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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 8 3624-3631
Copyright © 2002 by The Endocrine Society

Original Article

Lumbar Bone Mineral Density at Final Height and Prevalence of Fractures in Treated Children with GH Deficiency

Giampiero Igli Baroncelli, Silvano Bertelloni, Federica Sodini and Giuseppe Saggese

Endocrine Unit, Division of Pediatrics, Department of Reproductive Medicine and Pediatrics, University of Pisa, I-56125 Pisa, Italy

Address all correspondence and requests for reprints to: Giampiero I. Baroncelli, Endocrine Unit, Division of Pediatrics, Department of Reproductive Medicine and Pediatrics, University of Pisa, I-56125 Pisa, Italy. E-mail: . g.baroncelli{at}clp.med.unipi.it

Abstract

Lumbar bone mineral density (BMD) by dual energy x-ray absorptiometry was assessed in 46 (29 boys, 17 girls) treated patients with growth hormone deficiency (GHD) at final height, comparing the BMD results with normative data. Prevalence of fractures in patients during treatment and healthy controls (n = 100) during the corresponding time period was assessed. Lumbar BMD values at final height of fractured and fracture-free patients were compared between them.

Lumbar BMD corrected for bone area was significantly (P < 0.01) reduced (boys, -0.4 ± 0.8 Z score; girls, -0.5 ± 0.7 Z score), but lumbar BMD corrected for bone size (BMDvolume) did not differ [P = not significant (NS); boys -0.2 ± 1.0 Z score; girls, -0.3 ± 1.0 Z score] from normal mean. Approximately 22% of patients had reduced lumbar BMD (Z score, -1 to -2). The fact that patients had a complete or partial GHD did not influence lumbar BMD.

The prevalence of fractured patients did not differ (P = NS) from that of controls [n = 7 (15.2%) and n = 24 (24.0%), respectively; odds ratio, 1.837]. Lumbar BMDvolume of fractured patients was significantly (P < 0.02) lower than that of fracture-free (n = 39) patients (boys, 0.310 ± 0.005 and 0.351 ± 0.032 g/cm3, respectively; girls, 0.326 ± 0.027 and 0.382 ± 0.036 g/cm3, respectively). The percentage of the fractured patients with lumbar BMDvolume less than 1 SD of normal mean was significantly (P < 0.0001) higher than that of fracture-free patients [n = 6 (85.7%) and n = 4 (10.3%), respectively; odds ratio, 26.092). The fractured patients also showed reduced lumbar BMD corrected for bone area and BMDvolume at the time of fractures (-1.6 ± 0.4 and -1.5 ± 0.2 Z score, respectively).

The results show that treated patients with GHD have normal mean values of lumbar BMDvolume at final height, but some patients have reduced lumbar BMD (Z score <1) with an increased susceptibility to fractures.

GROWTH HORMONE DEFICIENCY (GHD) is associated not only with a decreased growth rate but also with a reduced bone mineral density (BMD) at both peripheral (1, 2, 3) and axial (4, 5) sites. Lumbar BMD assessment by dual energy x-ray absorptiometry (DXA) is affected by the anthropometric findings and bone size in normally growing children (6, 7, 8) as well as in children with GHD (4, 5). In children with GHD, we demonstrated that lumbar BMD value corrected for bone size (BMDvolume) was a more appropriate parameter to estimate bone density than BMD corrected for bone area (BMDarea), bone age, body height, and body mass index (BMI; Ref. 5).

A reduced BMD has been shown in adult patients with childhood or adult onset GHD (9). Moreover, it has been demonstrated that adults with GHD are at increased risk of fractures compared with the general population (10, 11). To our knowledge, there are not data on fracture prevalence in children with GHD.

In treated children with GHD, BMD improved at both peripheral (2, 3, 12, 13) and axial sites (4, 12). Radial and lumbar BMD was within 0.5 SD of age-matched mean levels in children with GHD who had received GH treatment for 56–81 months (12). On the other hand, reduced lumbar BMDarea and BMDvolume were found in patients with GHD at final height who had received a suboptimal GH treatment during childhood (12, 14, 15).

