Growth hormone therapy with three dosage regimens in children with idiopathic short stature

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Growth hormone therapy with three dosage regimens in children with idiopathic short stature

L. T. M. Rekers-Mombarg, MSc, G. G. Massa, MD, PhD, J. M. Wit, MD, PhD, A. M. C. Matranga, PhD, J. M. H. Buckler, MD, O. Butenandt, MD, PhD, J. L. Chaussain, MD, H. Frisch, MD, E. Leiberman, MD, R. Yturriaga, MD, on behalf of the European Study Group Participating investigators: D. Aarskog, P. G. Chatelain, M. Colle, C. Dacou-Voutetakis, H. A. Delemarre-van de Waal, F. Girard, J. J. Gosen, U. Irle, M. Jansen, R. Jean, J. C. Job, M. L. Kaar, F. Kollemann, H. L. Lenko, R. Mühlenberg, S. M. P. F. de Muinck Keizer-Schrama, W. Oostdijk, B. J. Otten, M. Piersson, M. A. Preece, D. A. Price, P. H. W. Rayner, C. Rouwé, K. Schmitt, W. G. Sippell, P. Blümel, T. Vulsma, and J. J. J. Waelkens Objective: In children with idiopathic short stature (ISS) we studied the growth-promoting effect at 4 years of recombinant human growth hormone (rhGH) therapy in three dose regimens and evaluated whether increasing the dosage after the first year could prevent a decline in height velocity (HV).

Design: Included were 223 patents who were treated with subcutaneous administrations of rhGH 6 days per week. They were randomized to three groups: 3 IU/m2 body surface/day, 4.5 IU/m2/day, and 3 IU/m2/day during the first year and 4.5 IU/m2/day thereafter, corresponding with dosages of 0.2 and 0.3 mg/kg body weight/week, respectively. Growth was compared with a standard of 229 untreated children with ISS [ISS standard].

Results: During the first year of treatment HV almost doubled and was higher with 4.5 IU/m2 than with 3 IU/m2. In the second year HV no longer differed among the groups, but increasing the dosage slowed the rate of the fall of HV. During 4 years of therapy the height SD score for age increased by a mean (SD) of 2.5 (1.0) [ISS standards], or 1.2 (0.7) (British standards), bone age increased by 4.8 (1.3) years, and predicted adult height SD score increased by 1.5 (0.7). After 4 years the results of the group with 4.5 IU/m2 were slightly better than those of the other groups. When dropouts were included in the analysis (assuming a stable height SD score after discontinuation of rhGH therapy), height gain was still significant.

Conclusions: During 4 years of rhGH therapy, growth and final height prognosis improved, slightly more with 4.5 IU/m2 than with 3 IU/m2 or 3 to 4.5 IU/m2. However, bone age advanced on average 4.8 years during this period; therefore, any effect on final height will probably be modest. (J Pediatr 1998;132:455-60)

From the Department of Pediatrics of the University Hospital of Leiden, The Netherlands; the Bureau of the Dutch Growth Foundation, Leiden, The Netherlands; Lilly Research Centre, Windlesham, U.K.; and the Departments of Pediatrics of the University Hospital of Leeds, U.K., Munich, Germany, Paris, France, Vienna, Austria, Beer Sheva, Israel, and Madrid, Spain. Supported by Eli Lilly. Submitted for publication Sept. 4, 1996; accepted May 30, 1997. Reprint requests: L. T. M. Rekers-Mombarg, Department of Pediatrics, Leiden University Medical Centre, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/21/83683

Idiopathic short stature, that is, short stature without a recognizable underlying pathologic condition, is the most common cause of short stature during childhood.1,2 This entity can be subdivided into familial short stature and nonfamilial short stature.3 When the onset of puberty has been delayed, the term constitutional delay of growth and adolescence has usually been used. Without treatment most of these children will end up as short adults.4-9 bs FSS HV ISS IUGR rhGH SDS TW2

Body surface Familial short stature Height velocity Idiopathic short stature Intrauterine growth retardation Recombinant human growth hormone Standard deviation score Tanner Whitehouse II RUS

Since recombinant human growth hormone has become available, several studies have been carried out on its effect on the growth of children with ISS. Height velocity usually almost doubles during the first year, followed by a decline in the following years.10-13 Bone maturation has been found to accelerate in some studies9,14-16 but not in others.10,17-19 Only a modest increment of final height of 3 cm was seen in some studies.4,9,16 In a recent study even a loss in final height was suggested.20 Weaknesses of the reported studies are the limited number of children, the treatment regimens and dosages that changed over time in an uncontrolled manner, and the lack of growth data on untreated control groups. The possible 455

