Osteoporosi in premenopausa una conseguenza trascurata dell'anoressia nervosa.


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Osteoporosi in premenopausa una conseguenza trascurata dell'anoressia nervosa.

  1. 1. REVIEW CME EDUCATIONAL OBJECTIVE: Readers will recognize the risk of osteoporosis in patients with anorexia nervosa CREDIT KATHRYN TENG, MD 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, OHPremenopausal osteoporosis,an overlooked consequenceof anorexia nervosa■ ABSTRACT Amongitsthe devastating effects ofover- orexia nervosa, and one that is easily looked, is impact on bone. an- Many young women with anorexia nervosa develop pre- menopausal osteoporosis. In particular, female athletes Probably more than half of young women have a much higher incidence of disordered eating than with anorexia nervosa develop osteoporosis, their peers and therefore are at a much higher risk of and relatively quickly. Baker et al1 obtained stress fractures and other traumatic bone pathology. This bone scans in a series of 56 young women, mean age 27 years, who had had an eating disorder for review summarizes factors affecting the development of a mean of about 10 years, and found that the premenopausal osteoporosis in these patients and identi- bone mineral density in the femur was below fies potential targets for intervention. the critical fracture threshold in 42 (75%).■ KEY POINTS Osteoporosis is particularly common and worrisome in female athletes (and is becoming Women gain 40% to 60% of their bone mass during increasingly common in male athletes as well). adolescence, a time coinciding with the peak incidence Female athletes have a much higher incidence of anorexia nervosa, and they attain their peak bone of disordered eating than their peers2 and there- fore are at a much higher risk of fractures. mass by the time they are in their 20s. This review summarizes the factors affect- ing the development of osteoporosis in these The etiology of osteoporosis in anorexia nervosa is complex patients and discusses potential targets for in- and multifaceted. Early detection and treatment are critical. tervention. Osteoporosis in premenopausal patients is defined as ■ ANOREXIA AND BONE HEALTH: low bone mineral density (a Z score below –2.0) in com- A COMPLEX RELATIONSHIP bination with risk factors such as chronic malnutrition, eating disorders, hypogonadism, glucocorticoid exposure, Anorexia nervosa is characterized by an intense and previous fractures. fear of gaining weight, a body weight less than 85% of expected, a distorted self-image, and, in women, missing three consecutive menstrual Restoring body weight is the key treatment. Vitamin D periods.3 The lifetime prevalence in women should be supplemented if low. Estrogen therapy has not is about 0.5%; it is much lower in men.3 The been shown to be effective, and exercise may be coun- prevalence of eating disorders in female ath- terproductive. Bisphosphonates and teriparatide should letes is much higher, estimated at 15% to 62%.2 be used with caution, if at all. The etiology of osteoporosis in patients with anorexia nervosa is complex and mul- doi:10.3949/ccjm.78a.10023 tifaceted. In these patients, bone resorption50 C L EVELAND CLINIC JOURNAL OF MEDICINE VOLUME 78 • NU M B E R 1 J A N U A RY 2 0 1 1
  2. 2. TENGis increased without a concomitant increase nervosa is related to hypothalamic suppres-in bone formation, resulting in a net loss of sion of the release of gonadotropin-releasingbone.4 Thus, markers of bone resorption such hormone, resulting in lower levels of follicle-as N-teleopeptide and deoxypyridoline are el- stimulating hormone and luteinizing hormoneevated, but markers of bone formation such as and a resultant prepubertal low-estrogen state.osteocalcin are not.4 In a study of 73 women with anorexia ner- The loss of bone may be rapid and can oc- vosa and a mean age of 17.2 years,8 20 monthscur relatively early in the disease. Some stud- of amenorrhea was the threshold above whichies suggest that an illness duration longer than the most severe osteopenia was seen, implying12 months predicts significant loss of bone that the duration of amenorrhea affects bonedensity.5 Thus, early diagnosis and interven- health.tion are important to minimize bone loss. Women gain from 40% to 60% of their Which factors besides amenorrhea influencebone mass during the pubertal growth spurt in bone density in premenopausal women?ages 11 to 14, the time when anorexia nervosa Undernutrition. Body weight has beenis most prevalent.6 Peak bone mass is attained suggested to have an independent effect onby the third decade of life, but the rate of bone mineral density, and density has beengrowth of bone mass is highest during adoles- found to increase following weight gain, evencence and early adulthood.7 Hence, it is impor- before the return of menses.1 Once a regulartant to optimize bone mass during this time, as menstrual cycle has been restored, significantsmall differences in bone density can have sig- increases in trabecular and cortical bone havenificant clinical implications later in life: a 5% been detected.1increase in bone density