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From the Clinical Research Centers |
Neuroendocrine Unit (S.G., K.M., C.C., J.K., C.A., S.P., A.K.) and the Eating Disorder Unit (D.H.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Methods |
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A total of 79 women were studied. Nineteen women with hypothalamic amenorrhea (HA), 30 women with AN, and 30 eumenorrheic age-matched control subjects (NL) were admitted to the General Clinical Research Center at the Massachusetts General Hospital for a 26-h period. All subjects were recruited through advertisement in local community newspapers, by posted advertisements on local college campuses, and by referral from local physicians for this prospective investigation. The subjects with HA had been amenorrheic for at least 3 months, weighed between 90–110% of ideal body weight (IBW), and had been of stable weight for at least 1 yr. Subjects with AN were diagnosed on the basis of DSM IV criteria, including weight less than 85% of IBW and amenorrhea for 3 months before the study. Subjects with abnormal TSH levels; elevated FSH, PRL, or testosterone levels; or a ratio of LH/FSH above 2.5 were excluded from participating in the study. None of the subjects received estrogen within 3 months of the study or was taking any other medications known to affect bone metabolism. Control subjects with regular menses were studied in the early follicular phase, defined as within 7 days of the onset of menses. All control subjects had normal menses throughout their lifetime. All subjects gave written consent as approved by the subcommittee on human studies of the Massachusetts General Hospital. Data on serum leptin levels in the controls and patients with HA have been previously reported (12).
Bone density and body composition analysis
Bone density [anterior-posterior (AP) lumbar spine, lateral spine, total hip, and total body] and fat and lean body masses were determined by dual energy x-ray absorptiometry using a Hologic 4500 densitometer (Hologic, Inc., Waltham, MA). The SD for measurement of bone density at the lumbar spine by the dual energy x-ray absorptiometry technique is 0.01 g/cm2 and does not vary with bone density (13).
Frame size
Frame size (small, medium, or large) was determined from a standardized measurement of elbow width, gender, and age (14, 15).
Biochemical assessment
Measurements of insulin-like growth factor I (IGF-I), estradiol, 25-hydroxyvitamin D, PTH, calcium, and osteocalcin were made at 0800 h after an overnight fast. IGF-I was measured by RIA after an alcohol extraction (intraassay coefficient of variation, 2.4–3.0%; Corning Nichols Institute Diagnostics, San Juan Capistrano, CA). Osteocalcin (intra-assay coefficient of variation, 5.7–8.1%, Corning Nichols Institute Diagnostics) was measured by RIA. Estradiol was measured by double antibody RIA with an intraassay coefficient of variation of 3.2–5.3% (Diagnostics Systems Laboratories, Inc., Webster, TX). Samples from each individual were measured in duplicate and run in the same assay. In addition, urine was collected over 24 h for the measurement of free cortisol, creatinine, and calcium. NTX was measured by enzyme-linked immunosorbent assay (intraassay coefficient of variation, <8%; Osteomark, Ostex International, Inc., Seattle, WA) and adjusted for urinary creatinine excretion in a 2-h specimen from 0800–1000 h after the first void. FSH, testosterone, free testosterone, LH, TSH, cortisol, 25-hydroxyvitamin D, PTH, and PRL were measured using previously described methods (16).
Nutritional assessment
Study subjects were maintained on an ad libitum diet, and their food intakes were observed in the hospital for 24 h. Analysis for total calorie, protein, fat, and carbohydrate contents was performed using the Minnesota Nutrition Data Systems, version 8A/2.6 (Minneapolis, MN). Current calcium and vitamin D supplementation were determined by diet history. For each patient, body mass index (BMI) and percent IBW were calculated as defined by the 1983 Metropolitan Life Tables (17).
Activity assessment
Physical activity was assessed by the Modifiable Activity Questionnaire (18, 19). Current (within the past 12 months) and prior (lifetime) participation in organized sports and leisure and occupational activities were determined. Leisure activity included running, biking, walking, volleyball, tennis, yoga, etc. Patients were considered athletes if they had been or were currently a member of an organized athletic team and/or if they ran approximately 40 miles/week or the equivalent in another form of regular, strenuous exercise.
Menstrual history and pregnancy history
Menstrual history was assessed in the following ways in all patients: 1) age of menarche, 2) time since last menstrual period, and 3) lifetime duration of amenorrhea, defined as the total number of months since menarche with absent menses. In addition, prior lifetime use of estrogen was quantified for each patient, and a prior pregnancy history was obtained for each patient.
