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Normal Volumetric Bone Mineral Density and Bone Turnover in Young Men with Histories of Constitutional Delay of Puberty

Endocrine Unit (S.B., G.I.B., G.S.), II Paediatric Clinic, Department of Reproductive Medicine and Paediatrics, Radioimmunometric Laboratory (M.F.), Department of Oncology, Department of Radiology (G.P.), University of Pisa, "Santa Chiara" Hospital, I-56125 Pisa, Italy

Address all correspondence and requests for reprints to: Dr. Silvano Bertelloni, M.D., Department of Reproductive Medicine and Pediatrics, "Santa Chiara" Hospital, via Roma 67, I-56125 Pisa, Italy.

	Abstract

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It has been suggested that an appropriate timing of puberty is necessary for normal bone mineral density (BMD) acquisition, which may not be achievable in children with constitutional delay of puberty (CDP). To assess the effect of pubertal delay on BMD, we measured areal BMD (aBMD) at lumbar spine, by dual-energy x-ray absorptiometry (DEXA), in a group of patients with CDP (n = 21; mean age, 21.8 ± 1.7 yr) at final height and in healthy controls (n = 12; mean age, 19.3 ± 1.3 yr). A subset of seven patients (group a) were untreated, whereas six subjects (group b) had received im testosterone depot (100 mg/month, for 6–12 months) and 8 boys (group c) oral oxandrolone (1.25–2.5 mg/daily, for 6–28 months) for their pubertal delay. Volumetric BMD (vBMD) was calculated from DEXA measurements. aBMD was reduced in patients with CDP (1.101 ± 0.134 g/cm²), in comparison with controls (1.222 ± 0.091 g/cm²; P < 0.009); no significant differences were found among the groups (group a, 1.089 ± 0.133 g/cm²; group b, 1.111 ± 0.118 g/cm²; group c, 1.103 ± 0.160 g/cm²). vBMD was not significantly different in patients with CDP (0.327 ± 0.021 g/cm³) and in controls (0.337 ± 0.017 g/cm³; P = not significant); no significant differences were found among the groups (group a, 0.326 ± 0.016 g/cm³; group b, 0.332 ± 0.022 g/cm³; group c, 0.330 ± 0.021 g/cm³). No differences were found in mineral metabolism and in bone markers between patients and controls; patients did not report an increased fracture rate, compared with controls.

Our data indicate that: 1) men with CDP have normal vBMD; 2) the reduced aBMD may be the result of uncritical use of DEXA measurements in subjects with altered growth pattern; and 3) androgen administration during pubertal years did not improve BMD in young men with a history of CDP.

	Introduction

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CONSTITUTIONAL delay of puberty (CDP) is a common clinical problem potentially affecting up to 3% of otherwise normal adolescents (1). This condition is considered an extreme normal variant of development rather than a clinical disorder: if left untreated, these subjects will attain a full sexual maturity spontaneously, albeit at later chronological age than their peers (1, 2, 3, 4).

Finkelstein and co-workers reported decreased radial (5), spinal (5, 6), and femoral (6) bone mineral density (BMD) in otherwise healthy adult men with a history of CDP, in comparison with controls (who had a normal onset in the timing of puberty). These authors suggested that the delay in pubertal development may impair the achievement of peak bone mass (5, 6). In their studies, Finkelstein et al. (5, 6) measured lumbar and femoral BMD as areal BMD (aBMD), by dual-energy x-ray absorptiometry (DEXA). aBMD is influenced by bone dimensions and skeletal growth (7, 8). Because CDP may affect height (1, 2, 3, 4) and impair spinal growth (9), the altered aBMD values may be a consequence of abnormal bone size, instead of delayed onset of puberty (10).

We found that adolescent boys with CDP have reduced radial BMD; BMD was still reduced, normalizing for the delayed bone age and statural growth (11). BMD significantly increased after a short course of testosterone treatment (11). No long-term studies confirmed these short-term data.

