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Carolina C J Smeets, Manouk van der Steen, Judith S Renes, Anita C S Hokken-Koelega, Bone Mineral Density After Cessation of GH Treatment in Young Adults Born SGA: A 5-Year Longitudinal Study, The Journal of Clinical Endocrinology & Metabolism, Volume 102, Issue 9, 1 September 2017, Pages 3508–3516, https://doi.org/10.1210/jc.2017-00269
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Abstract
Short children born small for gestational age (SGA) have below-average bone mineral density (BMD). Growth hormone (GH) treatment improves height and BMD in short SGA children. Longitudinal data on BMD in adults born SGA, after GH cessation (GH-stop), are lacking.
To determine BMD in young adults born SGA during 5 years after GH-stop.
In 173 GH-treated adults born SGA (SGA-GH), BMD of total body (BMDTB) and bone mineral apparent density of lumbar spine (BMADLS) were measured longitudinally at adult height (AH) and 6 months, 2 years, and 5 years thereafter. At 5 years after GH-stop (age 21 years), data were compared with 45 untreated short SGA adults (SGA-S), 59 SGA adults with spontaneous catch-up (SGA-CU), and 81 adults born appropriate for gestational age (AGA).
At GH-stop (mean age 16.4 years), estimated mean (standard error) BMDTB standard deviation score (SDS) was −0.40 (0.1) in males and −0.51 (0.1) in females, followed by a trend toward a decrease of BMDTB in males to −0.59 (0.1) at 5 years after GH-stop (P = 0.06), whereas it remained stable in females [−0.57 (0.1); P = 0.33]. At GH-stop, BMADLS SDS was −0.01 (0.1) in males and −0.29 (0.1) in females, followed by a decrease in males and females to −0.38 and −0.55, respectively, at 5 years after GH-stop (P < 0.001). At 5 years after GH-stop, BMDTB and BMADLS in SGA-GH were similar compared with SGA-S, SGA-CU, and AGA.
After GH-stop, there is a gradual decline of BMADLS, but at the age of 21 years, BMDTB and BMADLS are similar as in untreated short SGA adults.
Short stature persists in ∼10% of children born small for gestational age (SGA) (1). The mechanisms underlying this lack of catch-up growth are largely unknown but could be related to disturbances in the growth hormone (GH)–insulinlike growth factor-1 (IGF-1) axis, which are present in ∼60% of short SGA children (2).
Osteoporosis is a worldwide problem with high morbidity and increased mortality (3, 4). Bone mineral density (BMD) of the total body (BMDTB) and bone mineral apparent density of the lumbar spine (BMADLS) are important determinants of fracture risk and osteoporosis in later life (5, 6). BMDTB and BMADLS increase during childhood, and peak bone mass is normally attained between the ages of 18–20 years in girls and 18–23 years in boys (7). Bone strength in later life largely depends on this attained peak bone mass (8).
GH and IGF-1 have a well-recognized role not only in bone elongation and skeletal maturation but also in the regulation of BMD (9–11). This could explain why low BMDTB and BMADLS have been found in children with GH deficiency, idiopathic short stature, and Prader-Willi syndrome (12–14). Previous studies have shown that short SGA children have a lower-than-average BMDTB and BMADLS, even after correction for their short stature (15–17).
Short children born SGA can nowadays be treated with GH during childhood to improve adult height (AH). GH treatment also improves BMDTB and BMADLS on the short term. One study reported an increase of BMDTB from −0.9 to 0.2 standard deviation score (SDS) and an increase of BMADLS from −0.6 to 0.3 SDS during 3 years of GH treatment (15). A second study reported an increase of BMADLS with 0.5 SDS during 6 years of treatment (16). However, long-term studies on BMDTB and BMADLS in GH-treated short SGA patients are lacking, and the effects after cessation of treatment are unknown.
In this study, we investigated BMDTB and BMADLS longitudinally in young adults born SGA who were treated with GH during childhood and had attained an age of 21 years, so that peak bone mass could be evaluated. We hypothesized that BMDTB and BMADLS had improved during long-term GH treatment and would not be significantly different from 0 SDS at attainment of AH. We also hypothesized that BMDTB and BMADLS decline in the first months after cessation of GH treatment due to the loss of pharmacologic effects of GH. We compared the data at 5 years after cessation of GH treatment to young adults born SGA with persistent short stature who were never treated with GH, hypothesizing that BMDTB and BMADLS of GH-treated SGA adults would return to levels of untreated short young adults born SGA. Additionally, we compared the data at 5 years after cessation of GH to those of healthy young adults born appropriate for gestational age (AGA).
Methods
Subjects
The total study group comprised 358 young adults, of whom 173 born SGA had participated in a GH trial (18–20). These participants started GH when prepubertal, had a birth length and height below −2.5 SDS, and had no growth failure caused by other disorders. Subjects with a GH deficiency (defined as a serum GH peak response of <20 mU/L during a GH stimulation test) were excluded. Once daily, 1 mg/m2 biosynthetic GH (Norditropin; Novo Nordisk A/S, Måløv, Denmark) was given subcutaneously at bedtime. Every 3 months, the GH dose was adjusted to the calculated body surface area.
At attainment of AH (i.e., when height velocity dropped below 0.5 cm in 6 months and bone age was ≥15 years for girls and ≥16.5 years for boys), GH treatment was discontinued. Patients were invited to participate in the current longitudinal study evaluating BMD at four time points: at AH (GH-stop) and at 6 months, 2 years, and 5 years after GH cessation. Additionally, data at 5 years after GH cessation were compared with three clinically relevant groups of age-matched healthy young adults (21, 22): 45 untreated young adults born SGA (birth weight and/or birth length <−2 SDS) with persistent short stature (AH < −2 SDS [short SGA (SGA-S)]); 59 young adults born SGA (birth weight and/or birth length <−2 SDS) with catch-up growth resulting in a normal AH (> −1 SDS [SGA spontaneous catch-up (SGA-CU)]), and 81 young adults born AGA (birth length >−1 SDS) with a normal stature (AH >−1 SDS).
