Long-term GH Therapy Does Not Advance Skeletal Maturation in Children and Adolescents

Abstract

Context: There is no consensus on the effect of recombinant human GH (rhGH) therapy on skeletal maturation in children despite the current practice of annual monitoring of skeletal maturation with bone age in children on rhGH therapy.

Aims: To investigate the effects of long-term rhGH therapy on skeletal age in children and explore the accuracy of bone age-predicted adult height (BAPAH) at different ages based on 13 years of longitudinal data.

Methods: A retrospective longitudinal study of 71 subjects aged 2 to 16 years, mean 9.9 ± 3.8 years, treated with rhGH for nonsyndromic short stature for a duration of 2 to 14 years, mean, 5.5 ± 2.6 years. Subjects with syndromic short stature and systemic illnesses such as renal failure were excluded.

Results: Bone age minus chronological age (BA-CA) did not differ significantly between baseline and the end of rhGH therapy (-1.05 ± 1.42 vs -0.69 ± 1.63, P = 0.09). Piecewise regression, however, showed a quantifiable catch-up phenomenon in BA of 1.5 months per year of rhGH therapy in the first 6.5 years (P = 0.017) that plateaued thereafter (P = 0.88). BAPAH overestimated near-adult height in younger subjects but became more accurate in older subjects (P < 0.0001). IGF-I levels correlated significantly with increases in child's height and BA-CA.

Conclusion: Long-term rhGH therapy demonstrated an initial catch-up phenomenon in skeletal maturation in the first 6.5 years that plateaued thereafter with no overall significant advancement in bone age. These findings are reassuring and support strategic, but not the insurance company mandated reflexive annual monitoring of skeletal maturation with bone age in children receiving rhGH therapy.

Keywords: bone age; growth hormone deficiency; height velocity; short stature.

Figure 1.

CONSORT flow diagram.

Figure 2.

(A) Scatterplot of the relationship between bone age (BA) and chronological age (CA) at baseline, before recombinant human GH (rhGH) therapy, showing a strong correlation between BA and CA. Additionally, 81.4% of the subjects had BA values that were less than their CA. (B) Scatterplot of the relationship between BA and CA at the final visit showing a significant but reduced correlation between BA and CA when compared with the baseline relationship in Fig. 2A. Interestingly, 65.7% of the subjects still had BA values that were less than their CA, and such patients have the potential for further growth in height for a few more years even after the cessation of rhGH therapy.

Figure 3.

This figure shows that the initial catchup phase of bone age (BA) advancement following the institution of rhGH therapy spans the first 6.5 years and then slows down. This is represented in this graph of the Quasi-likelihood under the Independence Model Criterion (QIC) for generalized linear regression model (GENMOD) at various cutoff points in years. The QIC shows that the optimal time point for the change of slope of the scatter plots for BA minus chronological age (BA-CA) versus the duration of recombinant human GH (rhGH) occurred at the 6.5-year mark. QIC was used because of its precision as a measure of goodness-of-fit for generalized estimating equation (GEE) models, whereas a smaller QIC value denotes a better fit [36].

Figure 4.

(A) Scatterplots of the relationship between serial bone age minus chronological age (BA-CA) assessments and the duration of recombinant human GH (rhGH) therapy. (B) Graph of the relationship between serial BA-CA assessments and the duration of rhGH therapy. This graph shows that the delayed BA increases during the first 6.5 years of rhGH to approximate the CA but does not progress to BA advancement in this long-term study.

Figure 5.

(A) Graph of the relationship of bone age–predicted adult height (BAPAH) z score minus child’s concurrent height z score versus the duration of recombinant human GH (rhGH) therapy. The duration of rhGH therapy did not affect the difference between BAPAH z score and concurrent height z score (P = 0.68). (B) Graph of the relationship of BAPAH z score minus child’s concurrent height z score versus bone age. The difference between BAPAH z score and concurrent height z score was greater at a younger bone age but became negligible with advancing bone age (P < 0.0001), signifying a more accurate prediction of final adult height with advancing years. Thus, the Bayley-Pinneau prediction model may be inaccurate in the early years compared with the later years.