Premenopausal osteoporosis, an overlooked consequence of anorexia nervosa

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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.

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