This study was performed according to the Declaration of Helsinki. The Medical Ethics Committee of the Erasmus University Medical Center approved this study. Written informed consent was obtained from all participants and/or their parents.
Measurements
Height was measured to the nearest 0.1 cm (Harpenden stadiometer; Holtain, Pembs, United Kingdom), weight to the nearest 0.1 kg (Servo Balance KA-20-150S; Servo Berkel Prior, Alkmaar, Netherlands). Anthropometric measurements were performed twice according to standardized methods, after which the mean was calculated. Information regarding oral contraceptive use was obtained using questionnaires.
In all participants, BMDTB and BMD of the lumbar spine (BMDLS), bone mineral content, lean body mass (LBM), and fat mass percentage (FM%) were measured by dual-energy x-ray absorptiometry (Lunar Prodigy; GE Healthcare, Chalfont St. Giles, United Kingdom). BMDTB measurements included the head. All measurements, of both the GH-treated subjects and the control groups, were performed on one machine, and quality assurance was performed daily. All measurements were performed between 2003 and 2016 by the same personnel of the same department. The coefficients of variation were 0.64% for BMDTB and 1.04% for BMDLS (23).
Serum IGF-1 levels were expressed as SDS adjusted for age and sex, using reference values for healthy children with normal stature, determined in the same laboratory (24).
Calculations
Height and weight were expressed as SDS adjusted for age and sex according to Dutch reference data (25) and calculated using the Growth Analyser software (http://www.growthanalyser.org).
In all subjects with short stature, true BMDLS is underestimated by the areal presentation and should be corrected for bone size by calculating the BMADLS (26). BMADLS was calculated as follows: BMADLS = BMDLS × [4/(π × width)], with the width as the mean width of the second to fourth lumbar vertebral body.
Because BMDTB, BMADLS, and FM% are dependent on age and sex, SDSs were calculated based on age- and sex-matched reference values from the Dutch population (27, 28). Because LBM is strongly related to height, LBM was expressed as SDS for height and sex (27).
Statistical analysis
Distribution of variables was determined by Shapiro-Wilk tests and normal Q-Q plots. Data were compared with 0 using one-sample t tests. Longitudinal changes after cessation of GH treatment were analyzed using repeated measurements analyses with an unstructured covariance type, adjusting for missing data. Multiple linear regression analyses were performed to determine the associations between GH treatment and BMDTB and BMADLS, with corrections for the possible confounders age, sex, birth weight, height, LBM, FM%, and, in girls, oral contraceptive use. An analysis of covariance was used to compare the four groups, corrected for the confounders identified in the multiple regression analyses.
Results were considered statistically significant if the P value was <0.05. All analyses were performed with SPSS version 21.0 (SPSS Inc., Chicago, IL).
Results
Clinical characteristics
Table 1 shows the clinical characteristics of the 173 GH-treated SGA adults (82 males; 91 females), at start of GH treatment and at AH, when GH treatment was discontinued, and the follow-up study started. Mean [standard deviation (SD)] age at start of GH treatment was 6.2 (2.0) years and height −3.00 (0.6) SDS. After a mean (SD) treatment duration of 10.2 (2.1) years, subjects attained an AH of −1.69 (0.8) SDS.
. | At Start of GH . | At GH Cessation . | ||||
---|---|---|---|---|---|---|
Total . | Males . | Females . | Total . | Males . | Females . | |
N | 173 | 82 | 91 | 173 | 82 | 91 |
Age (y) | 6.2 (2.0) | 6.3 (2.1) | 6.1 (1.8) | 16.4 (1.3) | 17.2 (1.1) | 15.6 (0.9) |
Height SDS | −3.00 (0.6) | −3.08 (0.6) | −2.93 (0.6) | −1.69 (0.8) | −1.66 (0.9) | −1.72 (0.8) |
