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Premenopausal osteoporosis, an overlooked consequence of anorexia nervosa
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Kathryn Teng, MD, FACP

Among the devastating effects of anorexia nervosa, and one that is easily overlooked, is its impact on bone.

Probably more than half of young women with anorexia nervosa develop osteoporosis, and relatively quickly. Baker et al1 obtained bone scans in a series of 56 young women, mean age 27 years, who had had an eating disorder for a mean of about 10 years, and found that the bone mineral density in the femur was below the critical fracture threshold in 42 (75%).

Osteoporosis is particularly common and worrisome in female athletes (and is becoming increasingly common in male athletes as well). Female athletes have a much higher incidence of disordered eating than their peers2 and therefore are at a much higher risk of fractures.

This review summarizes the factors affecting the development of osteoporosis in these patients and discusses potential targets for intervention.

ANOREXIA AND BONE HEALTH: A COMPLEX RELATIONSHIP

Anorexia nervosa is characterized by an intense fear of gaining weight, a body weight less than 85% of expected, a distorted self-image, and, in women, missing three consecutive menstrual periods.3 The lifetime prevalence in women is about 0.5%; it is much lower in men.3 The prevalence of eating disorders in female athletes is much higher, estimated at 15% to 62%.2

The etiology of osteoporosis in patients with anorexia nervosa is complex and multifaceted. In these patients, bone resorption is increased without a concomitant increase in bone formation, resulting in a net loss of bone.4 Thus, markers of bone resorption such as N-teleopeptide and deoxypyridoline are elevated, but markers of bone formation such as osteocalcin are not.4

The loss of bone may be rapid and can occur relatively early in the disease. Some studies suggest that an illness duration longer than 12 months predicts significant loss of bone density.5 Thus, early diagnosis and intervention are important to minimize bone loss.

Women gain from 40% to 60% of their bone mass during the pubertal growth spurt in ages 11 to 14, the time when anorexia nervosa is most prevalent.6 Peak bone mass is attained by the third decade of life, but the rate of growth of bone mass is highest during adolescence and early adulthood.7 Hence, it is important to optimize bone mass during this time, as small differences in bone density can have significant clinical implications later in life: a 5% increase in bone density significantly decreases fracture risk, whereas a 10% decrease in adult bone mineral density is associated with a two to three times higher risk of fracture (reviewed by Rome and Ammerman6).

What is the role of amenorrhea in the development of osteoporosis in premenopausal patients?

Given that two of the most characteristic manifestations of anorexia nervosa are low body weight and the absence of menses, these factors have been hypothesized to be potential causes of osteoporosis.

In general, young women who present with amenorrhea should be evaluated to determine if the amenorrhea is primary or secondary. Primary amenorrhea is the absence of menarche by age 16; secondary amenorrhea is the absence of menses for more than three cycles or more than 6 months in someone who previously had had menses. The most common causes of secondary amenorrhea are ovarian disease, hypothalamic or pituitary disease, and uterine disease. Anorexia nervosa causes hypothalamic dysfunction and is a cause of secondary amenorrhea. In clinical practice, it is also important to remember that pregnancy can occur even in the setting of amenorrhea.

Amenorrhea in patients with anorexia nervosa is related to hypothalamic suppression of the release of gonadotropin-releasing hormone, resulting in lower levels of follicle-stimulating hormone and luteinizing hormone and a resultant prepubertal low-estrogen state.

In a study of 73 women with anorexia nervosa and a mean age of 17.2 years,8 20 months of amenorrhea was the threshold above which the most severe osteopenia was seen, implying that the duration of amenorrhea affects bone health.

Which factors besides amenorrhea influence bone density in premenopausal women?

Undernutrition. Body weight has been suggested to have an independent effect on bone mineral density, and density has been found to increase following weight gain, even before the return of menses.1 Once a regular menstrual cycle has been restored, significant increases in trabecular and cortical bone have been detected.1

Deficiency of insulin-like growth factor 1 (IGF-1). Anorexia nervosa is associated with decreased hepatic synthesis of IGF-I.9 Low levels of IGF-I reduce the levels of osteocalcin, a marker of bone formation, and cause abnormalities in osteoblast function.10 This deficiency is associated with the development of osteopenia in patients with anorexia nervosa.11

Low androgen levels are present in patients with anorexia nervosa, and levels appear to be further reduced by oral contraceptives.12 It remains to be determined whether the further reduction in androgens in women with anorexia nervosa using oral contraceptives is harmful to skeletal health. Low testosterone levels in boys with anorexia nervosa have been associated with lower libido, fewer erections, and potentially lower bone density.13

Hypercortisolemia. Elevated levels of total and free serum cortisol and high 24-hour urinary free cortisol excretion have been noted in anorectic patients. Levels of cortisol are inversely related to levels of osteocalcin, and hypercortisolism has been shown to be associated with osteoporosis.14,15 However, no study has yet shown causality in this population.

Osteoprotegerin has been recognized as an important regulator of bone resorption. Osteoprotegerin inhibits osteoclast differentiation and activation and stimulates osteoclast apoptosis, helping to preserve bone density.

Misra et al16 showed that adolescent girls with anorexia nervosa have higher serum osteoprotegerin levels than controls and that osteoprotegerin levels correlate inversely with markers of nutritional status and lumbar bone density Z scores.16 They and other investigators17 postulate that osteoprotegerin may be released as a compensatory response to the bone loss seen in these patients in an attempt to preserve bone health.

Leptin is an adipocyte-derived hormone that acts on receptors in the hypothalamus, decreasing food intake and increasing energy expenditure. Low leptin levels are a key endocrinologic feature of anorexia nervosa.18 Leptin helps to induce weight loss by stimulating neurons in the hypothalamus that express “weight-loss-inducing” neuropeptides such as pro-opiomelanocortin and inhibiting “weight-gain-inducing” peptides such as neuropeptide Y.19

Although leptin was first believed to be a hormone released to counteract obesity, recent studies19,20 suggest that it is part of a major signaling system that controls adaptation to starvation. These studies have shown that the body senses its corporeal fat through leptin and inhibits ovulation when fat reserves are low.19 In addition, luteinizing hormone and leptin levels have been shown to increase in parallel in patients with anorexia nervosa when weight is restored.20 Thus, rising leptin levels correlate with the resumption of menses in women with anorexia nervosa and in turn have potential consequences for bone health.

Not enough ghrelin, too much obestatin? Ghrelin, a gastric hormone, acts as a natural antagonist to leptin, resulting in an increase in food intake and body weight.19 Circulating ghrelin levels are higher in illness-induced anorexia as well as in anorexia nervosa, and they normalize with weight gain, perhaps as an adaptive mechanism to compensate for a negative energy balance.21

Several in vitro studies suggest that ghrelin directly promotes osteoblast proliferation and differentiation.22 However, human studies of ghrelin’s effects on bone are limited. In a study of healthy younger women, healthy boys, and anorexia nervosa patients, plasma ghrelin levels were only weakly associated with bone mineral density.23

The effects of obestatin, another gastric hormone, are still being investigated. Obestatin was initially shown to oppose the effects of ghrelin by decreasing appetite and weight gain. When given with ghrelin, obestatin appears to work with ghrelin at the hypothalamic level to modulate food intake and growth hormone secretion.24

Interestingly, obestatin and the ratio of ghrelin to obestatin are decreased in patients with anorexia nervosa, but the ratio is unchanged in thin women who have an equivalent body mass index but no eating disorder.25 It has been hypothesized that the ghrelin-obestatin ratio may be the key to explaining the eating restriction and reduced motivation to eat despite high ghrelin levels seen in anorexia nervosa.26 Further studies are needed to determine the role of obestatin and the ghrelin-obestatin ratio in the bone health of women with anorexia nervosa.

While factors such as low body weight and amenorrhea have long been understood to play a role in the development of osteoporosis in women with anorexia nervosa, many complex hormonal factors contribute to bone deficits as well. Further study is needed to fully elucidate these hormonal factors and how they work together to cause osteoporosis. A list of the factors that potentially influence bone density and risk for osteoporosis in patients with anorexia nervosa is presented in Table 1.