Statistical analysis
Bone density and other clinical variables were compared between groups by Student’s t test. Differences in bone density between the HA and AN groups were also tested in standard least square regression models, controlling for duration of amenorrhea, age of menarche, prior estrogen use, and last menstrual period. Among the amenorrheic patients, univariate and multivariate regression models, including BMI, duration of amenorrhea, duration of estrogen use, age of menarche, exercise, IGF-I, 25-hydroxyvitamin D, calcium intake, NTX, osteocalcin, lean body mass, and fat intake, were developed for each bone density site (JMP Statistical Discovery Software, SAS Institute, Inc., Cary, NC). Unless otherwise indicated, all data are expressed as the mean ± SEM.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Age was comparable in the three study groups. Lifetime duration of
amenorrhea, age of menarche, estradiol level, testosterone or free
testosterone level, prior use of estrogen, last menstrual period,
pregnancy history, and exercise were not significantly different in the
HA and AN groups. BMI, lean body mass, caloric intake, fat intake, fat
mass, lean body mass, and IGF-I were significantly reduced in the AN
compared to the HA patients and control subjects. Ionized calcium and
PTH were not significantly different between the groups.
25-Hydroxyvitamin D levels were lower among patients with AN compared
to those with HA, but were within the normal range in all patients.
Total calcium intake (diet plus supplemental) was not significantly
different in each group (Table 1), although subjects with AN were more
likely to be taking a calcium supplement (17%, 21%, and 53% of the
NL, HA, and AN receiving calcium supplements, respectively;
P < 0.01, AN vs. NL; P <
0.05, AN vs. HA), which accounted for 66, 132, and 431
mg/day in each of the three groups, respectively. Similarly, total
vitamin D intakes were similar among the groups, but vitamin D
supplementation was also increased in the AN patients (13%, 21%, and
62% of NL, HA, and AN patients receiving vitamin D supplements,
respectively; P < 0.01 for comparison between the
groups). NTX was increased among the patients with AN, whereas
osteocalcin levels were not different between the groups. The ratio of
NTX to osteocalcin was significantly increased in the AN patients.
Urinary free cortisol (UFC) levels were not different between the AN
and HA groups, but were increased above the normal range in 50% and
30% of patients in the HA and AN groups, respectively
(P = 0.295 for comparison of means and 0.112 for
comparison by percent increased). UFC levels were inversely correlated
with osteocalcin (r = -0.32; P = 0.03) among the
amenorrheic subjects. Exercise was not different between the AN and HA
subjects.
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Elbow width (6.1 ± 0.1 cm for all three groups) and overall
frame size were similar in all three groups (i.e.
percentages with medium frame size, 67%, 68%, and 72%; percentages
with small frame size, 17%, 21%, and 21%; in NL, HA, and AN,
respectively; P = 0.83, by 
2 test). In
addition, heights were similar among the groups (Table 1
).
Bone density
Bone density was lowest in the women with AN, intermediate in the
women with HA, and highest in the eumenorrheic controls at all sites
(lumbar spine, total hip, and total body; Table 2 and Fig. 1). In a comparison of t
scores, 87% of patients with AN vs. 37% of patients with
HA had a spinal bone density more than 1.0 SD
below the expected value, and 40% (AN) vs. 16% (HA)
demonstrated spinal bone density more than 2.0 SD
below the expected value (P < 0.0001, by
2 analysis). For the total hip, 63% of patients with AN
vs. 26% of patients with HA demonstrated bone density more
than 1.0 SD below the expected value, and 40%
(AN) vs. 5% (HA) demonstrated bone density more than 2.0
SD below the expected value (P <
0.0001, by 2 analysis).
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Regression models
Univariate. Among the amenorrheic subjects, age of menarche,
duration of amenorrhea, and NTX were inversely associated with bone
density at all sites (Table 3,
A–D).
In contrast, BMI, IGF-I, lean body mass, and fat intake were positively
correlated with bone density at all sites. Trends toward reduced bone
density in association with increased exercise were seen at the spine
(r = -0.21; P = 0.07) and total body (r =
-0.20; P = 0.07). In contrast, no association with
calcium intake or vitamin D was seen.
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]. In addition, age and BMI were independent predictive
factors of total hip bone density. Duration of amenorrhea, age of
menarche, exercise, NTX, and IGF-I were not significant in the
multivariate models. The r2 values for the models developed
were 0.63, 0.79, and 0.55 for AP spine, total hip, and total body bone
densities, respectively. Among the subjects with AN, bone density was
most significantly related to lean body mass (P = 0.05
and P = 0.03 for the spine and hip, respectively), but
not to duration of amenorrhea or other indexs of estrogen status (Table 3A). In contrast, bone density of the lumbar spine was significantly
related to weight (P = 0.03) and duration of amenorrhea
(P = 0.05) among patients with HA (Table IIIB).
