Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0086
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 2828-2830
Copyright © 2005 by The Endocrine Society
Bone Mineral Density and Markers of Bone Turnover in Boys with Constitutional Delay of Growth and Puberty
Beata Krupa and
Tomasz Miazgowski
Departments of Propaedeutics in Pediatrics (B.K.) and Endocrinology (T.M.), Hypertension and Metabolic Diseases, Pomeranian Medical University, 71-455 Szczecin, Poland
Address all correspondence and requests for reprints to: Tomasz Miazgowski, Department of Endocrinology, Pomeranian Medical University, ul. Arko
ska 4, 71-455 Szczecin, Poland. E-mail: miazgowski{at}interia.pl.
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Abstract
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It has been suggested that poor growth in childhood or puberty might be a correctable determinant of osteoporosis. To assess the effect of the growth and puberty delay on bone metabolism, we measured bone mineral density (BMD) and markers of bone turnover in 41 boys with constitutional delay of growth and puberty. Total body (TB) and lumbar spine (LS) BMD were measured by dual-energy x-ray absorptiometry. Serum osteocalcin, total alkaline phosphatase, and urinary deoxypyridinoline cross-links as markers of bone turnover were evaluated. BMD was decreased by at least 1 SD in TB in 23 boys (56%) and in LS in 27 boys (66%). After adjustment of BMD for bone age, TB was decreased in 11 boys (27%) and LS in 13 boys (32%). Bone age and chronological age significantly correlated with areal and volumetric BMD. The significant increments of height, weight, TB, and LS BMD between the consecutive pubertal stages were reported. Mean alkaline phosphatase, osteocalcin, and deoxypyridinoline were within reference ranges and showed no differences between pubertal stages. In conclusion, in boys with constitutional delay of growth and puberty, bone turnover is normal, and BMD increases in a manner similar to healthy children.
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Introduction
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DATA IN THE literature suggest that one third of children with short stature are children with constitutional delay of growth and puberty (CDGP) (1, 2). Children with CDGP have normal weight and height at the time of birth, and growth velocity is normal during the first months of life (2). Starting from the sixth month of life, a decrease of the growth velocity can be observed, and this results in a shift of the growth curve below the third centile in the second or third yr of life. After this, the growth curve may run below or parallel to the third centile. Bone age is delayed and matched to the height age. Similarly, puberty is correlated with bone age but not with chronological age. The incidence of CDGP is higher in boys in comparison with girls (2). Diagnostic criteria for CDGP have been discussed elsewhere (1, 3).
Bone mineral density (BMD) is determined by many demographic and lifestyle factors, such as sex, age, height, weight, dietary calcium intake, and physical activity (4). Bone mass increases with age, and its peak value is achieved after puberty (5, 6). It has been suggested that an appropriate timing of puberty is necessary for normal peak BMD acquisition, which may not be achievable in children with CDGP (6, 7, 8). To assess the effects of growth and of pubertal delay on bone metabolism, we measured BMD and biochemical markers of bone turnover in boys with CDGP.
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Subjects and Methods
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Study subjects
The study was performed on 41 boys aged 8–18 yr. CDGP was diagnosed on the basis of typical course of the growth curves (growth velocity below the third centile and a current height significantly lower than midparental height centile), retarded bone age (at least 2 yr), and positive familial history. Boys with concomitant diseases affecting the process of growth and physical development or defined hormonal and nonhormonal causes of height deficiency were excluded from the study. On the basis of the Tanner and Whitehouse criteria (9), boys were qualified into four groups corresponding with pubertal stages (Table 1
). Bone age was assessed by the x-ray of the left hand and wrist (10). In all cases, parental written informed consent was obtained for participation in the study.
Measurements
Height and weight were measured without shoes, height was measured with a single fixed stadiometer, and weight was measured on a standard clinical balance. Body mass index was calculated as weight (kilograms) divided by height (meters) squared.
BMD of the total body (TB) and L2–L4 lumbar spine (LS) were measured by dual-energy x-ray absorptiometry (Lunar, Madison, WI), using the pediatric medium scan mode. BMD values were expressed in grams per centimeter squared and as z-score (number of SDs from mean BMD for normal children, matched for sex and chronological age). Apparent BMD (vBMD; grams per centimeter cubed) of the LS was calculated using the formula: vBMD = BMD (4/[
x width]) (11).
Serum osteocalcin (OC), serum total alkaline phosphatase (ALP) activity, and urinary deoxypyridinoline (DPD) cross-links as markers of bone turnover were evaluated. OC was assessed by RIA (Osteocalcin I125; Incstar Corp., Stillwater, MN) and in all the boys was measured in one batch in serum that had been thawed for the first time (normal range, 0–18 ng/ml prepubertal; 25–39 ng/ml pubertal) (12). ALP was assessed by Cormey’s method, and the values were referred to the normal reference range for Polish children (age 0–10 yr, 100–450 U/liter; age 10–14 yr, 90–350 U/liter; age 14–18 yr, 80–250 U/liter) (13). DPD was evaluated in 24-h urine sample by ELISA (Pyrilinks-D; Metra Biosystems, Mountain View, CA), and the values were expressed relative to urinary creatinine (normal range: age 4–10 yr, 43.5 ± 13.8 nmol/mmol creatinine; age 10–12 yr, 50.4 ± 23.2 nmol/mmol creatinine; age 12–14 yr, 50.0 ± 17.4 nmol/mmol creatinine; age 14–16 yr, 29.3 ± 23.5 nmol/mmol creatinine; age 16–18 yr, 16.5 ± 13.6 nmol/mmol creatinine) (14).