 

 

HOW SHOULD WE DIAGNOSE OSTEOPOROSIS IN PREMENOPAUSAL PATIENTS?

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

NEW AND OLD TREATMENTS FOR LOW BONE DENSITY IN ANOREXIA NERVOSA

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.

 

 

What is the effect of exercise on bone health in these patients?

Several studies have examined the effect of weight-bearing exercise on bone density.

Young et al46 compared normal teenagers, ballet dancers, and young women with anorexia nervosa and found that weight-bearing exercise protected against osteoporosis, but only at weight-bearing sites. Athletes in weight-bearing sports had a 5% to 15% higher bone mineral density in weight-bearing sites (ie, the femur) compared with nonathletes, but had lower bone mineral density in the spine.

Therefore, a Z score below −1.0 in an athlete, especially in a distal site, warrants further investigation and treatment.32 In general, exercise does not necessarily protect against osteoporosis in this patient population, and it can sometimes mask underlying bone loss. In addition, keep in mind that many of these patients exercise compulsively, using it as a form of purging.

Insulin-like growth factor-1: More study needed

IGF-1 contributes to bone growth by stimulating osteoblasts, and patients with anorexia nervosa have been shown to have low levels of IGF-1.9

Grinspoon et al10 randomized 60 patients with anorexia nervosa to receive IGF-1 alone, IGF-1 plus an oral contraceptive, an oral contraceptive alone, or placebo. All patients were given calcium and vitamin D and were followed for 9 months. Total bone mass increased significantly in those taking IGF-1 compared with those taking placebo. Those taking an IGF-1 and an oral contraceptive had a significant increase in spinal bone mineral density compared with those on placebo group. At other skeletal sites, however, IGF-1 plus an oral contraceptive and IGF-1 alone failed to produce significant increases in bone mineral density compared with placebo.

Further study is needed to determine the role of IGF-1 in treating low bone mineral density in anorexia nervosa.

Bisphosphonates: Not approved for this indication

In premenopausal women, bisphosphonates are approved by the US Food and Drug Administration (FDA) for use only in those taking glucocorticoids. Although bisphosphonates have been shown to significantly increase bone mineral density in young women with anorexia nervosa,26 they should be used with caution in patients of childbearing age because they are teratogenic. Bisphosphonates have a long half-life and may continue to affect bone turnover for up to 2 years after they are discontinued.47 In addition, they are not recommended in patients with a history of purging via vomiting, due to a risk of esophageal ulceration.

Parathyroid hormone therapy: Studies ongoing

The parathyroid hormone fragment teriparatide (Forteo) is widely used for treating postmenopausal osteoporosis.

Before teriparatide was approved, there was concern that it might increase the risk of osteosarcoma, as almost 45% of rats treated with this drug at the highest-tested dose level developed this aggressive form of bone cancer.48 Balancing the proven benefits of teriparatide shown by clinical trials with the theoretic risk of teriparatide-induced osteosarcoma, the FDA mandated a “black-box” warning about this potential effect.

Studies of parathyroid hormone treatment in anorexia nervosa and other premenopausal patients are ongoing.26

Leptin: More study needed

Leptin is a potent stimulator of bone growth and has been shown to increase bone mineral density in vitro and in vivo.19 However, concerns have been raised about giving supra-physiologic doses of leptin to patients with anorexia nervosa, as this may increase the risk of further weight loss and relapse.

More work is needed to determine the role of leptin for the treatment of osteoporosis in anorexia nervosa.

Ghrelin: Probably not effective as a single agent

Pharmacologic use of ghrelin increases food intake in healthy humans,49 and it has been proposed as a treatment for weight restoration and bone health in anorexia nervosa. Preliminary studies have not shown it to increase appetite or weight gain,50 but it did increase slow-wave sleep.

Based on these studies, it is unlikely that ghrelin will be effective as a single agent to stimulate appetite, but it may be helpful in conjunction with other therapies.

Cannabinoids: Little ongoing research

Cannabinoids have been proposed as a treatment for anorexia nervosa in the hope that they would induce weight gain and in turn prevent osteoporosis.

Interest in their use in anorexia nervosa stems from the discovery of two cannabinoid receptors (CB1 and CB2) located in the brain and peripheral organ systems. Anorexia nervosa has been associated with different alleles of the CB1 gene,51 but the therapeutic implications of this are far from clear.

Cannabinoids appear to regulate eating behavior at several levels within the brain and periphery: the hypothalamus and hindbrain (integrative functions), the limbic system (for hedonic evaluation of foods), the intestinal system, and adipose tissue.52 At each of these levels, the endocannabinoid system interacts with a number of better known peptides involved in appetite regulation, including leptin, ghrelin, and the melanocortins. In mouse studies, genetic leptin deficiency is associated with elevated hypothalamic endocannabinoid levels.

Appetite stimulation by cannabinoids has been studied for several decades, particularly in relation to cachexia and malnutrition associated with cancer. Very few trials have studied cannabinoids for anorexia nervosa.

In a 4-week crossover trial in 11 patients with anorexia nervosa,53 tetrahydrocannabinol (THC) treatment resulted in an increase in sleep disturbances and interpersonal sensitivity, but it had no significant effect on weight gain compared with diazepam treatment.53

Another pilot study of nine outpatients with anorexia nervosa treated with THC showed a significant improvement in depression and perfectionism scores without any significant weight gain.19

Although this research was once promising, the risk was felt to outweigh the benefit, as cannabinoids may induce dependency in this patient group, who may already be at high risk of drug addiction, and very few have continued this line of investigation.

 

 

WHAT CAN WE DO FOR NOW?

  • Weight restoration and nutritional rehabilitation remain the keys to treatment of low bone density to reduce the risk of osteoporosis in patients with anorexia nervosa. However, as many as one-third of patients with anorexia nervosa relapse during their lifetime, and other treatments are needed to stabilize and prevent bone loss.
  • Vitamin D deficiency is clearly associated with a risk of osteoporosis and fracture, and patients with vitamin D deficiency should be treated with supplementation.
  • Standard therapies in postmenopausal patients (such as bisphosphonates and teriparatide) should be used with caution in premenopausal anorexia nervosa patients because of potential long-term health risks.
  • Although treatment of amenorrhea and estrogen deficiency has been shown to at least stabilize bone density in postmenopausal patients, this does not appear to be the case in premenopausal girls and young women.
  • As we learn more about hormonal factors in anorexia nervosa, we hope to identify interventions that will help restore weight and decrease the risk of osteoporosis. A summary of potential treatment strategies and targets for prevention of osteoporosis in anorexia nervosa is presented in Table 2.
     

 

Acknowledgment: The author thanks the General Internal Medicine Works in Progress Group for its editorial comments, and Dr. Ellen Rome for her mentorship and support.

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Address: Kathryn Teng, MD, FACP, Department of Internal Medicine, G10, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; tengk@ccf.org

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Kathryn Teng, MD, FACP
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Department of Internal Medicine, and Director, Clinical Integration of Personalized Healthcare, Executive Board Office, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Kathryn Teng, MD, FACP, Department of Internal Medicine, G10, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; tengk@ccf.org

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Kathryn Teng, MD, FACP
Department of Internal Medicine, and Director, Clinical Integration of Personalized Healthcare, Executive Board Office, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Kathryn Teng, MD, FACP, Department of Internal Medicine, G10, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; tengk@ccf.org

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Among the devastating effects of anorexia nervosa, and one that is easily overlooked, is its impact on bone.

Probably more than half of young women with anorexia nervosa develop osteoporosis, and relatively quickly. Baker et al1 obtained bone scans in a series of 56 young women, mean age 27 years, who had had an eating disorder for a mean of about 10 years, and found that the bone mineral density in the femur was below the critical fracture threshold in 42 (75%).

Osteoporosis is particularly common and worrisome in female athletes (and is becoming increasingly common in male athletes as well). Female athletes have a much higher incidence of disordered eating than their peers2 and therefore are at a much higher risk of fractures.

This review summarizes the factors affecting the development of osteoporosis in these patients and discusses potential targets for intervention.