Normal control subjects: For the normal controls, lean body
mass was the only significant factor for the lumbar spine
(P = 0.02; r2 = 0.66 for the model),
whereas fat intake was highly significant for the total hip
(P = 0.02; r2 = 0.58 for the model). BMI
(P = 0.03), NTX (P = 0.01), osteocalcin
(P = 0.02), lean body mass (P = 0.05),
and fat intake (P = 0.03) were significant in the model
for total body bone density (r2 = 0.73 for the model; Table 3D).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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HA is a highly prevalent condition, estimated to account for 15% of all cases of secondary amenorrhea (21, 22, 23). Similarly, AN is a prevalent condition estimated to occur among 0.5–1% of all college age women (3, 4). Subjects with HA had functional amenorrhea without obvious clinical or biochemical abnormality, including normal TSH, FSH, and PRL, and were of normal weight without a recent change in weight. In contrast, subjects with AN, defined by DSM IV criterion, were of severe low weight and also had significantly reduced caloric intake and body fat compared to subjects with HA. None of the subjects were taking any medication known to affect bone metabolism.
The bone densities of the lumbar spine, total hip, and total body were reduced in both amenorrheic groups compared to those in control subjects, but were significantly lower in women with AN than in those with HA. Of importance is the fact that frame size was similar in the patients in all three groups, such that the low bone density in patients with AN is not simply a function of differences in bone size. Although bone age was not determined in the patients, 48 of 49 patients had secondary amenorrhea, and the 1 patient with primary amenorrhea had previously been treated with oral contraceptives. Therefore, it is unlikely that the women in this study (age, >18 yr; mean, 24 ± 1 yr), all with prior estrogen exposure, had open epiphyses. We cannot, however, exclude the possibility that abnormalities in bone mass accretion played a role in the observed osteopenia in both groups of patients.
These data demonstrate more significant loss at both cortical and trabecular sites among patients with AN compared to those with HA. The mechanism contributing to greater bone loss in the patients with AN is unknown, but our data suggest that factors other than estrogen deficiency contribute to the observed differences in bone density. Age of menarche, prior estrogen use, and estradiol levels were not significantly different between the HA and AN groups. Furthermore, significant differences in bone density at all sites remained after controlling for these factors in regression models. Of note, the duration of amenorrhea and other indexes of estrogen status were not independent predictors of bone density in women with AN. In contrast, among women with HA in whom weight and other indexes of nutritional status were normal, duration of amenorrhea was a significant predictor of lumbar spine bone density in the multivariate model. Testosterone and free testosterone levels were not significantly different between subjects with AN and those with HA, demonstrating that differences in androgen status do not explain the significant differences in bone density between the groups.
One potentially important factor that differed between the groups was nutritional status. BMI, percent body fat, fat intake, lean body mass, and IGF-I were significantly different between the HA and AN groups. Bachrach et al. have previously shown a significant correlation between BMI and bone density in adolescent and premenopausal women with AN (5). Similarly, Shono et al. demonstrated a correlation between fat intake and bone density determined by ultrasound of the calcaneus in a small number of premenopausal women (24). The importance of fat intake as a determinant of bone density in amenorrheic premenopausal women was suggested by Frusztajer et al. in a study of ballet dancers, in whom stress fractures were associated with reduced caloric and fat intake (25). In contrast, fat intake was not a significant predictor of bone loss among amenorrheic subjects in this study, but was a significant factor among normal control subjects. IGF-I, a nutritionally dependent bone trophic factor with known effects on osteoblast function (26, 27, 28), may also contribute to reduced bone density in undernourished patients and was significantly reduced in the AN compared to HA patients.
Our data suggest that lean body mass, more than weight and other nutritional parameters, is the critical determinant of bone density among women with AN. Ho et al. demonstrated an effect of lean body mass together with age, physical activity and calcium intake to account for 19% of the variance in spinal bone density among healthy premenopausal women, aged 21–30 (29). Khosla et al. also demonstrated a significant, but again less pronounced, effect of lean body mass on spinal bone mineral density in healthy premenopausal women (30). In contrast, in our population of amenorrheic subjects, lean body mass alone accounted for a much greater degree of the variance in lumbar spine and hip bone densities. The mechanism by which lean body mass may contribute to bone density is not known, but it may relate to a direct effect of mechanical loading forces, i.e. muscle strength, on bone (31). A limitation of our study in this regard is that we did not measure muscle strength as a functional correlate of lean body mass. Alternatively, lean body mass may be a surrogate marker for as yet determined hormonal or nutritional factors that affect bone. These data suggest that reduced lean body mass may have clinical implications for patients with AN, and therefore, that interventions that increase lean body mass merit study in this population of patients.
