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Institute of Endocrinology and Diabetes (F.Y., W.H., B.M., C.T.C.) and Department of Nuclear Medicine (J.B., R.H.-G.), The Children’s Hospital at Westmead, Sydney, Australia 2145; Department of Pediatrics (F.Y.), KK Women’s and Children’s Hospital, Singapore 299899; and Department of Pediatrics and Adolescent Medicine (W.H.), University Hospital Innsbruck, Austria 6020
Address all correspondence and requests for reprints to: Christopher T. Cowell, Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Sydney, Australia. E-mail: chrisc{at}chw.edu.au.
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Abstract |
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Men with previous CD were shorter (P < 0.001) and had shorter height-adjusted arms compared with controls. Height-adjusted total-body bone mineral content (BMC) (P = 0.004), aBMD (P = 0.016), and bone area (P = 0.006) but not lean tissue mass (P = 0.507) were lower in CD men compared with controls; consequently, their BMC to lean tissue mass ratio was reduced (P < 0.001). Segment length-adjusted BMC and bone area of arms (P < 0.001) and legs (P < 0.03), but not trunk were lower in CD men than in controls. They had lower LS aBMD (P = 0.044) but normal LS and FN volumetric bone mineral density. Size-adjusted LS width and the hip cross-sectional area were lower than in controls. There was no difference in anthropometric or dual-energy x-ray absorptiometry results between untreated (n = 15) and androgen-treated (n = 17) CD men.
We conclude that men with previous CD have normal LS and FN volumetric density but reduced total-body bone mass, which was explained by reduced limb bone mass and size. Together with the reduced LS bone width and hip crosssectional area, these skeletal characteristics suggest impaired periosteal expansion during puberty. The skeletal phenotype of CD males may be altered by their late onset of puberty.
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Introduction |
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Size corrections are particularly important in the interpretation of DXA in children (7). Using volume assumptions to calculate vBMD at the LS and FN corrects for the planar nature of aBMD and avoids misdiagnosing osteoporosis in inherently smaller bones (13, 14). Total-body DXA data can also be interpreted by adjusting for body-size (height) (15). To date, assessment of total-body DXA, limb bone mass and size, and hip strength have not been reported in men with a previous history of CD. In addition, no study so far has investigated the muscle-bone relation in a CD cohort. We (15, 16) and others (17) have previously shown that lean tissue mass (LTM) is a major predictor of total-body bone mineral content (BMC) that needs to be assessed when determining the origin of osteopenia in individuals.
The primary objectives of our study were to determine the aBMD and vBMD of the LS and FN in an adult CD cohort, compared with normal controls; examine auxological and skeletal characteristics of CD men including final height, body composition and segment proportions, bone size (length, width), and hip strength; and determine size-adjusted total-body, limb, and trunk bone mass and size. Our secondary objectives included examining the muscle-bone relation for the total body and assessing the effects of prior androgen therapy on bone mass and final height.
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Subjects and Methods |
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One hundred nine men with a previous diagnosis of CD of puberty were identified in a review of hospital records and private clinic files. These men had been seen by pediatric endocrinologists at the Royal Alexandra Hospital for Children in Sydney between 1975 and 1985. Among the 94 former patients who could be contacted, 39 agreed to participate, of whom 32 met the key entry criteria of delayed onset of puberty. At boyhood evaluation, each subject met the CD definition of pubertal onset after the age of 14 yr (18), with documented testicular volumes of less than 4 ml. Data on pubertal staging, auxological parameters, and bone age at boyhood evaluation were obtained from the medical records. These boys measured 144.4 (7.9) cm tall, and the height SD score (SDS) was –2.44 (0.7): 31 of the 32 boys had a height SDS less than –1.5, whereas the height SDS was –1.11 in one boy. The bone age delay was 2.8 (0.7) yr: 31 of the 32 boys had a bone age delay of more than 1.5 yr compared with chronological age, whereas the bone age delay was 1.2 yr in one boy. We examined these 32 subjects in adulthood, where each was ascertained to have attained complete adult secondary sexual characteristics. Auxological measurements and densitometry studies were carried out by single separate investigators. None of the subjects had clinical evidence of syndromic or dysmorphic disorders, endocrine disease, chronic illnesses, or any disease likely to affect bone health. The Institutional Ethics Committee (The Children’s Hospital of Westmead, Sydney, Australia) approved this study, and written informed consent was obtained from all participants.
