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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1591
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 1 110-117
Copyright © 2008 by The Endocrine Society

Constitutional Thinness: Unusual Human Phenotype of Low Bone Quality

Bogdan Galusca, Mohamed Zouch, Natacha Germain, Cecile Bossu, Delphine Frere, Francois Lang, Marie-Helene Lafage-Proust, Thierry Thomas, Laurence Vico and Bruno Estour

Departments of Endocrinology (B.G., N.G., C.B., B.E.) and Psychiatry (F.L.), and Nuclear Medicine Laboratory (D.F.), Centre Hospitalier Universitaire Saint Etienne, 42055 Saint Etienne, France; Institut National de la Santé et de la Recherche Médicale U890 (M.Z., M.-H.L.-P., T.T., L.V.), F-42023 Saint Etienne, France; and Endocrinology Department (B.G.), Universitatea de Medicina si Farmacie, 700229 Iasi, Romania

Address all correspondence and requests for reprints to: Bruno Estour, Endocrinology Department, Centre Hospitalier Universitaire Saint Etienne, 42055 Saint Etienne, Cedex 2, France. E-mail: bruno.estour{at}chu-st-etienne.fr.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Low fat mass and hormonal or nutritional deficiencies are often incriminated in bone loss related to thinness. Constitutional thinness has been described in young women with low body mass index (BMI) but close-to-normal body composition, physiological menstruation, no hormonal abnormalities, and no anorexia nervosa (AN) psychological profile.

Objective: Our objective was to determine whether constitutional thinness is associated with impaired bone quality.

Design, Setting, and Participants: This was an observational, cross-sectional study on 25 constitutionally thin and 44 AN young women with similar low BMI (<16.5 kg/m2) and 28 age-matched controls.

Main Outcome Measures: Femoral and lumbar spine bone mineral density by dual-energy x-ray absorptiometry, distal tibia and radius bone architecture and breaking strength by three-dimensional peripheral quantitative computed tomography, and bone turnover markers were determined.

Results: Constitutionally thin subjects displayed a higher percentage of fat mass than AN subjects but had similar lumbar and femoral bone mineral density, which were significantly lower than in controls (P < 0.001). Constitutionally thin subjects displayed more markedly impaired trabecular and cortical bone parameters in the distal tibia than in the radius. AN bone structure was impaired only in subjects with a long history of disease. Calculated breaking strength was decreased in constitutional thinness and long-standing AN in both the radius and the tibia. Bone markers in constitutionally thin subjects were similar to those of controls. Osteoprotegerin to receptor activator of nuclear factor {kappa} B ligand ratio was higher in constitutionally thin subjects than in controls or AN women.

Conclusions: Young women with constitutional thinness present an unexpectedly high prevalence of low bone mass (44%) associated with small bone size, overall diminished breaking strength, but normal bone turnover. Mechanisms related to insufficient skeletal load and/or genetics are proposed to explain this new phenotype of impaired bone quality.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Bone mass and density are determined by various concurrent factors such as genetics, age, hormone levels, physical activity, nutrition, body composition, and body weight (1).

In middle-aged and elderly patients, bone loss has been related to thinness, mainly in a context of low fat mass (FM) (2). Consumptive (3), infectious (4), digestive (5), or chronic diseases or cachexia (6) inducing weight loss has also been incriminated.

Low bone mass related to low body weight has also been reported in young women, mainly in a context of anorexia nervosa (AN). More than 50% of young AN women present bone loss at both trabecular and cortical bone sites (7, 8), and fractures are reported to be increased in this population (9). An intricate network of multiple hormonal and nutritional abnormalities associated with low FM that impair osteoblast and/or osteoclast activities has been incriminated (7, 10, 11).

In the same age range as AN, a nonpathological state called constitutional thinness (CT) or leanness has been poorly described (12). These young women are severely thin but continue to have a close-to-normal FM percentage, normal physiological menstrual cycles, and no detectable abnormalities of cortisol, IGF-I, or free T3 secretory patterns (13), and normal energy metabolism (14). In this context, we wanted to determine whether constitutional thinness could still represent a phenotype of impaired bone quality, in terms of bone mass, bone macroarchitecture and microarchitecture, and bone turnover.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
This study was approved by the human research ethics committee of Centre Hospitalier Universitaire, Saint Etienne, France, and all subjects gave their written informed consent.

Subjects

Three groups of young age-matched Caucasian female subjects (18–30 yr) were recruited for the study: 25 constitutionally thin subjects, 44 AN subjects, and 28 controls. The constitutionally thin and AN subjects were matched by body mass index (BMI).

