by Steven K. Grinspoon, MD and Elizabeth R. Thomas, NP
Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
Reprinted from Eating Disorders Review
September/October 2000 Volume 11, Number 5
©2000 Gürze Books
Anorexia nervosa and related eating disorders affect up to 1% of college-age women in the United States.1,2 Bone loss is significant among women with anorexia nervosa: more than half of these patients have bone densities greater than two standard deviations below age- and gender-matched normal means.3, 4, 5 Each standard deviation below the mean approximately doubles the risk of fractures.
The young age at onset and the rapidity of bone loss in patients with anorexia nervosa are particularly striking. Bone loss can be detected after only 6 months of illness, and symptomatic compression fractures and kyphosis (spinal deformity) are not uncommon in this young population.6 The long-term consequences of bone loss associated with anorexia nervosa are not known, but a residual deficit can remain after weight recovery.6
Mechanisms of anorexia-related bone loss
The etiology of the bone loss associated with anorexia nervosa is not known; however, substantial progress has been made toward a more complete understanding of the mechanisms of anorexia-related bone loss. A number of different factors may contribute to bone loss in anorexia nervosa, including estrogen deficiency and malnutrition. Bone density correlates with the duration of amenorrhea in women with anorexia nervosa, 4,6 and estrogen deficiency accompanies other states associated with decreased bone density, such as menopause and hyperprolac-tinemia.7, 8 The degree of bone loss seen in anorexia nervosa, however, is unique in its severity compared to these other low-estrogen states.9, 10 In a recent study that compared age-matched patients with hypothalamic amenorrhea and anorexia nervosa, the severity of bone loss was significantly greater in the patients with anorexia nervosa, even though both groups had similar degrees and duration of estrogen deficiency.11
Estrogen therapy: Still a major question
Whether or not estrogen replacement therapy is an effective therapeutic option for the bone loss associated with anorexia nervosa remains a major question. In a randomized prospective study of 48 women followed for a mean of 1.5 years, estrogen/progestin replacement and calcium supplementation did not prevent or reverse bone loss in women with anorexia nervosa.12 In a subanalysis among patients with severe weight loss (those who weighed less than 70% of ideal body weight, or IBW) estrogen/progestin prevented bone loss but did not increase bone density. Nonetheless, primary care providers often prescribe estrogen replacement for young amenorrheic low-weight women. The overall inadequacy of estrogen therapy in anorexia nervosa stands in marked contrast to its efficacy in preventing bone loss in postmenopausal women. The data suggest other factors contribute to the bone loss associated with anorexia nervosa.
Elevated cortisol levels, excess physical activity, and decreased calcium intake may also contribute to bone loss in anorexia nervosa.13 Although patients with anorexia nervosa demonstrate elevated plasma cortisol levels, results of a recent study showed only mild elevations of urine-free cortisol in 22% of women with severe osteopenia.14 This suggests that although hypercortisolemia may contribute to abnormal bone density in a few patients, it does not account for the significant degree of bone loss in patients with anorexia nervosa. In addition, excess physical activity may contribute to the bone loss that accompanies anorexia nervosa. However, in several studies, physical activity has not been shown to correlate with bone density.3, 15 In addition, reduced calcium and vitamin D intake is not associated with low bone density in anorexia nervosa.12, 16
Malnutrition itself may be a critical element in anorexia-related bone loss. In women with anorexia nervosa, bone density correlates directly with nutritional indices such as BMI, caloric intake, fat mass, and leptin levels.3, 12 Weight gain correlates with increased bone density in women with anorexia nervosa prior to resumption of normal menstrual function.6 Furthermore, short-term fasting, such as over 4 days, results in a marked decrease of 50% in bone formation markers in healthy normal volunteers.18
Bone formation and resorption
Recent studies measuring specific markers of bone formation and resorption have provided new information on the mechanisms of bone loss in anorexia nervosa. Bone is in a continuous state of turnover, with new bone formed by osteoblasts (bone-forming cells) and old bone resorbed by osteoclasts (cells that absorb and remove bone tissue).
In women with anorexia nervosa, serum levels of osteocalcin, a marker of bone formation, are significantly decreased in comparison with the levels in age-matched healthy controls. Also notable is the increased urinary excretion of dexypyridinoline and N-telopeptide among women with anorexia nervosa, indicative of increased bone resorption.14 There is a reduction of bone formation in anorexia nervosa as well as increased bone resorption, whereas other estrogen-deficient conditions only feature increased bone resorption. This pattern of bone turnover, with reduced bone formation and increased bone resorption, is in contrast to that seen in other estrogen deficiency states. Reduced osteocalcin levels correlate with weight, suggesting an important role of nutrition in the pathogenesis of anorexia-nervosa-related bone loss.
Insulin-like growth factor deficiency
Deficiency of insulin-like growth factor I (IGF-I) may contribute to the decreased rate of bone formation and osteopenia seen in anorexia nervosa. IGF-I is a nutritionally dependent hormone that both stimulates and reduces deoxyribonucleic acid (DNA) and collagen synthesis.19, 20
Patients with anorexia nervosa are markedly IGF-I deficient. Serum levels of IGF-I decrease with weight loss, increase with weight recovery and, importantly, can be used to predict bone loss.12, 14,21,22
Short-term studies have shown that administration of recombinant human insulin-like growth factor (rhIGF-I) increases the markers of bone formation and at low doses does not stimulate bone resorption. IGF-I may therefore be a useful therapy to address the unbalanced rate of bone turnover that accompanies anorexia nervosa.13
At the current time, primary care providers should recommend that their female patients with anorexia nervosa take calcium supplements, 1000 to 1500 mg per day, and a daily multivitamin containing 400 international units of vitamin D. The decision as to whether to supplement estrogen should be made on an individual basis.