Androgen-treated patients
Of the 32 CD men, 17 had previously received androgens to promote growth or induce puberty. Fourteen subjects had received oral Oxandrolone at an average dose of 5 mg (range, 2.5–6.25 mg) for an average of 12 months (range, 6–27 months). Three subjects had received intramuscular testosterone preparations for 6–12 months. Treatment was commenced at a mean age of 14.0 yr (range, 13.0–16.3 yr).
Controls
Forty-five healthy men were recruited from the subject’s friends, hospital staff, and medical students. None of the controls had a history of bone disease, disorder of puberty, or medical illness. They were at least 19 yr of age, with established adult secondary sexual characteristics and an onset of puberty before 14 yr.
Auxology
In subjects and controls, height was measured with a Harpenden stadiometer to the nearest 1 mm and weight with an electronic scale to the nearest 10 g on the day of the DXA scan. Height and weight SDS were calculated as for an 18-yr-old male, based on the U.S. National Center for Health Statistics reference data (19). Body mass index (BMI; in kilograms per meter squared) was calculated. Pubertal stage was assessed according to Tanner and Whitehouse (20). Bone age was assessed using the method of Greulich and Pyle (21). Midparental height was determined using measured parental heights according to the formula: [(mother’s height + father’s height)/2 + 6.5 cm].
Densitometry (DXA)
Total-body analysis. Bone mass and body composition of subjects and controls were assessed by DXA using a pencil beam DPX (Lunar Corp., Madison, WI) total-body scanner. Total-body BMC, aBMD, bone area (BA), and LTM were measured. All scans were analyzed using software version 4.7 by a single technician. The technique and measurement protocol, including quality-assurance testing, has been described previously (16). In brief, the coefficients of variation for total-body BMC, LTM, and percent fat mass were 0.74, 0.82, and 1.59%, respectively. In the comparison between groups, total-body BMC, aBMD, BA, and LTM were adjusted for height (15).
Body segment analysis. Delineation of the total-body scan into body segments (arms, legs, and trunk) was performed using anatomical landmarks as recommended by the manufacturers, and special care was taken to ensure that tissue and bone were in the correct region. The trunk includes all central regions below the chin and includes the dorsal and LS, ribs, and pelvis, but excludes the head. The lengths of these body segments were determined from individual total-body DXA images using the ruler function: arm length, measured by adding the lengths of the right humerus and forearm; leg length, measured by adding the lengths of the right femur and tibia; and thoraco-lumbar (TL) length, measured from the first thoracic to the fifth lumbar vertebra. In the comparison between groups, BMC and BA results of each body segment were adjusted for the corresponding segment length.
Regional LS and FN scans and hip strength analysis. Separate DXA scans on the same DPX machine were performed at the LS (L1–4) and the FN. aBMD (grams per centimeter squared) was measured, and vBMD (grams per centimeter cubed) was derived from this areal measurement according to our previously described methods (13). Geometric measurements at the LS included the L1–4 length and average width. Hip strength analysis was performed as previously described (22). Average FN diameter, length (the distance from the center of the femoral head to the FN axis-shaft intersection along the FN axis), and the minimum cross-sectional area (CSA; millimeters squared) and cross-sectional moment of inertia (CSMI; mm4) were derived. The minimum CSMI represents a measure of the minimum resistance of bone to bending forces.
Statistics
Data were analyzed using the Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, version 11.5). Comparisons between CD and control groups, as well as androgen-treated and untreated CD men, were made using the Student’s t test. Height adjustments for total-body results and length adjustments for body segment results were derived using analysis of covariance. Data are presented as means (SD), and where applicable, the absolute range is provided. P < 0.05 was considered to be statistically significant.
