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Christie Hospital (S.M.S.), Manchester M20 4BX, United Kingdom; PSI (E.S.), 191119 St. Petersburg, Russia; Eli Lilly & Company (M.C., J.J.C., C.A.Q.), Indianapolis, Indiana 46285; Universität Klinik (E.K.), Leipzig D-04317, Germany; Palacky University Hospital (J.Z.), Olomouc 772 00, Czech Republic; Children’s Hospital (T.M.), Philadelphia, Pennsylvania 19104-4399; Eli Lilly and Company Windlesham (C.J.C.), Surrey GU20 6PH, United Kingdom; Bad Homburg (W.F.B.) D-61350, Germany; and Sesto Fiorentino (A.F.A.) 50019, Italy
Address all correspondence and requests for reprints to: Dr. Stephen M. Shalet, Department of Endocrinology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom. E-mail: stephen.m.shalet{at}man.ac.uk.
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Abstract |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In normal children, bone mass accumulation slows down at the end of statural growth (2) but still continues at a lower rate until the attainment of peak bone mass (3), which has been shown to be a major determinant of risk of osteoporosis in later life (4). Normal GH status during longitudinal growth as well as after final height is believed to be critical to optimize this maturational target, and several studies performed in GHD patients before and after completion of pediatric GH underline this conclusion (5, 6, 7, 8). As a result, it has been suggested that GH treatment should be continued until the attainment of peak bone mass, irrespective of the height achieved.
In the present study, we report the effects of a 2-yr treatment intervention in a cohort of patients with severe, persistent GHD. This prospective study was designed to evaluate the effect of GH replacement on bone mineralization in postpubertal GHD patients who had been treated with GH until final height. In addition, it addresses the important question of the optimal dosage, i.e. whether GH should be continued with a pediatric dose regimen or whether an adult dose regimen should be instituted for this purpose.
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Patients and Methods |
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This was a randomized, multinational, multicenter, open-label study of 2-yr duration carried out in accordance with good clinical practice guidelines, with appropriate ethical approval and signed informed consent for all patients. Thirty-eight centers in 11 countries participated in the study. Patients with a CO diagnosis of GHD, who had received GH treatment during childhood for at least 1 yr, had then been off GH treatment for a minimum of 6 wk to a maximum of 5 yr and had a height velocity less than 1 cm/yr, were screened for study eligibility. Patients who had received spinal or total body irradiation; had evidence of bone dysplasia; or had any clinically significant pulmonary, cardiac, hepatic, renal, joint, or neuromuscular disease were excluded from retesting. GHD was reconfirmed by a peak serum GH level less than 5 µg/liter in response to a stimulation test (insulin, arginine, glucagon or arginine/L-dopa) as well as a serum IGF-I concentration below the first percentile for age and gender. Standard replacement therapy for deficiencies of other pituitary hormones was stable and well documented. Using these criteria, 149 patients, of a total of 228 screened, were eligible for enrollment in the study. Baseline data for 92 patients who were assessed in an outcome comparison with AO GHD subjects have been previously reported (1).
Patients were randomized, in a 2:2:1 ratio within each country, to one of three treatment groups: group 1 (n = 59) received GH (Humatrope, Eli Lilly & Co., Indianapolis, IN) at 25 µg/kg·d (0.18 mg/kg·wk; pediatric dose), group 2 (n = 58) received GH at 12.5 µg/kg·d (0.09 mg/kg·wk; adult dose), and group 3 (n = 32) patients did not receive any GH (control). The study was powered to detect a 3% difference in the change in BMC between GH-treated patients (either dose group) and the control group.
Total BMC and bone mineral density (BMD), lumbar BMC, and hip BMC were assessed from dual-energy x-ray absorptiometry (DXA) at baseline, 12 months, and 24 months. Serum samples were taken for determination of IGF-I and IGF-binding protein (IGFBP)-3 at baseline and every 6 months during the study. At baseline, 12 months, and 24 months, serum samples were also drawn for determination of bone-specific alkaline phosphatase (BAP) as an assessment of bone formation, and urinary concentration of type I collagen 
-cross-linked C-terminal telopeptide (ICTP) was measured to assess bone resorption.
