in the untreated group. Therefore, rhIGF-I was able to prevent the severe continuing losses in bone density among osteopenic anorexia nervosa patients not yet weight recovered.
We chose to study physiologic replacement of rhIGF-I in the context of severe undernutrition and therefore chose a relatively low dose of rhIGF-I that resulted in an approximately 200 mg/dl increase in serum IGF-I concentrations. In this regard, larger effects may be seen with more supraphysiological dosing of rhIGF-I over a longer duration or with other more potent anabolic agents such as PTH (23).
Estrogen deficiency may also contribute to bone loss in amenorrheic women with anorexia nervosa. Prior studies have shown increased markers of bone resorption in association with reduced serum E2 concentrations in women with anorexia nervosa (24). However, estrogen deficiency alone does not seem to explain the extreme degree of osteopenia in such patients. Bone loss is more severe in young women with anorexia nervosa than in age-matched, normal-weight women with hypothalamic amenorrhea and an equivalent degree of estrogen deficiency (25). For example, we have previously shown that 40% of women with anorexia nervosa vs. 16% of women with hypothalamic amenorrhea demonstrate a lumbar spine T score less than -2.0 SD (P < 0.0001) (25). Nutritionally related factors such as IGF-I have been shown to correlate with bone density in patients with anorexia nervosa but not normal-weight patients with hypothalamic amenorrhea (25).
Low-dose conjugated estrogens have not previously been shown to increase bone density in patients with anorexia nervosa (9). In contrast, we used a standard OCP, containing 35 µg ethinyl estradiol and norethindrone 0.4 mg in the current study, and did not see a significant effect on bone density over 9 months. Urinary NTX decreased in response to OCP in this study, and it is possible that OCP might protect against bone loss over a longer treatment duration. Furthermore, it is also possible that the progestin agent in the OCP may have affected bone. A potential anabolic effect of progestin on bone has been postulated in the hypoestrogenic model (26); however, the data on progesterone are mixed and the effects of progesterone on bone are not completely understood. The lack of efficacy of OCP in patients with anorexia nervosa stands in marked contrast to the significant effects of even smaller doses of estrogen in normally nourished, estrogen-deficient women with postmenopausal osteoporosis, in whom overall bone turnover is increased with concordant increases in markers of resorption and formation. In contrast, although patients with anorexia are estrogen deficient and demonstrate increased markers of bone resorption, this occurs in the setting of severe undernutrition and decreased overall bone formation rates. Our data suggest that in the context of severe ongoing undernutrition and decreased bone formation, antiresorptive therapy with a standard OCP containing ethinyl estradiol may be inadequate as a treatment for osteoporosis.
The largest effects of rhIGF-I were seen in combination with OCP. We observed a 2.8% difference in spinal bone density between the patients receiving combined rhIGF-I and OCP (group I) and the untreated control subjects (group IV). The within-group change in this group (+1.8% over 9 months) was significant, suggesting the combined treatment strategy did more than prevent bone loss; it resulted in an actual increase in bone density. The duration of dosing, 9 months, was relatively short in this study, and it is possible that a longer duration of dosing might have resulted in a greater effect on bone density. Furthermore, it is possible that the increases seen in response to rhIGF-I will continue beyond the duration of therapy, as has been seen in response to GH therapy in GH-deficient patients (27). Combined rhIGF-I and OCP was most effective at the lumbar spine, which may reflect a greater sensitivity of trabecular bone to the anabolic effects of rhIGF-I. Of note, total body bone density decreased over 9 months in all treatment groups, suggesting that cortical bone may continue to decrease secondary to the underlying condition. Similar changes were seen at the one-third distal radius site, also comprised primarily of cortical bone. Further studies are needed to determine the relative sensitivities of different skeletal sites to combined anabolic/antiresorptive therapies.
Administration of rhIGF-I was safe and generally well tolerated. We used a dosing schedule that resulted in increased IGF-I levels generally within the physiologic range. One of the major potential adverse effects of rhIGF-I, hypoglycemia, was not observed, even among low-weight patients with relatively poor oral intake. Symptoms of excess IGF-I, including swelling and joint aches, were observed in association with increased IGF-I in two patients before dose titration. However, dose reductions were required in a minority of subjects, and mean IGF-I levels were within the normal range. This study investigated rhIGF-I in adults. Severe bone loss is known to occur in adolescents with anorexia nervosa, in association with failure to achieve peak bone mass, low IGF-I and bone formation, and increased bone resorption indices (8). It is unknown whether similar results with rhIGF-I could be achieved in this large subpopulation of patients with anorexia nervosa.
Our data demonstrate that treatment with standard doses of calcium and a multivitamin are inadequate to prevent ongoing bone loss in patients with anorexia nervosa. Lumbar spine bone density decreased 1% over 9 months in the control group receiving calcium (1500 mg/d) and a multivitamin containing 400 IU vitamin D.
The results from this study suggest a potentially important paradigm for the treatment of bone loss in anorexia nervosa. We chose to administer physiologic doses of IGF-I to increase bone mass in an osteopenic, severely undernourished group of patients with anorexia nervosa. Furthermore, we assessed the effects of OCP alone and in combination with rhIGF-I as an antiresorptive strategy in this estrogen-deficient population. Our data demonstrate that osteopenic women with anorexia nervosa treated with rhIGF-I showed more beneficial changes in bone density, compared with patients not treated with rhIGF-I. Our data suggest that anabolic therapies may be most effective when administered concomitantly with an antiresorptive agent in low-weight osteopenic women with anorexia nervosa. In this regard, other anabolic agents may also be investigated in such patients and may be most efficacious in conjunction with OCP or other antiresorptive agents such as bisphosphonates. Our study highlights the novel and potentially beneficial use of combined anabolic and antiresorptive therapy on bone density in patients with anorexia nervosa.