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Results |
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The characteristics of the composite CD group and controls are presented in Table 1
. There were no significant differences between CD men and controls for age, BMI, and percent body fat, but CD men were significantly shorter and lighter. Similar to height, the lengths of the TL spine, legs and arms were significantly shorter in CD men compared with controls (Table 2). To assess proportionality, adjustments for height were made (analysis of covariance), showing that CD men had similar TL and leg lengths, but shorter arm lengths (P = 0.001).
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The CD group had significantly lower values for BMC, aBMD, BA, and LTM than controls (P < 0.001). After adjusting for height, BMC (P = 0.004), aBMD (P = 0.016), and BA (P = 0.006) remained significantly lower in the CD group. However, the height-adjusted LTM was not significantly different between the groups (P = 0.507) (Table 3). The disproportionate height-adjusted reduction in BMC compared with LTM is reflected in a significantly lower BMC to LTM ratio (P < 0.001) in the CD men.
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Compared with controls, the CD group exhibited significantly reduced length-adjusted BMC in the arms [CD, 402 (61) g; controls, 463 (64) g] (P < 0.001) and legs [CD, 1099 (145) g; controls, 1220 (142) g] (P = 0.001) but not the trunk [CD, 882 (144) g; controls, 941 (143) g] (P = 0.090) (Fig. 1A). The CD group also demonstrated significantly reduced length-adjusted BA in their arms [CD, 415 (48) cm2; controls, 465 (46) cm2] (P < 0.001) and legs [CD, 842 (67) cm2; controls, 880 (66) cm2] (P = 0.022) but not the trunk [CD, 902 (87) cm2; controls, 922 (86) cm2] (P = 0.343) (Fig. 1B).
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aBMD of the LS was significantly lower in CD men compared with controls [CD, 1.20 (0.12) g/cm2; controls, 1.28 (0.14) g/cm2] (P = 0.044), whereas the FN aBMD was not different from the controls [CD, 1.10 (0.14) g/cm2; controls, 1.16 (0.13) g/cm2] (P = 0.061) (Fig. 2A). However, there were no significant differences in vBMD at both the LS [CD, 0.37 (0.04) g/cm3; controls, 0.37 (0.04) g/cm3] (P = 0.832) and FN [CD, 0.67 (0.11) g/cm3; controls, 0.67 (0.10) g/cm3) (P = 0.382) (Fig. 2B).
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The LS (L1–4) length (P = 0.004) and width (P < 0.001) were lower in CD men than in controls. The LS length was not different between the groups after adjustment for height. In contrast, the LS width remained persistently lower in CD men after adjustment for height (P = 0.039), TL (P = 0.005), or LS length (P < 0.001). The FN diameter and length were not different between the groups. However, FN CSA was lower (P = 0.024) in CD men with a similar tendency in CSMI (P = 0.064) (Table 2
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Effect of prior androgen therapy in CD men
No significant differences were found in terms of boyhood height and bone age delay, final height, height gain from prepuberty to adulthood, and difference between final height and midparental height among untreated (n = 15) and androgen-treated (n = 17) CD men. There were no differences in total-body or regional DXA results between the two groups.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Our study reports the largest sample of auxological and skeletal characteristics in CD men assessed by DXA so far. Subjects and controls were carefully selected, avoiding comparison of young men with different skeletal maturation (26). In addition, the characterization of length-adjusted body segment bone mass and size, the total-body muscle-bone relation, and hip strength analysis have not been previously reported. However, because BA measured by DXA is a two-dimensional measure of three-dimensional external bone size, more advanced techniques like peripheral quantitative computed tomography are needed to confirm our findings.
Conventionally defined as a benign variant of normal development, CD is a condition in which temporary growth deceleration occurs in association with delayed puberty in otherwise healthy young teenagers (27). Although males with CD can possess an excellent prognosis for normal stature (28), their final heights are often low for the family (3, 4, 29) and may be significantly reduced compared with age-matched controls (7), similar to the results of our study. Short stature was the specific characteristic that led to the existing disagreement (7, 8, 9) and ongoing debate (10, 11) about whether or not adult CD men are indeed osteopenic because size corrections are necessary in the interpretation of DXA (6, 13, 14).
