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Article: Nelly Mauras, Ora Hirsch Pescovitz, Vivek Allada, Michael Messig, Michael P. Wajnrajch, Barbara Lippe on Behalf of the Transition Study Group Limited efficacy of growth hormone (GH) during transition of GH deficient patients from adolescence to adulthood: a phase III multi-center, double blind, randomized two-year trial J Clin Endocrinol Metab 2005; 0: jc.2005-0208v1 [Abstract]

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GH use in adolescents in transition

Nelly Mauras, Ora Hirsch Pescovitz, Vivek Allada, Michael Messig, Michael P. Wajnrajch and Barbara Lippe   (6 December 2005)

Letter to the Editor

William M. Drake, P. V. Carroll, K. T. Maher, K. A. Metcalfe, C. Camacho-Hübner, N. J. Shaw, D. B. Dunger, T. D. Cheetham, M. O. Savage, J. P. Monson   (4 November 2005)

GH use in adolescents in transition 6 December 2005
Nelly Mauras, MD Nemours Children's Clinic -Jacksonville, Ora Hirsch Pescovitz, Vivek Allada, Michael Messig, Michael P. Wajnrajch and Barbara Lippe Send letter to journal: Re: GH use in adolescents in transition nmauras{at}nemours.org Nelly Mauras, et al.	We recently reported data on a large, double blind, placebo controlled, 2 year trial using GH in adolescents with GH deficiency that had completed their linear growth (1). Dr. Drake and colleagues, in a letter to the editor (2), have asked us for further clarification on certain aspects of our data set and analysis, particularly as it pertains to the issues of bone mineral density (BMD) accrual in the reported cohort. First, they wanted to know if the rate of BMD accrual, not just Z score changes, was truly comparable among the 3 groups (GH-treated, placebo (PL)-treated and controls). The mean (SD) net change from baseline in BMD at 24 months for lumbar spine was: GH: +0.036 (0.016); PL: +0.046 (0.027); Controls: +0.050 (0.014), p=0.732; for whole body: GH: +0.034 (0.007), PL: +0.014 (0.016); Controls: +0.036 (0.021), p=0.487. They also questioned whether differences in size could account for the reported lack of differences among the groups. However, the mean heights were remarkably similar among the groups at all time points, and at 24 months in particular for males: GH: 174 (9.5) cm, PL: 174.6 (8.0), Controls: 172.2 (8.4); females: GH: 160.4 (7.1), PL: 159.9 (3.9), Controls: 160.1 (8.6). They also queried the apparent decrease in lean body mass over 24 months observed even in the GH-treated group. This is not entirely surprising considering the substantial decrease in dose that these subjects received (~20µg/kg/d), which is an intermediate dose used in this transition phase, as compared to pre-study doses (~42µg/kg/d). Several differences in study characteristics between the Drake study (3) and ours are also worth further discussion. Their average pre-study dose was about half of the one received by our subjects during their actively growing years. Also, both the GH and non GH-treated groups in Drake’s open label trial had an increase in BMD after one year, however, it was only significant in the GH-treated group, possibly related to their smaller sample size. We agree that although all our subjects on re-testing with insulin-induced hypoglycemia had a peak GH <5ng/ml, the IGF-I ranges at 24mo suggest in some, a less profound level of deficiency. This, in turn, makes more compelling the argument of the great need for individualization of treatment before we commit youngsters with childhood onset GH deficiency to GH treatment for the rest of their lives. We agree that the higher doses conventionally used in the US to treat GH deficiency in childhood, likely explain the near normalization of bone mass and lean body mass we observed, allowing for the maintenance of BMD in the 2 years of study despite lack of GH treatment. Our data support the notion that in those GH deficient patients with normal body composition, BMD and IGF-I after completion of linear growth and discontinuation of GH therapy, careful follow up should determine whether and when the adult GH-deficiency syndrome develops and whether resumption of GH therapy is eventually warranted. This could in turn result in better patient selection and potentially better long-term treatment compliance. References 1. Mauras N, Pescovitz OH, Allada V, Messig M, Wajnrajch, MP, Lippe B. 2005. Limited efficacy of GH during transition of GH-deficient patients from adolescence to adulthood: a phase III multicenter, double blind, randomized tow year trial. J Clin Endocrinol Metab 90:3946-3955 2. Drake WM, Carroll PV, Maher KT, Metcalfe KA, Camacho-Hubner C, Shaw NJ,Dunger DB, Cheetham TD, Savage MO, Monson JP. E-Letter to the Editor, J Clin Endocrinol Metab (4 November 2005–on line) 3. Drake WM, Carroll PV, Maher KT, Metcalfe KA, Camacho-Hubner C, Shaw NJ, Dunger DB, Cheetham TD, Savage MO, Monson JP. 2003 The effect of cessation of GH therapy on bone mineral accretion in GH-deficient adolescents at the completion of linear growth. J Clin Endocrinol Metab 88: 1658-1663