These results support a key role for GH in the acquisition of bone mass during childhood and adolescence and in the maintenance of bone mass in adulthood. In addition, they suggest that GH therapy must be administered in adequate doses and for an adequate length of time to lead BMD within the normal range.

In this study, we assessed lumbar BMDarea and lumbar BMDvolume by DXA measurement in patients with GHD at final height who had received GH treatment from the diagnosis, comparing the BMD values with normative data. In addition, we assessed the prevalence of fractures in patients with GHD during all the time period of treatment, comparing the results with a population of healthy controls. Furthermore, we compared lumbar BMD values at final height of fractured patients with those of fracture-free patients.

Patients and Methods

Patients

A total of 46 Caucasian patients (29 boys, 17 girls) aged 14.8–19.9 yr with isolated GHD were recruited from our Endocrine Unit at the Department of Pediatrics of our university. At the start of GH treatment, all patients were prepubertal [chronological and bone ages: boys, 8.6 ± 1.6 yr (range, 5.9–11.1 yr) and 5.7 ± 1.0 yr (range, 3.5–8.0 yr), respectively; girls, 8.2 ± 1.4 yr (range, 5.0–10.1 yr) and 5.3 ± 0.9 yr (range, 2.5–7.8 yr), respectively) and fulfilled the clinical and diagnostic criteria for GHD (16). All patients showed GH peaks less than 10 µg/liter after two provocative pharmacological stimuli (levodopa and insulin tolerance test); 37 patients (24 boys, 13 girls) had GH peaks less than 5 µg/liter (2.8 ± 0.9 µg/liter) in both tests, whereas 9 patients (5 boys, 4 girls) had GH peaks less than 5 µg/liter (3.1 ± 0.6 µg/liter) after one test and between 5 and 10 µg/liter (6.2 ± 1.0 µg/liter) after the other test. All patients had reduced spontaneous GH secretion for 24 h (mean GH concentrations < 3 µg/liter; Ref. 16). They did not show any associated deficiency of other pituitary hormones both at diagnosis and during treatment. All patients had received recombinant human GH treatment in a dosage of 0.6 IU/kg·wk (30 µg/kg·d) during prepuberty and 0.9 IU/kg·wk (45 µg/kg·d) during puberty, sc at bedtime six times a week until final height. GH dose was adjusted every 6 months. The duration of GH treatment ranged from 6.0–13.2 yr with a mean of 8.6 ± 1.6 yr. No side effects of the treatment were observed. Compliance with the treatment was good in all patients. All patients had normal weight and length at birth, had normal renal and liver function, and did not take drugs known to affect bone or mineral metabolism. There was no history of any other chronic illness or bone disease. Karyotype, examined in all girls, was 46,XX. At the time of the study, all patients had attained their final height. All patients had spontaneous pubertal development during treatment, and pubertal stage was Ph5G5 and Ph5B5 in all boys and girls, respectively. In girls, mean years postmenarche was 1.2 ± 0.3 (range, 0.8–1.8 yr). Clinical data of patients at final height are reported in Table 1Go. The secretory response of GH to insulin tolerance test was reevaluated at final height, within 2 months after GH treatment was stopped; 26 patients (16 boys, 10 girls) had complete GHD (GH peak <5 µg/liter, 2.5 ± 0.8 µg/liter), and 20 patients (13 boys, 7 girls) had partial GHD (GH peak 5–10 µg/liter, 5.9 ± 0.6 µg/liter; Ref. 17). Fifteen patients (9 boys, 6 girls) had taken part in a previous study evaluating the dynamics of bone turnover until final height (18), and nine patients (6 boys, 3 girls) had taken part in a study longitudinally assessing BMD during long-term GH treatment (12).


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  		Table 1. Clinical data at final height in patients with GHD and controls

 
Controls

A total of 100 Caucasian adolescents (50 boys, 50 girls) were randomly enrolled in secondary schools and in the medical school of our university as age-matched controls to estimate the prevalence of fractures in a population sample (Table 1Go). All controls were healthy, with no known medical illness, and did not receive drugs known to affect bone or mineral metabolism. Pubertal stage was Ph5G5 and Ph5B5 in all boys and girls, respectively.