Our findings of significantly lower LS aBMD but normal FN and LS vBMD in CD men with conventionally defined (18, 30) delayed puberty are consistent with Bertelloni’s (7) data. The significantly reduced LS aBMD demonstrated by Finkelstein even after size correction may reflect different selection criteria including only CD men with very late pubertal onset after 15 yr (12). Therefore, it may be possible that extreme pubertal delay is linked with osteopenia, in analogy to girls with Turner Syndrome (31).
The height-adjusted LTM in our CD cohort was not different from the controls, in contrast to the significantly lower height-adjusted BMC and aBMD, resulting in a low BMC to LTM ratio. As LTM by DXA is a major predictor of BMC (15, 16, 17), the dissociation between normal LTM but low bone mass and BA acquisition suggests that CD men may have bones with reduced mineral content, contributed in part by their smaller size. To further explore the relative contributions of various body segments (arms, legs, and trunk) to the total body, we undertook a detailed BMC and BA analysis, making the necessary adjustment for their respective lengths.
The trunk demonstrated normal BMC and BA, consistent with the normal vBMD found at the LS and FN, but LS width was narrower compared with controls. The trunk BA (including thorax, clavicles, scapulae, spine, and pelvis) represents a less accurate bone size measure compared with LS length and width, which are measured by the high-resolution LS scan. In contrast, both upper and lower limbs had significantly reduced BMC as well as BA, suggesting narrower limb bones. Although DXA does not allow us to conclude whether the arms are truly osteopenic or not, the combined reduction in BMC of the upper (25% reduction) and lower (50% reduction) limbs accounted for 75% of the total BMC reduction (data not shown). These findings support the reduced size-corrected radial aBMD demonstrated in Finkelstein’s cohort (12).
In contrast to traditional concepts that state that the duration of puberty is independent of the timing of pubertal onset (27, 32, 33), there is good evidence that males with delayed puberty progress through puberty more rapidly compared with normal or early maturers (23). Because puberty is a critical window for BMC accrual (34) with peak velocity of acquisition lagging peak growth velocity (35), a shorter pubertal duration will attenuate bone mass accumulation. Additionally, the lower proportion of final height gained from the onset of puberty in later maturers vs. normal or early maturers (12 vs. 16–18%) (23) will reduce the capacity of pubertal bone mass accrual in CD men. Although we do not have data on the actual duration of puberty in our CD cohort, we speculate that as periosteal and cortical dimensions of a long bone expand mainly during puberty (36, 37), a shortened pubertal duration may specifically compromise limb bone size and bone mass accrual in CD men. The supposition of impaired periosteal expansion is supported by the lower hip CSA and the lower size-corrected limb BA and LS bone width in CD men compared with controls. The significantly shorter arms in our CD cohort raise the question whether limb growth could be affected as well, which requires further studies.
Although not the major focus of our study, we assessed the effects of prior androgen treatment in CD men on final height, bone mass, and density. The doses of Oxandrolone we employed were higher (2.5–6.25 mg) than previously used (1.25–2.5 mg) to manipulate growth in CD (38). However, no significant androgen effect on final height was found in our CD cohort, consistent with previous observation (39). There were also no long-term effects on total-body and regional bone mass variables.
In summary, men with a history of CD have normal LS and FN vBMD, truncal bone mass, and muscle mass acquisition. Peak bone mass reduction caused by reduced limb bone mass and narrow limb bones and vertebrae are key features of the skeletal phenotype of CD men. This characteristic skeletal phenotype may be caused by the different timing and duration of puberty in CD, which may impair periosteal expansion and bone mass acquisition during puberty. Although our results provide reassurance on the normal state of bone density of the axial skeleton, implications on fracture risk at the extremities deserve further consideration.
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Footnotes |
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Received January 11, 2004.
Accepted May 25, 2004.
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