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Table I. Total number of patients, the number per treatment regimen group, and the reasons of dropout during 4 years of rhGH treatment

Month of study

0

12

24

36

48*

223 73 78 72

213 71 72 70

202 68 71 63

168 55 61 52

134 47 50 37

No. of dropouts — Reason of dropout Decided to stop/lack of efficacy Lost to follow-up Protocol violation/not correct dosage Adverse event Unknown

10

11

34

34

5 3 — — 2

3 1 6 — 1

17 2 11 — 4

29 1 1 — 3

No. of patients in the analysis 3 IU/m2 4.5 IU/m2 3-4.5 IU/m2

*At 48 months 18 of the remaining 134 patients dropped out, but their data could be included into the analysis.

bias by not analyzing dropouts has not been taken into account. Furthermore, there are no controlled data on the doseresponse relationship in children with ISS, and it is unknown whether the waning effect of rhGH over the years can be prevented by increasing the dosage. We report on the effects of rhGH in three dosage regimens on statural growth and bone maturation observed in a randomized multicenter clinical trial including 223 children with ISS. Growth was compared not only with a standard population of “normal” children but also with a large group of untreated children with ISS. Besides the dose-response relationship, we studied whether increasing the dosage of rhGH could prevent the decline in HV after the first year of therapy. We analyzed which factors were associated with gain in height SD score (SDS) for age, and we adjusted the 4-year effects for the dropout of patients.

PATIENTS AND METHODS Patient Series Between 1988 and 1990, 223 children from nine European countries were enrolled (France: 62 patients, the Netherlands: 32, Germany: 27, United Kingdom: 28, Spain: 19, Austria: 16, Israel: 16, Greece: 10, Finland: 9, and Norway: 4). The children visited pediatric centers be456

cause of short stature. The inclusion criteria were age >5 years, bone age (Tanner Whitehouse II-RUS)21 <10 years (female) or <12 years (male), height >2 SD below the mean according to British standards,22 prepubertal (breast <2 or genitals <2)23,24 and stimulated growth hormone peak ≥20 mU/L (equivalent to 10 µg/L), no organic cause of growth failure, or dysmorphic syndrome. Subclassification of the children with ISS was based on an international consensus.3 FSS was defined by a height measurement in the pretreatment year higher than the parent specific lower limit of height SDS, in distinction from non-FSS. In this study we also included children with persisting short stature after intrauterine growth retardation (defined on the basis of a child’s birth weight < –2 SD for gestational age).25 The study was approved by the local ethical committees, and informed consent was obtained from the patients and their parents.

Growth Hormone Therapy By means of block randomization without stratification, the patients were assigned to three therapeutic regimens of rhGH (Humatrope, 1 IU = 0.33 mg, Eli Lilly, Indianapolis, Ind.) administered 6 days per week subcutaneously. The first group received 3 IU/m2 body surface/day (n = 73, “3 IU group”), the second group received 4.5 IU/m2 bs/day (n = 78, “4.5 IU group”), and the third group received 3 IU/m2 bs/day in the first year and 4.5

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IU/m2 bs/day thereafter (n = 72, “3 to 4.5 IU group”). Expressed in milligrams per kilograms body weight, the dosages were 0.2 and 0.3 mg/kg body weight/week. The patients were seen at the clinic every 3 months during the first 2 years and yearly thereafter. At each visit height was measured four times with a Harpenden stadiometer. The height measurements were expressed as SDS for age according to ISS7 and British standards.22 Target height was defined as (heightfather + heightmother)/2 + or –6.5 cm for boys and girls, respectively, and was expressed as SDS based on British standards.22 Pretreatment HV was calculated over a period of at least 6 months before rhGH treatment was begun. During treatment HV was calculated only in prepubertal children over full year periods and was expressed in centimeters per year and in SDS with the standards developed for prepubertal children.26 Bone age according to TW221 was determined yearly by the same experienced investigator. Predicted adult height was calculated also with TW221 and expressed as SDS for British standards.22