Physical activity of the controls did not differ [P = not significant (NS)] from that of patients (no activity, 72.4 ± 3.2% and 70.2 ± 3.1%, respectively; moderate activity, 27.6 ± 3.0% and 29.8 ± 3.2%, respectively).

Study design

In all patients, lumbar BMDarea and lumbar BMDvolume, as well as serum IGF-I concentrations, were assessed at final height. Lumbar BMDarea and lumbar BMDvolume values of patients were compared with appropriate sex- and age-reference values by using those reported by Boot et al. (19), which were obtained by the same DXA machinery we used.

In all patients and controls, prevalence, severity of injury causing fractures, chronological age at the time of fractures, and sites of fractures were recorded. The history of fractures was recorded from diagnosis up to final height in patients with GHD and during the corresponding time period in controls who recorded all of their fractures from the same mean age of patients at diagnosis. Data of patients were compared with those of controls.

Furthermore, lumbar BMDarea and lumbar BMDvolume values and serum IGF-I concentrations at final height were compared between patients who had a history of fractures (fractured) or who had never fractured (fracture-free). In fractured patients, lumbar BMD was also assessed at the time of their fractures.

Informed consent to perform the study was obtained from the parents of each patient or control when the chronological age of their child was lower than 18 and directly from each patient or control whose chronological age was higher than 18. The study was approved by the ethics committee for human investigation of our department. The headmaster and the school teacher committees of the enrolled schools approved the study for controls.

Assessment of anthropometric findings in patients with GHD and controls

Standing height and weight were measured with a wall-mounted stadiometer and standard clinical balance by one of us, respectively. To allow a comparison between different ages and genders, height was expressed as Z score with respect to height SD, according to the method of Tanner et al. (20) by using the formula: measured individual value - mean normal value for age and gender/SD of normal mean. BMI was calculated using the formula: weight (kg)/height (m2). BMI values were also expressed as Z scores by using the same formula we employed to calculate height Z score according to the reference values of Karlberg et al. (21). In patients, bone age was evaluated by using the method of Greulich and Pyle (22). Pubertal stage was assessed according to Tanner and Whitehouse (23), and the onset of puberty was assumed when breast stage B2 was reached in girls or testicular volume reached 4 ml in boys. Height was considered as final adult stature when height velocity during the last year was less than 2 cm and wrist epiphyses had fused (24).

Assessment of physical activity in patients with GHD and controls

Physical activity rate was estimated by a questionnaire as previously reported (25). Physical activities were arbitrarily graded as no activity (e.g. sleeping, eating, studying, watching television, or listening to music) or moderate activity (e.g. walking, cycling, playing).

Assessment of serum IGF-I concentrations in patients with GHD

Serum IGF-I concentrations were measured by a solid phase sandwich immunoradiometric assay (IGF-I-RIACT, CIS-Bio International, Gif-Yvette Cedex, France). Inter- and intra-assay variations were less than 9% and 6%, respectively. All blood samples were measured in duplicate.

Assessment of lumbar areal and volumetric BMD in patients with GHD

Lumbar BMDarea (bone mineral content corrected by the vertebral surface area scanned, expressed as grams per square centimeter) was measured by postero-anterior DXA (Lunar DPX-L, Lunar Radiation Corp., Madison, WI) in the lumbar spine at L2–L4 level, a site that provides a measure of integral (cortical plus trabecular) bone. Lumbar BMDvolume (expressed as grams per cubic centimeter) was calculated as bone mineral content per bone volume. The estimation of L2–L4 bone volume was based on the method proposed by Kroger et al. (26); in this model the lumbar vertebral body was assumed to have a cylindrical shape. The validity of this model was assessed using in vivo volumetric data obtained from magnetic resonance imaging of lumbar vertebrae (27). The bone volume of each vertebral body was calculated as follows: volume = {pi} x (diameter/2)2 x height, where diameter = width of vertebral body, and height = height of vertebral body. Although the volume correction is not anatomic, lumbar BMDvolume values provide a better approximation of the true bone density than lumbar BMDarea (8). Width, height, and bone area were provided by the DXA software program. The reference values for lumbar BMDvolume to compare the results of our patients were obtained by using the same formula and the same procedure of calculation we employed (19). The results were calculated as grams per square centimeter for lumbar BMDarea, grams per cubic centimeter for lumbar BMDvolume, and Z score by using the same formula we employed to calculate height Z score. The coefficient of precision in vivo was less than 1.0%.