Despite the lack of effective therapies, bone density measurement is an important assessment for these patients. With the results, clinicians can identify and advise patients whose bone densities are below the fracture threshold. This assessment also provides a valuable opportunity to counsel the patient on the long-term consequences of low weight and the benefits of weight gain.
Currently, there are few treatment options. Antiresorptive therapies used to reduce bone loss in postmenopausal women, such as with the bisphosphonates, may not be effective for patients with anorexia nervosa. These medications do not stimulate bone formation and their role in anorexia nervosa is still unclear.23 In contrast, weight gain is associated with increased bone turnover and improved bone density. Thus, nutritional counseling for at-risk patients is an important therapeutic strategy to minimize bone loss in this population.
Significant progress has been made in the understanding and treatment of anorexia-related bone loss. In addition to weight gain, novel strategies to stimulate bone formation may be appropriate for affected patients. Research on the use of these factors, including IGF-I, is ongoing.
- Lucas AR, Beard, CM, O’Fallon, et al. 50-year trends in the incidence of anorexia nervosa in Rochester, MN: A population-based study. Am J Psychiatry 1991;148:917.
- Pope GH Jr, Hudson JI, Yurgelun-Todd D. Prevalence of anorexia nervosa and bulimia in three student populations. Int J Eat Disord 1984; 3(3):45.
- Bachrach LK, Guido D, Katzman D, et al. Decreased bone density in adolescent girls with anorexia nervosa. Pediatrics 1990;86:440.
- Biller BMK, Saxe V, Herzog DB, et al. Mechanisms of osteoporosis in adult and adolescent women with anorexia nervosa. J Clin Endocrinol Metab1989; 68:548.
- Rigotti NA, Nussbaum SR, Herzog DB, et al. Osteoporosis in women with anorexia nervosa. N Engl J Med 1984; 311:1601.
- Bachrach L, Katzman D, Litt I, et al. Recovery from osteopenia in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab 1991;72:602.
- Christiansen C, Christiansen MS, Transbol I. Bone mass in post-menopausal women after withdrawal of oestrogen/gestagen replacement therapy. Lancet 1981;1:459.
- Klibanski A, Greenspan, SL. Increase in bone mass after treatment of hyperprolactinemic amenorrhea. N Engl J Med 1986;315:542.
- Biller BMK, Coughlin JF, Saxe V, et al. Osteopenia in women with hypothalamic amenorrhea. Obstet Gynecol 1991;78:996.
- Klibanski A, Biller BMK, Rosenthal DI, et al. Effects of prolactin and estrogen deficiency in amenorrheic bone loss. J Clin Endocrinol Metab 1988;67:124.
- Grinspoon S, Miller K, Coyle C, et al. Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea. J Clin Endocrinol Metab1999; 84:2049.
- Klibanski A, Biller BMK, Schoenfeld DA, et al. The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa. J Clin Endocrinol Metab 1995;80:898.
- Salisbury JJ, Mitchell JE. Bone mineral density and anorexia nervosa in women. Am J Psychiatry 1991;148:768.
- Grinspoon, S, Baum H, Lee K, et al. Effects of short-term recombinant human insulin-like growth factor administration on bone turnover in osteopenic women with anorexia nervosa. J Clin Endocrinol Metab 1996a; 81:3864.
- Joyce J, Warren D, Humphries L, et al. Osteoporosis in women with eating disorders: Comparison of physical parameters, exercise and menstrual status with SPA and DPA evaluation. J Nucl Med 1990;31:325.
- Rigotti NA, Neer RM, Skates SJ, et al. The clinical course of osteoporosis in anorexia nervosa. JAMA 1991;265:1133.
- Grinspoon S, Gulick T, Askari H, et al. Serum leptin levels in anorexia nervosa. J Clin Endocrinol Metab 1996b; 81:3861.
- Grinspoon S, Baum H, Kim V, et al. Decreased bone formation and increased mineral dissolution during acute fasting in young women. J Clin Endocrinol Metab 1995;80:3628.
- Hock JM, Centrella M, Canalis E. Insulin-like growth factor I has independent effects on bone matrix formation and cell replication. Endocrinology 1988;122:254.
- McCarthy TL, Centrella M, Canalis E. Regulatory effects of insulin-like growth factors I and II on bone collagen synthesis in rat calvarial cultures. Endocrinology 1989;124:301.
- Counts DR, Gwirtsman HE, Carlsson LMS. The effect of anorexia nervosa and refeeding on growth hormone-binding protein, the insulin-like growth factors (IGFs), and the IGF-binding proteins. J Clin Endocrinol Metab 1992;75:762.
- Winterer J, Gwirtsman HE, George DT, et al. Adrenocorticotropin-stimulated adrenal androgen secretion in anorexia nervosa: Impaired secretion at low weight with normalization after long-term weight recovery. J Clin Endocrinol Metab 1985; 61:693.
- Rodan GA, Fleisch HA. Bisphosphonates: Mechanisms of action. J Clin Invest 1996;97:2692.