Data Analysis Results are expressed as mean (SD) unless indicated otherwise. Baseline differences among the groups were tested by chi-squared test or analysis of variance (ANOVA). During rhGH therapy the repeated measures of a growth or bone maturation parameter were analyzed by mixed model ANOVA to adjust for multiple comparison.27 All effects were analyzed with F tests. Significant differences were investigated with paired or unpaired Student t tests. An intention-to-treat analysis was performed to evaluate the influence of the dropout of patients on the long-term effects of rhGH therapy on height. For this analysis we assumed that dropouts had grown further at the SDS level than they had at the moment of dropout, so that from the moment of dropout until 4 years after start, a patient’s height SDS would remain the same. To identify baseline determinants that are associated with an increase in height SDS for age, the data were analyzed with multivariate regression. The independent determinants were treatment group, sex,

THE JOURNAL OF PEDIATRICS Volume 132, Number 3, Part 1 birth weight SDS, target height SDS, pretreatment HV SDS, and age, bone age delay, and height SDS for age (ISS standards) at start. Significance level α was 0.05.

RESULTS Patients’ Characteristics Two hundred thirteen (96%) patients completed 1 year, 202 (91%) 2 years, 168 (75%) 3 years, and 134 (60%) 4 years of rhGH treatment. At the 4-year visit it was decided to stop therapy in another 18 patients. None of the patients dropped out because of an adverse event (Table I). Baseline characteristics of the children included in the 2-year analysis are shown in Table II. The mean age at start was 10.1 (2.3) years for boys and 8.7 (1.9) years for girls. No differences were found among the treatment groups except for height SDS for ISS standards, which was lower in the 3 IU group than in the 4.5 IU group (p = 0.01).

Two-Year Effects of rhGH Therapy HEIGHT SDS FOR AGE AND HV. In the three treatment groups height SDS for age based on ISS standards increased with time (p = 0.001, Fig. 1, Table III). The gain in height SDS was higher during the first year than during the second year (p < 0.001). The increase in height SDS differed among the treatment groups (p < 0.001), being higher in the 4.5 IU group than in the 3 IU or 3 to 4.5 IU groups (at 1 year p = 0.02 and p < 0.001 and at 2 years p = 0.006 and p = 0.003, respectively). With the British standards the increase in height SDS was less, but a similar trend was observed (Table III). Analysis of HV was based on 115 of the 202 patients, because 38 patients entered puberty during the first year and 49 during the second year. During the first year of rhGH therapy HV significantly increased (p < 0.001) from 4.4 (1.1) cm/yr to 8.6 (1.6) cm/yr (Fig. 2), with a higher increment in the 4.5 IU group than in the other groups (p = 0.009). In the second year HV decreased to 6.8 (1.3) cm/yr, still clearly higher than the pretreatment level (p < 0.001). During this year HV was sim-

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Table II. Baseline characteristics per dosage group for ISS children with complete 2 years follow-up

Sex: M/F Diagnosis IUGR FSS Non-FSS Unknown Age (yr) Bone age (yr)† Bone age delay (yr)† Pretreatment height velocity (cm/yr) Pretreatment HV SDS Height SDS for age (ISS standards) Height SDS for age (British standards) Predicted adult height SDS‡ Predicted adult height (cm)‡ Boys Girls Target height SDS§ Target height (cm)§ Boys Girls

3 IU (n = 68)

4.5 IU (n = 71)

3-4.5 IU (n = 63)

43/25

52/19

40/24

13 6 48 1 9.3(2.4) 8.4(2.5) 1.2(1.2) 4.3(1.1) –1.4(1.5) –0.9(1.3)* –2.7(0.7) –2.0(1.0)

10 3 58 — 9.9(2.2) 8.8(1.8) 0.9(1.2) 4.4(1.1) –1.0(1.5) –0.5(0.8) –2.5(0.4) –1.9(0.9)

6 5 49 3 9.8(2.1) 9.0(2.3) 0.8(1.2) 4.4(1.3) –0.9(1.8) –0.7(0.9) –2.6(0.5) –2.0(0.8)

158.0(5.1) 155.8(4.4) –1.0(0.9)

159.5(3.5) 157.4(4.3) –0.8(0.8)

159.4(4.2) 153.9(3.5) –0.8(0.9)

168.5(5.0) 156.2(6.6)

169.7(5.2) 156.1(5.6)

169.8(5.9) 157.5(5.6)

*p = 0.01 (3 IU vs 4.5 IU). †Total: n = 130 (3 IU: n = 46; 4.5 IU: n = 44; 3-4.5 IU: n = 40). ‡Total: n = 121 (3 IU: n = 42[M:28]; 4.5 IU: n = 43[M:33]; 3-4.5 IU: n = 36[M:25]. §Total: n = 197 (3 IU: n = 66[M:44]; 4.5 IU: n = 71[M:52]; 3-4.5 IU: n = 60[M:38]).

ilar in the three treatment groups. Increasing the dosage from 3 IU/m2 to 4.5 IU/m2 during the second year did not prevent the decline in HV but resulted in a smaller deceleration (3 to 4.5 IU group vs 3 and 4.5 IU groups combined, p = 0.008).