Assessment of fracture findings in patients with GHD and controls

In all patients and controls, prevalence, severity of injury, chronological age at the time of fractures, and sites of fractures were recorded by a questionnaire. The sites of fractures were confirmed by examining the plain radiographs and/or the x-ray medical report. The severity of injury causing fractures was classified as slight, moderate, or severe according to Landin (28). Slight trauma consisted of an injury caused by forces exerted by the injured individual (e.g. falling to the ground from standing on the same level, ball playing, running); moderate trauma consisted of an injury caused by forces connected to height above ground level (e.g. falling from between 0.5 and 3 m) or velocities (e.g. falling downstairs, from a bicycle or scooter, from swings or slides); severe trauma included falling from a height exceeding 3 m, all traffic accidents, or being hit by a moving, heavy object. In both patients and controls, fractures caused by a severe trauma were not included in the study. Two fractures of the same bone caused by the same injury were recorded as one fracture. Multiple fracture of the small bones of the hand or foot were recorded as one fracture regardless of the number of fractured bones. In both patients and controls, the time period of fracture was arbitrarily subdivided in three age groups: 8–11 yr, 12–14 yr, and more than 15 yr.

Statistical analysis

The results are expressed as mean ± SD. Comparison of lumbar BMD data between patients and reference values was assessed by the nonparametric Wilcoxon’s (Mann-Whitney) rank-sum test. Simple regression analysis was performed between lumbar BMDarea or lumbar BMDvolume and chronological age, height, weight, BMI, GH peak, serum IGF-I concentrations at final height, or duration of therapy, as well as between lumbar BMDarea or lumbar BMDvolume and years postmenarche in girls. Multiple regression analysis was performed between lumbar BMDarea or lumbar BMDvolume as dependent variables and chronological age, height, weight, BMI at final height, or duration of treatment as independent variables. The Mantel-Haenszel method was used for the calculation of the odds ratio, with 95% confidence intervals (CI), risk for fractures. A P value less than 0.05 was considered significant for all statistical analyses. All statistical analyses were performed using the SPSS (Statistical Package of Social Sciences, SPSS, Inc., Chicago, IL) for Windows software program, version 9.1.

Results

Lumbar BMD values at final height in patients with GHD

Mean and individual values of lumbar BMDarea (grams per square centimeter) and lumbar BMDvolume (grams per cubic centimeter) of patients compared with normative data are reported in Figs. 1Go and 2Go, respectively. In both sexes, mean values of lumbar BMDarea and lumbar BMDvolume did not differ (P = NS) from normal mean. Expressed as Z score, mean lumbar BMDarea was significantly reduced (boys, -0.4 ± 0.8, P < 0.01; girls, -0.5 ± 0.7, P < 0.01), but mean lumbar BMDvolume did not differ (boys, -0.2 ± 1.0, P = NS; girls, -0.3 ± 1.0, P = NS) from normal mean. A value of lumbar BMDarea and lumbar BMDvolume between -1 and -2 SD of the normal mean was found in 11 patients (23.9%) and 9 patients (19.6%), respectively.



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  		Figure 1. Mean and individual values of lumbar BMDarea (grams per square centimeter) in patients with GHD at final height (A, boys; B, girls) compared with normative data (19 ). The solid lines are mean and 1 SD and -1 SD, and the broken lines are 2 SD and -2 SD of normative data. *, P = NS in comparison with the mean of normative data.