Laboratory methods
DXA machines were all calibrated with the same phantom and DXA data were transferred electronically for all readings to be performed centrally (Synarc Inc., Portland, OR). All IGF-I and IGFBP-3 determinations were performed at a central laboratory (University Children’s Hospital, Geissen, Germany). IGF-I was assayed by an IGFBP-blocked RIA with an excess of added IGF-II, and IGFBP-3 was assayed using a specific RIA (9). Serum BAP and urinary ICTP were also determined centrally (Endocrine Research Laboratory, Mainz, Germany); ICTP was measured using a RIA kit (NordicBioscience Diagnostics, Herlev, Denmark) and results expressed as a ratio of ICTP/creatinine concentration, and BAP was determined by a specific RIA (Beckman Coulter Inc., Fullerton, CA).
Data analysis
IGF-I data are presented as actual concentrations and, where appropriate, as SD scores by reference to an age- and gender-matched normal population. For all variables, within-group changes from baseline were analyzed by paired t tests or signed rank tests, depending on normality of data. Differences among the three treatment groups were analyzed using an analysis of covariance (ANCOVA) model adjusting for baseline height and incorporating effects for treatment, country, and interactions. This was followed by pairwise comparisons using least square means to examine the overall treatment effects as differences between all GH-treated patients and controls as well as the dose effect as differences between the two GH doses. The same ANCOVA models were fitted separately for males and females. A one-way ANOVA model incorporating effects for gender was used for analysis of combined therapy groups at baseline and for analysis of changes in combined GH dose groups at the end of GH treatment. Correlations between time since last pediatric GH dose and bone turnover markers or changes in BMC were assessed using Spearman’s correlation coefficients.
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Results |
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The baseline demographic and diagnostic data of enrolled patients are presented in Table 1
by randomization group. Groups were well balanced with respect to gender, age, height, time since diagnosis of GHD, time since last GH injection, and GHD diagnostic criteria. The numbers of patients who completed the 2-yr study period were 30 control, 47 adult dose, and 46 pediatric dose patients. The reasons for discontinuation were mainly patient decision; only two patients discontinued because of adverse events (recurrence of a preexisting tumor and occurrence of scoliosis). The average GH dose during the 2-yr treatment period was 11.3 ± 1.9 µg/kg·d for patients on the adult dose and 23.7 ± 3.9 µg/kg·d for those on the pediatric dose.
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Mean baseline values for serum BAP and urinary ICTP/creatinine ratio did not differ significantly among the three groups (Table 2). As shown in Fig. 1, using data for all patients, highly significant negative correlations were found between the time since the last GH injection of pediatric treatment and the baseline values for BAP (r = 0.31, P < 0.001) and for ICTP/creatinine ratio (r = 0.31, P < 0.001). During the study, BAP and ICTP/creatinine values decreased in the control group but increased significantly in the two treatment groups (Table 2). The variation in the response was large, probably because of the differing baseline status of the individual patients. With GH treatment the mean percent change from 0–1 yr in BAP was 24.9% in the adult dose group and 25.9% in the pediatric dose group; the changes for 0–2 yr were 41.1% and 23.9%, respectively. Mean percentage changes for ICTP/creatinine in the adult and pediatric dose groups were 55.1 and 75.0%, respectively, in the first year and 3.1 and 43.0% for 0–2 yr. Although the overall treatment effect vs. the control group was statistically significant at the end of 2 yr for both bone turnover markers (BAP: P = 0.004, ICTP/creatinine: P < 0.001), there was no significant dose effect, although the pediatric dose tended to have a more pronounced effect on ICTP/creatinine than the adult dose.