Some biochemical markers have been proposed to provide information on bone turnover. Serum levels of osteocalcin and carboxylterminal propeptide of type I collagen (PICP) are considered valid indexes of bone formation (12, 13), whereas serum values of cross-linked carboxylterminal telopeptide of type I collagen (ICTP) seem to reflect the bone resorption rate (14). No data are available on biochemical bone markers in men with histories of CDP.

Here, we report on volumetric BMD (vBMD), which is less dependent on body and bone sizes (7), and on biochemical markers of bone turnover in a group of patients with CDP at their final height. We also explore the effect of androgen treatments, during pubertal years, on final height and BMD.

	Subjects and Methods

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Patients

Twenty-one Italian white young adult men that met the family history and the clinical criteria of CDP (3, 4) were studied. At diagnosis, the subjects fulfilled the following criteria for CDP: short stature (height more than 1.5 SD below the mean); delayed puberty (onset delayed more than 2 SD, that is, had not achieved 4-mL testes until age 14 yr); bone age below the 10th centile for chronological age (delayed by more than 1.5 yr); and no clinical or biochemical evidence of chronic disease or endocrinopathy (3, 4). All subjects were eating a diet assuring an adequate intake of calories, proteins, calcium, and phosphate. No boys had received drugs known to alter bone or calcium metabolism or had a family history of hereditary bone disease. Subsequently, all patients showed normal sexual maturation and complete adult virilization (pubertal stage G5, Ph5 at the time of BMD measurement) (15). Patients were subdivided into three groups according to the medical strategies for pubertal delay: group a (n = 7) had no hormonal therapy to induce puberty or growth spurt; group b (n = 6) were treated with im testosterone depot (100 mg/month, for 6–12 months); group c (n = 8) received oral oxandrolone (1.25–2.5 mg/daily, for 6–28 months). Any androgen therapy was stopped almost 2 yr before the BMD measurement (mean age at the discontinuation of androgen therapy: group b, 15.0 ± 0.7 yr; group c, 15.4 ± 0.9 yr). At diagnosis, clinical findings were not different among the groups (Table 1).

The control group consisted of 12 normal-statured, healthy young men at final height (chronological age, 19.3 ± 1.3 yr; mean height, 0.32 ± 0.94 SD score (SDS); pubertal stage G5, Ph5). To reduce the risk of underestimating BMD in patients for different periods in sex steroid exposure (5), the controls were approximately 1.5–2 yr younger than patients.

Life-styles

All subjects (patients and controls) had normal physical activity and were assuming a standard Mediterranean diet according to age. No subject had any food restriction or abnormal dietary habits. Most of them were mild drinkers (beer or wine during meals) without differences between patients and controls; 11 patients and 4 controls smoked less than 10 cigarettes/day; 1 patient usually smoked more than 10 cigarettes/day.

Consent

Informed consent was obtained from the parents of each subject when the chronological age was lower than 18 yr, and directly from each subject whose chronological age was higher than 18 yr. Our departments’ ethics committees for human investigation approved the study.

Assessment of clinical findings

Standing height was measured with a wall-mounted stadiometer. Height was expressed as SDS (SDS = measured individual value - mean normal value for age and gender/SD of normal mean) (16). Pubertal stage was assessed according to Tanner and Whitehouse (15). Bone age was assessed according to Greulich and Pyle (17). Predicted adult height was calculated using the Bayley-Pinneau method (18). Midparental height was calculated using measured parental heights adjusted for the child’s sex [(father’s height + mother’s height)/2 + 6.5 cm]. Final height was defined as a growth of less than 1.0 cm/yr during the preceding year and/or a bone age greater than 17 yr.

All subjects (patients and controls) were asked to detail histories of bone fractures.

Bone mineral analysis

aBMD (g/cm²) was measured by DEXA in the lumbar spine (L2-L4), a site which provides a measure of integral (cortical plus trabecular) bone, with a Lunar DPX-L densitometer (Lunar Corp., Madison, WI). Apparent vBMD (g/cm³) was calculated using the formula vBMD = aBMD x [4/( x width)] (19). In our laboratory, the in vivo coefficient of variation was smaller than 1.5% for healthy volunteer adolescents. For each patient, SDS was calculated according to age and sex, using the normative data published by Del Rio et al. for aBMD (20) and those of Kroger et al. for vBMD (19).