Increased cortisol levels were observed in a significant number of HA and AN patients and might have contributed to reduced bone density in the amenorrheic groups. Increased cortisol levels in AN and HA have been previously described (2, 6), and none of the patients had clinical stigmata of Cushing’s disease. Furthermore, among the amenorrheic patients, a significant inverse correlation between osteocalcin, a marker of bone formation, and UFC was observed, suggesting that increased cortisol levels may contribute to inappropriately low bone formation in the setting of estrogen deficiency. Alternatively, the observed correlation between osteocalcin and UFC levels may reflect a common relationship to the underlying metabolic abnormalities in AN. In contrast, no correlation between UFC and bone resorption was observed. Increased cortisol levels do not explain the more reduced bone density in the AN patients. Cortisol was increased in a higher percentage of patients with HA than in those with AN, and UFC was statistically higher than normal only in the HA group. However, we did not determine whether there were any differences in the diurnal rhythm of cortisol secretion.
Although exercise is generally protective of bone density, perhaps related to direct effects of mechanical loading on bone or improved nutritional status, excess exercise is associated with bone loss in amenorrheic athletes, in whom the negative effects of estrogen deficiency predominate on bone density (32, 33). In this study, exercise history was not different between the AN and HA patients. However, a relatively greater percentage of patients in the HA (84%) and AN (82%) group were previously athletes, as determined by participation in varsity sports or running more than 40 miles/week, compared to normal controls (70%). Among the amenorrheic patients in this study, increased exercise tended to correlate inversely with bone density at all sites, but was not significant in the multivariate analysis. However, it is possible that the relatively increased exercise patterns in the amenorrheic subjects contributed to underlying bone loss in each group.
Increased bone resorption, as measured by NTX, was seen among patients with AN compared to those with HA and may have contributed to the more severe bone loss in the AN group. Although estradiol levels and amenorrhea parameters were similarly low in both groups, NTX was increased in the AN group. No differences in PTH, 25-hydroxyvitamin D, and total calcium intake were seen between the groups to account for increased NTX, although only current calcium and vitamin D intake were assessed. Furthermore, the ratio of NTX to osteocalcin was highest in the AN group. One potential mechanism of severe bone loss in this population is therefore a relative effect of undernutrition to decrease osteoblast function (34) or at least to prevent the expected coupled rise in formation in association with resorption.
Because this is a cross-sectional study, it has a number of potential limitations. First, it is difficult to establish with certainty the estrogen status of our patients during the important years of adolescence, when the majority of bone is formed. Furthermore, patients in each group were relatively young and may not have achieved peak bone mass, and reduced bone density in the groups may relate in part to this mechanism. However, no significant differences in age of menarche, duration of amenorrhea, or estrogen use were observed between the AN and HA groups, and the differences in bone density remained highly significant even when controlling for these factors in regression models. Although it is possible that a relatively greater degree of estrogen deficiency in the AN patients accounts for some of the observed differences in bone density, our data demonstrate that estrogen status alone does not account for the large differences in bone density between the groups and suggest an important independent effect of nutritional factors on bone density in women with AN.
These data demonstrate that bone loss is more severe among women with AN than in patients with HA. Almost half of all AN patients in this study demonstrated significant osteopenia (>2.0 SD), whereas this degree of osteopenia was demonstrated in a much smaller percentage of patients with HA. The major differences in bone density between the AN and HA patients demonstrated in this study are of clinical relevance in terms of fracture potential. Although the precise mechanisms for this difference are as yet unknown, the markedly increased severity of osteopenia in HA compared to AN was related not to the degree or duration of estrogen deficiency, but, rather, to differences in nutritional parameters, most significantly lean body mass, between the study groups. These data suggest the critical importance of nutritional factors among premenopausal women with estrogen-deficient bone loss. Further studies are needed to address the time course and mechanisms of nutritional effects on bone and the importance of lean body mass to preserve bone density in this population.
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Acknowledgments |
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Footnotes |
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1 This work was supported in part by NIH Grants R01-DK-52625,
M01-RR-01066, and P32-DK-07028. 
Received December 7, 1998.
Revised March 11, 1999.
Accepted March 15, 1999.
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, P
< 0.01 vs. controls; §, P < 0.001
vs. controls; ¶, P < 0.0001
vs. controls; §§, P < 0.001
vs. HA; ¶¶, P < 0.0001
vs. HA. Results are the mean ± SEM.