Weight for height SDS | −1.22 (1.2) | −1.22 (1.1) | −1.22 (1.4) | 0.58 (0.8) | 0.65 (0.6) | 0.52 (1.0) |
BMI SDS | −1.21 (1.1) | −1.17 (1.0) | −1.24 (1.2) | −0.04 (0.9) | −0.05 (0.8) | −0.04 (1.1) |
BMDTB SDS | −1.00 (1.0)a | −1.32 (1.2) | −0.73 (1.0) | −0.44 (0.9) | −0.43 (1.1) | −0.45 (0.9) |
BMADLS SDS | −0.48 (0.8)a | −0.33 (0.6) | −0.61 (0.9) | −0.14 (1.1) | 0.04 (1.2) | −0.30 (0.9) |
BMC SDS | −2.43 (0.9)a | −2.92 (1.0) | −2.03 (0.4) | −1.23 (0.7) | −1.25 (0.8) | −1.21 (0.7) |
IGF-1 SDS | −0.53 (1.1) | −0.42 (1.1) | −0.63 (1.3) | 1.22 (0.8) | 1.28 (0.8) | 1.17 (0.8) |
GH duration (y) | NA | NA | NA | 10.2 (2.1) | 10.9 (2.2) | 9.5 (1.7) |
. | At Start of GH . | At GH Cessation . | ||||
---|---|---|---|---|---|---|
Total . | Males . | Females . | Total . | Males . | Females . | |
N | 173 | 82 | 91 | 173 | 82 | 91 |
Age (y) | 6.2 (2.0) | 6.3 (2.1) | 6.1 (1.8) | 16.4 (1.3) | 17.2 (1.1) | 15.6 (0.9) |
Height SDS | −3.00 (0.6) | −3.08 (0.6) | −2.93 (0.6) | −1.69 (0.8) | −1.66 (0.9) | −1.72 (0.8) |
Weight for height SDS | −1.22 (1.2) | −1.22 (1.1) | −1.22 (1.4) | 0.58 (0.8) | 0.65 (0.6) | 0.52 (1.0) |
BMI SDS | −1.21 (1.1) | −1.17 (1.0) | −1.24 (1.2) | −0.04 (0.9) | −0.05 (0.8) | −0.04 (1.1) |
BMDTB SDS | −1.00 (1.0)a | −1.32 (1.2) | −0.73 (1.0) | −0.44 (0.9) | −0.43 (1.1) | −0.45 (0.9) |
BMADLS SDS | −0.48 (0.8)a | −0.33 (0.6) | −0.61 (0.9) | −0.14 (1.1) | 0.04 (1.2) | −0.30 (0.9) |
BMC SDS | −2.43 (0.9)a | −2.92 (1.0) | −2.03 (0.4) | −1.23 (0.7) | −1.25 (0.8) | −1.21 (0.7) |
IGF-1 SDS | −0.53 (1.1) | −0.42 (1.1) | −0.63 (1.3) | 1.22 (0.8) | 1.28 (0.8) | 1.17 (0.8) |
GH duration (y) | NA | NA | NA | 10.2 (2.1) | 10.9 (2.2) | 9.5 (1.7) |
Data are expressed as mean (standard deviation).
Abbreviations: BMC, bone mineral content; NA, not applicable.
At start of GH, data available for only 31 participants.
. | At Start of GH . | At GH Cessation . | ||||
---|---|---|---|---|---|---|
Total . | Males . | Females . | Total . | Males . | Females . | |
N | 173 | 82 | 91 | 173 | 82 | 91 |
Age (y) | 6.2 (2.0) | 6.3 (2.1) | 6.1 (1.8) | 16.4 (1.3) | 17.2 (1.1) | 15.6 (0.9) |
Height SDS | −3.00 (0.6) | −3.08 (0.6) | −2.93 (0.6) | −1.69 (0.8) | −1.66 (0.9) | −1.72 (0.8) |
Weight for height SDS | −1.22 (1.2) | −1.22 (1.1) | −1.22 (1.4) | 0.58 (0.8) | 0.65 (0.6) | 0.52 (1.0) |
BMI SDS | −1.21 (1.1) | −1.17 (1.0) | −1.24 (1.2) | −0.04 (0.9) | −0.05 (0.8) | −0.04 (1.1) |
BMDTB SDS | −1.00 (1.0)a | −1.32 (1.2) | −0.73 (1.0) | −0.44 (0.9) | −0.43 (1.1) | −0.45 (0.9) |
BMADLS SDS | −0.48 (0.8)a | −0.33 (0.6) | −0.61 (0.9) | −0.14 (1.1) | 0.04 (1.2) | −0.30 (0.9) |
BMC SDS | −2.43 (0.9)a | −2.92 (1.0) | −2.03 (0.4) | −1.23 (0.7) | −1.25 (0.8) | −1.21 (0.7) |
IGF-1 SDS | −0.53 (1.1) | −0.42 (1.1) | −0.63 (1.3) | 1.22 (0.8) | 1.28 (0.8) | 1.17 (0.8) |
GH duration (y) | NA | NA | NA | 10.2 (2.1) | 10.9 (2.2) | 9.5 (1.7) |
. | At Start of GH . | At GH Cessation . | ||||
---|---|---|---|---|---|---|
Total . | Males . | Females . | Total . | Males . | Females . | |
N | 173 | 82 | 91 | 173 | 82 | 91 |
Age (y) | 6.2 (2.0) | 6.3 (2.1) | 6.1 (1.8) | 16.4 (1.3) | 17.2 (1.1) | 15.6 (0.9) |
Height SDS | −3.00 (0.6) | −3.08 (0.6) | −2.93 (0.6) | −1.69 (0.8) | −1.66 (0.9) | −1.72 (0.8) |
Weight for height SDS | −1.22 (1.2) | −1.22 (1.1) | −1.22 (1.4) | 0.58 (0.8) | 0.65 (0.6) | 0.52 (1.0) |
BMI SDS | −1.21 (1.1) | −1.17 (1.0) | −1.24 (1.2) | −0.04 (0.9) | −0.05 (0.8) | −0.04 (1.1) |
BMDTB SDS | −1.00 (1.0)a | −1.32 (1.2) | −0.73 (1.0) | −0.44 (0.9) | −0.43 (1.1) | −0.45 (0.9) |
BMADLS SDS | −0.48 (0.8)a | −0.33 (0.6) | −0.61 (0.9) | −0.14 (1.1) | 0.04 (1.2) | −0.30 (0.9) |
BMC SDS | −2.43 (0.9)a | −2.92 (1.0) | −2.03 (0.4) | −1.23 (0.7) | −1.25 (0.8) | −1.21 (0.7) |
IGF-1 SDS | −0.53 (1.1) | −0.42 (1.1) | −0.63 (1.3) | 1.22 (0.8) | 1.28 (0.8) | 1.17 (0.8) |
GH duration (y) | NA | NA | NA | 10.2 (2.1) | 10.9 (2.2) | 9.5 (1.7) |
Data are expressed as mean (standard deviation).
Abbreviations: BMC, bone mineral content; NA, not applicable.
