BOSTON – After more than 2 decades of follow-up, mortality rates were significantly higher in patients who had been treated with recombinant growth hormone for short stature as children, especially those who received the highest doses.
Notable increases in mortality were observed related to bone tumors and diseases of the circulatory system such a subarachnoid or intracerebral hemorrhage, according to Dr. Jean-Claude Carel of the Hôpital Robert Debré and Université Denis Diderot in Paris, who presented the results at the annual meeting of the Endocrine Society.
According to Dr. Carel, although there has been a considerable amount of data linking recombinant growth hormone and health, few studies have provided long-term follow-up. The data released were French data from the SAGHE (Safety and Appropriateness of Growth Hormone Treatments in Europe) trial, a large study from eight European countries evaluating the health of individuals treated in childhood for idiopathic growth hormone deficiency (75% of the group), idiopathic short stature, and body length at birth that was short for gestational age. The study was initiated first in France (2 years before the rest of Europe), and thus the longest follow-up is available for this cohort.
The group consisted of 6,928 children who were treated during 1985-1996. Follow-up data on vital status were available in September 2009 for almost 95% of the patients, providing 116,403 person-years of observation. The mean age at the end of treatment was 15 years and the mean duration of treatment was almost 9 years. During the follow-up, 93 deaths were observed, compared with 69.6 expected deaths, yielding a higher standardized mortality ratio (SMR) of 1.33, which Dr. Carel said was significant but moderate.
Although the mean dose was 24.6 mcg/kg per day – lower than doses currently recommended today – there was a significant trend of increasing mortality and growth hormone dose (P = .04). In multivariate analysis adjusted for height at the start of treatment, mortality rates in the 285 who received high doses (greater than 50 mcg/kg per day) was almost three times that of the low-dose group (adjusted SMR, 2.94; 95% confidence interval, 1.22-7.07). No significant effects were seen for treatment duration or overall growth hormone exposure. Mortality was elevated in children with the shortest stature at treatment initiation (SMR, 1.57).
Further analysis about cause of death found that although overall cancer-related mortality was not higher than that of the general population, deaths resulting from bone tumors were five times higher than expected (SMR, 5.00; 95% CI, 1.01-14.63), and deaths resulting from diseases of the circulatory system were threefold higher (SMR, 3.07; 95% CI, 1.40-5.83). Particularly concerning were findings of more than a sixfold increase in deaths resulting from subarachnoid or intracerebral hemorrhage (SMR, 6.66; 95% CI, 1.79-17.05) and a sevenfold increase in other heart diseases (cardiomyopathy and cardiomegaly, SMR, 7.11; 95% CI, 0.80-25.67).
"These preliminary results should be taken with caution due to the low event rate, limited power, and potentially undetected confounders. Causality cannot be determined. Additional data are needed, including additional data from other European countries participating" in SAGHE, said Dr. Carel.
Dr. Carel reported ties to Lilly USA and Pfizer Global Research and Development.