significantly decreases Deficiency of insulin-like growth factor 1fracture risk, whereas a 10% decrease in adult (IGF-1). Anorexia nervosa is associated withbone mineral density is associated with a two decreased hepatic synthesis of IGF-I.9 Low lev-to three times higher risk of fracture (reviewed els of IGF-I reduce the levels of osteocalcin, aby Rome and Ammerman6). marker of bone formation, and cause abnormal- ities in osteoblast function.10 This deficiency is Loss of boneWhat is the role of amenorrhea associated with the development of osteopenia mineral densityin the development of osteoporosis in patients with anorexia nervosa.11in premenopausal patients? Low androgen levels are present in pa- in anorexiaGiven that two of the most characteristic tients with anorexia nervosa, and levels appear may be rapidmanifestations of anorexia nervosa are low to be further reduced by oral contraceptives.12body weight and the absence of menses, these It remains to be determined whether the fur- and may occurfactors have been hypothesized to be potential ther reduction in androgens in women with earlycauses of osteoporosis. anorexia nervosa using oral contraceptives is in the disease In general, young women who present harmful to skeletal health. Low testosteronewith amenorrhea should be evaluated to de- levels in boys with anorexia nervosa havetermine if the amenorrhea is primary or sec- been associated with lower libido, fewer erec-ondary. Primary amenorrhea is the absence of tions, and potentially lower bone density.13menarche by age 16; secondary amenorrhea Hypercortisolemia. Elevated levels of to-is the absence of menses for more than three tal and free serum cortisol and high 24-hourcycles or more than 6 months in someone who urinary free cortisol excretion have been not-previously had had menses. The most com- ed in anorectic patients. Levels of cortisol aremon causes of secondary amenorrhea are ovar- inversely related to levels of osteocalcin, andian disease, hypothalamic or pituitary disease, hypercortisolism has been shown to be associ-and uterine disease. Anorexia nervosa causes ated with osteoporosis.14,15 However, no studyhypothalamic dysfunction and is a cause of has yet shown causality in this population.secondary amenorrhea. In clinical practice, it Osteoprotegerin has been recognized as anis also important to remember that pregnancy important regulator of bone resorption. Os-can occur even in the setting of amenorrhea. teoprotegerin inhibits osteoclast differentia- Amenorrhea in patients with anorexia tion and activation and stimulates osteoclast CLEVELAN D C L I N I C J O U R N A L O F M E D I C I N E VOLUME 78 • NUMBER 1 J A N U A RY 2 0 1 1 51
  3. 3. ANOREXIA AND OSTEOPOROSIS feature of anorexia nervosa.18 Leptin helps to TABLE 1 induce weight loss by stimulating neurons in Potential factors influencing the hypothalamus that express “weight-loss- bone density in anorexia nervosa inducing” neuropeptides such as pro-opiomela- nocortin and inhibiting “weight-gain-inducing” Undernutrition peptides such as neuropeptide Y.19 Seems to have an independent effect on bone mineral density Although leptin was first believed to be a Exercise hormone released to counteract obesity, re- Increases bone mineral density at weight-bearing sites but not cent studies19,20 suggest that it is part of a major necessarily at non-weight-bearing sites signaling system that controls adaptation to Caution is advised before recommending exercise, as these patients may starvation. These studies have shown that the use it as a form of purging body senses its corporeal fat through leptin Deficiency of insulin-like growth factor 1 and inhibits ovulation when fat reserves are Associated with the development of osteopenia low.19 In addition, luteinizing hormone and leptin levels have been shown to increase Low androgen levels in parallel in patients with anorexia nervosa Correlate with bone resorption and formation markers in anorexia nervosa when weight is restored.20 Thus, rising leptin levels correlate with the resumption of menses Hypercortisolemia in women with anorexia nervosa and in turn Correlates inversely with osteocalcin levels and may decrease bone have potential consequences for bone health. formation Not enough ghrelin, too much obestatin? Increased osteoprogerin Ghrelin, a gastric hormone, acts as a natural Higher levels seen in anorexia nervosa antagonist to leptin, resulting in an increase May be released to preserve bone health in food intake and body weight.19 Circulating Reduced leptin ghrelin levels are higher in illness-induced May have a role in adaptation to starvation anorexia as well as in anorexia nervosa, and A relationship with bone formation has not yet been established they normalize with weight gain, perhaps as an adaptive mechanism to compensate for a Ghrelin and obestatin negative energy balance.21 In vitro studies suggest that ghrelin promotes osteoblast proliferation and differentiation Several in vitro studies suggest that ghrelin In vivo studies in anorexia nervosa show only a weak association directly promotes osteoblast proliferation and with bone mineral