At start of GH, data available for only 31 participants.
Longitudinal changes in BMDTB and BMADLS after GH cessation
Figure 1 shows the longitudinal changes in BMDTB and BMADLS SDS in males and females, until 5 years after GH cessation. At GH cessation, estimated mean [standard error (SE)] BMDTB SDS was −0.40 (0.1) in males and −0.51 (0.1) in females. This was both within the normal range but significantly lower than 0 SDS (P < 0.001). Both males and females had a significantly higher BMDTB at cessation of GH treatment compared with at onset of treatment (P < 0.001 and P = 0.002, respectively). In the 6 months after GH cessation, BMDTB SDS increased significantly in males to −0.30 (0.1) (P = 0.008), followed by a decrease from then onward (P = 0.004). At 5 years after GH cessation, estimated mean (SE) BMDTB SDS was −0.59 (0.1) in males (P = 0.06 compared with BMDTB at GH cessation and P < 0.001 compared with 0 SDS). In females, BMDTB SDS remained stable after cessation of GH treatment: BMDTB SDS was −0.57 (0.1) at 5 years after GH cessation (P = 0.33 compared with BMDTB at GH cessation and P < 0.001 compared with 0 SDS).
At GH cessation, estimated mean (SE) BMADLS SDS was −0.01 (0.1) in males (P = 0.76 compared with 0 SDS) and −0.29 (0.1) in females (P = 0.003 compared with 0 SDS). Both males and females had a significantly higher BMADLS at cessation of GH treatment compared with at onset of treatment (P = 0.006 and P = 0.002, respectively). In both males and females, BMADLS SDS did not change in the 6 months after GH cessation but started to decrease in the 18 months thereafter in males (P < 0.001) and between 2 and 5 years after GH cessation in females (P < 0.001). At 5 years after GH cessation, estimated mean (SE) BMADLS SDS was −0.38 (0.1) in males (P < 0.001 compared with BMADLS at GH cessation and P = 0.02 compared with 0 SDS) and −0.55 (0.1) in females (P < 0.001 compared with BMADLS at GH cessation and 0 SDS).
To compare the individual BMDTB and BMADLS of the SGA-GH patients to the healthy population, BMDTB and BMADLS data points at GH cessation and 2 and 5 years thereafter were plotted against the reference curve of the healthy Dutch population (Fig. 2). At GH cessation, 5.2% of the study population (males and females) had a BMDTB ≤−2 SDS, which was a higher proportion than the expected 2.3% in the reference population (P = 0.019). At 5 years after GH cessation, only 1.3% of the study group had a BMDTB ≤−2 SDS, which was similar to the expected proportion in the reference population (P = 0.48). At GH cessation, 3.5% had a BMADLS ≤−2 SDS (P = 0.21 compared with 2.3%). Also at 5 years after GH cessation, the proportion of patients with a BMADLS ≤−2 SDS was not significantly different from the expected 2.3% (P = 0.66).
Factors influencing the change in BMDTB and BMADLS during the 5 years after GH cessation
From GH cessation until 5 years thereafter, there was a decrease in LBM of 0.39 SDS and an increase in FM% of 0.56 SDS. We analyzed whether there was a correlation between these changes in body composition and the deterioration in BMDTB and BMADLS SDS during the 5 years after GH cessation. There was neither a correlation between ΔLBM SDS and ΔBMDTB SDS (r = 0.17; P = 0.24) nor between ΔFM% SDS and ΔBMDTB SDS (r = 0.05; P = 0.75) and neither between ΔLBM SDS and ΔBMADLS SDS (r = 0.17; P = 0.24) nor between ΔFM% SDS and BMADLS (r= 0.18; P = 0.22).
From GH cessation until 5 years thereafter, serum IGF-1 levels decreased with 1.66 SDS. There was no correlation between ΔIGF-1 SDS and ΔBMDTB SDS (r= 0.40; P = 0.20). However, there was a trend toward a significant correlation between the decrease in IGF-1 SDS and the decrease in BMADLS SDS (r= 0.57; P = 0.05).
BMDTB and BMADLS at 5 years after GH cessation compared with SGA-S, SGA-CU, and AGA
Table 2 shows the clinical characteristics of the SGA-GH young adults at 5 years after GH cessation compared with the SGA-S, SGA-CU, and AGA young adults. The percentage of males/females was similar in the four groups. Mean age was ∼21 years in all groups. Due to the selection criteria, there were considerable differences in birth length SDS, birth weight SDS, height SDS, weight for age SDS, and body composition. The percentage of smokers and of girls who used oral contraceptives was similar in all groups.
