Effects of rhIGF-1 administration on surrogate markers of bone turnover in adolescents with anorexia nervosa☆
Introduction
Anorexia nervosa (AN), an eating disorder characterized by self-imposed severe nutritional restriction and weight loss, has a high prevalence (0.2–4.0%) amongst adolescent and college-aged women [1], [2]. Low bone mineral density (BMD) is common in adolescents with AN [3], [4] and is of particular importance in this younger age group because the pubertal years are critical for bone mass accrual. In fact, BMD is more severely affected when AN develops in childhood than when it develops in adult life, despite a similar duration of amenorrhea [5]. Hormonal contributors of low BMD in adolescents with AN include hypogonadism, relative hypercortisolemia, and alterations in other hormones that affect bone metabolism such as ghrelin, leptin, adiponectin and peptide YY [4], [6], [7], [8], [9], [10]. Although hypoestrogenemia is an important contributing factor to low BMD given the known anti-resorptive effects of estrogen [11], estrogen containing oral contraceptive pills do not increase BMD in this condition [12], [13]. These data suggest that correction of nutritionally dependent factors in addition to estrogen deficiency may be essential to improve BMD in adolescents with AN.
An important observation regarding low bone mass in girls with AN has been that a nutritionally acquired resistance to growth hormone (GH) with low levels of insulin like growth factor-1 (IGF-1) occurs [7]. IGF-1 is a nutritionally dependent bone trophic hormone which stimulates osteoblast function and collagen formation [14], [15], [16], and IGF-1 levels peak around mid-puberty [17], in concordance with rising GH levels. GH and IGF-1 levels are markedly increased in adolescent girls compared to adults and play a major role in bone accretion. Our group has demonstrated that girls with AN have significantly lower IGF-1 levels than healthy adolescents [7], [18], and increases in IGF-1 with weight recovery predict increases in bone formation markers [18]. These data indicate that low circulating or local IGF-I resulting from undernutrition may contribute to low BMD in AN. However, the impact of rhIGF-1 administration on bone formation in children with AN has not been studied.
Our group previously used an experimental model of short-term caloric restriction in normal adult women leading to low levels of IGF-I and low levels of markers of bone turnover to investigate effects of recombinant human (rh) IGF-I administration. In such women as well as in adult women with AN, rhIGF-1 caused an increase in surrogate markers of bone formation [19], [20]. However, there are no studies investigating effects of rhIGF-1 administration on bone metabolism in adolescent girls with AN. Bone accretion in children is a physiologically different state from the maintenance of bone mass in adults, with the former being a high formation and resorption state (especially in early puberty) [21] with formation exceeding resorption leading to a net increase in bone mass, while in the latter, similar rates of bone formation and resorption result in no net changes in bone mass. Because IGF-1 is an important determinant of the pubertal increase in bone mass [14], effects of rhIGF-1 may differ in adolescent AN girls than observed in adults with this disorder and are important to determine. In addition, the safety of rhIGF-1 administration in adolescents with this disorder is unknown.
To investigate the hypothesis that subcutaneous rhIGF-1 administration in adolescents with AN would stimulate bone formation, we investigated responses of a surrogate marker of bone formation (PINP: N-terminal propeptide of type 1 procollagen) and of bone resorption (CTX: C-telopeptide) to short-term rhIGF-I administration for a 7–9 day period in 10 consecutive adolescent girls with AN. We also assessed the safety profile of rhIGF-1 administration. In addition, we assessed changes in levels of PINP and CTX over a similar duration in 10 girls with AN matched for age and pubertal stage, who did not receive rhIGF-1.
Section snippets
Subject selection
All study subjects were between 12 and 18 years old and met DSM-IV criteria for the diagnosis of AN [22] as confirmed by the treating physician and the study psychiatrist. Ten consecutive adolescent girls with AN (16.2 ± 0.4 years) who met inclusion criteria were enrolled to receive rhIGF-1 for 7–9 days. These girls were matched for age and pubertal stage with 10 AN girls (16.3 ± 0.6 years), who were followed without intervention for a similar duration. The AN girls who served as controls were
Baseline characteristics
Girls with AN who received rhIGF-1 did not differ from girls not receiving rhIGF-1 for age, bone age, height, weight, BMI, BMI SDS, fat mass, lean mass or IGF-1 levels (Table 1).