 


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  		Figure 2. Mean and individual values of lumbar BMDvolume (grams per cubic centimeter) in patients with GHD at final height (A, boys; B, girls) compared with normative data (19 ). The solid lines are mean and 1 SD and -1 SD, and the broken lines are 2 SD and -2 SD of the normative data. *, P = NS in comparison with the mean of normative data.

 
In both sexes, mean values of lumbar BMDarea and lumbar BMDvolume did not differ (P = NS) between patients with complete and partial GHD (boys, lumbar BMDarea, 1.157 ± 0.115 g/cm2 and 1.163 ± 0.103 g/cm2; lumbar BMDvolume, 0.346 ± 0.037 g/cm3 and 0.344 ± 0.029 g/cm3, respectively; girls, lumbar BMDarea, 1.146 ± 0.099 g/cm2 and 1.136 ± 0.060 g/cm2; lumbar BMDvolume, 0.371 ± 0.033 g/cm3 and 0.374 ± 0.049 g/cm3, respectively). In both sexes, mean chronological age, final height, weight, BMI, serum IGF-I concentrations, or duration of treatment did not differ (P = NS) between patients with complete and partial GHD (data not shown).

Prevalence, severity of injury, sites of fractures, and age-group in patients with GHD and controls

Prevalence of fractures and severity of injury in patients and controls are reported in Table 2Go. The total number of fractures was significantly lower (P < 0.05) in all patients as a whole and in male patients, but not in female patients, than in controls. A history of fractures was found in 7 patients (4 boys, 3 girls) from diagnosis up to final height and 24 controls (15 boys, 9 girls) during the corresponding time period. Although the prevalence of fractured patients was lower than that of controls, the difference did not reach significance (P = NS). The majority of patients and controls suffered from one fracture during the recorded time period. Among the patients, only one boy had a history of two fractures, whereas no patient had more than two fractures during treatment. Among the controls, four boys and three girls had a history of two fractures, and only one boy and two girls had more than two fractures during the recorded time period. There was not any difference (P = NS) in the severity of injury causing fractures between patients and controls. In both patients and controls, the majority of fractures occurred as a consequence of a slight trauma.


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  		Table 2. Prevalence of fractures and severity of injury in patients with GHD and controls

 
The upper limb was the unique site of fractures in patients (radius shaft, n = 1; wrist, n = 4; hand bones, n = 3) and the most frequent site of fractures in controls (humerus shaft, n = 3; radius shaft, n = 5; wrist, n = 7; hand bones, n = 10). In controls, other sites of fractures were tibia shaft (n = 1), ankle (n = 6), foot bones (n = 3), clavicle (n = 1), and pelvis (n = 2). The prevalence in the sites of fractures did not differ (P = NS) between patients and controls. No patient or control had vertebral or femoral fractures, as well as stress fractures.

Among the age groups, the distribution of fractures in patients and controls was: 8–11 yr, n = 1 and n = 9; 12–14 yr, n = 3 and n = 15; more than 15 yr, n = 4 and n = 14, respectively.

Lumbar BMD values and serum IGF-I concentrations at final height in fractured and fracture-free patients with GHD

Mean and individual values of lumbar BMDarea and lumbar BMDvolume at final height in fractured and fracture-free patients compared with reference values are reported in Figs. 3Go and 4Go, respectively. Although mean values of lumbar BMDarea (grams per square centimeter) of fractured patients was lower than that of fracture-free patients, it reached significance only in girls (P < 0.03; Fig. 3Go); lumbar BMDarea was reduced by approximately 13% and 3.5% in fractured and fracture-free patients, respectively. Expressed as Z score, mean values of lumbar BMDarea were significantly reduced in fractured patients (boys, -1.1 ± 0.4, P < 0.01; girls, -1.2 ± 0.2, P < 0.01) but not in fracture-free patients (boys, -0.3 ± 0.8, P = NS; girls, -0.3 ± 0.6, P = NS) in comparison with normal mean. Four (57.1%, 2 boys and 2 girls) fractured patients and seven (17.9%, 6 boys and 1 girl) fracture-free patients had a lumbar BMDarea Z score that lay between -1 and -2 of normal mean; no patient had a value of lumbar BMDarea less than 2 SD of normal mean (Fig. 3Go). The percentage of fractured girls having a value of lumbar BMDarea less than 1 SD of normal mean was significantly higher (P < 0.05) than that of fracture-free girls (odds ratio, 26.000; 95% CI, 1.118–604.491), whereas it did not differ (P = NS) between fractured and fracture-free boys (odds ratio, 3.167; 95% CI, 0.364–27.575).