ANOREXIA AND BONE HEALTH: A COMPLEX RELATIONSHIP

Anorexia nervosa is characterized by an intense fear of gaining weight, a body weight less than 85% of expected, a distorted self-image, and, in women, missing three consecutive menstrual periods.3 The lifetime prevalence in women is about 0.5%; it is much lower in men.3 The prevalence of eating disorders in female athletes is much higher, estimated at 15% to 62%.2

The etiology of osteoporosis in patients with anorexia nervosa is complex and multifaceted. In these patients, bone resorption is increased without a concomitant increase in bone formation, resulting in a net loss of bone.4 Thus, markers of bone resorption such as N-teleopeptide and deoxypyridoline are elevated, but markers of bone formation such as osteocalcin are not.4

The loss of bone may be rapid and can occur relatively early in the disease. Some studies suggest that an illness duration longer than 12 months predicts significant loss of bone density.5 Thus, early diagnosis and intervention are important to minimize bone loss.

Women gain from 40% to 60% of their bone mass during the pubertal growth spurt in ages 11 to 14, the time when anorexia nervosa is most prevalent.6 Peak bone mass is attained by the third decade of life, but the rate of growth of bone mass is highest during adolescence and early adulthood.7 Hence, it is important to optimize bone mass during this time, as small differences in bone density can have significant clinical implications later in life: a 5% increase in bone density significantly decreases fracture risk, whereas a 10% decrease in adult bone mineral density is associated with a two to three times higher risk of fracture (reviewed by Rome and Ammerman6).

What is the role of amenorrhea in the development of osteoporosis in premenopausal patients?

Given that two of the most characteristic manifestations of anorexia nervosa are low body weight and the absence of menses, these factors have been hypothesized to be potential causes of osteoporosis.

In general, young women who present with amenorrhea should be evaluated to determine if the amenorrhea is primary or secondary. Primary amenorrhea is the absence of menarche by age 16; secondary amenorrhea is the absence of menses for more than three cycles or more than 6 months in someone who previously had had menses. The most common causes of secondary amenorrhea are ovarian disease, hypothalamic or pituitary disease, and uterine disease. Anorexia nervosa causes hypothalamic dysfunction and is a cause of secondary amenorrhea. In clinical practice, it is also important to remember that pregnancy can occur even in the setting of amenorrhea.

Amenorrhea in patients with anorexia nervosa is related to hypothalamic suppression of the release of gonadotropin-releasing hormone, resulting in lower levels of follicle-stimulating hormone and luteinizing hormone and a resultant prepubertal low-estrogen state.

In a study of 73 women with anorexia nervosa and a mean age of 17.2 years,8 20 months of amenorrhea was the threshold above which the most severe osteopenia was seen, implying that the duration of amenorrhea affects bone health.

Which factors besides amenorrhea influence bone density in premenopausal women?

Undernutrition. Body weight has been suggested to have an independent effect on bone mineral density, and density has been found to increase following weight gain, even before the return of menses.1 Once a regular menstrual cycle has been restored, significant increases in trabecular and cortical bone have been detected.1

Deficiency of insulin-like growth factor 1 (IGF-1). Anorexia nervosa is associated with decreased hepatic synthesis of IGF-I.9 Low levels of IGF-I reduce the levels of osteocalcin, a marker of bone formation, and cause abnormalities in osteoblast function.10 This deficiency is associated with the development of osteopenia in patients with anorexia nervosa.11

Low androgen levels are present in patients with anorexia nervosa, and levels appear to be further reduced by oral contraceptives.12 It remains to be determined whether the further reduction in androgens in women with anorexia nervosa using oral contraceptives is harmful to skeletal health. Low testosterone levels in boys with anorexia nervosa have been associated with lower libido, fewer erections, and potentially lower bone density.13

Hypercortisolemia. Elevated levels of total and free serum cortisol and high 24-hour urinary free cortisol excretion have been noted in anorectic patients. Levels of cortisol are inversely related to levels of osteocalcin, and hypercortisolism has been shown to be associated with osteoporosis.14,15 However, no study has yet shown causality in this population.

Osteoprotegerin has been recognized as an important regulator of bone resorption. Osteoprotegerin inhibits osteoclast differentiation and activation and stimulates osteoclast apoptosis, helping to preserve bone density.

Misra et al16 showed that adolescent girls with anorexia nervosa have higher serum osteoprotegerin levels than controls and that osteoprotegerin levels correlate inversely with markers of nutritional status and lumbar bone density Z scores.16 They and other investigators17 postulate that osteoprotegerin may be released as a compensatory response to the bone loss seen in these patients in an attempt to preserve bone health.

Leptin is an adipocyte-derived hormone that acts on receptors in the hypothalamus, decreasing food intake and increasing energy expenditure. Low leptin levels are a key endocrinologic feature of anorexia nervosa.18 Leptin helps to induce weight loss by stimulating neurons in the hypothalamus that express “weight-loss-inducing” neuropeptides such as pro-opiomelanocortin and inhibiting “weight-gain-inducing” peptides such as neuropeptide Y.19

Although leptin was first believed to be a hormone released to counteract obesity, recent studies19,20 suggest that it is part of a major signaling system that controls adaptation to starvation. These studies have shown that the body senses its corporeal fat through leptin and inhibits ovulation when fat reserves are low.19 In addition, luteinizing hormone and leptin levels have been shown to increase in parallel in patients with anorexia nervosa when weight is restored.20 Thus, rising leptin levels correlate with the resumption of menses in women with anorexia nervosa and in turn have potential consequences for bone health.

Not enough ghrelin, too much obestatin? Ghrelin, a gastric hormone, acts as a natural antagonist to leptin, resulting in an increase in food intake and body weight.19 Circulating ghrelin levels are higher in illness-induced anorexia as well as in anorexia nervosa, and they normalize with weight gain, perhaps as an adaptive mechanism to compensate for a negative energy balance.21

Several in vitro studies suggest that ghrelin directly promotes osteoblast proliferation and differentiation.22 However, human studies of ghrelin’s effects on bone are limited. In a study of healthy younger women, healthy boys, and anorexia nervosa patients, plasma ghrelin levels were only weakly associated with bone mineral density.23

The effects of obestatin, another gastric hormone, are still being investigated. Obestatin was initially shown to oppose the effects of ghrelin by decreasing appetite and weight gain. When given with ghrelin, obestatin appears to work with ghrelin at the hypothalamic level to modulate food intake and growth hormone secretion.24

Interestingly, obestatin and the ratio of ghrelin to obestatin are decreased in patients with anorexia nervosa, but the ratio is unchanged in thin women who have an equivalent body mass index but no eating disorder.25 It has been hypothesized that the ghrelin-obestatin ratio may be the key to explaining the eating restriction and reduced motivation to eat despite high ghrelin levels seen in anorexia nervosa.26 Further studies are needed to determine the role of obestatin and the ghrelin-obestatin ratio in the bone health of women with anorexia nervosa.

While factors such as low body weight and amenorrhea have long been understood to play a role in the development of osteoporosis in women with anorexia nervosa, many complex hormonal factors contribute to bone deficits as well. Further study is needed to fully elucidate these hormonal factors and how they work together to cause osteoporosis. A list of the factors that potentially influence bone density and risk for osteoporosis in patients with anorexia nervosa is presented in Table 1.

 

 

HOW SHOULD WE DIAGNOSE OSTEOPOROSIS IN PREMENOPAUSAL PATIENTS?

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

NEW AND OLD TREATMENTS FOR LOW BONE DENSITY IN ANOREXIA NERVOSA

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.

 

 

What is the effect of exercise on bone health in these patients?

Several studies have examined the effect of weight-bearing exercise on bone density.

Young et al46 compared normal teenagers, ballet dancers, and young women with anorexia nervosa and found that weight-bearing exercise protected against osteoporosis, but only at weight-bearing sites. Athletes in weight-bearing sports had a 5% to 15% higher bone mineral density in weight-bearing sites (ie, the femur) compared with nonathletes, but had lower bone mineral density in the spine.

Therefore, a Z score below −1.0 in an athlete, especially in a distal site, warrants further investigation and treatment.32 In general, exercise does not necessarily protect against osteoporosis in this patient population, and it can sometimes mask underlying bone loss. In addition, keep in mind that many of these patients exercise compulsively, using it as a form of purging.

