Hormone predictors of abnormal bone microarchitecture in women with anorexia nervosa
Introduction
Anorexia nervosa (AN) is a psychiatric disease affecting 0.3% of the female population and is characterized by self-induced chronic starvation and associated with severe bone loss and increased risk of fractures [1]. In a study of outpatient women with AN (mean age = 24 years), 92% had osteopenia and 38% had osteoporosis by dual energy X-ray absorptiometry (DXA) [2]. A two- to three-fold increase in fracture risk has been reported in this population [3], [4]. The mechanism for AN-induced bone loss is multifactorial, and a low formation, high resorption state has been identified [5]. Low endogenous estrogen and testosterone secretion and decreased levels of nutritionally dependent hormones, including IGF-I and leptin, have been implicated [6]. IGF-I, a nutritionally regulated anabolic hormone that is low in states of chronic starvation, is thought to be a particularly important mediator of AN-induced bone loss. Low levels of IGF-I in women with AN are associated with decreased levels of bone formation [5]. Administration of rhIGF-I increases markers of bone formation and, in estrogen-treated patients, is the only therapy that has been shown in a randomized, placebo-controlled study to improve bone mineral density (BMD) in women with AN [7]. In contrast, studies of estrogen–progestin therapy, effective in treating postmenopausal osteoporosis, have failed to show efficacy in preventing or improving AN-associated bone loss [7], [8]. Serum androgen levels have been demonstrated to be low in women with AN [9] and short-term administration of low-dose testosterone increases procollagen type I C-terminal peptide (PICP), a marker of bone formation [10].
As in other populations at risk for osteoporosis, BMD has been the primary method used to evaluate skeletal integrity in women with AN in both clinical and research settings. However, it is increasingly clear that other measures of bone quality, particularly parameters of microarchitecture, are significant independent predictors of fracture risk in other populations [11], [12], [13], [14] and therefore may be important in AN. Newer imaging technologies, including ultra-high-resolution flat-panel-based volume CT (fpVCT), allow for noninvasive visualization of bone microstructure [15], [16]. There is limited information about bone microarchitecture, and to our knowledge, there are no studies investigating the role of hormones in modulating microarchitectural parameters in AN. This study investigates the relationship between structural integrity of bone utilizing fpVCT and endocrine abnormalities in AN. Specifically, we hypothesized that IGF-I and other nutritionally dependent hormones would predict parameters of bone microstructure.
Section snippets
Protocol
Twenty-three women aged 18–45 years, including 12 women with AN and 11 HC of similar age, were studied. All women with AN were ambulatory and fulfilled all the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for AN, including weight < 85% of ideal body weight (7). Exclusion criteria for AN and HC included pregnancy, diabetes mellitus, thyroid, cardiac, liver or renal disease, or medications known to affect bone metabolism, including estrogens, progestins,
Patient characteristics
Baseline clinical characteristics are described in Table 1. Women with AN and HC were of similar age. As expected, women with AN had lower weight, percent of ideal body weight (IBW), body mass index (BMI), percent fat mass, and lean body mass.
Bone mineral density and trabecular microarchitecture
Differences in BMD and trabecular microarchitecture between the groups are shown in Figs. 1 and 2. Women with AN had lower mean BMD Z-scores than HC at all sites. Mean app. BV/TV, app. TbTh, and TbN were significantly lower and TbSp was higher in women
Discussion
Hormonal abnormalities associated with severe undernutrition are important in the pathogenesis of bone loss in AN. However, they have not previously been examined in relation to trabecular microarchitecture, an important determinant of fracture risk. In contrast to postmenopausal osteoporosis where estrogen is the key factor, AN-mediated bone loss is driven by chronic starvation. We show that nutritionally mediated hormones, including IGF-I and leptin, and androgen levels predict bone
Conflict of interests
The authors have no conflicts to declare.
Acknowledgments
We thank the nurses and bionutritionists in the Massachusetts General Hospital Clinical Research Center and the patients who participated in the study.
This work was supported in part by the following grants from the National Institutes of Health: RO1 DK052625, MO1 RR01066, UL1 RR02575801.
We also acknowledge the support of the Clinical Investigator Training Program: Harvard/MIT Health Sciences and Technology—Beth Israel Deaconess Medical Center, in collaboration with Pfizer Inc. and Merck and Co.
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I) are key bone trophic hormones, whose rising levels during puberty are critical for pubertal bone accrual. Conditions of GH deficiency and genetic resistance impact cortical and trabecular bone deleteriously with reduced estimates of bone strength. In humans, conditions of undernutrition (as in anorexia nervosa (AN), or subsequent to chronic illnesses) are associated with low IGF-I levels, which correlate with disease severity, and also with lower bone mineral density (BMD), impaired bone structure and lower strength estimates. In adolescents and adults with AN, studies have demonstrated a nutritionally acquired GH resistance with low IGF-I levels despite high concentrations of GH. IGF-I levels go up with increasing body weight, and are associated with rising levels of bone turnover markers. In short-term studies lasting 6–10 days, recombinant human IGF-I (rhIGF-I) administration in physiologic replacement doses normalized IGF-I levels and increased levels of bone formation markers in both adults and adolescents with AN. In a randomized controlled trial in adults with AN in which participants were randomized to one of four arms: (i) rhIGF-I with oral estrogen-progesterone (EP), (ii) rhIGF-I alone, (iii) EP alone, or (iv) neither for 9 months, a significant increase in bone formation markers was noted in the groups that received rhIGF-I, and a significant decrease in bone resorption markers in the groups that received EP. The group that received both rhIGF-I and EP had a significant increase in bone density at the spine and hip compared to the group that received neither. Side effects were minimal, with no documented fingerstick glucose of <50 mg/dl. These data thus suggest a potential role for rhIGF-I administration in optimizing bone accrual in states of undernutrition associated with low IGF-I.