The 25 constitutionally thin subjects were recruited at our outpatient clinic among the patients evaluated for leanness, referred by internists after exclusion of celiac disease, infectious diseases, cancer, or other consumptive diseases. Inclusion criteria were as follows: BMI between 12.0 and 16.5 kg/m2, called "severe underweight" according to the World Health Organization classification (15), stable throughout the growth period until the age of 18 (14); presence of physiological menstruation without estrogen-progestin therapy; and desire for weight gain as the main reason for medical consultation.

All 44 AN subjects displayed active psychiatric illness according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders (16). All patients presented restrictive-type AN (no binge/purge crises). Before disease, the subjects’ BMI ranged between 19.1 and 26.0 kg/m2. None of these patients used oral contraceptives, and all presented secondary amenorrhea for more than 6 months. Secondary amenorrhea occurred at least 12 months after the first menstrual period. To evaluate the effect of duration of undernutrition on bone parameters, two subgroups of AN were distinguished using a cutoff point of 24-month disease duration (17): 23 recently diagnosed patients, 21 patients with a long history of disease.

A total of 28 medical students were recruited as normal-weight controls.

In constitutionally thin subjects and controls, all data were collected during the follicular phase of the menstrual cycle.

None of the subjects included in this study were documented to have any form of addictive or abusive consumption (alcohol, smoking, drugs, or physical activity, etc.). None of these subjects were taking calcium, vitamin supplements, or any other medications.

Bone mineral density (BMD) and body composition

Femoral neck and lumbar spine (L1–L4) BMD were measured by dual-energy x-ray absorptiometry (DXA) (Delphi W, Hologic, Inc., Waltham, MA). The SD value for lumbar bone density measurement is 0.01 g/cm2 and does not vary with bone density. Z score was calculated using a manufacturer-supplied reference data set of healthy young adult female BMD values. According to the International Society for Clinical Densitometry official position concerning premenopausal women (18), Z scores less than –2.0 were classified as "below expected range for age."

Fat and lean body mass were determined using the same DXA device.

Bone evaluation by three-dimensional peripheral quantitative computed tomography (3D-pQCT)

Multislice 3D-pQCT was performed on the distal radius and distal tibia of the nondominant forearm and leg, respectively (XtremeCT; Scanco Medica AG Bassersdorf, Switzerland). The XtremeCT system uses a two-dimensional detector array in combination with a 0.08-mm point-focus x-ray tube, enabling simultaneous acquisition of a stack of parallel computed tomography slices with a nominal resolution (voxel size) of 82 µm.

Methods used to process computed tomography data have been previously described in detail (19). The following parameters were considered: D100, mean whole bone (cortical and trabecular) density in grams hydroxyapatite (HA) equivalence per cm3; Dtrab, density of the trabecular area of bone (g HA/cm3); Dmeta, density of the subcortical area of trabecular bone (g HA/cm3); Dinn, density of the central part of trabecular bone (g HA/cm3); BV/TV, relative bone volume as a percentage of total volume, derived from trabecular density; TbN, absolute trabecular number per mm3; mean trabecular thickness (mm); TbSp, mean trabecular separation (mm); Dcomp, bone density of cortical bone (g HA/cm3); CTh, absolute thickness of cortical bone (mm); and mean cross-sectional area of slices (mm2). Short-term coefficients of variation (CVs) of densitometric and structural parameters were evaluated from two repeated measurements on nine women 25–40 yr old within 1 wk, and ranged between 0.34 and 4.3%.

Parameters of total and cortical bone strength at both radius and tibia level were calculated using additional software in accordance with previous descriptions (20, 21, 22): Ixx, Iyy, Imax, Imin – moment of inertia (MOI) around x-axis, y-axis, shorter axis, and longer axis, respectively. Section modulus was calculated (S = I/C, where I = MOI about an axis through the centroid, and C is the distance from the centroid to the extreme edge of the section), which relates to the breaking strength of the bone: Ixx/Cy – MOI around x-axis divided by maximum extent in y direction; Iyy/Cx; Imax/Cmax – MOI around new y-axis divided by maximum extent in x direction; and Imin/Cmin.

Hormonal and bone marker study

Venous blood samples were collected on dry glass tubes containing EDTA and centrifuged, and plasma was aliquoted and kept frozen at –80 C before the assay. After an overnight fast, blood was obtained at 0800 h for measurement of serum leptin, GH, IGF-I, cortisol, 17β-estradiol, sulfate salt of dehydroepiandrosterone (DHEAS), SHBG, total testosterone, free T3, PTH, and 25-hydroxy vitamin D3. Samples were collected every 4 h for a period of 24 h to measure bone markers.

