Reviews

Premenopausal osteoporosis, an overlooked consequence of anorexia nervosa

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ABSTRACTMany young women with anorexia nervosa develop premenopausal osteoporosis. In particular, female athletes have a much higher incidence of disordered eating than their peers and therefore are at a much higher risk of stress fractures and other traumatic bone pathology. This review summarizes factors affecting the development of premenopausal osteoporosis in these patients and identifies potential targets for intervention.

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.


 

References

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.

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