BONE AGE DELAY AND PREDICTED ADULT HEIGHT. Complete data on bone maturation were available in 130 of 202 patients. During 2 years of rhGH therapy, bone maturation accelerated by 2.4 (1.0) years, so that bone age delay became less (Table IV). In contrast to the 3.0 and 4.5 IU groups, bone age of the 3 to 4.5 IU group did not accelerate. This difference in time pattern among the groups was significant (p = 0.007). However, the degree of bone age delay was not significantly different among the groups at start, 1 year, or 2 years of treatment. Predicted adult height at start could not be determined in 9 of the 130 patients (too

young). During 2 years of rhGH treatment predicted adult height SDS increased with 1.09 (0.51) (p < 0.001) (Table IV), with significant differences among the treatment groups (p = 0.003). The 2year gain in predicted adult height was 0.89 (0.47) SDS in the 3 IU group, which was less compared with that in the other groups (4.5 IU, 1.20 [0.54] SDS, p = 0.006; 3 to 4.5 IU, 1.18 [0.47] SDS, p = 0.008).

IUGR. At baseline, patients with IUGR (n = 29) were shorter (ISS standards, –1.5 [1.6] SDS vs –0.6 [0.9] SDS, p = 0.005; British standards,–3.0 [0.9] vs –2.5 [0.5] SDS, respectively, p = 0.006), and predicted adult height SDS was less favorable compared with that in children without IUGR (n = 173) (–2.3 [0.9] SDS vs –1.9 [0.9] SDS, respectively, p = 0.04). Pretreatment height velocity and bone age delay at start were similar. During treat457

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Fig. 1. Height SDS for age based on ISS standards for children with ISS treated with rhGH for 2 years. Mean and 95% confidence interval of mean are presented. +, 3 IU; solid circles, 4.5 IU; empty squares, 3 to 4.5 IU.

Fig. 2. Height velocity for prepubertal children with ISS treated with rhGH for 2 years. Mean and 95% confidence interval of mean are presented. +, 3 IU; solid circles, 4.5 IU; empty squares, 3 to 4.5 IU.

ment the evolution in time of height SDS for age, bone age delay, and predicted adult height SDS was not significantly different among the treatment groups (data not shown).

dropout of the stop group was compared with the HV in the corresponding year of the ongoing group. HV in the second year was lower in the stop group compared with that in the ongoing group (6.0 [1.3] cm/yr and 7.0 [1.2] cm/yr, respectively, p < 0.01). During the third year an almost similar difference was observed (stop, 5.5 [1.0] cm/yr; ongoing, 6.3 [0.8] cm/yr, p < 0.01). Fig. 3 shows the results of the analysis based on the assumption that patients in the stop group had grown further at the SDS level than they had at the moment of dropout. For both groups combined the yearly gain in height SDS would then be 1.10 (0.51) in the first year, 0.56 (0.41) in the second year, 0.31 (0.37) in the third year, and 0.15 (0.35) in the fourth year. At each study year this increase was different from zero (each year p < 0.001). In this analysis the difference among the treatment groups with regard to the 4-year gain in height SDS just did not reach statistical significance (p = 0.06).

Four-Year Effects of rhGH Therapy ANALYSIS OF PATIENTS WHO COMPLETED 4 YEARS OF THERAPY. The 4year response of the 4.5 IU group was slightly better than that of the other groups (Table V), but of the evaluated parameters only the gain in height SDS for ISS standards differed significantly among the treatment groups (ANOVA, p = 0.03). Eighty-five percent of the boys and 83% of the girls entered puberty during 4 years of therapy. In boys the mean age at onset of puberty was 13.1 (1.4) years, and in girls, 11.4 (0.9) years.

