The influence of gender on the short and long-term effects of growth hormone replacement on bone metabolism and bone mineral density in hypopituitary adults: a 5-year study

OBJECTIVES: The objectives of this study were to investigate the effects of GH replacement therapy in hypopituitary adults with growth hormone deficiency (GHD) on activation of bone remodelling during dose titration and on BMD over a median of 58 months of continuous therapy. STUDY DESIGN: Open label study in adult patients with GHD. rhGH was commenced at dose of 0.8 IU subcutaneously daily (0.4 IU if hypertensive or glucose tolerance impaired) with subsequent dose titration based on 2 weekly measurement of serum IGF-I until levels reached the target range (between the median and upper end of the age related reference range). In patients previously commenced on GH using weight based regimens the dose of GH was adjusted during clinical follow-up in order to maintain serum IGF-I in the target range. PATIENTS: Initial effects of GH on bone remodelling during dose titration were studied in 17 patients (8F). Long-term effects of GH were determined in a separate group of 13 GHD adults (6F) over a median period of 58 months (range 44-72). MEASUREMENTS: Osteoblastic activity was estimated by measuring serum bone specific alkaline phosphatase (S-BAP). BMD was determined at both lumbar spine (L2-L4) and femoral neck by dual energy X-ray absorptiometry (DEXA). RESULTS: During dose titration a significant increment in S-BAP was observed by 10 weeks in females but occurred later in males (12-26 weeks). In the long term treatment group there was a significant increment in S-BAP compared to baseline (P = 0.013) after 6 months GH treatment. After long-term GH treatment (median 58 months) S-BAP levels decreased and were no longer statistically significantly different from baseline at the end of the study period. A similar response was observed in male and female patients. There were no significant differences in baseline BMD between male and female patients at either lumbar spine or femoral neck in the long term treatment group. No significant changes were observed in BMD after 6 months GH treatment in either lumbar spine or femoral neck but BMD increased over the remainder of the study at both sites (P = 0.023 and P = 0.03 respectively). When analysed by gender male patients showed a clear positive change in BMD after longer-term replacement in both lumbar spine and femoral neck (P = 0.01 and P = 0.02 respectively) but female patients showed no significant changes. Qualitatively similar results were observed when analysing changes in BMD expressed as Z scores. CONCLUSION: This study demonstrates an earlier onset of GH activation of bone remodelling as reflected by S-BAP in females compared to males and confirms that long-term GH treatment in hypopituitary adults with GH deficiency increases or preserves BMD both at lumbar spine and femoral neck. However male patients seem to derive the greater benefits in BMD from long-term GH replacement; in females BMD appears simply to be stabilized rather than increased. This constitutes a genuine gender difference in susceptibility given that serum IGF-I was in the upper part of the reference range in all subjects.