Assessment of biochemical markers

Serum samples were obtained after an overnight fast (between 0800–0900 h; February–April) from patients and controls; the samples were separated within 2 h after sampling and were stored at -20 C until assayed. Calcium (normal values, 2.1–2.7 mmol/L), phosphate (1.2–2.0 mmol/L), magnesium (0.8–1.3 mmol/L), alkaline phosphatase (1.5–7.0 µkat/L), 25-hydroxyvitamin D (60–110 nmol/L), and PTH (1.5–6.0 pmol/L) were assayed as described (11). Serum osteocalcin values were measured by a two-site immunoradiometric assay kit (Human OC, Nichols Inst., San Juan Capistrano, CA). In our laboratory, interassay and intraassay coefficients of variation, sensitivity, and normal values for young adults were 6.3%, 5.2%, 0.05 µg/L, and 7.0 ± 3.0 µg/L (21). Serum PICP and ICTP concentrations were detected by commercial RIA methods (Orion Diagn., Espoo, Finland). In our laboratory, interassay and intraassay coefficients of variation, sensitivity, and normal values for young adults were 4.7%, 3.5%, 1.2 µg/L, and 121.5 ± 45.0 µg/L for PICP; 6.8%, 5.0%, 0.5 µg/L, and 4.0 ± 1.3 µg/L for ICTP (21).

Statistical analyses

Results are expressed as mean ± SD. The differences between the groups were assessed by nonparametric statistical analysis (Mann-Whitney rank-sum test) or by Student’s t test with Bonferroni adjustment for multiple comparisons, where appropriate. A P value less than 0.05 was considered to be significant in all statistic analyses. All statistics were obtained by using a statistical program (Labstat .303, SIBIOC, Milan, Italy).

	Results

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Auxological data

Clinical data at final height are reported in Table 1.

The mean final height in the untreated subjects (group a) was not significantly different than those of the treated group b (testosterone) and group c (oxandrolone) (Table 1). No difference in final height was found, with respect to treatment regimens between the patients of groups b and c (Table 1). In all groups, final height was not significantly different, with respect to the predicted adult height at first visit and to midparental height (Table 1), but it was significantly reduced in comparison with that of controls (P < 0.001) and with male adult normative values (P < 0.001 vs. 0).

BMD data

Individual data of aBMD and vBMD in patients and in controls are shown in Figs. 1 and 2, respectively.

View larger version (11K): [in this window] [in a new window]   Figure 1. Individual aBMD values in controls (•) and in young adult men with histories of CDP (). Group a, Untreated; group b, testosterone treated; group c, oxandrolone treated.

View larger version (10K): [in this window] [in a new window]   Figure 2. Individual vBMD values in controls (•) and in young adult men with histories of CDP (). Group a, Untreated; group b, testosterone treated; group c, oxandrolone treated.

The mean vBMD values were not significantly different among the three groups of patients (group a: 0.326 ± 0.016 g/cm³; group b: 0.332 ± 0.022 g/cm³; group c: 0.330 ± 0.021 g/cm³). In all groups, vBMD values were slightly below the normative mean, but they were not significantly reduced for age and sex (group a: -0.38 ± 0.76 SDS, P = NS from 0; group b: -0.34 ± 0.74 SDS, P = NS from 0; group c: -0.40 ± 0.77 SDS, P = NS from 0). Among the three groups, the vBMD SDS values were not different.

Combining data of all patients, vBMD was slightly (but not significantly) reduced, in comparison with that of the controls (patients, 0.327 ± 0.021 g/cm³; controls, 0.337 ± 0.017 g/cm³; P = NS). vBMD in controls was slightly below the normative values (-0.18 ± 0.57 SDS, P = NS from 0). vBMD was below -1 SD of the control mean in 8 of 21 patients (38.1%: 3 in group a; 2 in group b; 3 in group c) (Fig. 2); vBMD was below -2 SD in 1 patient (4.8%: group c) (Fig. 2).