density differentiation.22 However, human studies of The ghrelin-obestatin ratio is decreased in anorexia nervosa ghrelin’s effects on bone are limited. In a study Further study is needed to determine the role of the ghrelin- of healthy younger women, healthy boys, and obestatin ratio in osteoporosis risk anorexia nervosa patients, plasma ghrelin levels were only weakly associated with bone mineral density.23 apoptosis, helping to preserve bone density. The effects of obestatin, another gas- Misra et al16 showed that adolescent girls tric hormone, are still being investigated. with anorexia nervosa have higher serum os- Obestatin was initially shown to oppose teoprotegerin levels than controls and that the effects of ghrelin by decreasing appetite osteoprotegerin levels correlate inversely with and weight gain. When given with ghrelin, markers of nutritional status and lumbar bone obestatin appears to work with ghrelin at the density Z scores.16 They and other investiga- hypothalamic level to modulate food intake tors17 postulate that osteoprotegerin may be and growth hormone secretion.24 released as a compensatory response to the Interestingly, obestatin and the ratio of bone loss seen in these patients in an attempt ghrelin to obestatin are decreased in patients to preserve bone health. with anorexia nervosa, but the ratio is un- Leptin is an adipocyte-derived hormone that changed in thin women who have an equiva- acts on receptors in the hypothalamus, decreas- lent body mass index but no eating disorder.25 ing food intake and increasing energy expendi- It has been hypothesized that the ghrelin- ture. Low leptin levels are a key endocrinologic obestatin ratio may be the key to explaining52 C L EVELAND CLINIC JOURNAL OF MEDICINE VOLUME 78 • NU M B E R 1 J A N U A RY 2 0 1 1
  4. 4. TENGthe eating restriction and reduced motivation of dual-energy x-ray absorptiometry. This testto eat despite high ghrelin levels seen in an- may not be able to distinguish bone that isorexia nervosa.26 Further studies are needed small but of normal density from bone that isto determine the role of obestatin and the of low density.26ghrelin-obestatin ratio in the bone health of Despite its limitations, until newer risk as-women with anorexia nervosa. sessment tools are available for this patient While factors such as low body weight population, measuring bone mineral density isand amenorrhea have long been understood still recommended in addition to assessing clin-to play a role in the development of osteopo- ical risk factors to diagnose osteoporosis. Also,rosis in women with anorexia nervosa, many changes in bone mineral density over time cancomplex hormonal factors contribute to bone help to assess risk and guide treatment.deficits as well. Further study is needed to ful-ly elucidate these hormonal factors and how When should a patient with anorexiathey work together to cause osteoporosis. A be screened for osteoporosis?list of the factors that potentially influence Because bone loss may begin early in thebone density and risk for osteoporosis in pa- course of anorexia and progress rapidly (po-tients with anorexia nervosa is presented in tentially inexorably), baseline screening isTABLE 1. recommended for all patients who have had anorexia nervosa or amenorrhea for more than■ HOW SHOULD WE DIAGNOSE 6 to 12 months.30 The National Osteoporosis OSTEOPOROSIS IN PREMENOPAUSAL Foundation recommends screening in women PATIENTS? under age 65 who have a low body weight.31 The American College of Sports MedicineOur approach to screening for and diagnosing recommends screening for osteoporosis inosteoporosis is still largely based on measuring athletes with a history of hypoestrogenismbone mineral density, although density by it- or disordered eating for a cumulative total ofself is not a perfect tool for predicting who will 6 months or more, or with a history of stressor will not experience a fracture, particularly fracture or fracture from minimal trauma.32 Some girlsin premenopausal women.26,27 Most premeno- Knowledge of low bone mineral density with anorexiapausal women with low bone mineral density and fracture risk can often guide treatmentbut no other risk factors for fracture such as and prompt behavioral change. Given that nervosaprevious fractures or glucocorticoid therapy most osteoporosis treatments do not lead to exerciseare at very low short-term risk of fracture.26 detectable changes in bone density until 18 For these reasons, in premenopausal wom- months to 2 years, it is reasonable to repeat compulsively,en and adolescents, the International Society testing at this interval.33 using it as afor Clinical Densitometry28 advises against form of purgingdiagnosing osteoporosis on the basis of bone ■ NEW AND OLD TREATMENTS FOR LOWmineral density alone. Instead, it should be BONE DENSITY IN ANOREXIA NERVOSAdiagnosed in this population only if the bonemineral density is low (defined as a Z score Weight restoration is the cornerstonebelow −2.0) and the patient has risk factors Restoration of body weight and nutritionalthat suggest a higher short-term risk of bone rehabilitation remain the cornerstones