Insulin-like growth factor-1: More study needed

IGF-1 contributes to bone growth by stimulating osteoblasts, and patients with anorexia nervosa have been shown to have low levels of IGF-1.9

Grinspoon et al10 randomized 60 patients with anorexia nervosa to receive IGF-1 alone, IGF-1 plus an oral contraceptive, an oral contraceptive alone, or placebo. All patients were given calcium and vitamin D and were followed for 9 months. Total bone mass increased significantly in those taking IGF-1 compared with those taking placebo. Those taking an IGF-1 and an oral contraceptive had a significant increase in spinal bone mineral density compared with those on placebo group. At other skeletal sites, however, IGF-1 plus an oral contraceptive and IGF-1 alone failed to produce significant increases in bone mineral density compared with placebo.

Further study is needed to determine the role of IGF-1 in treating low bone mineral density in anorexia nervosa.

Bisphosphonates: Not approved for this indication

In premenopausal women, bisphosphonates are approved by the US Food and Drug Administration (FDA) for use only in those taking glucocorticoids. Although bisphosphonates have been shown to significantly increase bone mineral density in young women with anorexia nervosa,26 they should be used with caution in patients of childbearing age because they are teratogenic. Bisphosphonates have a long half-life and may continue to affect bone turnover for up to 2 years after they are discontinued.47 In addition, they are not recommended in patients with a history of purging via vomiting, due to a risk of esophageal ulceration.

Parathyroid hormone therapy: Studies ongoing

The parathyroid hormone fragment teriparatide (Forteo) is widely used for treating postmenopausal osteoporosis.

Before teriparatide was approved, there was concern that it might increase the risk of osteosarcoma, as almost 45% of rats treated with this drug at the highest-tested dose level developed this aggressive form of bone cancer.48 Balancing the proven benefits of teriparatide shown by clinical trials with the theoretic risk of teriparatide-induced osteosarcoma, the FDA mandated a “black-box” warning about this potential effect.

Studies of parathyroid hormone treatment in anorexia nervosa and other premenopausal patients are ongoing.26

Leptin: More study needed

Leptin is a potent stimulator of bone growth and has been shown to increase bone mineral density in vitro and in vivo.19 However, concerns have been raised about giving supra-physiologic doses of leptin to patients with anorexia nervosa, as this may increase the risk of further weight loss and relapse.

More work is needed to determine the role of leptin for the treatment of osteoporosis in anorexia nervosa.

Ghrelin: Probably not effective as a single agent

Pharmacologic use of ghrelin increases food intake in healthy humans,49 and it has been proposed as a treatment for weight restoration and bone health in anorexia nervosa. Preliminary studies have not shown it to increase appetite or weight gain,50 but it did increase slow-wave sleep.

Based on these studies, it is unlikely that ghrelin will be effective as a single agent to stimulate appetite, but it may be helpful in conjunction with other therapies.

Cannabinoids: Little ongoing research

Cannabinoids have been proposed as a treatment for anorexia nervosa in the hope that they would induce weight gain and in turn prevent osteoporosis.

Interest in their use in anorexia nervosa stems from the discovery of two cannabinoid receptors (CB1 and CB2) located in the brain and peripheral organ systems. Anorexia nervosa has been associated with different alleles of the CB1 gene,51 but the therapeutic implications of this are far from clear.

Cannabinoids appear to regulate eating behavior at several levels within the brain and periphery: the hypothalamus and hindbrain (integrative functions), the limbic system (for hedonic evaluation of foods), the intestinal system, and adipose tissue.52 At each of these levels, the endocannabinoid system interacts with a number of better known peptides involved in appetite regulation, including leptin, ghrelin, and the melanocortins. In mouse studies, genetic leptin deficiency is associated with elevated hypothalamic endocannabinoid levels.

Appetite stimulation by cannabinoids has been studied for several decades, particularly in relation to cachexia and malnutrition associated with cancer. Very few trials have studied cannabinoids for anorexia nervosa.

In a 4-week crossover trial in 11 patients with anorexia nervosa,53 tetrahydrocannabinol (THC) treatment resulted in an increase in sleep disturbances and interpersonal sensitivity, but it had no significant effect on weight gain compared with diazepam treatment.53

Another pilot study of nine outpatients with anorexia nervosa treated with THC showed a significant improvement in depression and perfectionism scores without any significant weight gain.19

Although this research was once promising, the risk was felt to outweigh the benefit, as cannabinoids may induce dependency in this patient group, who may already be at high risk of drug addiction, and very few have continued this line of investigation.

 

 

WHAT CAN WE DO FOR NOW?

  • Weight restoration and nutritional rehabilitation remain the keys to treatment of low bone density to reduce the risk of osteoporosis in patients with anorexia nervosa. However, as many as one-third of patients with anorexia nervosa relapse during their lifetime, and other treatments are needed to stabilize and prevent bone loss.
  • Vitamin D deficiency is clearly associated with a risk of osteoporosis and fracture, and patients with vitamin D deficiency should be treated with supplementation.
  • Standard therapies in postmenopausal patients (such as bisphosphonates and teriparatide) should be used with caution in premenopausal anorexia nervosa patients because of potential long-term health risks.
  • Although treatment of amenorrhea and estrogen deficiency has been shown to at least stabilize bone density in postmenopausal patients, this does not appear to be the case in premenopausal girls and young women.
  • As we learn more about hormonal factors in anorexia nervosa, we hope to identify interventions that will help restore weight and decrease the risk of osteoporosis. A summary of potential treatment strategies and targets for prevention of osteoporosis in anorexia nervosa is presented in Table 2.
     

 

Acknowledgment: The author thanks the General Internal Medicine Works in Progress Group for its editorial comments, and Dr. Ellen Rome for her mentorship and support.

Among the devastating effects of anorexia nervosa, and one that is easily overlooked, is its impact on bone.

Probably more than half of young women with anorexia nervosa develop osteoporosis, and relatively quickly. Baker et al1 obtained bone scans in a series of 56 young women, mean age 27 years, who had had an eating disorder for a mean of about 10 years, and found that the bone mineral density in the femur was below the critical fracture threshold in 42 (75%).

Osteoporosis is particularly common and worrisome in female athletes (and is becoming increasingly common in male athletes as well). Female athletes have a much higher incidence of disordered eating than their peers2 and therefore are at a much higher risk of fractures.

This review summarizes the factors affecting the development of osteoporosis in these patients and discusses potential targets for intervention.

ANOREXIA AND BONE HEALTH: A COMPLEX RELATIONSHIP

Anorexia nervosa is characterized by an intense fear of gaining weight, a body weight less than 85% of expected, a distorted self-image, and, in women, missing three consecutive menstrual periods.3 The lifetime prevalence in women is about 0.5%; it is much lower in men.3 The prevalence of eating disorders in female athletes is much higher, estimated at 15% to 62%.2

The etiology of osteoporosis in patients with anorexia nervosa is complex and multifaceted. In these patients, bone resorption is increased without a concomitant increase in bone formation, resulting in a net loss of bone.4 Thus, markers of bone resorption such as N-teleopeptide and deoxypyridoline are elevated, but markers of bone formation such as osteocalcin are not.4

The loss of bone may be rapid and can occur relatively early in the disease. Some studies suggest that an illness duration longer than 12 months predicts significant loss of bone density.5 Thus, early diagnosis and intervention are important to minimize bone loss.

Women gain from 40% to 60% of their bone mass during the pubertal growth spurt in ages 11 to 14, the time when anorexia nervosa is most prevalent.6 Peak bone mass is attained by the third decade of life, but the rate of growth of bone mass is highest during adolescence and early adulthood.7 Hence, it is important to optimize bone mass during this time, as small differences in bone density can have significant clinical implications later in life: a 5% increase in bone density significantly decreases fracture risk, whereas a 10% decrease in adult bone mineral density is associated with a two to three times higher risk of fracture (reviewed by Rome and Ammerman6).

What is the role of amenorrhea in the development of osteoporosis in premenopausal patients?

Given that two of the most characteristic manifestations of anorexia nervosa are low body weight and the absence of menses, these factors have been hypothesized to be potential causes of osteoporosis.

