[ARTICLE] Bone Loss in Anorexia Nervosa: Mechanisms and Treatment Options
Filed Under: Nutrition
Mar 2, 2012
Steven K. Grinspoon, MD and Elizabeth R. Thomas, NP
Bone Loss in Anorexia Nervosa:
Mechanisms and Treatment Options
Reprinted from Eating Disorders Review
by Steven K. Grinspoon, MD and Elizabeth R. Thomas, NP
September/October 2000 Volume 11, Number 5
©2000 Gürze Books
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
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
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.
For a list of Bone Disease Websites click here.
- Lucas AR, Beard, CM, OÕFallon, et al. 50-year trends in the
incidence of anorexia nervosa in Rochester, MN: A population-based
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- Klibanski A, Greenspan, SL. Increase in bone mass after treatment of hyperprolactinemic amenorrhea. N Engl J Med 1986;315:542.
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- Winterer J, Gwirtsman HE, George DT, et al.
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Invest 1996;97:2692. (Possible quote) The overall inadequacy of estrogen
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