ofmineral loss and fracture. Risk factors include treatment. All patients with anorexia nervosachronic malnutrition, eating disorders, hypo- should be referred to a nutritionist to developgonadism, glucocorticoid exposure, and previ- a meal plan that is adjusted for the amount ofous fracture.29 energy expended. The challenges lie in man- A pitfall in interpreting low bone mineral aging the complications of refeeding and thedensity in premenopausal women younger high relapse rate. The treatment goals in disor-than age 30 is the possibility that they may dered eating are to optimize the overall nutri-not yet have reached their peak bone mass. tional status, normalize eating behavior, mod-In addition, small stature and body size (and ify unhealthy thought processes that maintaintherefore bone size) also influence the results the disorder, and treat possible emotional is- CLEVELAN D C L I N I C J O U R N A L O F M E D I C I N E VOLUME 78 • NUMBER 1 J A N U A RY 2 0 1 1 53
  5. 5. ANOREXIA AND OSTEOPOROSIS sues that help create or maintain the disorder. formation. In premenopausal anorexia, how- The younger the patient, the more the ever, bone loss appears to be due to a unique family’s involvement is recommended. In uncoupling of osteoblastic and osteoclastic addition to nutritional counseling, the care functions, resulting in both reduced bone for- team should include a psychotherapist, a psy- mation and increased bone resorption, which chiatrist, and a primary care physician to assist estrogen therapy may not improve.5 with management and screening of medical Despite the documented association be- complications. tween anorexia nervosa and estrogen defi- ciency and the strong correlation between Vitamin D for all osteoporosis and the duration of amenorrhea, Low vitamin D levels have long been associ- most studies have found no improvement in ated with low bone mineral density and risk of bone mass with hormonal therapy.9 In particu- hip fracture.34 lar, three randomized, placebo-controlled tri- Vitamin D insufficiency is very common. als have been published to date, and not one More than 90% of blacks, Hispanics, and showed a significant improvement in bone Asians and nearly 75% of whites have insuf- mineral density with estrogen therapy com- ficient levels of vitamin D (25-hydroxyvita- pared with placebo in patients with anorexia min D3 level < 30 ng/mL).35 In a study of 307 nervosa.41–43 healthy adolescents, vitamin D insufficiency Klibanski et al,41 in the first of these tri- (a 25-hydroxyvitamin D3 level < 20 ng/mL) als, found no significant difference in spinal was found in 42% and vitamin D deficiency bone mineral density between treated patients (a level < 15 ng/mL) in 24.1%.36 In addition, and controls. However, estrogen-treated pa- this study confirmed an inverse correlation tients whose initial body weight was very low between body mass index and serum 25-hy- (< 70% of expected) had a significant increase droxyvitamin D3 concentration. in their bone mineral density, whereas those Therefore, while vitamin D supplementa- in the control group lost bone density. tion has not been consistently shown to im- Baker et al44 suggest that hormone thera-IGF-1 deficiency prove bone loss in anorectic patients,9 given py might protect bone mass in athletes withhas been linked the prevalence of vitamin D deficiency and amenorrhea, citing a study that found that insufficiency, supplementation is almost uni- women with a history of stress fractures wereto the versally recommended. less likely to have used oral contraceptivesdevelopment There is no consensus as to the amount of previously than athletes without fractures.45 supplementation to recommend for women However, no prospective randomized study toof osteopenia with anorexia nervosa. The American Col- date has established that hormone therapy ef-in anorexia lege of Sports Medicine recommends a total fectively preserves bone mass in athletes withnervosa daily intake of 800 IU of vitamin D (ie, from amenorrhea. diet and supplements). Therapy should be ti- Based on the data presented above, we trated to doses that result in normocalcemia have little evidence for using estrogen to treat and a serum 25-hydroxyvitamin D3 concen- or prevent premenopausal osteoporosis. tration of at least 30 ng/mL.37,38 The American College of Sports Medi- cine32 recommends consideration of estrogen Does hormone treatment therapy if there is evidence of a decline in bone improve bone density? mineral density in an athlete over the age of In postmenopausal osteoporosis, estrogen ther- 16 with persistent functional hypothalamic apy maintains or improves bone density and amenorrhea despite adequate nutritional in- appears to reduce the rate of vertebral frac- take and weight. However, it acknowledges tures.39,40 Perhaps not so with premenopausal that restoring regular menstrual cycles with osteoporosis due to anorexia nervosa. oral contraceptive pills will not normalize the Why should this be? In postmenopausal metabolic factors that impair bone formation, women, estrogen therapy appears to work by health, and performance and is not likely to impairing osteoclast-mediated bone resorp- fully reverse low bone mineral density in this tion, but it has only limited effects on bone population. 54 C L EVELAND CLINIC JOURNAL OF MEDICINE VOLUME 78 • NU M B E R 1 J A N U A RY 2 0 1 1