In general, young women who present with amenorrhea should be evaluated to determine if the amenorrhea is primary or secondary. Primary amenorrhea is the absence of menarche by age 16; secondary amenorrhea is the absence of menses for more than three cycles or more than 6 months in someone who previously had had menses. The most common causes of secondary amenorrhea are ovarian disease, hypothalamic or pituitary disease, and uterine disease. Anorexia nervosa causes hypothalamic dysfunction and is a cause of secondary amenorrhea. In clinical practice, it is also important to remember that pregnancy can occur even in the setting of amenorrhea.

Amenorrhea in patients with anorexia nervosa is related to hypothalamic suppression of the release of gonadotropin-releasing hormone, resulting in lower levels of follicle-stimulating hormone and luteinizing hormone and a resultant prepubertal low-estrogen state.

In a study of 73 women with anorexia nervosa and a mean age of 17.2 years,8 20 months of amenorrhea was the threshold above which the most severe osteopenia was seen, implying that the duration of amenorrhea affects bone health.

Which factors besides amenorrhea influence bone density in premenopausal women?

Undernutrition. Body weight has been suggested to have an independent effect on bone mineral density, and density has been found to increase following weight gain, even before the return of menses.1 Once a regular menstrual cycle has been restored, significant increases in trabecular and cortical bone have been detected.1

Deficiency of insulin-like growth factor 1 (IGF-1). Anorexia nervosa is associated with decreased hepatic synthesis of IGF-I.9 Low levels of IGF-I reduce the levels of osteocalcin, a marker of bone formation, and cause abnormalities in osteoblast function.10 This deficiency is associated with the development of osteopenia in patients with anorexia nervosa.11

Low androgen levels are present in patients with anorexia nervosa, and levels appear to be further reduced by oral contraceptives.12 It remains to be determined whether the further reduction in androgens in women with anorexia nervosa using oral contraceptives is harmful to skeletal health. Low testosterone levels in boys with anorexia nervosa have been associated with lower libido, fewer erections, and potentially lower bone density.13

Hypercortisolemia. Elevated levels of total and free serum cortisol and high 24-hour urinary free cortisol excretion have been noted in anorectic patients. Levels of cortisol are inversely related to levels of osteocalcin, and hypercortisolism has been shown to be associated with osteoporosis.14,15 However, no study has yet shown causality in this population.

Osteoprotegerin has been recognized as an important regulator of bone resorption. Osteoprotegerin inhibits osteoclast differentiation and activation and stimulates osteoclast apoptosis, helping to preserve bone density.

Misra et al16 showed that adolescent girls with anorexia nervosa have higher serum osteoprotegerin levels than controls and that osteoprotegerin levels correlate inversely with markers of nutritional status and lumbar bone density Z scores.16 They and other investigators17 postulate that osteoprotegerin may be released as a compensatory response to the bone loss seen in these patients in an attempt to preserve bone health.

Leptin is an adipocyte-derived hormone that acts on receptors in the hypothalamus, decreasing food intake and increasing energy expenditure. Low leptin levels are a key endocrinologic feature of anorexia nervosa.18 Leptin helps to induce weight loss by stimulating neurons in the hypothalamus that express “weight-loss-inducing” neuropeptides such as pro-opiomelanocortin and inhibiting “weight-gain-inducing” peptides such as neuropeptide Y.19

Although leptin was first believed to be a hormone released to counteract obesity, recent studies19,20 suggest that it is part of a major signaling system that controls adaptation to starvation. These studies have shown that the body senses its corporeal fat through leptin and inhibits ovulation when fat reserves are low.19 In addition, luteinizing hormone and leptin levels have been shown to increase in parallel in patients with anorexia nervosa when weight is restored.20 Thus, rising leptin levels correlate with the resumption of menses in women with anorexia nervosa and in turn have potential consequences for bone health.

Not enough ghrelin, too much obestatin? Ghrelin, a gastric hormone, acts as a natural antagonist to leptin, resulting in an increase in food intake and body weight.19 Circulating ghrelin levels are higher in illness-induced anorexia as well as in anorexia nervosa, and they normalize with weight gain, perhaps as an adaptive mechanism to compensate for a negative energy balance.21

Several in vitro studies suggest that ghrelin directly promotes osteoblast proliferation and differentiation.22 However, human studies of ghrelin’s effects on bone are limited. In a study of healthy younger women, healthy boys, and anorexia nervosa patients, plasma ghrelin levels were only weakly associated with bone mineral density.23

The effects of obestatin, another gastric hormone, are still being investigated. Obestatin was initially shown to oppose the effects of ghrelin by decreasing appetite and weight gain. When given with ghrelin, obestatin appears to work with ghrelin at the hypothalamic level to modulate food intake and growth hormone secretion.24

Interestingly, obestatin and the ratio of ghrelin to obestatin are decreased in patients with anorexia nervosa, but the ratio is unchanged in thin women who have an equivalent body mass index but no eating disorder.25 It has been hypothesized that the ghrelin-obestatin ratio may be the key to explaining the eating restriction and reduced motivation to eat despite high ghrelin levels seen in anorexia nervosa.26 Further studies are needed to determine the role of obestatin and the ghrelin-obestatin ratio in the bone health of women with anorexia nervosa.

While factors such as low body weight and amenorrhea have long been understood to play a role in the development of osteoporosis in women with anorexia nervosa, many complex hormonal factors contribute to bone deficits as well. Further study is needed to fully elucidate these hormonal factors and how they work together to cause osteoporosis. A list of the factors that potentially influence bone density and risk for osteoporosis in patients with anorexia nervosa is presented in Table 1.

 

 

HOW SHOULD WE DIAGNOSE OSTEOPOROSIS IN PREMENOPAUSAL PATIENTS?

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

NEW AND OLD TREATMENTS FOR LOW BONE DENSITY IN ANOREXIA NERVOSA

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.

 

 

What is the effect of exercise on bone health in these patients?

Several studies have examined the effect of weight-bearing exercise on bone density.

Young et al46 compared normal teenagers, ballet dancers, and young women with anorexia nervosa and found that weight-bearing exercise protected against osteoporosis, but only at weight-bearing sites. Athletes in weight-bearing sports had a 5% to 15% higher bone mineral density in weight-bearing sites (ie, the femur) compared with nonathletes, but had lower bone mineral density in the spine.

Therefore, a Z score below −1.0 in an athlete, especially in a distal site, warrants further investigation and treatment.32 In general, exercise does not necessarily protect against osteoporosis in this patient population, and it can sometimes mask underlying bone loss. In addition, keep in mind that many of these patients exercise compulsively, using it as a form of purging.

Insulin-like growth factor-1: More study needed

IGF-1 contributes to bone growth by stimulating osteoblasts, and patients with anorexia nervosa have been shown to have low levels of IGF-1.9

Grinspoon et al10 randomized 60 patients with anorexia nervosa to receive IGF-1 alone, IGF-1 plus an oral contraceptive, an oral contraceptive alone, or placebo. All patients were given calcium and vitamin D and were followed for 9 months. Total bone mass increased significantly in those taking IGF-1 compared with those taking placebo. Those taking an IGF-1 and an oral contraceptive had a significant increase in spinal bone mineral density compared with those on placebo group. At other skeletal sites, however, IGF-1 plus an oral contraceptive and IGF-1 alone failed to produce significant increases in bone mineral density compared with placebo.

Further study is needed to determine the role of IGF-1 in treating low bone mineral density in anorexia nervosa.

Bisphosphonates: Not approved for this indication

In premenopausal women, bisphosphonates are approved by the US Food and Drug Administration (FDA) for use only in those taking glucocorticoids. Although bisphosphonates have been shown to significantly increase bone mineral density in young women with anorexia nervosa,26 they should be used with caution in patients of childbearing age because they are teratogenic. Bisphosphonates have a long half-life and may continue to affect bone turnover for up to 2 years after they are discontinued.47 In addition, they are not recommended in patients with a history of purging via vomiting, due to a risk of esophageal ulceration.

Parathyroid hormone therapy: Studies ongoing

The parathyroid hormone fragment teriparatide (Forteo) is widely used for treating postmenopausal osteoporosis.