. | SGA-GH . | SGA-S . | SGA-CU . | AGA . |
---|---|---|---|---|
N | 89 | 45 | 59 | 81 |
Male/female | 38/51 | 15/30 | 22/37 | 30/51 |
Gestational age (wk) | 36.3 (3.6)a | 39.5 (1.5)b | 38.3 (1.5)c | 39.4 (1.7) |
Birth length SDS | −3.21 (1.7)c | −3.01 (1.1)c | −2.90 (0.8)c | 0.07 (0.7) |
Birth weight SDS | −2.39 (1.2)c,d | −1.92 (0.9)c,e | −2.37 (0.8)c | −0.10 (1.3) |
Age | 21.4 (1.5)d,f | 20.7 (1.7) | 21.1 (1.5) | 20.8 (1.7) |
Height SDS | −1.56 (0.9)a | −2.62 (0.6)b,c | −0.14 (0.8)f | 0.24 (0.9) |
BMI SDS | −0.36 (1.7) | 0.13 (1.1) | 0.11 (1.3) | −0.06 (1.0) |
LBM SDS | −0.94 (1.3)f,g | 0.04 (1.5)e,f | −0.67 (1.3) | −0.54 (1.1) |
FM% SDS | 0.85 (0.9) | 0.79 (0.8) | 0.90 (0.8) | 0.78 (0.8) |
OC use (% of females) | 89.5 | 78.3 | 80.0 | 71.1 |
IGF-1 SDS | −0.46 (1.0) | −0.29 (0.8) | −0.26 (0.7) | −0.26 (0.8) |
. | SGA-GH . | SGA-S . | SGA-CU . | AGA . |
---|---|---|---|---|
N | 89 | 45 | 59 | 81 |
Male/female | 38/51 | 15/30 | 22/37 | 30/51 |
Gestational age (wk) | 36.3 (3.6)a | 39.5 (1.5)b | 38.3 (1.5)c | 39.4 (1.7) |
Birth length SDS | −3.21 (1.7)c | −3.01 (1.1)c | −2.90 (0.8)c | 0.07 (0.7) |
Birth weight SDS | −2.39 (1.2)c,d | −1.92 (0.9)c,e | −2.37 (0.8)c | −0.10 (1.3) |
Age | 21.4 (1.5)d,f | 20.7 (1.7) | 21.1 (1.5) | 20.8 (1.7) |
Height SDS | −1.56 (0.9)a | −2.62 (0.6)b,c | −0.14 (0.8)f | 0.24 (0.9) |
BMI SDS | −0.36 (1.7) | 0.13 (1.1) | 0.11 (1.3) | −0.06 (1.0) |
LBM SDS | −0.94 (1.3)f,g | 0.04 (1.5)e,f | −0.67 (1.3) | −0.54 (1.1) |
FM% SDS | 0.85 (0.9) | 0.79 (0.8) | 0.90 (0.8) | 0.78 (0.8) |
OC use (% of females) | 89.5 | 78.3 | 80.0 | 71.1 |
IGF-1 SDS | −0.46 (1.0) | −0.29 (0.8) | −0.26 (0.7) | −0.26 (0.8) |
Data are expressed as mean (standard deviation). LBM was corrected for height and sex. FM% was corrected for age and sex.
Abbreviation: OC, oral contraceptive.
P < 0.001 compared with the other groups.
P < 0.001 compared with SGA-CU.
P < 0.001 compared with AGA.
P < 0.05 compared with SGA-S.
P < 0.05 compared with SGA-CU.
P < 0.05 compared with AGA.
P < 0.001 compared with SGA-S.
. | SGA-GH . | SGA-S . | SGA-CU . | AGA . |
---|---|---|---|---|
N | 89 | 45 | 59 | 81 |
Male/female | 38/51 | 15/30 | 22/37 | 30/51 |
Gestational age (wk) | 36.3 (3.6)a | 39.5 (1.5)b | 38.3 (1.5)c | 39.4 (1.7) |
Birth length SDS | −3.21 (1.7)c | −3.01 (1.1)c | −2.90 (0.8)c | 0.07 (0.7) |
Birth weight SDS | −2.39 (1.2)c,d | −1.92 (0.9)c,e | −2.37 (0.8)c | −0.10 (1.3) |
Age | 21.4 (1.5)d,f | 20.7 (1.7) | 21.1 (1.5) | 20.8 (1.7) |
Height SDS | −1.56 (0.9)a | −2.62 (0.6)b,c | −0.14 (0.8)f | 0.24 (0.9) |
BMI SDS | −0.36 (1.7) | 0.13 (1.1) | 0.11 (1.3) | −0.06 (1.0) |
LBM SDS | −0.94 (1.3)f,g | 0.04 (1.5)e,f | −0.67 (1.3) | −0.54 (1.1) |
FM% SDS | 0.85 (0.9) | 0.79 (0.8) | 0.90 (0.8) | 0.78 (0.8) |
OC use (% of females) | 89.5 | 78.3 | 80.0 | 71.1 |
IGF-1 SDS | −0.46 (1.0) | −0.29 (0.8) | −0.26 (0.7) | −0.26 (0.8) |
. | SGA-GH . | SGA-S . | SGA-CU . | AGA . |
---|---|---|---|---|
N | 89 | 45 | 59 | 81 |
Male/female | 38/51 | 15/30 | 22/37 | 30/51 |
Gestational age (wk) | 36.3 (3.6)a | 39.5 (1.5)b | 38.3 (1.5)c | 39.4 (1.7) |
Birth length SDS | −3.21 (1.7)c | −3.01 (1.1)c | −2.90 (0.8)c | 0.07 (0.7) |
Birth weight SDS | −2.39 (1.2)c,d | −1.92 (0.9)c,e | −2.37 (0.8)c | −0.10 (1.3) |
Age | 21.4 (1.5)d,f | 20.7 (1.7) | 21.1 (1.5) | 20.8 (1.7) |
Height SDS | −1.56 (0.9)a | −2.62 (0.6)b,c | −0.14 (0.8)f | 0.24 (0.9) |
BMI SDS | −0.36 (1.7) | 0.13 (1.1) | 0.11 (1.3) | −0.06 (1.0) |
LBM SDS | −0.94 (1.3)f,g | 0.04 (1.5)e,f | −0.67 (1.3) | −0.54 (1.1) |
FM% SDS | 0.85 (0.9) | 0.79 (0.8) | 0.90 (0.8) | 0.78 (0.8) |
OC use (% of females) | 89.5 | 78.3 | 80.0 | 71.1 |
IGF-1 SDS | −0.46 (1.0) | −0.29 (0.8) | −0.26 (0.7) | −0.26 (0.8) |
Data are expressed as mean (standard deviation). LBM was corrected for height and sex. FM% was corrected for age and sex.