  6. 6. TENGWhat is the effect of exercise ministration (FDA) for use only in thoseon bone health in these patients? taking glucocorticoids. Although bisphos-Several studies have examined the effect of phonates have been shown to significantly in-weight-bearing exercise on bone density. crease bone mineral density in young women Young et al46 compared normal teenagers, with anorexia nervosa,26 they should be usedballet dancers, and young women with anorex- with caution in patients of childbearing ageia nervosa and found that weight-bearing ex- because they are teratogenic. Bisphosphonatesercise protected against osteoporosis, but only have a long half-life and may continue to af-at weight-bearing sites. Athletes in weight- fect bone turnover for up to 2 years after theybearing sports had a 5% to 15% higher bone are discontinued.47 In addition, they are notmineral density in weight-bearing sites (ie, the recommended in patients with a history offemur) compared with nonathletes, but had purging via vomiting, due to a risk of esopha-lower bone mineral density in the spine. geal ulceration. Therefore, a Z score below –1.0 in an ath-lete, especially in a distal site, warrants further Parathyroid hormone therapy:investigation and treatment.32 In general, ex- Studies ongoingercise does not necessarily protect against os- The parathyroid hormone fragment teripara-teoporosis in this patient population, and it tide (Forteo) is widely used for treating post-can sometimes mask underlying bone loss. In menopausal osteoporosis.addition, keep in mind that many of these pa- Before teriparatide was approved, there wastients exercise compulsively, using it as a form concern that it might increase the risk of os-of purging. teosarcoma, as almost 45% of rats treated with this drug at the highest-tested dose level de-Insulin-like growth factor-1: veloped this aggressive form of bone cancer.48More study needed Balancing the proven benefits of teriparatideIGF-1 contributes to bone growth by stimu- shown by clinical trials with the theoreticlating osteoblasts, and patients with anorexia risk of teriparatide-induced osteosarcoma, thenervosa have been shown to have low levels FDA mandated a “black-box” warning about Screeningof IGF-1.9 this potential effect. of bone mineral Grinspoon et al10 randomized 60 patients Studies of parathyroid hormone treat-with anorexia nervosa to receive IGF-1 alone, ment in anorexia nervosa and other pre- density isIGF-1 plus an oral contraceptive, an oral con- menopausal patients are ongoing.26 recommendedtraceptive alone, or placebo. All patients weregiven calcium and vitamin D and were fol- Leptin: More study needed for all patientslowed for 9 months. Total bone mass increased Leptin is a potent stimulator of bone growth who have hadsignificantly in those taking IGF-1 compared and has been shown to increase bone min- anorexiawith those taking placebo. Those taking an eral density in vitro and in vivo.19 However,IGF-1 and an oral contraceptive had a signifi- concerns have been raised about giving supra- nervosacant increase in spinal bone mineral density physiologic doses of leptin to patients with an- or amenorrheacompared with those on placebo group. At orexia nervosa, as this may increase the risk ofother skeletal sites, however, IGF-1 plus an further weight loss and relapse. for more thanoral contraceptive and IGF-1 alone failed to More work is needed to determine the role 6 to 12 monthsproduce significant increases in bone mineral of leptin for the treatment of osteoporosis indensity compared with placebo. anorexia nervosa. Further study is needed to determine therole of IGF-1 in treating low bone mineral Ghrelin:density in anorexia nervosa. Probably not effective as a single agent Pharmacologic use of ghrelin increases foodBisphosphonates: intake in healthy humans,49 and it has beenNot approved for this indication proposed as a treatment for weight restorationIn premenopausal women, bisphosphonates and bone health in anorexia nervosa. Pre-are approved by the US Food and Drug Ad- liminary studies have not shown it to increase CLEVELAN D C L I N I C J O U R N A L O F M E D I C I N E VOLUME 78 • NUMBER 1 J A N U A RY 2 0 1 1 55