The following techniques were used to measure: leptin, RIA [Nichols Institute Diagnostics, San Juan Capistrano, CA; manufacturer’s reference range for a normal BMI 3.7–11.1 µg/liter (18, 19, 20, 21, 22, 23, 24, 25)]; GH, IRMA (Beckman Coulter, Inc., Fullerton, CA; manufacturer’s reference level < 5 mU/liter); IGF-I, IRMA (Beckman Coulter; intraassay and interassay CVs, 7 and 16% respectively, manufacturer’s reference range 107–310 µg/liter); plasma cortisol, RIA (Immunotech, Marseille, France; intra-assay and interassay CVs, 7 and 8%, respectively, detection limit 10 nmol/24 h, normal range 107–310 ng/ml); 17β-estradiol, RIA (Dia Sorin, Antony, France; manufacturer’s reference range during the follicular phase 30–50 ng/liter); DHEAS, RIA (Beckman Coulter; normal range 85–225 µg/dl); SHBG, IRMA (bioMérieux sa, Marcy l’Etoile, France; manufacturer’s reference range 30–100 nmol/liter); testosterone, RIA [Beckman Coulter; extraction and chromatography, manufacturer’s reference range 7–65 ng/dl, calculated free testosterone index (= testosterone/SHBG)]; free T3, RIA (Beckman Coulter; manufacturer’s reference range 2.5–5.8 pmol/liter); intact PTH, Allegro IRMA diagnostic kits (Nichols Institute Diagnostics; manufacturer’s reference range 10–65 ng/ml); and vitamin D (25 OHD3), kit RIA Incstar (Incstar Corp., Stillwater MN; manufacturer’s reference range 10–44 µg/liter, calcium).

Elsa Ost-Nat (Cis Bio Intl., Gif-sur-Yvette, France), a two-site assay, was used to quantify intact osteocalcin. Intraassay and interassay CVs were less than 5% (23, 24). The manufacturer’s mean and reference range for females 21–30 yr were 13.4 and 7.6–25.6 µg/ml, respectively.

Bone alkaline phosphatase (bALP) was measured using Tandem-R Ostase two-site Immunoradiometric Assay (Beckman Coulter). The interassay CV was less than 8%. The manufacturer’s mean ± SD for premenopausal women was 8.7 ± 2.7 µg/ml.

Serum cross-linked C telopeptide of collagen type I (sCTX) assessment is a competitive immunoassay (CrossLaps-S Elisa; Osteometer A/S, Rodovre, Denmark). The crosslaps antigen coated on the microwell is a synthetic peptide with an amino acid sequence specific for the C telopeptide of the {alpha}1 chain of type 1 collagen (Glu-Lys-Ala-His-Asp-Gly-Gly-Arg: crosslaps antigen) (25). The intraassay and interassay CVs were less than 5 and 8.1%, respectively, and the detection limit was 92 pmol/liter. The manufacturer’s reference range in premenopausal females was 788-7579 pmol/liter.

Tartrate-resistant acid phosphatase type 5b (TRACP 5b) activity was detected using BoneTRAP assay (Immunodiagnostic Systems, Tyne and Wear, UK). Intraassay and interassay CVs were less than 12.3 and 13.9%, respectively, and the detection limit was 1 U/liter. The manufacturer’s reference range in healthy premenopausal females was 1.03–4.15 U/liter.

Osteoprotegerin (OPG) was measured by an OPG ELISA kit (Immunodiagnostic Systems). Intraassay and interassay CVs were less than 10 and 7%, respectively, and the detection limit was 0.14 pmol/liter.

Soluble receptor activator of nuclear factor {kappa}B ligand (RANKL) measurements were performed with a Biomedica Medizinprodukte GmbH (Vienna, Austria) prototype (ELISA format). Interassay and intraassay CVs were 7–10% and less than 7%, respectively.