Abbreviation: OC, oral contraceptive.
P < 0.001 compared with the other groups.
P < 0.001 compared with SGA-CU.
P < 0.001 compared with AGA.
P < 0.05 compared with SGA-S.
P < 0.05 compared with SGA-CU.
P < 0.05 compared with AGA.
P < 0.001 compared with SGA-S.
We analyzed which variables contributed to BMDTB and BMADLS in the total group consisting of SGA-GH, SGA-S, SGA-CU, and AGA at 21 years in a multiple regression analysis (Table 3). In the first model with BMDTB as dependent variable, we included the variables sex, age, birth weight SDS, height SDS, LBM SDS (corrected for height and sex), and FM% SDS (corrected for age and sex). Male sex, height SDS, LBM SDS, and FM% SDS were all positively associated with BMDTB (P < 0.001 for sex, height, and LBM and P = 0.01 for FM%). Age and birth weight SDS were not associated with BMDTB. This model accounted for 38% of the variance in BMDTB. In the second model, we evaluated the effect of oral contraceptive use in girls, which was not a significant predictor of BMDTB (P = 0.27). In model 3, we included the subjects who were GH-treated during childhood as a dummy variable, showing that GH treatment was not a significant predictor of BMDTB at 5 years after GH cessation (P = 0.63).
. | BMDTB (g/cm2) . | BMADLS (g/cm3) . | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Model 1 . | Model 2 . | Model 3 . | Model 1 . | Model 2 . | Model 3 . | |||||||
β . | P . | β . | P . | β . | P . | β . | P . | β . | P . | β . | P . | |
Male sex | 0.06 | <0.001 | 0.04 | 0.04 | 0.06 | <0.001 | −0.04 | <0.001 | −0.05 | <0.001 | −0.04 | <0.001 |
Age (y) | 0.01 | 0.22 | 0.01 | 0.15 | 0.01 | 0.22 | 0.00 | 0.60 | 0.00 | 0.99 | 0.00 | 0.58 |
Birth weight SDS | 0.00 | 0.89 | −0.00 | 0.85 | 0.00 | 0.81 | −0.00 | 0.64 | −0.00 | 0.52 | −0.00 | 0.43 |
Height SDS | 0.03 | <0.001 | 0.03 | <0.001 | 0.03 | <0.001 | 0.00 | 0.91 | 0.00 | 0.94 | −0.00 | 0.68 |
LBM SDS | 0.02 | <0.001 | 0.02 | <0.001 | 0.02 | <0.001 | 0.01 | 0.04 | 0.00 | 0.16 | 0.00 | 0.07 |
FM% SDS | 0.02 | 0.01 | 0.01 | 0.10 | 0.02 | 0.01 | 0.01 | 0.001 | 0.01 | 0.06 | 0.01 | 0.001 |
OC use | −0.02 | 0.27 | −0.01 | 0.28 | ||||||||
GH treatment | 0.01 | 0.63 | −0.00 | 0.14 | ||||||||
Overall P value | <0.001 | <0.001 | <0.001 | <0.001 | 0.001 | <0.001 | ||||||
R2 adjusted | 0.38 | 0.34 | 0.37 | 0.18 | 0.12 | 0.19 |
. | BMDTB (g/cm2) . | BMADLS (g/cm3) . | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Model 1 . | Model 2 . | Model 3 . | Model 1 . | Model 2 . | Model 3 . | |||||||
β . | P . | β . | P . | β . | P . | β . | P . | β . | P . | β . | P . | |
Male sex | 0.06 | <0.001 | 0.04 | 0.04 | 0.06 | <0.001 | −0.04 | <0.001 | −0.05 | <0.001 | −0.04 | <0.001 |
Age (y) | 0.01 | 0.22 | 0.01 | 0.15 | 0.01 | 0.22 | 0.00 | 0.60 | 0.00 | 0.99 | 0.00 | 0.58 |
Birth weight SDS | 0.00 | 0.89 | −0.00 | 0.85 | 0.00 | 0.81 | −0.00 | 0.64 | −0.00 | 0.52 | −0.00 | 0.43 |
Height SDS | 0.03 | <0.001 | 0.03 | <0.001 | 0.03 | <0.001 | 0.00 | 0.91 | 0.00 | 0.94 | −0.00 | 0.68 |
LBM SDS | 0.02 | <0.001 | 0.02 | <0.001 | 0.02 | <0.001 | 0.01 | 0.04 | 0.00 | 0.16 | 0.00 | 0.07 |
FM% SDS | 0.02 | 0.01 | 0.01 | 0.10 | 0.02 | 0.01 | 0.01 | 0.001 | 0.01 | 0.06 | 0.01 | 0.001 |
OC use | −0.02 | 0.27 | −0.01 | 0.28 | ||||||||
GH treatment | 0.01 | 0.63 | −0.00 | 0.14 | ||||||||
Overall P value | <0.001 | <0.001 | <0.001 | <0.001 | 0.001 | <0.001 | ||||||
R2 adjusted | 0.38 | 0.34 | 0.37 | 0.18 | 0.12 | 0.19 |
P values <0.05 in boldface. LBM SDS was corrected for height and sex. FM% SDS was corrected for age and sex.
Abbreviation: OC, oral contraceptive.