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). In the control group, BMC continued to accumulate, with a significant (P < 0.001) increase from baseline over 2 yr. Over the same period, the BMC increases in both the adult and pediatric dose groups were significantly higher than in the control group, resulting in a pronounced treatment effect (P = 0.003 for GH-treated, compared with control). The treatment effect was more marked in the adult dose group than with the pediatric dose, although the difference between doses was not statistically significant (P = 0.315). BMD changes followed the BMC pattern, with a small but significant increase in the control group after 2 yr and a significant (P = 0.045) treatment effect vs. controls, with gains in both adult and pediatric dose groups but particularly with the adult dose (P = 0.051).
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The magnitude of the BMC and BMD changes seen in controls and treatment groups at the hip, femoral neck, and lumbar spine was comparable with that seen for total body values, but variability of response was large. Compared with controls, the GH treatment effect was statistically significant only for lumbar spine BMC (control: 4.1 ± 6.7%, adult dose 10.1 ± 11.2%, pediatric dose 7.6 ± 8.7%, P = 0.013) and BMD (3.1 ± 4.4%, 6.1 ± 7.4%, and 5.1 ± 7.1%, respectively, P = 0.027). Similar to total BMC and BMD, there were no statistically significant dose effects at any specific bone site (data not shown).
Changes by gender
Baseline IGF-I concentrations (all patients) were significantly higher in males (78.0 ± 51.5 µg/liter) than females (58.4 ± 47.4 µg/liter; P = 0.011). With GH treatment, IGF-I increased significantly (P < 0.001) at 2 yr in male patients with both the adult and pediatric doses (Fig. 2) but with no significant difference between doses (P = 0.606). In females, there was a significant dose response, and the mean concentration at 2 yr with the pediatric dose was significantly (P < 0.001) higher than with the adult dose. Expressed as SD scores, the 2-yr IGF-I value in females was -4.9 ± 2.4 with the lower (adult) and -0.87 ± 2.5 with the higher (pediatric) dose; corresponding SD scores in males were -2.4 ± 3.5 and -1.4 ± 1.2. By-gender changes in bone markers, BMC and BMD in the control group as well as in the two treatment arms, matched the pattern of changes seen in the overall study population. Unlike the IGF-I response, there was no significant dose effect on gender-specific changes in BMC and, when by-gender changes in BMC were analyzed for the combined GH treatment groups, the percent increase was 9.1 ± 8.2% in males and 7.2 ± 7.5% in females (P = 0.102). Patterns of change for BMD (data not shown) did not differ from those seen for BMC.
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Serious adverse events were reported by seven patients with no statistically significant difference among groups. Three of these events were considered clinically relevant: One case of obstructive sleep apnea (control group), one recurrence of an optic glioma (adult dose), and one osteolytic lesion in a patient with Langerhans cell histiocytosis (adult dose). The remaining serious events were two episodes of epilepsy and occurrence of urticaria in one patient, a case of spontaneous pneumothorax, an episode of dizziness, and a surgical procedure of shunt replacement.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In patients with CO GHD, accrual of bone mass continues after GH cessation and a 5.6% increase in BMC was observed in the control group during the 2-yr study period. This change is consistent with the 4.5% increase described by Fors et al. (11) in a smaller group of CO GHD patients after discontinuation of GH treatment. The same authors also noted a decrease in bone turnover markers after discontinuation of GH. In our study population, this decrease showed a significant negative correlation with time since the last GH injection, indicating that the BMC increase observed in the control group occurred preferentially in those patients in whom the interruption of GH treatment had been short. These findings confirm the concept that the GH effect on bone persists for 1–2 yr after cessation of GH treatment (14) but eventually disappears.
Reinstitution of GH replacement produced a significant acceleration of bone turnover, similar to other studies (15). In parallel, we observed a statistically significant increase in bone mass over 2 yr in GH-treated patients in comparison with controls. In spite of centralized laboratory and DXA assessments, considerable variance was observed for the changes in bone turnover markers as well as BMC and BMD. Many factors such as nutrition and physical activity could affect these parameters, but the patients in the study continued their normal daily activities and there were no indications that these were different between groups. The probable major source of variation was the relatively protracted time interval (6 wk to 5 yr) since the last GH injection, which would therefore determine the magnitude and pattern of response to GH reinstitution.