Statistical analysis

All values are presented as mean ± SEM. The principal components analysis multivariate analysis technique using an Orthotran/Varimax transformation was performed to extract and rotate factors to best represent the 18 variables measured or calculated by 3D-pQCT. ANOVA was used to perform a three-group analysis comparing constitutionally thin women with anorexic women and controls. When ANOVA was significant, post hoc ANOVA tests (Tukey-Kramer) were performed for comparisons within all groups. The limit of statistical significance was set at P < 0.05. Analysis was performed with and without subject height as covariate for architectural bone parameters measured by 3D-pQCT. Linear regression was performed to evaluate several interactions within the following pooled groups: constitutionally thin + controls, AN + controls. This pooling was decided because a nonlinear relationship was found in the overall group for several parameters. Bonferroni’s correction was applied to compensate for multiple tests per variable (26). All statistical analyses were performed with StatView software (SAS Institute Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical and hormonal parameters (Table 1Go)

Constitutionally thin women with a very low BMI (15.8 ± 0.1 kg/m2) not significantly different from that of AN subjects (15.5 ± 0.1 kg/m2) were included in this study. In this context of severe underweight, constitutionally thin subjects displayed a higher percentage of FM than AN subjects (18.6 ± 0.7 vs. 9.8 ± 1.1; P < 0.001), and implicitly had a lower percentage of fat-free mass (FFM). Percentage values of FM were significantly lower in constitutionally thin subjects than in controls. CT leptin levels were intermediate between AN subjects and controls. No significant difference between constitutionally thin subjects and controls was observed for the other hormones. GH, IGF-I, cortisol, 17β-estradiol, free T3, and DHEAS were significantly different in the AN group compared with both constitutionally thin subjects and controls. No difference in serum calcium levels between the three groups was observed.


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  		TABLE 1. Body weight composition, BMD, nutritional and food intake parameters, and several hormones (mean levels ± SEM) in AN, CT, and controls

 
BMD (Table 1Go)

Constitutionally thin subjects had markedly lower BMD than the control group, in both the femoral neck and lumbar spine (P < 0.001). Similar low BMDs were found in lean women with AN. Up to 44% of constitutionally thin subjects and 50% of AN patients presented low bone mass (Z score < –2.0). None of the controls presented a Z score below the expected range for age.

When pooling constitutionally thin and controls, lumbar spine and femoral neck BMD were positively correlated with BMI, but not with body composition parameters (FM and FFM) or leptin. Inversely, when pooling AN and controls, BMD was correlated with BMI, FM, and leptin (Table 2Go).


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  		TABLE 2. Linear regression between femoral neck and lumbar spine BMD and BMI, body composition parameters, leptin

 
Bone evaluation by 3D-pQCT (Table 3Go and Fig. 1Go)

Principal components analysis extracted three rotated factors for both radius and tibia measurements, characterizing: 1) breaking strength (grouping Ixx, Iyy, Imax, Imin, Ixx/Cy, Iyy/Cx, Imax/Cmax, and Imin/Cmin); 2) trabecular density and structure (grouping D100, Dtrab, Dmeta, Dinn, BV/TV, TbN, and TbSp); and 3) cortical density and structure (grouping Dcomp and CTh).


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  		TABLE 3. Trabecular and cortical 3D-pQCT parameters of distal radius and distal tibia (mean levels ± SEM) in subjects with CT, AN patients, and controls

 

Figure 1
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  		FIG. 1. 3D-pQCT image reconstruction of distal tibia in controls (A) and constitutionally thin women (B). Lower panel, Cross-sectional area measured by 3D-pQCT and calculated breaking strength of distal radius and distal tibia in recently diagnosed AN, AN with long history of the disease, constitutionally thin (CT) subjects, and controls (C). The cross-sectional area (1 ) and cortical thickness (2 ) are shown in A. Lower panel, Bars indicated by asterisk (*) are significantly different from controls (Cs) at P < 0.05, based on ANOVA and Tukey’s test as post hoc test.

 
The CT group displayed significantly different trabecular bone parameters compared with controls in the distal tibia, but not in the radius: lower bone density (Dtrab), significantly lower trabecular number (TbN), and larger trabecular separation (TbSp). Cortical bone in the distal tibia presented reduced thickness (CTh) but normal density (Dcomp) compared with controls. The distal radius and tibial cross-sectional areas were significantly lower in the constitutionally thin group than in controls or AN subjects.

Only those AN subjects with a long history of disease displayed impaired cortical and trabecular bone density and microarchitecture. These abnormalities were detected in both the distal tibia and the radius.

Parameters reflecting the resistance of a bone (total and cortical) to stress (Ixx, Iyy, Imax, Imin, Ixx/Cy, Iyy/Cx, Imax/Cmax, and Imin/min) were decreased in both the radius and the tibia in constitutionally thin and long-standing AN subjects.

Adjustment of architectural bone parameters for subject height did not modify the significance of these differences.