Statistical analysis
The results were expressed as the mean ± SD, assuming P < 0.05 as a significant difference between means. The differences were tested by Wilcoxon test or Mann-Whitney nonparametric U test as appropriate. The 
2 statistics were used to test for associations between categorical variables. Linear correlation and regression or nonparametric Kendall regression analysis were used to test for relationships between studied parameters.
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Results
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The history revealed that all fathers of studied boys had a delay of growth and puberty in the history. Clinical characteristics, BMD, and markers of bone turnover in boys with CDGP are summarized in Table 2. Significant differences in the chronological and bone age between stages I–IV were reported. Height and weight progressively increased from stages I–IV, and body mass index remained unchanged. TB BMD was decreased by at least 2 SD in four boys (10%) and by 1 to 2 SD in 19 boys (46%); LS BMD was decreased in six (15%) and 21 (51%) boys, respectively. Mean z-score for TB was –1.02 ± 1.4 SD, for LS –1.18 ± 1.9 SD, and for vBMD –1.09 and did not differ significantly between the consecutive stages of puberty. When BMD was adjusted for bone age, TB was decreased by more than 2 SD in two boys (5%) and by 1–2 SD in nine boys (22%); LS was decreased by at least 2 SD in three cases (7%) and by 1–2 SD in 10 cases (24%). Mean z-score was –0.76 ± 0.9 SD (TB), –0.81 ± 1.1 SD (LS), and –0.62 ± 0.72 SD (vBMD), respectively. BMD significantly correlated both with bone and chronological age: chronological age with TB (r = 0.70; P < 0.0001), LS (r = 0.72; P < 0.0001), and vBMD (r = 0.65; P < 0.0001) and bone age with TB (r = 0.68; P < 0.0001), LS (r = 0.67; P < 0.0001), and vBMD (r = 0.62; P < 0.0001), respectively. The ANOVA showed significant increments of height (P < 0.0001), weight (P < 0.007), TB (P < 0.0001), LS (P < 0.0001), and vBMD (P < 0.0001) between the consecutive stages of puberty.
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TABLE 2. Clinical characteristics, BMD values, and markers of bone turnover in boys with CDPG in relation to pubertal stages
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In 31 boys, mean values of ALP were within the normal reference range. In 10 boys (24%), ALP was slightly, but not significantly, increased above the upper normal limit. There was a positive correlation between ALP and height (r = 0.34; P < 0.05). Mean serum OC was normal in 33 boys and decreased in another eight boys, and a weak, positive correlation between OC and chronological age was found (r = 0.38; P < 0.02). There was no relationship between stages of puberty and serum ALP and OC. Urinary DPD was normal in all boys regardless of the pubertal stage.
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Discussion
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It has been suggested that the appropriate timing of puberty is an important factor for normal peak bone mass acquisition (8, 11). Several studies demonstrated that 95–99% of peak bone mass is achieved by age 18 yr (15–16 yr in girls and 16–18 in boys), which suggests that bone mass in late puberty may be a prognostic factor for development of osteoporosis in the future (6, 15). In boys with CDGP, we found the significant increments of TB, LS, and vBMD in the consecutive stages of puberty. There have been no previous reports on BMD values in the relation to particular pubertal stages in boys with CDGP. Some earlier studies suggest the decreased bone mass in prepubertal children with CDGP (7, 15, 16, 17). Other studies in healthy boys indicate the highest rate of bone mineral content cumulation at the late puberty (18). Bonjour et al. (4) found spine BMD values less than 0.8 g/cm2 from stages I–III with the subsequent accelerated BMD increase from stages III–IV beyond the value 0.9 g/cm2 and a lower increment between stages IV and V in the group of normal boys. The authors conclude that, for peak bone mass in LS, the period between 17 and 20 yr seems the most important. Our results indicate that, in boys with CDGP, like in normal boys, BMD adjusted for bone age increases parallel to the stages of puberty, and the most significant BMD increments are between stages III and IV, which may suggest that pharmacological intervention for the increase of bone mass before the puberty has been completed is not warranted, but nonpharmacological treatment, including an increase of dietary calcium intake and physical activity, seems to be a strongly recommended way to increase the bone mass. These findings correspond with some earlier studies on normal BMD and bone turnover in adult young men with histories of CDGP (11).
Markers of bone turnover are considered as a useful tool in evaluation of bone formation and resorption. We measured total serum ALP activity and serum OC as markers of bone formation. In boys with CDGP, mean ALP was only slightly changed between stages I and II but, between stages II and III, ALP was increased by approximately 50 U/liter, reaching the highest mean increments, although changes were not statistically significant. From stages III–IV, a further but considerably slower increase of ALP was observed. Some studies in children with a normal growth suggest that ALP increases in the first two stages of puberty with a peak value in stage III and the subsequent slight decrease (19). In children with normal puberty, a positive correlation among ALP, OC, and BMD was reported (18). We did not find such a relationship in boys with CDGP. OC seems to be more specific marker of bone formation than total but not bone-specific ALP (19). In boys with CDGP, serum OC not significantly increased from stages I–IV of puberty. Similar findings but in children with a normal growth have been reported (20). There have been no previous reports on DPD in CDGP. Our results indicate that DPD was a stable parameter during puberty and also showed marked deviations from the mean.
In conclusion, in boys with CDGP, bone turnover is normal, and BMD adjusted for bone age increases throughout pubertal stages in a similar manner as healthy children.
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Footnotes
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First Published Online February 1, 2005
Abbreviations: ALP, Alkaline phosphatase; BMD, bone mineral density; CDGP, constitutional delay of growth and puberty; DPD, deoxypyridinoline; LS, lumbar spine; OC, osteocalcin; TB, total body; vBMD, apparent BMD.
Received January 14, 2005.
Accepted January 24, 2005.
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Abstract
Introduction