. | BMDTB (g/cm2) . | BMADLS (g/cm3) . | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Model 1 . | Model 2 . | Model 3 . | Model 1 . | Model 2 . | Model 3 . | |||||||
β . | P . | β . | P . | β . | P . | β . | P . | β . | P . | β . | P . | |
Male sex | 0.06 | <0.001 | 0.04 | 0.04 | 0.06 | <0.001 | −0.04 | <0.001 | −0.05 | <0.001 | −0.04 | <0.001 |
Age (y) | 0.01 | 0.22 | 0.01 | 0.15 | 0.01 | 0.22 | 0.00 | 0.60 | 0.00 | 0.99 | 0.00 | 0.58 |
Birth weight SDS | 0.00 | 0.89 | −0.00 | 0.85 | 0.00 | 0.81 | −0.00 | 0.64 | −0.00 | 0.52 | −0.00 | 0.43 |
Height SDS | 0.03 | <0.001 | 0.03 | <0.001 | 0.03 | <0.001 | 0.00 | 0.91 | 0.00 | 0.94 | −0.00 | 0.68 |
LBM SDS | 0.02 | <0.001 | 0.02 | <0.001 | 0.02 | <0.001 | 0.01 | 0.04 | 0.00 | 0.16 | 0.00 | 0.07 |
FM% SDS | 0.02 | 0.01 | 0.01 | 0.10 | 0.02 | 0.01 | 0.01 | 0.001 | 0.01 | 0.06 | 0.01 | 0.001 |
OC use | −0.02 | 0.27 | −0.01 | 0.28 | ||||||||
GH treatment | 0.01 | 0.63 | −0.00 | 0.14 | ||||||||
Overall P value | <0.001 | <0.001 | <0.001 | <0.001 | 0.001 | <0.001 | ||||||
R2 adjusted | 0.38 | 0.34 | 0.37 | 0.18 | 0.12 | 0.19 |
. | BMDTB (g/cm2) . | BMADLS (g/cm3) . | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Model 1 . | Model 2 . | Model 3 . | Model 1 . | Model 2 . | Model 3 . | |||||||
β . | P . | β . | P . | β . | P . | β . | P . | β . | P . | β . | P . | |
Male sex | 0.06 | <0.001 | 0.04 | 0.04 | 0.06 | <0.001 | −0.04 | <0.001 | −0.05 | <0.001 | −0.04 | <0.001 |
Age (y) | 0.01 | 0.22 | 0.01 | 0.15 | 0.01 | 0.22 | 0.00 | 0.60 | 0.00 | 0.99 | 0.00 | 0.58 |
Birth weight SDS | 0.00 | 0.89 | −0.00 | 0.85 | 0.00 | 0.81 | −0.00 | 0.64 | −0.00 | 0.52 | −0.00 | 0.43 |
Height SDS | 0.03 | <0.001 | 0.03 | <0.001 | 0.03 | <0.001 | 0.00 | 0.91 | 0.00 | 0.94 | −0.00 | 0.68 |
LBM SDS | 0.02 | <0.001 | 0.02 | <0.001 | 0.02 | <0.001 | 0.01 | 0.04 | 0.00 | 0.16 | 0.00 | 0.07 |
FM% SDS | 0.02 | 0.01 | 0.01 | 0.10 | 0.02 | 0.01 | 0.01 | 0.001 | 0.01 | 0.06 | 0.01 | 0.001 |
OC use | −0.02 | 0.27 | −0.01 | 0.28 | ||||||||
GH treatment | 0.01 | 0.63 | −0.00 | 0.14 | ||||||||
Overall P value | <0.001 | <0.001 | <0.001 | <0.001 | 0.001 | <0.001 | ||||||
R2 adjusted | 0.38 | 0.34 | 0.37 | 0.18 | 0.12 | 0.19 |
P values <0.05 in boldface. LBM SDS was corrected for height and sex. FM% SDS was corrected for age and sex.
Abbreviation: OC, oral contraceptive.
The same variables were then included in the model with BMADLS as dependent variable. Male sex was negatively associated with BMADLS (P < 0.001). Height SDS was not significantly associated with BMADLS, which was expected because BMADLS is already corrected for bone size. LBM SDS and FM% SDS were positively associated with BMADLS (P = 0.04 and P = 0.001, respectively). This model accounted for 18% of the variance in BMADLS. In the second model, we evaluated the effect of oral contraceptive use in girls. This model showed that oral contraceptive use did not influence BMADLS (P = 0.28). Finally, the dummy GH treatment was included in the model, showing that this was not a predictor of BMADLS (P = 0.14).
Figure 3 shows the comparisons of BMDTB and BMADLS between the SGA-GH young adults at 5 years after GH cessation and the SGA-S, SGA-CU, and AGA young adults. Adjustments were made based on the noteworthy predictors in the multiple regression analysis. BMDTB in SGA-GH, adjusted for sex, height SDS, LBM SDS, and FM% SDS, was not different from BMDTB in SGA-S and SGA-CU (P = 0.22 and P = 0.76, respectively). There was a trend toward a lower BMDTB in SGA-GH than in AGA (P = 0.09). SGA-S and SGA-CU had a similar BMDTB, but both lower than AGA (P = 0.03). BMADLS SDS, adjusted for sex, LBM SDS, and FM% SDS, was similar in SGA-GH and SGA-S, SGA-CU, and AGA (P = 0.63, P = 0.72, and P = 0.26, respectively).
Discussion
This study presents 5-year longitudinal data on BMDTB and BMADLS after cessation of GH treatment in young adults born SGA. We show that cessation of GH treatment is accompanied with a trend toward a decline of BMDTB in males and a gradual decline of BMADLS in males and females. However, at 5 years after cessation of treatment, previously GH-treated SGA young adults had a similar BMDTB and BMADLS as young adults who remained untreated and as controls born AGA with a normal stature.
