Introduction: Untreated growth hormone deficiency (GHD) is linked to decreased bone mineral density (BMD) and bone mineral content (BMC) as well an increased risk for fracture. Previous studies suggest that treatment with recombinant human GH (rhGH) replacement for up to 7 years results in progressive increases in BMD followed by plateau. The present study was designed to investigate the effects of up to 15 years of treatment with rhGH replacement.
Methods: The study included 230 adults (53% female) with GHD who had been receiving rhGH replacement therapy for at least 5 years. The majority of the group (88%) had adult-onset GHD. Multiple pituitary hormone deficiencies were found in nearly all the participants.
The starting dose for GH replacement was 0.2 mg/day, which was adjusted monthly in the first 6 months and annually thereafter with the goal of maintaining IGF-1 concentrations within a standard deviation score (SDS) between 0 and +2.
The participants underwent assessments of bone turnover markers, BMD, BMC, T-scores at the lumbar spine and femoral neck, and clinical fractures, at baseline and on a yearly basis after starting rhGH replacement therapy.
Results: Significant increases in mean lumbar spine BMD, BMC, and T-scores occurred during the first 10 years of treatment with rhGH replacement and remained stable thereafter (Table). These beneficial effects were greater in men than in women, with men having a significantly greater increase in lumbar spine BMD and BMC (but not femoral neck BMD) than women at all time points (P<0.01). Men also had a greater increase in lumbar spine T-scores than women after 10 and 15 years of treatment (data not shown).
The treatment did not significantly alter BMD at the femoral neck. However, given that this measurement did not decrease during the 15 years of the study as would be expected with increasing age over time, the authors suggested that rhGH replacement does exert a beneficial effect at the femoral neck.
Concomitant use of bisphosphonates did not add to the effects of rhGH replacement on BMD. Low BMD at baseline was associated with a significantly greater increase in BMD and BMC over time. In contrast, a higher GH dose at year 1 was associated with a significantly decreased response to rhGH replacement on BMC.
The incidence of clinical fracture was 20.1 per 1,000 person-years, which the authors note is not increased compared with that found in the Rotterdam Study; the Rotterdam study followed a healthy population age > 55 years and found a vertebral fracture rate of 10.9 per 1,000 person-years and a nonvertebral fracture rate of 25.0 per 1,000 person-years in women and 9.6 per 1,000 person-years in men.1,2
The mean vitamin D levels and bone turnover rates were within normal ranges throughout the study period.
Conclusion: The long-term effects of rhGH replacement in adults with GHD include an increase in lumbar spine BMD, BMC, and T-scores in the first 10 years of treatment followed by stabilization thereafter for up to 15 years. These beneficial effects on lumbar spine BMD and BMC were greater among men than women at all time points. The overall beneficial effects were not altered by concomitant use of bisphosphonates.
Appelman-Dijkstra NM, Claessen KM, Hamdy NA, Pereira AM, Biermasz NR. 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. Clin Endocrinol (Oxf). 2014;81(5):727-735.
1. Schuit SC. van der Klift M, Weel AE, et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone. 2004;34:195-202.
2. Van der Klift M, De Laet CE, McCloskey EV, Hofman A, Pols HA. The incidence of vertebral fractures in men and women: the Rotterdam Study. J Bone Miner Res. 2002;17(6):1051-1056.
Commentary by Tamara L Wexler MD, PhD
Tamara L. Wexler, MD, PhD, is an endocrinologist specializing in neuroendocrinology and reproductive endocrinology. She is the Director of the NYU Langone Medical Center Pituitary Center in New York, NY, as well as an Attending in Medicine at Massachusetts General Hospital, Boston, MA.
Growth hormone deficiency is a low bone turnover state, with associated poorer BMD and BMC and osteoporosis. GH replacement increases bone turnover, seen clinically as increased BMD after a short period of reduction/stabilization. While not all studies consistently demonstrate a positive impact of GH replacement on BMD,1,2 there is evidence (from this and other groups) suggesting that BMD/BMC increase with rhGH for study periods of up to 5 to 7 years, after which they may plateau. In one study that followed hypopituitary subjects with adult-onset GHD for 15 years,3 lumbar and total body BMD/BMC increased over the full 15 years, while femoral BMD/BMC peaked at 7 years before beginning a gradual decline.