  7. 7. ANOREXIA AND OSTEOPOROSIS they would induce weight gain and in turn TABLE 2 prevent osteoporosis. Potential strategies for preventing Interest in their use in anorexia nervosa osteoporosis in anorexia nervosa stems from the discovery of two cannabinoid receptors (CB1 and CB2) located in the brain Weight restoration and peripheral organ systems. Anorexia ner- Restoration of weight is the cornerstone of treatment. The treatment vosa has been associated with different alleles team should include a nutritionist, a psychologist, a psychiatrist, and of the CB1 gene,51 but the therapeutic impli- a medical provider. cations of this are far from clear. Vitamin D Cannabinoids appear to regulate eating Given the prevalence of vitamin D insufficiency and deficiency, behavior at several levels within the brain and especially in the setting of low body mass index, vitamin D periphery: the hypothalamus and hindbrain supplementation should be considered at a minimum of 800 IU/day. (integrative functions), the limbic system Titration is recommended to a serum 25-hydroxyvitamin D3 level of (for hedonic evaluation of foods), the intes- at least 30 ng/mL. tinal system, and adipose tissue.52 At each of Insulin-like growth factor 1 these levels, the endocannabinoid system in- Initial studies show an increase in spinal bone mineral density with teracts with a number of better known pep- insulin-like growth factor 1 plus an oral contraceptive, but not at tides involved in appetite regulation, includ- other skeletal sites. Further study is needed. ing leptin, ghrelin, and the melanocortins. Bisphosphonates In mouse studies, genetic leptin deficiency is They increase bone mineral density in anorexia nervosa but should associated with elevated hypothalamic endo- be used with caution in females of childbearing age, as they are cannabinoid levels. teratogenic. They are also not advisable in patients who purge via Appetite stimulation by cannabinoids has vomiting. been studied for several decades, particularly Parathyroid hormone therapy in relation to cachexia and malnutrition asso- Studies are ongoing. Concerns have been raised about the risk of ciated with cancer. Very few trials have stud- osteosarcoma. ied cannabinoids for anorexia nervosa. In a 4-week crossover trial in 11 patients Leptin In vitro studies have shown leptin to be a potent stimulator of bone with anorexia nervosa,53 tetrahydrocannabi- growth. Further study is needed to determine improvement in bone nol (THC) treatment resulted in an increase mineral density in anorexia nervosa. in sleep disturbances and interpersonal sensi- tivity, but it had no significant effect on weight Ghrelin gain compared with diazepam treatment.53 Preliminary studies have not shown ghrelin treatment to improve Another pilot study of nine outpatients appetite in anorexia nervosa patients. Further study is needed of its effect on bone mineral density. with anorexia nervosa treated with THC showed a significant improvement in depres- Cannabinoids sion and perfectionism scores without any sig- Further study is needed to determine their effect on appetite nificant weight gain.19 stimulation and subsequent bone health in anorexia nervosa. Although this research was once promis- Dependency is a concern. ing, the risk was felt to outweigh the benefit, as cannabinoids may induce dependency in this patient group, who may already be at high appetite or weight gain,50 but it did increase risk of drug addiction, and very few have con- slow-wave sleep. tinued this line of investigation. Based on these studies, it is unlikely that ghrelin will be effective as a single agent to ■ WHAT CAN WE DO FOR NOW? stimulate appetite, but it may be helpful in conjunction with other therapies. • Weight restoration and nutritional reha- bilitation remain the keys to treatment Cannabinoids: Little ongoing research of low bone density to reduce the risk of Cannabinoids have been proposed as a treat- osteoporosis in patients with anorexia ment for anorexia nervosa in the hope that nervosa. However, as many as one-third56 C L EVELAND CLINIC JOURNAL OF MEDICINE VOLUME 78 • NU M B E R 1 J A N U A RY 2 0 1 1
  8. 8. TENG of patients with anorexia nervosa relapse trogen deficiency has been shown to at least during their lifetime, and other treat- stabilize bone density in postmenopausal ments are needed to stabilize and prevent patients, this does not appear to be the case bone loss. in premenopausal girls and young women.• Vitamin D deficiency is clearly associated • As we learn more about hormonal factors in with a risk of osteoporosis and fracture, and anorexia nervosa, we hope to identify inter- patients with vitamin D deficiency should ventions that will help restore weight and be treated with supplementation. decrease the risk of osteoporosis. A summary• Standard therapies in postmenopausal pa- of potential treatment strategies and targets tients (such as bisphosphonates and terip- for prevention of osteoporosis in anorexia aratide) should be used with caution in nervosa is presented in TABLE 2. ■ premenopausal anorexia nervosa patients because of potential long-term health risks. ACkNOwLEDgmENT: The author thanks the General Internal Medicine Works in Progress Group for its editorial comments,• Although treatment of amenorrhea and es- and Dr. Ellen Rome for her mentorship and support.■ REFERENCES 19. Støving RK, Andries A, Brixen K, Flyvbjerg A, Hørder K, Frystyk J. Leptin, ghrelin, and endocannabinoids: potential therapeutic targets in anorexia 1. Baker D, Roberts R, Towell T. Factors predictive of bone mineral density nervosa. J Psychiatr Res 2009; 43:671–679. in eating-disordered women: a longitudinal study. Int J Eat Disord 2000; 20. Audi L, Mantzoros CS, Vidal-Puig A, Vargas D, Gussinye M, Carrascosa 27:29–35. A. Leptin in relation to resumption of menses in women with anorexia 2. Rome ES. Eating disorders. Obstet Gynecol Clin North Am 2003; nervosa. Mol Psychiatry 1998; 3:544–547. 