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  		Figure 3. Mean and individual values of lumbar BMDarea (grams per square centimeter) in fractured and fracture-free patients with GHD at final height (A, boys; B, girls). The solid lines are mean and 1 SD and -1 SD, and the broken lines are 2 SD and -2 SD of the normative data (19 ). *, P = NS; §, P < 0.03 between fractured and fracture-free patients.

 


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  		Figure 4. Mean and individual values of lumbar BMDvolume (grams per cubic centimeter) in fractured and fracture-free patients with GHD at final height (A, boys; B, girls). The solid lines are mean and 1 SD and -1 SD, and the broken lines are 2 SD and -2 SD of the normative data (19 ). {ddagger}, P < 0.02 between fractured and fracture-free patients.

 
Mean values of lumbar BMDvolume of fractured patients was significantly (P < 0.02) lower than that of fracture-free patients (Fig. 4Go); lumbar BMDvolume was reduced by approximately 14% and 0.5% in fractured and fracture-free patients, respectively. Expressed as Z score, mean values of lumbar BMDvolume were significantly reduced in fractured boys (-1.2 ± 0.1, P < 0.001) but not in fractured girls (-1.5 ± 0.7; P = NS) or in fracture-free patients (boys, 0.1 ± 0.9, P = NS; girls, -0.1 ± 0.9, P = NS) in comparison with normal mean. All fractured boys and one fractured girl showed a lumbar BMDvolume Z score that lay between -1 and -2 of normal mean; and one fractured girl had a value less than 2 SD of normal mean (Fig. 4Go). The percentage of fractured patients having a value of lumbar BMDvolume less than 1 SD of normal mean was significantly higher (P < 0.0001) than that of fracture-free patients (odds ratio, 26.092; 95% CI, 3.321–204.975). Mean chronological age, final height, weight, BMI, GH peak, serum IGF-I concentrations, or duration of treatment, as well as mean years postmenarche in girls, did not differ (P = NS) between fractured and fracture-free patients (data not shown).

Lumbar BMD values in fractured patients with GHD at the time of fractures

In fractured patients, mean values of lumbar BMDarea were -1.6 ± 0.4 Z score (range, -1.1 to -2.3 Z score; n = 7) and mean values of lumbar BMDvolume were -1.5 ± 0.2 Z score (range, -1.2 to -1.8 Z score; n = 6) at the time of their fractures.

Correlation between clinical findings, GH peak, or serum IGF-I concentrations and lumbar BMDarea or lumbar BMDvolume in patients with GHD

There was no correlation, by univariate regression, between chronological age, height, weight, BMI, GH peak, and serum IGF-I concentrations at final height, or duration of therapy and lumbar BMDarea or lumbar BMDvolume in both male (r2 = 0.001–0.122; P = NS) and female (r2 = 0.001–0.109; P = NS) patients. In girls, years postmenarche did not correlate with lumbar BMDarea or lumbar BMDvolume (r2 = 0.121, P = NS; and r2 = 0.003, P = NS, respectively). In both boys and girls, the composite interaction of all independent variables (chronological age, final height, weight, BMI, and duration of therapy) did not predict lumbar BMDarea (r2 = 0.271, P = NS; and r2 = 0.195, P = NS, respectively) or lumbar BMDvolume (r2 = 0.154, P = NS; and r2 = 0.175, P = NS, respectively).