ANALYSIS OF PATIENTS WHO DROPPED OUT OF THE STUDY. To investigate whether the dropout of patients biased the long-term results, patients who dropped out (stop group, n = 107) were compared with patients who were ongoing at 4 years of therapy (ongoing group, n = 116). At baseline both groups were similar (data not shown). For prepubertal children the HV in the year before 458

Linear Regression Analysis To evaluate which baseline determinants (independent determinants) besides rhGH therapy could be associated with the 2- and 4-year increase in height SDS for age, a regression analysis was performed. All determinants together with treatment group were included in a multi-

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Fig. 3. Estimated height SDS for age (ISS standards) of children who dropped out during 4 years of therapy (n = 107) and observed height SDS for age of children who were still receiving rhGH therapy after 4 years (n = 116). Mean and 95% confidence interval of mean are presented. Dashed line, dropouts; solid line, ongoing patients.

ple linear regression on analysis (∆ height SDS for age 0 to 2 years, R2 = 0.36, p < 0.001). The 2-year gain in height SDS for age was only significantly related to age at start (–0.19 [SE 0.03], p < 0.001) and therapy group (4.5 IU vs remaining groups, 0.43 [SE 0.11], p < 0.001). Age at start was the most important determinant in this model and in the 4-year model (data not shown). Therapy group was not significantly related to the 4-year gain in height SDS for age.

DISCUSSION This study, based on a large number of children with ISS, confirms data from earlier studies that rhGH treatment results in an increase in body stature over a period of at least 4 years. A clear dose-response relationship was seen in the first year, in agreement with earlier findings,28,29 but in the following years the effect of the dosage on height gain rapidly diminished. After 4 years only the increment in height SDS for the ISS standards was still significantly higher in children treated with 4.5 IU than with the other regimens.

THE JOURNAL OF PEDIATRICS Volume 132, Number 3, Part 1 We also determined whether the efficacy of the rhGH treatment could be improved by preventing the waning effect, which is also seen in other treated populations such as patients with growth hormone deficiency, chronic renal insufficiency, and Turner’s syndrome. Therefore we increased the dose of rhGH by 50% during the second year of treatment. This increase resulted in a smaller decrease of height velocity but could not prevent the waning effect. Over the long term the effect of the dosage increase was no longer significant. In an uncontrolled study in which the rhGH dose was increased was increased from 12 to 20 IU/m2/week after 2 years, HV was reported to increase significantly.12 Doubling the injection frequency from 3 to 6 injections a week during the second year of treatment resulted in stabilization of the height velocity.13 Recombinant human growth hormone therapy not only stimulated growth but also led to an accelerated bone maturation. After 4 years of rhGH treatment the bone age increment was 4.8 years without significant differences among the three groups. This phenomenon was also observed in some other long-term studies9,14-16 but not in others.10,17-19 The increment in predicted adult height SDS after 4 years was similar to that in most other studies9,12,14,19 with the exception of two.16,30 The results indicate that the average effect of rhGH on final height will probably be modest, in line with earlier data by us and others,4,9,16 with a large interindividual variation.16 Long-term studies with an intensive treatment for a relatively benign condition make great demands on the motivation of the patients to complete the full protocol. In our study 75% of patients completed 3 years and 60% completed 4 years of therapy, similar to an earlier study.14 None of the patients in our study stopped because of an adverse event. An important reason to stop was probably the children’s disappointment about their growth; during the year before discontinuation the height velocity of the dropouts was 1 cm/yr lower than in the ongoing patients. To estimate the influence of the dropouts on the 4-year results, we assumed that they had grown further at the same SDS level than they had at the mo-

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Table III. Cumulative change in height SDS during 2 years of treatment for the three dosage groups of patients with ISS with complete 2 years of follow-up.

Study months

3 IU (n = 68)

4.5 IU (n = 71)

3-4.5 IU (n = 63)

1.3(0.5)* 2.0(0.8)†

1.0(0.4) 1.6(0.7)

0.7(0.3)* 1.0(0.5)†

0.5(0.2) 0.8(0.5)

Height SDS for age (ISS standards) 0-12 1.1(0.5) 0-24 1.7(0.8) Height SDS for age (British standards) 0-12 0.6(0.3) 0-24 0.8(0.4) *4.5 IU vs 3-4.5 IU: p ≤ 0.01. †4.5 IU vs 3 IU: p ≤ 0.01; 4.5 IU vs 3-4.5 IU: p ≤ 0.01.