30:353–377. 21. Wong IP, Baldock PA, Herzog H. Gastrointestinal peptides and bone 3. First MB, editor. Diagnostic and Statistical Manual of Mental Disorders— health. Curr Opin Endocrinol Diabetes Obes 2010; 17:44–50. 4th edition. Washington, DC: American Psychiatric Association, 2000. 22. Fukushima N, Hanada R, Teranishi H, et al. Ghrelin directly regulates 4. Mehler PS, MacKenzie TD. Treatment of osteopenia and osteoporosis in bone formation. J Bone Miner Res 2005; 20:790–798. anorexia nervosa: a systematic review of the literature. Int J Eat Disord 23. Makovey J, Naganathan V, Seibel M, Sambrook P. Gender differences 2009; 42:195–201. in plasma ghrelin and its relations to body composition and bone—an 5. Wong JC, Lewindon P, Mortimer R, Shepherd R. Bone mineral density in opposite-sex twin study. Clin Endocrinol (Oxf) 2007; 66:530–537. adolescent females with recently diagnosed anorexia nervosa. Int J Eat 24. Hassouna R, Zizzari P, Tolle V. The ghrelin/obestatin balance in the physi- Disord 2001; 29:11–16. ological and pathological control of growth hormone secretion, body 6. Rome ES, Ammerman S. Medical complications of eating disorders: an composition and food intake. J Neuroendocrinol 2010; 22:793–804. update. J Adolesc Health 2003; 33:418–426. 25. Germain N, Galusca B, Grouselle D, et al. Ghrelin/obestatin ratio in two 7. Recker RR, Davies KM, Hinders SM, Heaney RP, Stegman MR, Kimmel populations with low body weight: constitutional thinness and anorexia DB. Bone gain in young adult women. JAMA 1992; 268:2403–2408. nervosa. Psychoneuroendocrinology 2009; 34:413–419. 8. Sterling WM, Golden NH, Jacobson MS, Ornstein RM, Hertz SM. Meta- 26. Cohen A, Shane E. Treatment of premenopausal women with low bone bolic assessment of menstruating and nonmenstruating normal weight mineral density. Curr Osteoporos Rep 2008; 6:39–46. adolescents. Int J Eat Disord 2009; 42:658–663. 27. Licata A. Bone density vs bone quality: what’s a clinician to do? Cleve Clin 9. Legroux-Gerot I, Vignau J, Collier F, Cortet B. Bone loss associated with anorexia nervosa. Joint Bone Spine 2005; 72:489–495. J Med 2009; 76:331–336.10. Grinspoon S, Thomas L, Miller K, Herzog D, Klibanski A. Effects of 28. Bianchi ML, Baim S, Bishop NJ, et al. Official positions of the Internation- recombinant human IGF-I and oral contraceptive administration on bone al Society for Clinical Densitometry (ISCD) on DXA evaluation in children density in anorexia nervosa. J Clin Endocrinol Metab 2002; 87:2883–2891. and adolescents. Pediatr Nephrol 2010; 25:37–47.11. Soyka LA, Grinspoon S, Levitsky LL, Herzog DB, Klibanski A. The effects 29. Mendelsohn FA, Warren MP. Anorexia, bulimia, and the female athlete of anorexia nervosa on bone metabolism in female adolescents. J Clin triad: evaluation and management. Endocrinol Metab Clin North Am Endocrinol Metab 1999; 84:4489–4496. 2010; 39:155–167.12. Miller KK, Lawson EA, Mathur V, et al. Androgens in women with 30. Mehler PS, Krantz M. Anorexia nervosa medical issues. J Womens Health anorexia nervosa and normal-weight women with hypothalamic amen- (Larchmt) 2003; 12:331–340. orrhea. J Clin Endocrinol Metab 2007; 92:1334–1339. 31. Watts NB, Lewiecki EM, Miller PD, Baim S. National Osteoporosis Foun-13. Misra M, Katzman DK, Cord J, et al. Bone metabolism in adolescent boys dation 2008 Clinician’s Guide to Prevention and Treatment of Osteopo- with anorexia nervosa. J Clin Endocrinol Metab 2008; 93:3029–3036. rosis and the World Health Organization Fracture Risk Assessment Tool14. Misra M, Miller KK, Almazan C, et al. Alterations in cortisol secretory (FRAX): what they mean to the bone densitometrist and bone technolo- dynamics in adolescent girls with anorexia nervosa and effects on bone gist. J Clin Densitom 2008; 11:473–477. metabolism. J Clin Endocrinol Metab 2004; 89:4972–4980. 32. Nattiv A, Loucks AB, Manore MM, Sanborn CF, Sundgot-Borgen J,15. Chiodini I, Mascia ML, Muscarella S, et al. Subclinical hypercortisolism Warren MP; American College of Sports Medicine. American College of among outpatients referred for osteoporosis. Ann Intern Med 2007; Sports Medicine position stand. The female athlete triad. Med Sci Sports 147:541–548. Exerc 2007; 39:1867–1882.16. Misra M, Soyka LA, Miller KK, et al. Serum osteoprotegerin in adolescent 33. Cummings SR, Palermo L, Browner W, et al. Monitoring osteoporosis girls with anorexia nervosa. J Clin Endocrinol Metab 2003; 88:3816–3822. therapy with bone densitometry: misleading changes and regression17. Ohwada R, Hotta M, Sato K, Shibasaki T, Takano K. The relationship to the mean. Fracture Intervention Trial Research Group. JAMA 2000; between serum levels of estradiol and osteoprotegerin in patients with 283:1318–1321. anorexia nervosa. Endocr J 2007; 54:953–959. 34. LeBoff MS, Kohlmeier L, Hurwitz S, Franklin J, Wright J, Glowacki J. Oc-18. Müller TD, Föcker M, Holtkamp K, Herpertz-Dahlmann B, Hebebrand cult vitamin D deficiency in postmenopausal US women with acute hip J. Leptin-mediated neuroendocrine alterations in anorexia nervosa: fracture. JAMA 1999; 281:1505–1511. somatic and behavioral implications. Child Adolesc Psychiatr Clin N Am 35. Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab 2009; 18:117–129. 2010; 95:471–478. CLEVELAN D C L I N I C J O U R N A L O F M E D I C I N E VOLUME 78 • NUMBER 1 J A N U A RY 2 0 1 1 57