Letter to the Editor 4 November 2005
William M. Drake, MD St. Bartholomew’s Hospital, University of London, P. V. Carroll, K. T. Maher, K. A. Metcalfe, C. Camacho-Hübner, N. J. Shaw, D. B. Dunger, T. D. Cheetham, M. O. Savage, J. P. Monson Send letter to journal: Re: Letter to the Editor w.m.drake{at}qmul.ac.uk William M. Drake, et al.	We read the recent report of Mauras et al on the consequences of continuation of growth hormone (GH) therapy in GH deficient (GHD) adolescents at the completion of linear growth (1). Their data for bone mineral density (BMD) Z-scores are apparently at odds with our previous finding of a beneficial effect of continuation of GH replacement in a similar patient group (2). Here, we seek to clarify some aspects of their methodology and results to explore the apparent discrepancies in the effect of GH in this patient group (2, 3). It would have been instructive to include the raw data for bone mineral content (BMC) and height. Dual-energy X-ray absorptiometry (DXA) measures areal BMD, which in adolescents is dependent, in part, on growth. DXA-BMD (Z-scores) may, therefore, change with alterations in BMC, vertebral size or both. Is it possible that an absolute BMC advantage in the GH-treated group could have been concealed by an increase in height, thereby resulting in equivalent BMD measurements/Z-scores at the study conclusion? Although the authors state that there was no statistically significant difference in Z-scores between GH- and placebo- treated patients, table 5 shows that LS Z-score fell in all three groups. This does not necessarily imply an absolute fall in BMD, but indicates a failure of bone mass accrual relative to age-matched healthy subjects. Assuming a constant vertebral size and cross-sectional area, a fall in LS Z-score of ~0.7 SD (placebo group, spine and whole body, table 5) could be compatible with a static BMD in the Mauras patients. However, this would have to be accompanied by far greater increases in BMD in the densitometer reference population than in cross-sectional studies of normal individuals (4, 5). Assuming a standard increment in LS-BMD in the reference population, a fall in Z-score of 0.7 would represent an absolute decline in BMD in the Mauras patients; this would be highly abnormal in adolescent individuals. A similar, surprising fall in % lean body mass, which characteristically parallels changes in BMC, is evident in table 4. Why might GH-treated hypopituitary adolescents lose BMD on discontinuing/reducing GH therapy? One explanation lies in table 3 (serum IGF-I concentrations). Age-related reference ranges for serum IGF-I are less robustly defined for adolescents than adults, but the authors report a median (range) of 262 ng/ml (133-310) in ‘control’ patients with normal GH reserve 12 months after discontinuation of GH. Against this reference point, median (range) serum IGF-I values of 402 ng/ml (69-668, GH-treated) and 427 ng/ml (151-821, placebo) would imply significantly supraphysiological GH exposure at the time of completion of linear growth and randomization. Excess GH is associated with increased bone mass and density -- changes that are corrected by successful surgical and/or medical treatment. Further, although a substantial proportion of adults with severe GHD have a serum IGF-I in the lower half of the reference range, a value of 355 ng/ml in an adolescent with severe GHD is very atypical. What was the peak GH concentration to dynamic testing in this subject? We suggest that all these observations may complicate interpretation of the data and between-group comparisons. Finally, we concur that the approach to the GH-deficient adolescent in transition should be individualized and have previously articulated this in detail. References 1. Mauras, N, Pescovitz, OH, Allada, V, Messig, M, Wajnrajch, MP, Lippe, B. 2005 Limited Efficacy of Growth Hormone (GH) during Transition of GH-Deficient Patients from Adolescence to Adulthood: A Phase III Multicenter, Double-Blind, Randomized Two-Year Trial. J Clin Endocrinol Metab 90:3946-3955 2. Drake WM, Carroll PV, Maher KT, Metcalfe K. A, Camacho-Hubner C, Shaw NJ, Dunger DB, Cheetham TD, Savage MO, Monson JP. 2003 The effect of cessation of growth hormone (GH) therapy on bone mineral accretion in GH- deficient adolescents at the completion of linear growth. J Clin Endocrinol Metab 88:1658-1663 3. Shalet SM, Shavrikova E, Cromer M, Child CJ, Keller E, Zapletalova J, Moshang T, Blum WF, Chipman JJ, Quigley CA, Attanasio AF. 2003 Effect of growth hormone (GH) on bone in postpubertal GH-deficient patients: a 2 year randomized, controlled dose-ranging study. J Clin Endocrinol Metab 88:4124-4129 4. Bonjour JP, Theintz G, Buchs B, Slosman D, Rizzoli R. 1991 Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence. J Clin Endocrinol Metab 73:555-563 5. Matkovic V, Jelic T, Wardlaw GM, Ilich, JC, Goel PK, Wright JK, Andon MB, Smith KT, Heaney R. 1994 Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis: inference from a cross-sectional model. J Clin Invest 93:799-808