In normal children the majority of total adult BMC/BMD is accrued by the end of puberty, between 13 and 15 yr in girls and 15 and 18 yr in boys (16). Given the age range (14.2–25.8 yr in females and 16.2–24.7 yr in males) and the postpubertal status of our patients, we can assume that the BMC and BMD increases seen during the study period are no longer associated with gender-specific timing of pubertal events, and in fact no gender-related difference was seen in the response to treatment. Without GH treatment the net gain in total BMC was about 5% and with GH treatment about 10%, confirming the hypothesis that continued GH treatment after attainment of final height induces significant additional bone maturation in patients with severe GHD. Our observation period was 2 yr, but, given the prolonged effect of GH on bone, it is likely that further progression to peak bone mass would have been observed with a longer follow-up period. Of important clinical relevance in this context, the changes were statistically significant at the lumbar spine, a site particularly at risk of osteoporotic fractures in later life (4, 17).
The primary study objective was to demonstrate a clinically significant, GH-dependent effect on bone mass accumulation in postpubertal GHD patients. An equally important objective was to determine whether this effect is more pronounced with continuation of a pediatric GH dose or with institution of a lower adult GH dose. In this respect, the observation that the overall treatment effect was substantially the same with both dosages was unexpected. One possible explanation of this finding is that different dosages may have had different effects on bone turnover. In fact, although differences were statistically nonsignificant, the increase in ICTP/creatinine was greater with the higher dose and the opposite was the case for BAP. It has been shown that high GH doses in young GHD adults cause desynchronization of bone turnover with predominance of bone resorption over bone formation (18). Thus, the trends seen in the present study suggest a similar mechanism and indicate that the pediatric dose was inappropriately high for adequate bone mass accumulation.
A dose-dependent increase in mean IGF-I concentration was seen in females only; the IGF-I response to the lower adult GH dose was markedly reduced in the females, compared with the males. This is in agreement with the IGF-I response to GH treatment seen in adults with GHD (19); females are less sensitive to a standard GH replacement dosage than males, confirming that the transition period after final height is characterized by an adult type IGF-I response to GH. On the other hand, when IGF-I values were expressed in SD scores, mean treatment values for both males and females were below normal (<-2 SD score) with the adult dose and still in the low normal range for the pediatric dose (>-2 SD score). In other words, using appropriate cross-sectional reference ranges, IGF-I concentrations did not normalize in a large proportion of patients with the GH doses used in our study. Other studies in CO GHD patients of comparable age and maturation have reported higher average IGF-I values at baseline and normalization under GH treatment (6, 7, 8), but this difference with our data likely reflects the severity of GHD in our patient population.
The IGF-I increase from baseline was 3- to 5-fold with either dosage, and the lower dose was sufficient for clinical efficacy. This suggests that in these patients with severe GHD, the very low baseline IGF-I levels are a major determinant of the concentrations achieved in response to GH treatment. We previously speculated that the low IGF-I concentrations seen in these patients reflect inadequate maturation of the IGF-I secretory capacity (1). The response to 2 yr of GH treatment in the present study would confirm that IGF-I synthesis and production has not reached adult capacity at completion of pediatric GH treatment.
In summary, this study demonstrated that withdrawal of GH replacement at final height may limit progression to peak bone mass in patients with severe CO GHD and that adequate GH replacement is required to continue this process. The effect on bone is obtained with a dose regimen, which is in the high adult replacement range and is of clinical relevance for subsequent bone health in adult life. The data also indicate that for optimal progress to peak bone mass, GH treatment after attainment of final height should not be discontinued.
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Acknowledgments |
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Footnotes |
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-cross-linked C-terminal telopeptide; IGFBP, IGF-binding protein. Received January 27, 2003.
Accepted May 20, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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