In the AN group, age and disease duration were negatively correlated with BMD, measured by DXA or 3D-pQCT, and with some bone structure parameters, whereas no correlation was found between age and these parameters in the CT group (Table 4Go).


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  		TABLE 4. Correlation between bone parameters and age (in AN and CT groups) and disease duration (AN group)

 
Bone remodeling markers

Circadian profiles of the measured bone markers are illustrated in Fig. 2Go, with mean values presented in Table 1Go. Osteocalcin, sCTX, and TRACP 5b were not significantly different between the CT group and controls. Conversely, AN subjects displayed lower levels of osteocalcin and higher levels of sCTX and TRACP 5b than controls or constitutionally thin subjects. bALP was not significantly different between groups.


Figure 2
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  		FIG. 2. Circadian profile of plasma osteocalcin (top left panel), sCTX (bottom left panel), OPG (top right panel), and RANKL (bottom right panel) in constitutionally thin women (CT) compared with AN subjects and controls (C). ANOVA with repeated measures followed by post hoc tests was used to evaluate intergroup differences.

 
A strong positive correlation was found between osteocalcin and sCTX in constitutionally thin subjects (r = 0.58; P < 0.001) and controls (r = 0.46; P < 0.001), whereas no correlation was observed between these two markers in the AN group.

RANKL was significantly lower in constitutionally thin subjects compared with controls or AN subjects. OPG was significantly higher in AN subjects (Fig. 2Go), and the OPG to RANKL ratio was higher in constitutionally thin subjects than in controls and AN subjects (P < 0.001).

No significant differences for hormonal parameters and bone markers were observed between subjects with newly diagnosed AN and those with long-standing AN.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In young women, low bone density related to low body weight was described only in patients with AN.

Our study evaluated bone characteristics in another population of young women, called constitutional thinness, presenting the same BMI less than 16.5 kg/m2 with no identified eating disorder. The nonpathological state of constitutional thinness is supported by the absence of Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for AN, normal menstruation (27), normal hormonal profile (13), normal levels of sc adipose tissue (28) and, as we have recently described, a normal energy metabolism (14). This entity was initially described in African and Australian aboriginal populations (28, 29), whereas no estimate of prevalence has been performed in Western populations. No bone quality data have previously been published on young women with constitutional thinness.

In the present study, in a well-selected population of young women with constitutional thinness, we report an unexpectedly high prevalence of low bone mass (44%), characterized by four aspects: normal bone turnover, high OPG-to-RANKL ratio, small bone size, and selective bone structural impairment predominantly affecting weight-bearing skeletal regions. In our AN population, we observed the same prevalence of low bone density but differences in terms of bone turnover, bone size, and bone architecture. The CT impaired bone quality model has not been previously reported.

In young women with constitutional thinness, the normal bone remodeling markers and a strong correlation between bone formation and bone resorption parameters similar to controls suggest that the uncoupling of bone turnover observed in AN (10) does not characterize their low bone density. The coupling of bone turnover seen in constitutional thinness is in accordance with the normal hormonal status observed in these young women.

Over recent years it has become clear that RANKL and OPG are essential determinants of osteoclast cell biology and bone resorption. An increase in the OPG-to-RANKL ratio normally inhibits osteoclastogenesis, slows down bone resorption, and reduces bone loss (30). Although interpretation of serum levels of these cytokines has not been fully elucidated, the increased OPG-to-RANKL ratio in constitutional thinness could be considered effective because bone resorption markers, sCTX and TRACP 5b, were situated in the same range as in controls. The high levels of OPG found in AN patients confirm recently published data (31) that are difficult to interpret in a context of increased bone resorption rate. In addition, we report for the first time that RANKL levels and OPG-to-RANKL ratio are normal in AN subjects.

Bone structure evaluated by 3D-pQCT was altered in constitutionally thin subjects mainly in the distal tibia, a bone region affected by weight bearing. Only one study has previously been published on AN bone structure using 3D-pQCT and reported similar bone structural impairments in the distal radius, an appendicular skeletal site without a weight-bearing effect (32). The present study confirms these data in both the radius and tibia in AN patients, but only in those with long-standing disease. Strong correlations with age and disease duration emphasize the importance of duration of AN on bone.

Bone size assessment indicated that constitutionally thin subjects have smaller bones than controls or AN subjects. In accordance with previous studies (33), AN subjects displayed no modification of appendicular bone size.