  9. 9. ANOREXIA AND OSTEOPOROSIS 36. Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ. Prevalence of 46. Young N, Formica C, Szmukler G, Seeman E. Bone density at weight- vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc bearing and nonweight-bearing sites in ballet dancers: the effects of Med 2004; 158:531–537. exercise, hypogonadism, and body weight. J Clin Endocrinol Metab 37. Hofbauer LC, Hamann C, Ebeling PR. Approach to the patient with 1994; 78:449–454. secondary osteoporosis. Eur J Endocrinol 2010; 162:1009–1020. 47. Stock JL, Bell NH, Chesnut CH 3rd, et al. Increments in bone mineral 38. Stoffman N, Gordon CM. Vitamin D and adolescents: what do we know? density of the lumbar spine and hip and suppression of bone turnover Curr Opin Pediatr 2009; 21:465–471. are maintained after discontinuation of alendronate in postmenopausal 39. Bone HG, Greenspan SL, McKeever C, et al. Alendronate and estrogen women. Am J Med 1997; 103:291–297. effects in postmenopausal women with low bone mineral density. 48. Subbiah V, Madsen VS, Raymond AK, Benjamin RS, Ludwig JA. Of mice Alendronate/Estrogen Study Group. J Clin Endocrinol Metab 2000; and men: divergent risks of teriparatide-induced osteosarcoma. Osteo- 85:720–726. poros Int 2010; 21:1041–1045. 40. Barrett-Connor E, Wenger NK, Grady D, et al. Hormone and nonhor- 49. Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and mone therapy for the maintenance of postmenopausal health: the need increases food intake in humans. J Clin Endocrinol Metab 2001; for randomized controlled trials of estrogen and raloxifene. J Womens 86:5992. Health 1998; 7:839–847. 50. Miljic D, Pekic S, Djurovic M, et al. Ghrelin has partial or no effect on ap- 41. Klibanski A, Biller BM, Schoenfeld DA, Herzog DB, Saxe VC. The effects petite, growth hormone, prolactin, and cortisol release in patients with of estrogen administration on trabecular bone loss in young women anorexia nervosa. J Clin Endocrinol Metab 2006; 914:1491–1495. with anorexia nervosa. J Clin Endocrinol Metab 1995; 80:898–904. 51. Siegfried Z, Kanyas K, Latzer Y, et al. Association study of cannabinoid 42. Stokosch GR, Friedman AJ, Wu SC, Kamin M. Effects of an oral contra- receptor gene (CNR1) alleles and anorexia nervosa: differences between ceptive (norgestimate/ethinyl estradiol) on bone mineral density in ado- restricting and binging/purging subtypes. Am J Med Genet B Neuropsy- lescent females with anorexia nervosa: double-blind, placebo-controlled chiatr Genet 2004; 125B:126–130. study. J Adolesc Health 2006; 39:819–827. 52. Cota D, Marsicano G, Lutz B, et al. Endogenous cannabinoid system 43. Golden NH, Lanzkowsky L, Schebendach J, Palestro CJ, Jacobson MS, as a modulator of food intake. Int J Obes Relat Metab Disord 2003; Shenker IR. The effect of estrogen-progestin treatment on bone mineral 27:289–301. density in anorexia nervosa. J Pediatr Adolesc Gynecol 2002; 15:135–143. 53. Gross H, Ebert MH, Faden VB, et al. A double-blind trial of delta 9-tetra- 44. Robinson E, Bachrach LK, Katzman DK. Use of hormone replacement hydrocannabinol in primary anorexia nervosa. J Clin Psychopharmacol therapy to reduce the risk of osteopenia in adolescent girls with an- 1983; 3:165–171. orexia nervosa. J Adolesc Health 2000; 26:343–348. 45. Myburgh KH, Hutchins J, Fataar AB, et al. Low bone density is an ADDRESS: Kathryn Teng, MD, Department of Internal Medicine, G10, etiologic factor for stress fractures in athletes. Ann Intern Med 1990; Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; tengk@ccf. 113:754–759. org. 80 Years ago in the Cleveland Clinic Bulletin At the Cleveland Clinic we do routine blood sugars in all new cases. The percent- age of patients with unsuspected diabetes, discovered in this manner is considerable.1931 2011 You can imagine how chagrinned a physician feels when he has taken a careful his- tory and has done a thorough physical examination and has sought the counsel of one or more specialists for whatever seemed indicated, and then a blood sugar report of 380 mg. per c.c. comes from the laboratory. This settles the problem of diagnosis, yet when the history is re-examined, there is not an inkling of a symptom or a complaint which would even suggest diabetes. … By the prevention of obesity and infections, much can be done to prevent the development of diabetes. As compared with this, the treatment of diabetes plays but a secondary role, and is but a mere palliative measure. Prevention presents a challenge to accomplish something construc- tive. The symptomatic treatment of malaria did not solve the problem of malaria. The elimina- tion of the mosquito was not treatment; but it did solve the problem of malaria! John HJ. Some practical considerations in diabetes mellitus. Cleve Clin Bull 1931; 1(3):49-66. 58 C L EVELAND CLINIC JOURNAL OF MEDICINE VOLUME 78 • NU M B E R 1 J A N U A RY 2 0 1 1