Discussion

Our results show that mean values of lumbar BMDarea (grams per square centimeter) and lumbar BMDvolume (grams per cubic centimeter) in treated patients with GHD at final height did not differ from normative data, confirming previous preliminary studies (29, 30). The majority of our patients showed a value of lumbar BMDarea and lumbar BMDvolume within the range of ±1 SD of age-matched mean levels, but approximately 22% of patients had reduced lumbar BMD (Z score -1 to -2), and one girl had a lumbar BMDvolume less than 2 SD of normal mean.

The values of lumbar BMDarea or lumbar BMDvolume were not correlated with clinical findings, GH secretion, and serum IGF-I concentrations at final height, or duration of treatment. Similar results have been reported in young healthy men (19–30 yr old) in whom lumbar BMDarea did not correlate with anthropometric findings, total nocturnal GH secretion, or serum IGF-I concentrations (31). These data suggest that the interaction between GH secretion and BMD at skeletal sites, such as lumbar spine, having a high proportion of trabecular bone may be not related to the GH peak after a provocative test or the magnitude of endogenous GH secretion, and that the effect of GH on bone mass may not be mediated by systemic IGF-I concentrations. Indeed, we did not find any difference of lumbar BMD values or serum IGF-I concentrations between patients with complete and partial GHD at final height. However, peripheral skeletal sites should also be assessed to clarify the interaction between GH secretion or serum IGF-I concentrations and BMD.

Although the precise age at which peak bone mass is achieved is still uncertain and may be site-dependent, recent studies by DXA indicate that lumbar peak bone mass assessed as BMDarea is likely achieved around 15–16 yr and 17.0–18.5 yr in healthy girls and boys, respectively (7, 26, 32, 33, 34). Similar data are reported for lumbar peak bone mass assessed as BMDvolume (26, 34). Thus, on the basis of chronological age, some of our patients should have already achieved their lumbar peak bone mass. However, it has been shown that in normal individuals lumbar peak bone mass may be achieved 1–2 yr after the attainment of final height (33, 35, 36), and that the occurrence of menarche in girls is not associated with an arrest of bone mass accumulation at lumbar spine, but a slight gain is observed during the first 2 yr after menarche (32, 37, 38). In our female patients, years postmenarche ranged from 0.8–1.8 at time of BMD measurement, but years postmenarche did not correlate with lumbar BMD values at final height. It has been reported that there is not an effect of menarcheal age on BMD (35, 38), and that BMD at menarche is similar between girls with a slow and fast rate of pubertal maturation (38). These findings suggest that the reduced lumbar BMD we found in some patients may be related, at least in part, to the fact that they had not yet attained their lumbar peak bone mass at the time of final height. Moreover, it must be considered that lumbar BMD still may increase in our patients after the discontinuation of treatment for a persisting effect of GH administration. However, we are not able to confirm this hypothesis because we did not longitudinally assess lumbar BMD after the final height.

Two retrospective studies showed that adult patients with hypopituitarism and untreated GHD have a 3-fold increased fracture frequency compared with the general population, suggesting that GHD itself may be considered as a risk factor for osteoporosis (10, 11). Our results showed that the prevalence and the severity of injury in fractured patients were similar to those of controls, but the total number of fractures was lower in patients as a whole and in male patients than in controls. The calculation of the overall annual incidence rate of fractures in controls (15.85 per 1000), age-adjusted for the population of our district, was similar to that reported in other European populations of children and adolescents (15.27–21.20 per 1000; Refs. 28 , 39), whereas it was 3.35 per 1000 in our patients with GHD. These data indicate that our patients had approximately a 4-fold decreased fracture frequency compared with controls. The upper limb was the unique site of fracture in patients, and the most frequent site of fracture in controls according to epidemiological data in healthy children and adolescents (28, 39, 40, 41) and with a recent study in fractured girls (42). Although we had no untreated GHD controls, these data seem to suggest that children with GHD do not have an increased prevalence of fractures from diagnosis up to final height, which may be due to a protective effect of GH treatment. However, the small sample size of patients could affect our results.