Table IV. Growth and bone maturation parameters per treatment group for patients with ISS with complete 2-year data on bone age

Month of study

3 IU (n = 46)

4.5 IU (n = 44)

3-4.5 IU (n= 40)

0.9(1.2) 0.4(1.2) 0.3(1.2)

0.8(1.2) 0.8(1.0) 0.8(1.0)

–2.4(0.4)* –1.8(0.5)† –1.4(0.7)†

–2.6(0.5) –2.1(0.5) –1.8(0.6)

–1.9(0.9) –1.1(0.9) –0.7(1.0)

–2.0(0.8) –1.3(0.9) –0.8(1.0)

Bone age delay (yr) 0 1.2(1.3) 12 0.8(1.2) 24 0.6(1.2) Height SDS for age (British standards) 0 –2.7(0.7) 12 –2.2(0.7) 24 –2.0(0.7) Predicted adult height SDS (British standards) 0‡ –2.0(1.0) 12 –1.5(1.2) 24 –1.2(1.2)

*4.5 IU vs 3 IU, p ≤ 0.01. †4.5 IU vs 3 IU, p ≤ 0.01; 4.5 IU vs 3 IU, p ≤ 0.01. ‡n = 121 as nine children were too young to determine predicted adult height SDS.

Table V. Increment over 4-year period in growth and maturation parameters per treatment group for patients with ISS who completed 4 years of therapy

Height SDS for age (ISS standards) Height SDS for age (British standards) Bone age (years)† Predicted adult height SDS (British standards)‡

3 IU (n = 47)

4.5 IU (n = 50)

3-4.5 IU (n = 37)

2.3(1.1) 1.1(0.7) 4.9(1.5) 1.4(0.5)

2.8(1.0)* 1.4(0.5) 4.8(1.2) 1.7(0.7)

2.4(1.2) 1.1(0.7) 4.7(1.4) 1.5(0.7)

*p ≤ 0.05 (3 IU vs 4.5 IU). †Total: n = 102 (3 IU: n = 36; 4.5 IU: n = 38; 3-4.5 IU: n = 28). ‡Total: n = 94 (3 IU: n = 32; 4.5 IU: n = 37; 3-4.5 IU: n= 25).

ment of dropout. When the observed height SDS of the ongoing patients was combined with the assumed height SDS of the dropouts, the yearly gain in height SDS was still significantly different from zero, suggesting that growth hormone therapy resulted in an improvement of

growth also during the third and fourth year, even if all dropouts would have remained in the study. We evaluated which baseline determinants besides rhGH treatment were associated with 2- and 4-year increases in height SDS for age in a multiple linear re459

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gression analysis. During the first 2 years a higher dosage of rhGH resulted in a significantly higher gain in height SDS for age. After 4 years, however, this gain was no longer demonstrable. This result is in line with a study of Guyda31 in which (near) final height data of 99 short normal subjects were compiled and no significant dose-response relationship was found. Both the 2- and 4-year multivariate regression models showed that the older the patient is at the start, the less the gain in height SDS for age will be. Similar results were found by Zadik et al.,32 who observed an inverse relation between age at start and the 4-year gain in height SDS for age. We conclude that increasing the dosage of rhGH from 3 IU/m2/day to 4.5 IU/m2/day after the first year could only partially prevent the decline in HV. After 4 years the height gain was slightly better with the higher dosage. However, bone age advanced on average 4.8 years during this period, and the modest gain in predicted adult height was similar for the three dosage regimens. After correction was done for dropouts, the height gain over a 4-year period remained significant. Any effect on final height would probably be modest and remains to be determined. We thank Eli Lilly for supply of growth hormone, M. Killey for assistance, Dr. R. G. J. Westendorp and Dr. A. H. Zwinderman for epidemiologic and statistical advice, and Dr. L. Cox for bone age assessment.

REFERENCES 1. Ranke MB. The KIGS aetiology classification system. In: Ranke MB, Gunnamson R, editors. Progress in growth hormone therapy — 5 years of KIGS. Mannheim: J & J Verlag; 1994. p. 51-61. 2. Ivarsson SA. Can growth hormone treatment increase final height in constitutional short stature? Acta Paediatr Scand Suppl 1989;362:56-60. 3. Ranke MB. Towards a consensus on the definition of idiopathic short stature [summary]. Horm Res 1996;45(suppl 2):64-6. 4. Wit JM, Kamp GA, Rikken B. Spontaneous growth and response to growth hormone treatment in children with growth hormone deficiency and idiopathic short stature. Pediatr Res 1996;39:295-302. 5. Guyda HJ. Use of growth hormone in children with short stature and normal growth

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