Mineral and bone metabolism

No significant differences in mineral metabolism and bone markers were found among the groups of patients (Table 2). Also, no significant differences in mineral metabolism and bone markers were found, comparing data of patients with those of controls (Table 2).

Neither patients with CDP nor controls experienced traumatic or nontraumatic fractures.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We demonstrated normal vBMD and biochemical bone markers in young adults with histories of CDP, whereas aBMD was reduced. We also found that androgen treatment in pubertal years did not increase either aBMD or vBMD in these patients. In addition, we confirmed that such treatments had no inference on final height (3, 4, 22, 23).

Finkelstein et al. (5, 6) first measured aBMD in men with a history of CDP showing significantly reduced values. From such data, they and other authors concluded that delayed timing of puberty may affect the achievement of peak bone mass (5, 6, 24), leading to claim early treatment in the attempt to ensure more optimal BMD in adulthood (2, 5, 9, 24). However, the reduced aBMD in men with CDP (5, 6) may be solely the consequence of uncritical use of DEXA.

In fact, aBMD is an areal density measurement, which is highly influenced by somatic growth and bone size of examined sites (7, 8, 25, 26). In men with CDP, final height was reduced, in comparison with that of the general population (3, 9, 27), as we confirmed in the present series of patients. Albanese and Stanhope (9) demonstrated that impaired vertebral growth was a main cause of the altered final height. Our study showed that the reduced aBMD in men with a history of CDP disappeared by calculating vBMD, confirming smaller vertebral size in these men. Moore et al. (28) recently found similar results also for femoral neck. Thus, our and other (28) data, indicating normal vBMD in young adults with a history of CDP, support the concept that aBMD is not appropriate for assessment of bone density in subjects with growth disorders (25), because it may induce clinically relevant errors (25, 26).

vBMD is an estimated bone density that likely overtakes previous measurement techniques in patients with altered growth pattern. True bone density, which is a function of bone mineral content per volume of bone (7, 8), is independent from growth variables and can really be assessed only by quantitative computed tomography (7, 8, 10). Because this technique requires high radiation exposure, it is impractical in a clinical setting. Thus, mathematical models have been validated to calculate apparent vBMD from data obtained by DEXA measurements (29). Although calculated vBMD is a mathematical extrapolation not directly comparable with values measured by computed tomography, our data suggest that it is able to correct for the confounding inferences related to bone size and growth variables (25).

We found that the patients who received androgen administration during adolescence did not have higher aBMD and vBMD in young adulthood, in comparison with the untreated subjects, confirming the early report of Moore et al. (28). Thus, the increase in radial BMD we found in CDP adolescents after short-term androgen administration (11) seems to be irrelevant for adult bone health.

We did not find any difference in calcium metabolism and/or serum levels of biochemical bone markers between our men with CDP and controls. In addition, we did not find any history of fractures. These data suggest normal bone turnover in the patients at their final height and a fracture risk comparable with that of the general population. Although we examined a small group of patients, to our knowledge, increased fracture rates in boys with CDP or in adults who experienced delayed puberty has not been found. Altogether, these data indicate that, in CDP, important alterations in bone mineralization during adolescence, leading to higher fracture risk, likely do not occur; but further studies in larger number of patients are advisable.

In conclusion, our results indicate that young men with a history of CDP have normal vBMD; the reduced aBMD is likely the consequence of the inference of bone size in the measurement of bone density. Our data also indicate that men with a history of CDP are not at increased risk for osteoporotic fractures and that the decision whether to treat, with androgens, boys who have delayed puberty should not be made with the objective to improve either final height or BMD. Longitudinal studies should be done to clarify the behavior of BMD in CDP, from prepuberty to adulthood.

Received March 20, 1998.

Revised August 27, 1998.

Accepted September 14, 1998.

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