Premenopausal osteoporosis, an overlooked consequence of anorexia nervosa

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Our approach to screening for and diagnosing osteoporosis is still largely based on measuring bone mineral density, although density by itself is not a perfect tool for predicting who will or will not experience a fracture, particularly in premenopausal women.26,27 Most premenopausal women with low bone mineral density but no other risk factors for fracture such as previous fractures or glucocorticoid therapy are at very low short-term risk of fracture.26

For these reasons, in premenopausal women and adolescents, the International Society for Clinical Densitometry28 advises against diagnosing osteoporosis on the basis of bone mineral density alone. Instead, it should be diagnosed in this population only if the bone mineral density is low (defined as a Z score below −2.0) and the patient has risk factors that suggest a higher short-term risk of bone mineral loss and fracture. Risk factors include chronic malnutrition, eating disorders, hypogonadism, glucocorticoid exposure, and previous fracture.29

A pitfall in interpreting low bone mineral density in premenopausal women younger than age 30 is the possibility that they may not yet have reached their peak bone mass. In addition, small stature and body size (and therefore bone size) also influence the results of dual-energy x-ray absorptiometry. This test may not be able to distinguish bone that is small but of normal density from bone that is of low density.26

Despite its limitations, until newer risk assessment tools are available for this patient population, measuring bone mineral density is still recommended in addition to assessing clinical risk factors to diagnose osteoporosis. Also, changes in bone mineral density over time can help to assess risk and guide treatment.

When should a patient with anorexia be screened for osteoporosis?

Because bone loss may begin early in the course of anorexia and progress rapidly (potentially inexorably), baseline screening is recommended for all patients who have had anorexia nervosa or amenorrhea for more than 6 to 12 months.30 The National Osteoporosis Foundation recommends screening in women under age 65 who have a low body weight.31 The American College of Sports Medicine recommends screening for osteoporosis in athletes with a history of hypoestrogenism or disordered eating for a cumulative total of 6 months or more, or with a history of stress fracture or fracture from minimal trauma.32

Knowledge of low bone mineral density and fracture risk can often guide treatment and prompt behavioral change. Given that most osteoporosis treatments do not lead to detectable changes in bone density until 18 months to 2 years, it is reasonable to repeat testing at this interval.33


Weight restoration is the cornerstone

Restoration of body weight and nutritional rehabilitation remain the cornerstones of treatment. All patients with anorexia nervosa should be referred to a nutritionist to develop a meal plan that is adjusted for the amount of energy expended. The challenges lie in managing the complications of refeeding and the high relapse rate. The treatment goals in disordered eating are to optimize the overall nutritional status, normalize eating behavior, modify unhealthy thought processes that maintain the disorder, and treat possible emotional issues that help create or maintain the disorder.

The younger the patient, the more the family’s involvement is recommended. In addition to nutritional counseling, the care team should include a psychotherapist, a psychiatrist, and a primary care physician to assist with management and screening of medical complications.

Vitamin D for all

Low vitamin D levels have long been associated with low bone mineral density and risk of hip fracture.34

Vitamin D insufficiency is very common. More than 90% of blacks, Hispanics, and Asians and nearly 75% of whites have insufficient levels of vitamin D (25-hydroxyvitamin D3 level < 30 ng/mL).35 In a study of 307 healthy adolescents, vitamin D insufficiency (a 25-hydroxyvitamin D3 level < 20 ng/mL) was found in 42% and vitamin D deficiency (a level < 15 ng/mL) in 24.1%.36 In addition, this study confirmed an inverse correlation between body mass index and serum 25-hydroxyvitamin D3 concentration.

Therefore, while vitamin D supplementation has not been consistently shown to improve bone loss in anorectic patients,9 given the prevalence of vitamin D deficiency and insufficiency, supplementation is almost universally recommended.

There is no consensus as to the amount of supplementation to recommend for women with anorexia nervosa. The American College of Sports Medicine recommends a total daily intake of 800 IU of vitamin D (ie, from diet and supplements). Therapy should be titrated to doses that result in normocalcemia and a serum 25-hydroxyvitamin D3 concentration of at least 30 ng/mL.37,38

Does hormone treatment improve bone density?

In postmenopausal osteoporosis, estrogen therapy maintains or improves bone density and appears to reduce the rate of vertebral fractures.39,40 Perhaps not so with premenopausal osteoporosis due to anorexia nervosa.

Why should this be? In postmenopausal women, estrogen therapy appears to work by impairing osteoclast-mediated bone resorption, but it has only limited effects on bone formation. In premenopausal anorexia, however, bone loss appears to be due to a unique uncoupling of osteoblastic and osteoclastic functions, resulting in both reduced bone formation and increased bone resorption, which estrogen therapy may not improve.5

Despite the documented association between anorexia nervosa and estrogen deficiency and the strong correlation between osteoporosis and the duration of amenorrhea, most studies have found no improvement in bone mass with hormonal therapy.9 In particular, three randomized, placebo-controlled trials have been published to date, and not one showed a significant improvement in bone mineral density with estrogen therapy compared with placebo in patients with anorexia nervosa.41–43

Klibanski et al,41 in the first of these trials, found no significant difference in spinal bone mineral density between treated patients and controls. However, estrogen-treated patients whose initial body weight was very low (< 70% of expected) had a significant increase in their bone mineral density, whereas those in the control group lost bone density.

Baker et al44 suggest that hormone therapy might protect bone mass in athletes with amenorrhea, citing a study that found that women with a history of stress fractures were less likely to have used oral contraceptives previously than athletes without fractures.45 However, no prospective randomized study to date has established that hormone therapy effectively preserves bone mass in athletes with amenorrhea.

Based on the data presented above, we have little evidence for using estrogen to treat or prevent premenopausal osteoporosis.

The American College of Sports Medicine32 recommends consideration of estrogen therapy if there is evidence of a decline in bone mineral density in an athlete over the age of 16 with persistent functional hypothalamic amenorrhea despite adequate nutritional intake and weight. However, it acknowledges that restoring regular menstrual cycles with oral contraceptive pills will not normalize the metabolic factors that impair bone formation, health, and performance and is not likely to fully reverse low bone mineral density in this population.

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