Before teriparatide was approved, there was concern that it might increase the risk of osteosarcoma, as almost 45% of rats treated with this drug at the highest-tested dose level developed this aggressive form of bone cancer.48 Balancing the proven benefits of teriparatide shown by clinical trials with the theoretic risk of teriparatide-induced osteosarcoma, the FDA mandated a “black-box” warning about this potential effect.

Studies of parathyroid hormone treatment in anorexia nervosa and other premenopausal patients are ongoing.26

Leptin: More study needed

Leptin is a potent stimulator of bone growth and has been shown to increase bone mineral density in vitro and in vivo.19 However, concerns have been raised about giving supra-physiologic doses of leptin to patients with anorexia nervosa, as this may increase the risk of further weight loss and relapse.

More work is needed to determine the role of leptin for the treatment of osteoporosis in anorexia nervosa.

Ghrelin: Probably not effective as a single agent

Pharmacologic use of ghrelin increases food intake in healthy humans,49 and it has been proposed as a treatment for weight restoration and bone health in anorexia nervosa. Preliminary studies have not shown it to increase appetite or weight gain,50 but it did increase slow-wave sleep.

Based on these studies, it is unlikely that ghrelin will be effective as a single agent to stimulate appetite, but it may be helpful in conjunction with other therapies.

Cannabinoids: Little ongoing research

Cannabinoids have been proposed as a treatment for anorexia nervosa in the hope that they would induce weight gain and in turn prevent osteoporosis.

Interest in their use in anorexia nervosa stems from the discovery of two cannabinoid receptors (CB1 and CB2) located in the brain and peripheral organ systems. Anorexia nervosa has been associated with different alleles of the CB1 gene,51 but the therapeutic implications of this are far from clear.

Cannabinoids appear to regulate eating behavior at several levels within the brain and periphery: the hypothalamus and hindbrain (integrative functions), the limbic system (for hedonic evaluation of foods), the intestinal system, and adipose tissue.52 At each of these levels, the endocannabinoid system interacts with a number of better known peptides involved in appetite regulation, including leptin, ghrelin, and the melanocortins. In mouse studies, genetic leptin deficiency is associated with elevated hypothalamic endocannabinoid levels.

Appetite stimulation by cannabinoids has been studied for several decades, particularly in relation to cachexia and malnutrition associated with cancer. Very few trials have studied cannabinoids for anorexia nervosa.

In a 4-week crossover trial in 11 patients with anorexia nervosa,53 tetrahydrocannabinol (THC) treatment resulted in an increase in sleep disturbances and interpersonal sensitivity, but it had no significant effect on weight gain compared with diazepam treatment.53

Another pilot study of nine outpatients with anorexia nervosa treated with THC showed a significant improvement in depression and perfectionism scores without any significant weight gain.19

Although this research was once promising, the risk was felt to outweigh the benefit, as cannabinoids may induce dependency in this patient group, who may already be at high risk of drug addiction, and very few have continued this line of investigation.

 

 

WHAT CAN WE DO FOR NOW?

  • Weight restoration and nutritional rehabilitation remain the keys to treatment of low bone density to reduce the risk of osteoporosis in patients with anorexia nervosa. However, as many as one-third of patients with anorexia nervosa relapse during their lifetime, and other treatments are needed to stabilize and prevent bone loss.
  • Vitamin D deficiency is clearly associated with a risk of osteoporosis and fracture, and patients with vitamin D deficiency should be treated with supplementation.
  • Standard therapies in postmenopausal patients (such as bisphosphonates and teriparatide) should be used with caution in premenopausal anorexia nervosa patients because of potential long-term health risks.
  • Although treatment of amenorrhea and estrogen deficiency has been shown to at least stabilize bone density in postmenopausal patients, this does not appear to be the case in premenopausal girls and young women.
  • As we learn more about hormonal factors in anorexia nervosa, we hope to identify interventions that will help restore weight and decrease the risk of osteoporosis. A summary of potential treatment strategies and targets for prevention of osteoporosis in anorexia nervosa is presented in Table 2.
     

 

Acknowledgment: The author thanks the General Internal Medicine Works in Progress Group for its editorial comments, and Dr. Ellen Rome for her mentorship and support.