Appelman-Dijkstra and colleagues set out to investigate the longer-term impact of GH replacement on bone in the Leiden Cohort Study, a cohort of adult patients with GHD enrolled from 1994, including those patients who had been on GH replacement for at least 5 years. They followed 230 adult GHD patients (mean age 47.1 years, 52.6% female, and 88% with adult-onset GHD) for 15 years on rhGH; subjects were on stable replacement of other pituitary deficiencies. GHD was diagnosed by insulin tolerance test (ITT) (GH peak < 3 μg/L) or GHRH-arginine stimulation test (if ITT was contraindicated) with BMI-adjusted threshold levels; all 12% of included subjects with childhood-onset GHD had been retested for GHD after 3 months off GH replacement. The rhGH dose was initiated at 0.2 mg/day, adjusted monthly in the first 6 months and yearly thereafter to target IGF-1 values in the appropriate reference range (SDS 0 to +2). Bone parameters measured included yearly BMD (by DXA) at the lumbar spine and femoral neck; BMC; bone turnover markers; and clinical fracture data per medical records, with vertebral fracture diagnosed either clinically or radiographically. Other bone-modulating therapeutic agents were allowed when prescribed by patient physicians. BMI range of the included subjects was 16.9-57.1 kg/m2, with mean of 27.3 kg/m2.
Of the 230 subjects enrolled, 211 subjects completed 5 years of rhGH replacement therapy 98 subjects completed 10 years, and 43 subjects completed 15 years.
Bone markers indicated normal bone turnover during the study period of stable rhGH replacement. Lumbar BMD did increase, with T-scores increasing over first 10 years from -0.69 to -0.43; of note, the T-score at 15 years was -0.54, but this change did not reach statistical significance (see Table). There was no statistically significant difference in clinical fracture incidence noted over 15 years.
The authors noted higher increases in lumbar spine BMD and BMC in men than in women across time-points. They also note that women required higher GH doses over the first 10 years. It is interesting to note, as well, that the IGF-1 SDS was higher in men at baseline, 5 years, and 10 years (eg, 1.64 in men and 0.83 in women after 10 years);a it would be interesting to determine whether aiming for a similar IGF-1 SDS would impact the relative difference in BMD/BMC increase. This is not the only study to note a gender difference in the impact of GHD on bone parameters. In a 2-year prospective multi-center study of 94 GHD adults (49 men; 67 with adult-onset GHD), Kuzma and colleagues noted a greater difference in both lumbar and femoral BMD in men than in women (though increases were seen in both genders at both sites).4 In one recent meta-analysis by Barake and colleagues, subgroup analysis showed a significant increase in both lumbar and femoral BMD over time in men, but not in women.5
The authors inferred a lack of additional benefit from bisphosphonates based on stratification of BMD/BMC results by bisphosphonate use (with no significant difference in results). Of note, the number of subjects on bisphosphonates at timepoints was relatively small, varying from 4% to 19% of subjects at various timepoints in the study.
In addition to conducting a univariate analysis of bisphonsponate use, the authors looked at childhood- vs adult-onset, cortisol/thyroid replacement, hypogonadism, and vitamin D levels; none of these altered the observed effect of rhGH on femoral BMD or lumbar BMD/BMC. Lower baseline BMD and low GH dose at 1 year were correlated with stronger response to rhGH therapy.
This research represents the long-term study of rhGH replacement in a carefully followed cohort. Given the number of subjects that remained for 15 years, certain conclusions (such as whether there is an independent bisphosphonate effect) may benefit from study in larger populations, but the results presented confirm other study results that GHR offers benefit in adults with defined GHD.
aIGF-1 SDS values per Appelman-Djikstra et al, page 729.
1. Hazem A, Elamin MB, Bancos I, et al. Body composition and quality of life in adults treated with GH therapy: a systematic review and meta-analysis. Eur J Endocrinol. 2012;166(1):13-20.
2. Al Mukaddam M, Rajapakse CS, Bhagat YA, et al. Effects of testosterone and growth hormone on the structural and mechanical properties of bone by micro-MRI in the distal tibia of men with hypopituitarism. J Clin Endocrinol Metab. 2014;99(4):1236-1244.
3. Elbornsson M, Götherström G, Bosæus I, Bengtsson BÅ, Johannsson G, Svensson J. Fifteen years of GH replacement increases bone mineral density in hypopituitary patients with adult-onset GH deficiency. Eur J Endocrinol. 2012;166(5):787-795.
4. Kuzma M, Homerova Z, Dlesk A, et al. Effect of growth hormone on bone status in growth hormone-deficient adults. Bratisl Lek Listy. 2013;114(12):689-695.
5. Barake M, Klibanski A, Tritos NA. Effects of recombinant human growth hormone therapy on bone mineral density in adults with growth hormone deficiency: a meta-analysis. J Clin Endocrinol Metab. 2014;99(3):852-860.