To our knowledge, this is the first study describing BMDTB and BMADLS after cessation of GH treatment in a large group of young adults born SGA. Until now, there were limited data available. Our research group reported on BMDTB and BMADLS in children born SGA during GH treatment (15, 16). These studies were performed during 3 and 6 years, respectively, of treatment and reported a BMDTB SDS of −0.9 and a BMADLS SDS of −0.6 at onset of treatment. Although we found that BMDTB was lower than average at cessation of GH treatment, both BMDTB and BMADLS were higher than the baseline BMDs reported in previous studies. The same studies showed that during the first years of GH treatment, there was an increase of BMDTB and BMADLS, which were maintained at the same level up to 6 years after the start of treatment. We can now conclude that these positive effects are maintained until AH attainment.
During the 5 years after cessation of GH treatment, there was a gradual decline of BMADLS and a trend toward a decline of BMDTB in males, probably due to the loss of pharmacological effects of GH treatment. The correlation between the decline in IGF-1 SDS levels and the deterioration in BMADLS in the 5 years after GH cessation provides support for this explanation. In contrast to other metabolic changes after GH cessation (29), the decrease in BMDTB and BMADLS did not commence directly after cessation. In males, there was even an increase of BMDTB in the first 6 months after GH cessation. It could be that GH treatment has relatively longer-lasting effects on bone metabolism than on body mass and fat mass and that, therefore, there is not an immediate effect of GH cessation on BMD. Despite the deteriorations in the years after GH cessation, average BMDTB and BMADLS at 5 years after GH cessation were above −1 SDS, and only a small percentage of all subjects had a BMDTB or BMADLS below −2 SDS, which is reassuring. Most of the skeletal mass in the total body and lumbar spine is attained in the first years of the third decade (28, 30, 31). This attained peak bone mass is an important determinant of osteoporosis in later life (8). The higher BMDTB and BMADLS at young adult age, the lower the risk of osteoporosis in later life. Thus, although BMDTB and BMADLS in formerly GH-treated subjects were within the normal range, it is unfortunate that the beneficial effects of GH treatment disappear after cessation of treatment. Future studies should aim at investigating how BMDTB and BMADLS progress when GH-treated subjects born SGA get older and what the long-term clinical implications will be.
Our multiple regression analysis could explain a relatively large part of the total variance in BMDTB and BMADLS. Sex, height, LBM, and FM% were significant determinants of BMDTB and sex, LBM, and FM% of BMADLS. The combination of LBM and FM% can also be seen as a measure of physical fitness, which is an important determinant of BMDTB and BMADLS (32, 33). Although GH-treated subjects had BMDTB and BMADLS below average at 5 years after GH cessation, this did not significantly influence BMDTB and BMADLS of the total group at the age of 21 years. We found no effect of oral contraceptive use in girls on BMDTB and BMADLS, although the small number of girls who did not use oral contraceptives makes it difficult to draw definite conclusions. Another factor influencing BMDTB and BMADLS in adolescence is pubertal stage, but because all participants were postpubertal in our cohort, this was already considered. Although the most important determinants of BMDTB and BMADLS in a healthy young population were assessed in this study, there are of course other determining factors, such as calcium and vitamin D status. Unfortunately, there were no data on these factors available.
At 5 years after cessation of GH treatment, we additionally compared the data of the GH-treated subjects to age-matched clinically relevant subgroups of young adults born SGA with persistent short stature who were never treated with GH, young adults born SGA who showed spontaneous catch-up growth, and AGA-born controls with a normal stature. After correction for the noteworthy determinants of BMDTB and BMADLS, we found no differences between the GH-treated and untreated young adults born SGA who remained short. There was a trend toward a lower BMDTB in the GH-treated subjects than in the AGA-born controls. Interestingly, subjects born SGA with spontaneous catch-up growth had also a lower BMDTB than the AGA-born subjects, suggesting that BMDTB in subjects born SGA is not only reduced due to short stature but also to other determining factors of BMDTB that are disturbed in subjects born SGA. BMADLS was, however, similar in all groups.
In conclusion, this study shows that GH treatment improves BMDTB and BMADLS in subjects born SGA. However, after GH cessation, BMADLS gradually deteriorates, and there is a trend toward a deterioration of BMDTB in males. At the age of 21 years, BMDTB and BMADLS are, however, similar in GH-treated and untreated subjects born SGA. Although this study describes the largest and longest follow-up thus far on BMDTB and BMADLS measured by dual-energy x-ray absorptiometry in young adults born SGA who were treated with GH during their childhood, for definite conclusions, a longer follow-up is required to see how these parameters develop as subjects progress further into adulthood.
Abbreviations:
- AGA
appropriate for gestational age
- AH
adult height
- BMADLS
bone mineral apparent density of lumbar spine
- BMD
bone mineral density
- BMDLS
bone mineral density of the lumbar spine
- BMDTB
bone mineral density of the total body
- FM%
fat mass percentage
- GH
growth hormone
- GH-stop
growth hormone cessation
- IGF1
insulinlike growth factor-1
- LBM
lean body mass
- SE
standard error
- SGA
small for gestational age
- SGA-CU
small for gestational age adults with spontaneous catch-up
- SGA-GH
growth hormone–treated adults born small for gestational age
- SGA-S
short small-for-gestational-age adults.
Acknowledgments
We thank all of the participants and all of the research nurses for their assistance.
This work was supported by an investigator-initiated independent research grant from Novo Nordisk B.V. (Netherlands).
Clinical trial registry: ClinicalTrials.gov nos. ISRCTN65230311 (registered 19 July 2006) and ISRCTN96883876 (registered 27 January 2006).
Disclosure Summary: A.C.S.H.-K. received an independent research grant from Novo Nordisk. The remaining authors have nothing to disclose.
References