References
  1. Baker D, Roberts R, Towell T. Factors predictive of bone mineral density in eating-disordered women: a longitudinal study. Int J Eat Disord 2000; 27:29–35.
  2. Rome ES. Eating disorders. Obstet Gynecol Clin North Am 2003; 30:353–377.
  3. First MB, editor. Diagnostic and Statistical Manual of Mental Disorders—4th edition. Washington, DC: American Psychiatric Association, 2000.
  4. Mehler PS, MacKenzie TD. Treatment of osteopenia and osteoporosis in anorexia nervosa: a systematic review of the literature. Int J Eat Disord 2009; 42:195–201.
  5. Wong JC, Lewindon P, Mortimer R, Shepherd R. Bone mineral density in adolescent females with recently diagnosed anorexia nervosa. Int J Eat Disord 2001; 29:11–16.
  6. Rome ES, Ammerman S. Medical complications of eating disorders: an update. J Adolesc Health 2003; 33:418–426.
  7. Recker RR, Davies KM, Hinders SM, Heaney RP, Stegman MR, Kimmel DB. Bone gain in young adult women. JAMA 1992; 268:2403–2408.
  8. Sterling WM, Golden NH, Jacobson MS, Ornstein RM, Hertz SM. Metabolic assessment of menstruating and nonmenstruating normal weight adolescents. Int J Eat Disord 2009; 42:658–663.
  9. Legroux-Gerot I, Vignau J, Collier F, Cortet B. Bone loss associated with anorexia nervosa. Joint Bone Spine 2005; 72:489–495.
  10. Grinspoon S, Thomas L, Miller K, Herzog D, Klibanski A. Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa. J Clin Endocrinol Metab 2002; 87:2883–2891.
  11. Soyka LA, Grinspoon S, Levitsky LL, Herzog DB, Klibanski A. The effects of anorexia nervosa on bone metabolism in female adolescents. J Clin Endocrinol Metab 1999; 84:4489–4496.
  12. Miller KK, Lawson EA, Mathur V, et al. Androgens in women with anorexia nervosa and normal-weight women with hypothalamic amenorrhea. J Clin Endocrinol Metab 2007; 92:1334–1339.
  13. Misra M, Katzman DK, Cord J, et al. Bone metabolism in adolescent boys with anorexia nervosa. J Clin Endocrinol Metab 2008; 93:3029–3036.
  14. Misra M, Miller KK, Almazan C, et al. Alterations in cortisol secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab 2004; 89:4972–4980.
  15. Chiodini I, Mascia ML, Muscarella S, et al. Subclinical hypercortisolism among outpatients referred for osteoporosis. Ann Intern Med 2007; 147:541–548.
  16. Misra M, Soyka LA, Miller KK, et al. Serum osteoprotegerin in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab 2003; 88:3816–3822.
  17. Ohwada R, Hotta M, Sato K, Shibasaki T, Takano K. The relationship between serum levels of estradiol and osteoprotegerin in patients with anorexia nervosa. Endocr J 2007; 54:953–959.
  18. Müller TD, Föcker M, Holtkamp K, Herpertz-Dahlmann B, Hebebrand J. Leptin-mediated neuroendocrine alterations in anorexia nervosa: somatic and behavioral implications. Child Adolesc Psychiatr Clin N Am 2009; 18:117–129.
  19. Støving RK, Andries A, Brixen K, Flyvbjerg A, Hørder K, Frystyk J. Leptin, ghrelin, and endocannabinoids: potential therapeutic targets in anorexia nervosa. J Psychiatr Res 2009; 43:671–679.
  20. Audi L, Mantzoros CS, Vidal-Puig A, Vargas D, Gussinye M, Carrascosa A. Leptin in relation to resumption of menses in women with anorexia nervosa. Mol Psychiatry 1998; 3:544–547.
  21. Wong IP, Baldock PA, Herzog H. Gastrointestinal peptides and bone health. Curr Opin Endocrinol Diabetes Obes 2010; 17:44–50.
  22. Fukushima N, Hanada R, Teranishi H, et al. Ghrelin directly regulates bone formation. J Bone Miner Res 2005; 20:790–798.
  23. Makovey J, Naganathan V, Seibel M, Sambrook P. Gender differences in plasma ghrelin and its relations to body composition and bone—an opposite-sex twin study. Clin Endocrinol (Oxf) 2007; 66:530–537.
  24. Hassouna R, Zizzari P, Tolle V. The ghrelin/obestatin balance in the physiological and pathological control of growth hormone secretion, body composition and food intake. J Neuroendocrinol 2010; 22:793–804.
  25. Germain N, Galusca B, Grouselle D, et al. Ghrelin/obestatin ratio in two populations with low body weight: constitutional thinness and anorexia nervosa. Psychoneuroendocrinology 2009; 34:413–419.
  26. Cohen A, Shane E. Treatment of premenopausal women with low bone mineral density. Curr Osteoporos Rep 2008; 6:39–46.
  27. Licata A. Bone density vs bone quality: what’s a clinician to do? Cleve Clin J Med 2009; 76:331–336.
  28. Bianchi ML, Baim S, Bishop NJ, et al. Official positions of the International Society for Clinical Densitometry (ISCD) on DXA evaluation in children and adolescents. Pediatr Nephrol 2010; 25:37–47.
  29. Mendelsohn FA, Warren MP. Anorexia, bulimia, and the female athlete triad: evaluation and management. Endocrinol Metab Clin North Am 2010; 39:155–167.
  30. Mehler PS, Krantz M. Anorexia nervosa medical issues. J Womens Health (Larchmt) 2003; 12:331–340.
  31. Watts NB, Lewiecki EM, Miller PD, Baim S. National Osteoporosis Foundation 2008 Clinician’s Guide to Prevention and Treatment of Osteoporosis and the World Health Organization Fracture Risk Assessment Tool (FRAX): what they mean to the bone densitometrist and bone technologist. J Clin Densitom 2008; 11:473–477.
  32. Nattiv A, Loucks AB, Manore MM, Sanborn CF, Sundgot-Borgen J, Warren MP; American College of Sports Medicine. American College of Sports Medicine position stand. The female athlete triad. Med Sci Sports Exerc 2007; 39:1867–1882.
  33. Cummings SR, Palermo L, Browner W, et al. Monitoring osteoporosis therapy with bone densitometry: misleading changes and regression to the mean. Fracture Intervention Trial Research Group. JAMA 2000; 283:1318–1321.
  34. LeBoff MS, Kohlmeier L, Hurwitz S, Franklin J, Wright J, Glowacki J. Occult vitamin D deficiency in postmenopausal US women with acute hip fracture. JAMA 1999; 281:1505–1511.
  35. Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab 2010; 95:471–478.
  36. Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med 2004; 158:531–537.
  37. Hofbauer LC, Hamann C, Ebeling PR. Approach to the patient with secondary osteoporosis. Eur J Endocrinol 2010; 162:1009–1020.
  38. Stoffman N, Gordon CM. Vitamin D and adolescents: what do we know? Curr Opin Pediatr 2009; 21:465–471.
  39. Bone HG, Greenspan SL, McKeever C, et al. Alendronate and estrogen effects in postmenopausal women with low bone mineral density. Alendronate/Estrogen Study Group. J Clin Endocrinol Metab 2000; 85:720–726.
  40. Barrett-Connor E, Wenger NK, Grady D, et al. Hormone and nonhormone therapy for the maintenance of postmenopausal health: the need for randomized controlled trials of estrogen and raloxifene. J Womens Health 1998; 7:839–847.
  41. Klibanski A, Biller BM, Schoenfeld DA, Herzog DB, Saxe VC. The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa. J Clin Endocrinol Metab 1995; 80:898–904.
  42. Stokosch GR, Friedman AJ, Wu SC, Kamin M. Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in adolescent females with anorexia nervosa: double-blind, placebo-controlled study. J Adolesc Health 2006; 39:819–827.
  43. Golden NH, Lanzkowsky L, Schebendach J, Palestro CJ, Jacobson MS, Shenker IR. The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa. J Pediatr Adolesc Gynecol 2002; 15:135–143.
  44. Robinson E, Bachrach LK, Katzman DK. Use of hormone replacement therapy to reduce the risk of osteopenia in adolescent girls with anorexia nervosa. J Adolesc Health 2000; 26:343–348.
  45. Myburgh KH, Hutchins J, Fataar AB, et al. Low bone density is an etiologic factor for stress fractures in athletes. Ann Intern Med 1990; 113:754–759.
  46. Young N, Formica C, Szmukler G, Seeman E. Bone density at weight-bearing and nonweight-bearing sites in ballet dancers: the effects of exercise, hypogonadism, and body weight. J Clin Endocrinol Metab 1994; 78:449–454.
  47. Stock JL, Bell NH, Chesnut CH, et al. Increments in bone mineral density of the lumbar spine and hip and suppression of bone turnover are maintained after discontinuation of alendronate in postmenopausal women. Am J Med 1997; 103:291–297.
  48. Subbiah V, Madsen VS, Raymond AK, Benjamin RS, Ludwig JA. Of mice and men: divergent risks of teriparatide-induced osteosarcoma. Osteoporos Int 2010; 21:1041–1045.
  49. Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001; 86:5992.
  50. Miljic D, Pekic S, Djurovic M, et al. Ghrelin has partial or no effect on appetite, growth hormone, prolactin, and cortisol release in patients with anorexia nervosa. J Clin Endocrinol Metab 2006; 914:1491–1495.
  51. Siegfried Z, Kanyas K, Latzer Y, et al. Association study of cannabinoid receptor gene (CNR1) alleles and anorexia nervosa: differences between restricting and binging/purging subtypes. Am J Med Genet B Neuropsychiatr Genet 2004; 125B:126–130.
  52. Cota D, Marsicano G, Lutz B, et al. Endogenous cannabinoid system as a modulator of food intake. Int J Obes Relat Metab Disord 2003; 27:289–301.
  53. Gross H, Ebert MH, Faden VB, et al. A double-blind trial of delta 9-tetrahydrocannabinol in primary anorexia nervosa. J Clin Psychopharmacol 1983; 3:165–171.
References
  1. Baker D, Roberts R, Towell T. Factors predictive of bone mineral density in eating-disordered women: a longitudinal study. Int J Eat Disord 2000; 27:29–35.
