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By
Steven K. Grinspoon, MD and Elizabeth R. Thomas, NP
Neuroendocrine Unit Massachusetts General Hospital
Boston, Massachusetts
Anorexia
nervosa and related eating disorders affect up to 1%
of college-age women in the United States.1,2 Bone loss
is significant among women with anorexia nervosa: more
than half of these patients have bone densities greater
than two standard deviations below age- and gender-matched
normal means.3, 4, 5 Each standard deviation below the
mean approximately doubles the risk of fractures. The
young age at onset and the rapidity of bone loss in
patients with anorexia nervosa are particularly striking.
Bone loss can be detected after only 6 months of illness,
and symptomatic compression fractures and kyphosis (spinal
deformity) are not uncommon in this young population.6
The long-term consequences of bone loss associated with
anorexia nervosa are not known, but a residual deficit
can remain even after weight recovery.6
Mechanisms of anorexia-related bone loss
The etiology of the bone loss associated with anorexia
nervosa is not known; however, substantial progress
has been made toward a more complete understanding of
the mechanisms of anorexia-related bone loss. A number
of different factors may contribute to bone loss in
anorexia nervosa, including estrogen deficiency and
malnutrition. Bone density correlates with the duration
of amenorrhea in women with anorexia nervosa, 4,6 and
estrogen deficiency accompanies other states associated
with decreased bone density, such as menopause and hyperprolactinemia.7,
8 The degree of bone loss seen in anorexia nervosa,
however, is unique in its severity compared to these
other low-estrogen states.9, 10 In a recent study that
compared age-matched patients with hypothalamic amenorrhea
and anorexia nervosa, the severity of bone loss was
significantly greater in the patients with anorexia
nervosa, even though both groups had similar degrees
and duration of estrogen deficiency.11
Estrogen therapy: Still a major question
Whether or not estrogen replacement therapy is an effective
therapeutic option for the bone loss associated with
anorexia nervosa remains a major question. In a randomized
prospective study of 48 women followed for a mean of
1.5 years, estrogen/progestin replacement and calcium
supplementation did not prevent or reverse bone loss
in women with anorexia nervosa.12 In a subanalysis among
patients with severe weight loss (those who weighed
less than 70% of ideal body weight, or IBW) estrogen/progestin
prevented bone loss but did not increase bone density.
Nonetheless, primary care providers often prescribe
estrogen replacement for young amenorrheic low-weight
women. The overall inadequacy of estrogen therapy in
anorexia nervosa stands in marked contrast to its efficacy
in preventing bone loss in postmenopausal women. The
data suggest other factors contribute to the bone loss
associated with anorexia nervosa. Elevated cortisol
levels, excess physical activity, and decreased calcium
intake may also contribute to bone loss in anorexia
nervosa.13 Although patients with anorexia nervosa demonstrate
elevated plasma cortisol levels, results of a recent
study showed only mild elevations of urine-free cortisol
in 22% of women with severe osteopenia.14 This suggests
that although hypercortisolemia may contribute to abnormal
bone density in a few patients, it does not account
for the significant degree of bone loss in patients
with anorexia nervosa. In addition, excess physical
activity may contribute to the bone loss that accompanies
anorexia nervosa. However, in several studies, physical
activity has not been shown to correlate with bone density.3,
15 In addition, reduced calcium and vitamin D intake
is not associated with low bone density in anorexia
nervosa.12, 16
Poor nutrition
Malnutrition itself may be a critical element in anorexia-related
bone loss. In women with anorexia nervosa, bone density
correlates directly with nutritional indices such as
BMI, caloric intake, fat mass, and leptin levels.3,
12 Weight gain correlates with increased bone density
in women with anorexia nervosa prior to resumption of
normal menstrual function.6 Furthermore, short-term
fasting, such as over 4 days, results in a marked decrease
of 50% in bone formation markers in healthy normal volunteers.18
Bone formation and resorption
Recent studies measuring specific markers of bone formation
and resorption have provided new information on the
mechanisms of bone loss in anorexia nervosa. Bone is
in a continuous state of turnover, with new bone formed
by osteoblasts (bone-forming cells) and old bone resorbed
by osteoclasts (cells that absorb and remove bone tissue).
In women with anorexia nervosa, serum levels of osteocalcin,
a marker of bone formation, are significantly decreased
in comparison with the levels in age-matched healthy
controls. Also notable is the increased urinary excretion
of dexypyridinoline and N-telopeptide among women with
anorexia nervosa, indicative of increased bone resorption.14
There is a reduction of bone formation in anorexia nervosa
as well as increased bone resorption, whereas other
estrogen-deficient conditions only feature increased
bone resorption. This pattern of bone turnover, with
reduced bone formation and increased bone resorption,
is in contrast to that seen in other estrogen deficiency
states. Reduced osteocalcin levels correlate with weight,
suggesting an important role of nutrition in the pathogenesis
of anorexia-nervosa-related bone loss.
Insulin-like growth factor deficiency
Deficiency of insulin-like growth factor I (IGF-I) may
contribute to the decreased rate of bone formation and
osteopenia seen in anorexia nervosa. IGF-I is a nutritionally
dependent hormone that both stimulates and reduces deoxyribonucleic
acid (DNA).and collagen synthesis.19, 20 Patients with
anorexia nervosa are markedly IGF-I deficient. Serum
levels of IGF-I decrease with weight loss, increase
with weight recovery and, importantly, can be used to
predict bone loss.12, 14,21,22 Short-term studies have
shown that administration of recombinant human insulin-like
growth factor (rhIGF-I) increases the markers of bone
formation and at low-doses does not stimulate bone resorption.
IGF-I may therefore be a useful therapy to address the
unbalanced rate of bone turnover that accompanies anorexia
nervosa.13
Recommendations
At the current time, primary care providers should recommend
that their female patients with anorexia nervosa take
calcium supplements, 1000 to 1500 mg per day, and a
daily multivitamin containing 400 international units
of vitamin D. The decision as to whether to supplement
estrogen should be made on an individual basis. Despite
the lack of effective therapies, bone density measurement
is an important assessment for these patients. With
the results, clinicians can identify and advise patients
whose bone densities are below the fracture threshold.
This assessment also provides a valuable opportunity
to counsel the patient on the long-term consequences
of low weight and the benefits of weight gain. Currently,
there are few treatment options. Antiresorptive therapies
used to reduce bone loss in postmenopausal women, such
as with the bisphosphonates, may not be effective for
patients with anorexia nervosa. These medications do
not stimulate bone formation and their role in anorexia
nervosa is still unclear.23 In contrast, weight gain
is associated with increased bone turnover and improved
bone density. Thus, nutritional counseling for at-risk
patients is an important therapeutic strategy to minimize
bone loss in this population. Significant progress has
been made in the understanding and treatment of anorexia-related
bone loss. In addition to weight gain, novel strategies
to stimulate bone formation may be appropriate for affected
patients. Research on the use of these factors, including
IGF-I, is ongoing.
Excerpt taken from the Eating
Disorders Review, Sept/Oct. 2000 issue.
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References
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The overall inadequacy of estrogen therapy in anorexia
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bone loss in postmenopausal women.
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