Changes in IGF-1, PINP and CTX with or without RhIGF-1 administration
Changes in IGF-1 and in levels of surrogate markers of bone turnover in girls with AN who received rhIGF-1 or were followed without rhIGF-1 administration are shown in Table 2. IGF-1 levels increased significantly in girls with AN with rhIGF-1 administration, but did not change in girls with AN who did not receive
Discussion
Our data are the first to examine the effects of rhIGF-1 administration on bone formation markers in adolescents with AN. We found that rhIGF-1, when given in a dose of 30–40 mcg/k twice daily, successfully increases IGF-1 levels to a high normal range in adolescent girls with AN and is associated with significant selective increases in levels of PINP, a marker of bone formation, without a concomitant increase in CTX, a bone resorption marker. The effect of rhIGF-1 administration is immediate;
Acknowledgments
We would like to thank the research nurses and bionutritionists at the General Clinical Research Center of Massachusetts General Hospital and our subjects, without whom this study would not have been possible. We would also like to thank Patrick Sluss, PhD, of Massachusetts General Hospital, and Dr. Clifford Rosen at Maine Medical Center Research Institute, Portland, ME, for performing the IGF-1, PINP and CTX assays. We would like to thank Hang Lee, PhD, for support with the statistical
References (34)
- et al.
Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in adolescent females with anorexia nervosa: a double-blind, placebo-controlled study
J. Adolesc. Health
(2006) - et al.
IGF-I secreted by osteoblasts acts as a potent chemotactic factor for osteoblasts
Bone
(2008) Acquisition of optimal bone mass in childhood and adolescence
Trends Endocrinol. Metab.
(2001)- et al.
50-year trends in the incidence of anorexia nervosa in Rochester, MN: a population-based study
Am. J. Psychiatry
(1991) - et al.
Prevalence of anorexia nervosa and bulimia in three student populations
Int. J. Eat. Disord.
(1984) - et al.
Decreased bone density in adolescent girls with anorexia nervosa
Pediatrics
(1990) - et al.
Effects of anorexia nervosa on clinical, hematologic, biochemical, and bone density parameters in community-dwelling adolescent girls
Pediatrics
(2004) - et al.
Mechanisms of osteoporosis in adult and adolescent women with anorexia nervosa
J. Clin. Endocrinol. Metab.
(1989) - et al.
Alterations in cortisol secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism
J. Clin. Endocrinol. Metab.
(2004) - et al.
Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism
J. Clin. Endocrinol. Metab.
(2003)
Ghrelin and bone metabolism in adolescent girls with anorexia nervosa and healthy adolescents
J. Clin. Endocrinol. Metab.
Elevated peptide YY levels in adolescent girls with anorexia nervosa
J. Clin. Endocrinol. Metab.
Administration of recombinant human growth hormone normalizes GH-IGF1 axis and improves malnutrition-related disorders in patients with anorexia nervosa
Endocr. J.
Sex steroids and the construction and conservation of the adult skeleton
Endocr. Rev.
The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa
J. Clin. Endocrinol. Metab.
Growth hormone, insulin-like growth factors, and the skeleton
Endocr. Rev.
Growth hormone and bone
Endocr. Rev.
Cited by (75)
Potential applications for rhIGF-I: Bone disease and IGF[sbnd]I
2020, Growth Hormone and IGF ResearchDiabetes mellitus: How being too sweet leads to skeletal fragility
2020, Diabetes Mellitus: Impact on Bone, Dental and Musculoskeletal HealthOsteoporosis associated with eating disorders
2020, Marcus and Feldman’s OsteoporosisBone metabolism in anorexia nervosa and hypothalamic amenorrhea
2018, Metabolism: Clinical and ExperimentalPharmacological treatment options for low Bone Mineral Density and secondary osteoporosis in Anorexia Nervosa: A systematic review of the literature
2017, Journal of Psychosomatic ResearchCitation Excerpt :They confirmed the findings of Shibi-Rahhal et al. and found a 6–10% increase in spine BMD after 6 months of teriparatide and an increase in serum P1NP levels in the TPT group [39]. RhIGF-1 replacement results in an increase in bone formation markers in both adolescents and adults with AN [23,31,40]. Furthermore, increases in both spine and hip BMD are found when rhIGF1 is combined with an estrogen–progesterone combination pill in a placebo-controlled trial (1.8% ± 0.8% vs. − 1.0% ± 1.3% at the spine, P < 0.05) [31].
- ☆
Statement of Financial Support: The study was supported by an investigator initiated grant received from Tercica, and in part by NIH grants R01 DK 062249, K23 RR018851 and M01-RR-01066.