  2. Rome ES. Eating disorders. Obstet Gynecol Clin North Am 2003; 30:353–377.
  3. First MB, editor. Diagnostic and Statistical Manual of Mental Disorders—4th edition. Washington, DC: American Psychiatric Association, 2000.
  4. Mehler PS, MacKenzie TD. Treatment of osteopenia and osteoporosis in anorexia nervosa: a systematic review of the literature. Int J Eat Disord 2009; 42:195–201.
  5. Wong JC, Lewindon P, Mortimer R, Shepherd R. Bone mineral density in adolescent females with recently diagnosed anorexia nervosa. Int J Eat Disord 2001; 29:11–16.
  6. Rome ES, Ammerman S. Medical complications of eating disorders: an update. J Adolesc Health 2003; 33:418–426.
  7. Recker RR, Davies KM, Hinders SM, Heaney RP, Stegman MR, Kimmel DB. Bone gain in young adult women. JAMA 1992; 268:2403–2408.
  8. Sterling WM, Golden NH, Jacobson MS, Ornstein RM, Hertz SM. Metabolic assessment of menstruating and nonmenstruating normal weight adolescents. Int J Eat Disord 2009; 42:658–663.
  9. Legroux-Gerot I, Vignau J, Collier F, Cortet B. Bone loss associated with anorexia nervosa. Joint Bone Spine 2005; 72:489–495.
  10. Grinspoon S, Thomas L, Miller K, Herzog D, Klibanski A. Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa. J Clin Endocrinol Metab 2002; 87:2883–2891.
  11. Soyka LA, Grinspoon S, Levitsky LL, Herzog DB, Klibanski A. The effects of anorexia nervosa on bone metabolism in female adolescents. J Clin Endocrinol Metab 1999; 84:4489–4496.
  12. Miller KK, Lawson EA, Mathur V, et al. Androgens in women with anorexia nervosa and normal-weight women with hypothalamic amenorrhea. J Clin Endocrinol Metab 2007; 92:1334–1339.
  13. Misra M, Katzman DK, Cord J, et al. Bone metabolism in adolescent boys with anorexia nervosa. J Clin Endocrinol Metab 2008; 93:3029–3036.
  14. Misra M, Miller KK, Almazan C, et al. Alterations in cortisol secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab 2004; 89:4972–4980.
  15. Chiodini I, Mascia ML, Muscarella S, et al. Subclinical hypercortisolism among outpatients referred for osteoporosis. Ann Intern Med 2007; 147:541–548.
  16. Misra M, Soyka LA, Miller KK, et al. Serum osteoprotegerin in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab 2003; 88:3816–3822.
  17. Ohwada R, Hotta M, Sato K, Shibasaki T, Takano K. The relationship between serum levels of estradiol and osteoprotegerin in patients with anorexia nervosa. Endocr J 2007; 54:953–959.
  18. Müller TD, Föcker M, Holtkamp K, Herpertz-Dahlmann B, Hebebrand J. Leptin-mediated neuroendocrine alterations in anorexia nervosa: somatic and behavioral implications. Child Adolesc Psychiatr Clin N Am 2009; 18:117–129.
  19. Støving RK, Andries A, Brixen K, Flyvbjerg A, Hørder K, Frystyk J. Leptin, ghrelin, and endocannabinoids: potential therapeutic targets in anorexia nervosa. J Psychiatr Res 2009; 43:671–679.
  20. Audi L, Mantzoros CS, Vidal-Puig A, Vargas D, Gussinye M, Carrascosa A. Leptin in relation to resumption of menses in women with anorexia nervosa. Mol Psychiatry 1998; 3:544–547.
  21. Wong IP, Baldock PA, Herzog H. Gastrointestinal peptides and bone health. Curr Opin Endocrinol Diabetes Obes 2010; 17:44–50.
  22. Fukushima N, Hanada R, Teranishi H, et al. Ghrelin directly regulates bone formation. J Bone Miner Res 2005; 20:790–798.
  23. Makovey J, Naganathan V, Seibel M, Sambrook P. Gender differences in plasma ghrelin and its relations to body composition and bone—an opposite-sex twin study. Clin Endocrinol (Oxf) 2007; 66:530–537.
  24. Hassouna R, Zizzari P, Tolle V. The ghrelin/obestatin balance in the physiological and pathological control of growth hormone secretion, body composition and food intake. J Neuroendocrinol 2010; 22:793–804.
  25. Germain N, Galusca B, Grouselle D, et al. Ghrelin/obestatin ratio in two populations with low body weight: constitutional thinness and anorexia nervosa. Psychoneuroendocrinology 2009; 34:413–419.
  26. Cohen A, Shane E. Treatment of premenopausal women with low bone mineral density. Curr Osteoporos Rep 2008; 6:39–46.
  27. Licata A. Bone density vs bone quality: what’s a clinician to do? Cleve Clin J Med 2009; 76:331–336.
  28. Bianchi ML, Baim S, Bishop NJ, et al. Official positions of the International Society for Clinical Densitometry (ISCD) on DXA evaluation in children and adolescents. Pediatr Nephrol 2010; 25:37–47.
  29. Mendelsohn FA, Warren MP. Anorexia, bulimia, and the female athlete triad: evaluation and management. Endocrinol Metab Clin North Am 2010; 39:155–167.
  30. Mehler PS, Krantz M. Anorexia nervosa medical issues. J Womens Health (Larchmt) 2003; 12:331–340.
  31. Watts NB, Lewiecki EM, Miller PD, Baim S. National Osteoporosis Foundation 2008 Clinician’s Guide to Prevention and Treatment of Osteoporosis and the World Health Organization Fracture Risk Assessment Tool (FRAX): what they mean to the bone densitometrist and bone technologist. J Clin Densitom 2008; 11:473–477.
  32. Nattiv A, Loucks AB, Manore MM, Sanborn CF, Sundgot-Borgen J, Warren MP; American College of Sports Medicine. American College of Sports Medicine position stand. The female athlete triad. Med Sci Sports Exerc 2007; 39:1867–1882.
  33. Cummings SR, Palermo L, Browner W, et al. Monitoring osteoporosis therapy with bone densitometry: misleading changes and regression to the mean. Fracture Intervention Trial Research Group. JAMA 2000; 283:1318–1321.
  34. LeBoff MS, Kohlmeier L, Hurwitz S, Franklin J, Wright J, Glowacki J. Occult vitamin D deficiency in postmenopausal US women with acute hip fracture. JAMA 1999; 281:1505–1511.
  35. Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab 2010; 95:471–478.
  36. Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med 2004; 158:531–537.
  37. Hofbauer LC, Hamann C, Ebeling PR. Approach to the patient with secondary osteoporosis. Eur J Endocrinol 2010; 162:1009–1020.
  38. Stoffman N, Gordon CM. Vitamin D and adolescents: what do we know? Curr Opin Pediatr 2009; 21:465–471.
  39. Bone HG, Greenspan SL, McKeever C, et al. Alendronate and estrogen effects in postmenopausal women with low bone mineral density. Alendronate/Estrogen Study Group. J Clin Endocrinol Metab 2000; 85:720–726.
  40. Barrett-Connor E, Wenger NK, Grady D, et al. Hormone and nonhormone therapy for the maintenance of postmenopausal health: the need for randomized controlled trials of estrogen and raloxifene. J Womens Health 1998; 7:839–847.
  41. Klibanski A, Biller BM, Schoenfeld DA, Herzog DB, Saxe VC. The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa. J Clin Endocrinol Metab 1995; 80:898–904.
  42. Stokosch GR, Friedman AJ, Wu SC, Kamin M. Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in adolescent females with anorexia nervosa: double-blind, placebo-controlled study. J Adolesc Health 2006; 39:819–827.
  43. Golden NH, Lanzkowsky L, Schebendach J, Palestro CJ, Jacobson MS, Shenker IR. The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa. J Pediatr Adolesc Gynecol 2002; 15:135–143.
  44. Robinson E, Bachrach LK, Katzman DK. Use of hormone replacement therapy to reduce the risk of osteopenia in adolescent girls with anorexia nervosa. J Adolesc Health 2000; 26:343–348.
  45. Myburgh KH, Hutchins J, Fataar AB, et al. Low bone density is an etiologic factor for stress fractures in athletes. Ann Intern Med 1990; 113:754–759.
  46. Young N, Formica C, Szmukler G, Seeman E. Bone density at weight-bearing and nonweight-bearing sites in ballet dancers: the effects of exercise, hypogonadism, and body weight. J Clin Endocrinol Metab 1994; 78:449–454.
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Issue
Cleveland Clinic Journal of Medicine - 78(1)
Issue
Cleveland Clinic Journal of Medicine - 78(1)
Page Number
50-58
Page Number
50-58
Publications
Cleveland Clinic Journal of Medicine
Publications
Cleveland Clinic Journal of Medicine
Topics
Adolescent Medicine
Obesity
Women's Health
Mental Health
Endocrinology
Article Type
Article
Display Headline
Premenopausal osteoporosis, an overlooked consequence of anorexia nervosa
Display Headline
Premenopausal osteoporosis, an overlooked consequence of anorexia nervosa
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KEY POINTS

  • Women gain 40% to 60% of their bone mass during adolescence, a time coinciding with the peak incidence of anorexia nervosa, and they attain their peak bone mass by the time they are in their 20s.
  • The etiology of osteoporosis in anorexia nervosa is complex and multifaceted. Early detection and treatment are critical.
  • Osteoporosis in premenopausal patients is defined as low bone mineral density (a Z score below −2.0) in combination with risk factors such as chronic malnutrition, eating disorders, hypogonadism, glucocorticoid exposure, and previous fractures.
  • Restoring body weight is the key treatment. Vitamin D should be supplemented if low. Estrogen therapy has not been shown to be effective, and exercise may be counterproductive. Bisphosphonates and teriparatide should be used with caution, if at all.
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