The unusual combination of low bone density and size coupled to normal bone turnover found in constitutionally thin women needs to be explained. First, low bone density in constitutional thinness is clearly not related to hormonal influences. The main hormonal mechanisms identified as being responsible for low bone mass in AN involve estrogen deficiency (34), hypercorticism (24, 34), high GH levels, and low IGF-I (35). The present study did not demonstrate any difference for these hormones between the constitutionally thin group and age-matched controls, despite the very low range of body weight (BMI 12.0–16.5 kg/m2). It is well known that low bone density in AN is strongly related to severe FM reduction and leptin deficiency (11). In constitutional thinness, leptin is significantly reduced compared with controls and could partly explain the low bone density observed. On the other hand, leptin interacts with and stimulates GnRH neurons. A leptin threshold has been proposed as the metabolic gate to gonadotropin secretion in AN (36). In constitutional thinness, gonadal function is preserved, providing evidence that leptin acts normally in these subjects despite lower levels than in normal weight subjects. By analogy, we postulate that leptin is able to stimulate bone formation in constitutional thinness. In the present study, leptin was not correlated with BMD when constitutionally thin subjects and controls were pooled. Some authors have proposed that FFM is a regulator of bone mass and bone metabolism (37). However, no strong correlation was observed in our study between FFM and bone parameters after application of the Bonferroni correction.

Because no obvious hormonal or body composition causality was found, we propose that constitutionally thin bone impairment may be caused by an insufficient skeletal load and/or genetic factors.

The correlation between BMD and BMI in constitutionally thin women suggests a possible direct causality of low body weight on bone density, structure, or strength, as demonstrated in microgravity models with insufficient skeletal load (38, 39). The effect of mechanical unloading may be cumulative in constitutionally thin patients because they have a constant low weight during the growth period (12, 14, 40). This hypothesis is supported by our current findings indicating that the bone structure of these subjects is mainly impaired in weight-bearing bone regions. In contrast with constitutional thinness, microgravity bone deficit models display bone uncoupling (41) and a low OPG to RANKL ratio (38), suggesting that this hypothesis must be interpreted cautiously.

The low bone mass and overall bone size reduction in constitutional thinness associated with normal hormonal parameters led us to hypothesize a genetic causality. We have previously reported that the families of the constitutionally thin subjects frequently have low BMI (14), in line with previous studies (28, 29, 40, 42). Therefore, the genetic determinism of severe underweight was postulated. This hypothesis is supported by previous publications (40) suggesting that genes associated with low bone mass and severe underweight might be related.

Peak bone mass achieved before the age of 30 yr is one of the main determinants of bone mass in the elderly, and the most important period is the bone-building years before the age of 20 yr (43). The reduced bone breaking strength observed in 20-yr-old constitutionally thin subjects, similar to that observed in long-standing AN, suggests an increased lifetime fracture risk (44).

In conclusion, young women with constitutional thinness, associated with low bone mass and normal bone turnover and no identified hormonal or nutritional causality, represent an unusual model of low peak bone mass and implicitly low bone quality.


   Footnotes
 
Disclosure Statement: The authors have nothing to declare.

First Published Online October 23, 2007

Abbreviations: AN, Anorexia nervosa; bALP, bone alkaline phosphatase; BMD, bone mineral density; BMI, body mass index; BV/TV, relative bone volume as a percentage of total volume, derived from trabecular density; CT, constitutional thinness; CTh, absolute thickness of cortical bone; CV, coefficient of variation; 3D-pQCT, three-dimensional peripheral quantitative computed tomography; D100, mean whole bone (cortical and trabecular) density; Dcomp, bone density of cortical bone; DHEAS, sulfate salt of dehydroepiandrosterone; Dinn, density of the central part of trabecular bone; Dmeta, density of the subcortical area of trabecular bone; Dtrab, density of the trabecular area of bone; DXA, dual-energy x-ray absorptiometry; FFM, fat-free mass; FM, fat mass; HA, hydroxyapatite; MOI, moment of inertia; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor {kappa}B ligand; sCTX, serum cross-linked C telopeptides of collagen type I; TbN, absolute trabecular number per mm3; TbSp, mean trabecular separation; TRACP 5b, tartrate-resistant acid phosphatase type 5b.

Received July 17, 2007.

Accepted October 12, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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M. A. Bredella, M. Misra, K. K. Miller, I. Madisch, A. Sarwar, A. Cheung, A. Klibanski, and R. Gupta
Distal Radius in Adolescent Girls with Anorexia Nervosa: Trabecular Structure Analysis with High-Resolution Flat-Panel Volume CT
Radiology, December 1, 2008; 249(3): 938 - 946.
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