Additional Beneficial Effects of Alendronate in Growth Hormone (GH)-Deficient Adults with Osteoporosis Receiving Long-Term Recombinant Human GH Replacement Therapy: A Randomized Controlled Trial

Abstract

We conducted a randomized controlled trial in osteoporotic adult GH-deficient (GHD) patients to assess whether additional treatment with a bisphosphonate would further favorably influence parameters of bone turnover and bone mineral density measurements (BMD). All patients were receiving stable recombinant human (rhGH) replacement therapy for 4 yr at the start of the study. Eighteen GHD patients with osteoporosis were randomized to continue their rhGH maintenance dose or to receive combination therapy with rhGH and alendronate for 12 months. All patients were calcium and vitamin replete, and there were no changes in calcium, vitamin D, or hormone replacement therapy for the duration of the study. At baseline there were no significant differences between the alendronate and the control group in parameters of bone turnover, BMD, or prevalence of vertebral fractures. Childhood-onset and adult-onset GHD were equally distributed between the groups, with no statistical differences in age and gender or other parameters between groups. Mean serum osteocalcin, serum bone-specific alkaline phosphatase, and urinary N-telopeptide/creatinine ratio were within the normal range at the start of the study. In the alendronate group all measured parameters of bone turnover, i.e. bone-specific alkaline phosphatase, osteocalcin, and urinary N-telopeptide/creatinine ratio, significantly decreased after 6 months, with no further decrease thereafter. No changes were observed in the control group. In the alendronate-treated patients serum bone-specific alkaline phosphatase decreased from 10.9 +/- 0.9 to 6.8 +/- 0.7 microg/L at 6 months (P < 0.001), serum osteocalcin decreased from 3.9 +/- 0.4 to 1.7 +/- 0.3 microg/L (P < 0.001), and the urinary N-telopeptide/creatinine ratio decreased from 27.3 +/- 7.0 to 6.4 +/- 0.8 nmol/mmol (P = 0.01). In this group, lumbar spine BMD significantly increased from baseline by 3.4% at 6 months (P = 0.001) and by 4.4% at 12 months (P < 0.001) of treatment, with no further significant increase between 6 and 12 months (P = 0.217). No changes in lumbar spine BMD were observed in the control group. There were no significant changes in femoral neck BMD in either group for the duration of the study. No incident vertebral or peripheral fractures were documented in either group at the end of the study. In summary, this is the first report indicating that treatment with alendronate was able to significantly increase BMD at the lumbar spine in GHD patients with osteoporosis receiving stable rhGH replacement for 4 yr. This increase was significantly greater in alendronate-treated patients than in patients maintained on rhGH. The increase in lumbar spine BMD in the alendronate-treated patients was associated with a decrease in the measured markers of bone turnover, whereas these markers did not change further in the patients maintained on rhGH. This controlled study suggests that additional treatment with alendronate in GHD patients with osteoporosis receiving stable rhGH replacement therapy is effective in increasin...

Effects of up to 15 years of recombinant human GH (rhGH) replacement on bone metabolism in adults with Growth Hormone Deficiency (GHD): The Leiden Cohort Study

“…We have previously shown that 2 years of physiological dose of rhGH in GHD adults increased bone turnover in favour of bone formation, as reflected by a significant increase in BMD that sustained after 7 years of treatment . In addition, during the first 4 years of rhGH supplementation, we observed a significant greater increase in BMD in GHD patients with osteoporosis with additional bisphosphonate treatment . These additional beneficial effects of bisphosphonates were preserved during another 3 years of rhGH replacement …”

“…Untreated GHD in adults is characterized by low bone turnover, decreased BMD and BMC, which increased or even normalized by short‐term rhGH replacement . We have previously shown that 2 years of physiological dose of rhGH in GHD adults increased bone turnover in favour of bone formation, as reflected by a significant increase in BMD that sustained after 7 years of treatment . In addition, during the first 4 years of rhGH supplementation, we observed a significant greater increase in BMD in GHD patients with osteoporosis with additional bisphosphonate treatment .…”

Additional Beneficial Effects of Recombinant Growth Hormone in Alendronate-treated Patients with Idiopathic Osteoporosis

“…A randomized controlled trial in osteoporotic GHdeficient adult patients receiving stable doses of rhGH for 4 years reported the beneficial effects of adding bisphophonates [13]. The increase in lumbar spine shown in table 3.…”

“…In order to prevent such effect, bisphosphonates have been successfully associated with growth hormone in IGF-1-deficient mice [12] and GH-deficient patients [13].…”

Bone Metabolism During Chronic Growth Hormone Deficiency – Experimental and Clinical Studies

“…38 Additional treatment with alendronate in GHD patients receiving stable GH replacement therapy is effective in further increasing BMD at the lumbar spine. 41 Also, treatment of GHD adults with IGF-1 increases bone formation without increasing bone resorption, suggesting that IGF-1 may exert a direct anabolic effect on bone forming cells in vivo and that local increases in IGF-1 gene and protein expression are secondary to effects of GH on osteoblasts. 42 Similar effects are found in GH-deficient transgenic mice treated with IGF-1.…”