At final height, mean values of lumbar BMDarea of fractured patients was lower than that of fracture-free patients only in girls, but mean values of lumbar BMDvolume of fractured patients was lower than that of fracture-free patients in both sexes. These results were not affected by anthropometric findings, GH secretion, serum IGF-I concentrations, or duration of treatment, as well as years postmenarche in girls. The percentage of patients having a value of lumbar BMDvolume less than 1 SD of normal mean was higher in fractured patients than in fracture-free patients. In addition, the fractured patients showed a value of lumbar BMDarea and lumbar BMDvolume less than 1 SD of normal mean at the time of their fractures. These data indicate that a reduced lumbar BMD should be more common in patients with a history of fractures during treatment. In fractured patients, mean lumbar BMDarea and lumbar BMDvolume were reduced by approximately 13% and 14%, respectively. This percentage was higher than that reported by Landin et al. (43) at forearm (8%) and by Goulding et al. (44) at lumbar spine (9%) in children who had recently sustained fractures.

Prospective studies in postmenopausal women showed that a 1 SD reduction in BMD from the age-specific mean population confers a 2- to 3-fold increase in fracture risk (45, 46), suggesting that osteopenia (T-score of BMD that lies between -1 and -2.5; Ref. 46) may be a condition with increased risk of fractures. Goulding et al. (42) in young girls found that a reduction of 1 SD of lumbar BMDvolume, but not of lumbar BMDarea, increased the risk (by 1.3-fold) of fracture at any site during 4 yr of follow-up. These data suggest that patients with GHD may have an increased susceptibility to fractures when their lumbar BMDvolume is less than 1 SD of normal mean. The cause(s) of reduced lumbar BMD at final height in our patients was not clearly defined. In this regard, because the distribution of BMD is normal, approximately 15% of the population has a value of lumbar BMDarea between -1 and -2 SD of normal mean (45). Therefore, the reduced lumbar BMD values we found in approximately 22% of patients at final height could reflect, at least in part, a normal distribution of BMD. On the other hand, although all patients had received the same GH dose, based on body weight and pubertal status, and the compliance with the treatment was good, it might not be the optimal treatment for bone mineral accrual for all patients.

In conclusion, treated patients with GHD have normal mean values of lumbar BMDarea and BMDvolume at final height. However, the patients with a history of fractures have mean values of lumbar BMDvolume lower than that of patients who had never fractured, and the percentage of patients having a value of lumbar BMDvolume less than 1 SD of normal mean was higher in fractured than in fracture-free patients. All of the fractured patients also had reduced lumbar BMD values at the time of their fractures. These findings suggest that some treated children with GHD may have an increased susceptibility to fractures when their lumbar BMD is less than 1 SD of normal mean. Therefore, longitudinal BMD measurement until time of achievement of peak bone mass and continued fracture surveillance in GHD patients with reduced BMD at time of final height and/or fracture history should be recommended.

Further studies are needed to clarify which factors may influence the accrual of BMD at both peripheral and axial skeletal sites in children with GHD during treatment, whether GH dose should be adjusted on the basis of BMD accretion and the impact of reduced lumbar BMD at final height during early adulthood.

Note Added in Proof

Since this paper was accepted for publication, a study in treated adolescents with GHD [Fors H, Bjarnason R, Wirén L, Albertsson-Wikland K, Bosaeus I, Bengtsson BA, Johannsson G 2001 Currently used growth-promoting treatment of children results in normal bone mass and density. A prospective trial of discontinuing growth hormone treatment in adolescents. Clin Endocrinol (Oxf) 55:617–624] showed that their lumbar BMDarea (grams per square centimeter) was not different (P = NS) from normal controls at final height, in accordance with our results.

Acknowledgments

We are indebted to F. De Terlizzi (IGEA Biophysics Laboratory, Carpi, Modena, Italy) for skillful performance of statistical analysis. We thank the headmasters, school teachers, and parents who gave their consent for the enrollment of controls.

Footnotes

Abbreviations: BMD, Bone mineral density; BMDarea, BMD corrected for bone area; BMDvolume, BMD corrected for bone size; BMI, body mass index; CI, confidence interval; DXA, dual energy x-ray absorptiometry; GHD, GH deficiency; NS, not significant.

Received November 14, 2001.

Accepted April 28, 2002.

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