Acknowledgments
We thank the nursing and bionutrition staffs, including Ellen Anderson, M.S.R.D., and Jane Hubbard, M.S.R.D., of the Massachusetts General Hospital General Clinical Research Center for their dedicated patient care. The rhIGF-I was supplied by Genentech, Inc. under FDA IND 38,809.
Footnotes
This work was supported in part by NIH Grants R0l DK 52625 and MO1-RR300088, The Harvard Eating Disorders Center, and The Rubinstein Foundation.
Abbreviations: ANCOVA, Analysis of covariance; AP, anteroposterior; NTX, N-telopeptide; OCP, oral contraceptive administration; 25-OHD, 25 hydroxy vitamin D; PICP, procollagen carboxyl-terminal propeptide; rhIGF, recombinant human IGF-I.
Received September 24, 2001.
Accepted March 5, 2002.
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 S L Liu and C M Lebrun Effect of oral contraceptives and hormone replacement therapy on bone mineral density in premenopausal and perimenopausal women: a systematic review Br. J. Sports Med., January 1, 2006; 40(1): 11 - 24. [Abstract] [Full Text] [PDF]
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J. Yager and A. E. Andersen Anorexia Nervosa N. Engl. J. Med., October 6, 2005; 353(14): 1481 - 1488. [Full Text] [PDF]
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 J. Yager, M. J. Devlin, K. A. Halmi, D. B. Herzog, J. E. Mitchell, P. S. Powers, and K. J. Zerbe Eating Disorders Focus, October 1, 2005; 3(4): 503 - 510. [Abstract] [Full Text] [PDF]
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J. Yager, M. J. Devlin, K. A. Halmi, D. B. Herzog, J. E. Mitchell, P. S. Powers, and K. J. Zerbe Guideline Watch: Practice Guideline for the Treatment of Patients With Eating Disorders, 2nd Edition Focus, October 1, 2005; 3(4): 546 - 551. [Full Text] [PDF]
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 The ESHRE Capri Workshop Group Noncontraceptive health benefits of combined oral contraception Hum. Reprod. Update, September 1, 2005; 11(5): 513 - 525. [Abstract] [Full Text] [PDF]
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 A. Mueller, R. Dittrich, H. Binder, W. Kuehnel, T. Maltaris, I. Hoffmann, and M. W Beckmann High dose estrogen treatment increases bone mineral density in male-to-female transsexuals receiving gonadotropin-releasing hormone agonist in the absence of testosterone Eur. J. Endocrinol., July 1, 2005; 153(1): 107 - 113. [Abstract] [Full Text] [PDF]
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N. H. Golden, E. A. Iglesias, M. S. Jacobson, D. Carey, W. Meyer, J. Schebendach, S. Hertz, and I. R. Shenker Alendronate for the Treatment of Osteopenia in Anorexia Nervosa: A Randomized, Double-Blind, Placebo-Controlled Trial J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3179 - 3185. [Abstract] [Full Text] [PDF]
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 K. K. Miller, S. K. Grinspoon, J. Ciampa, J. Hier, D. Herzog, and A. Klibanski Medical Findings in Outpatients With Anorexia Nervosa Arch Intern Med, March 14, 2005; 165(5): 561 - 566. [Abstract] [Full Text] [PDF]
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C. K. Welt, J. L. Chan, J. Bullen, R. Murphy, P. Smith, A. M. DePaoli, A. Karalis, and C. S. Mantzoros Recombinant Human Leptin in Women with Hypothalamic Amenorrhea N. Engl. J. Med., September 2, 2004; 351(10): 987 - 997. [Abstract] [Full Text] [PDF]
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M. Heer, C. Mika, I. Grzella, N. Heussen, and B. Herpertz-Dahlmann Bone turnover during inpatient nutritional therapy and outpatient follow-up in patients with anorexia nervosa compared with that in healthy control subjects Am. J. Clinical Nutrition, September 1, 2004; 80(3): 774 - 781. [Abstract] [Full Text] [PDF]
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K. K. Miller, S. Grinspoon, S. Gleysteen, K. A. Grieco, J. Ciampa, J. Breu, D. B. Herzog, and A. Klibanski Preservation of Neuroendocrine Control of Reproductive Function Despite Severe Undernutrition J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4434 - 4438. [Abstract] [Full Text] [PDF]
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S. Grinspoon, K. K. Miller, D. B. Herzog, K. A. Grieco, and A. Klibanski Effects of Estrogen and Recombinant Human Insulin-Like Growth Factor-I on Ghrelin Secretion in Severe Undernutrition J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3988 - 3993. [Abstract] [Full Text] [PDF]
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S. Grinspoon, K. Miller, D. Herzog, D. Clemmons, and A. Klibanski Effects of Recombinant Human Insulin-Like Growth Factor (IGF)-I and Estrogen Administration on IGF-I, IGF Binding Protein (IGFBP)-2, and IGFBP-3 in Anorexia Nervosa: A Randomized-Controlled Study J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1142 - 1149. [Abstract] [Full Text] [PDF]
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