Comment
Growth hormone deficiency has been associated in crosssectional studies with low bone turnover, osteoporosis, and an increased prevalence of clinical and radiological fractures, in line with the fact that growth hormone is a bone anabolic hormone.1 As for other clinical endpoints,2 few data are available for the bone protective role of growth hormone replacement therapy. Previous studies reported decreased risk of incident clinical fractures in male patients with hypopituitarism receiving growth hormone compared with patients without growth hormone deficiency,3 and a protective effect of early growth hormone treatment in patients with growth hormone deficiency has been reported for prevalent radiological vertebral fractures.4 The Article by Daojun Mo and colleagues5 is one of the first attempts to show potential protection from incidence of fractures by growth hormone replacement therapy in a large population of adults with growth hormone deficiency. In the context of the Hypopituitary Control and Complications Study (HypoCCS), the authors followed-up 8374 patients that received growth hormone and 1267 patients that did not for more than 4 years and identified that the annual incidence of clinical fractures was decreased in patients that received growth hormone compared with those that did not (hazard ratio [HR] 0·69, 95% CI 0·54–0·88), with an effect size similar to that of clinical trials of bone-active drugs in osteoporosis.6 This finding points towards a beneficial effect of growth hormone on bone in growth hormone-deficient patients. In view of the fact that the clinical and social burden of fractures is well known,7 this finding is substantial. Are these findings the end of a long-lasting quest for clinically convincing data to support growth hormone replacement therapy in adults with growth hormone deficiency?8 Unfortunately, not quite: the data of Mo and colleagues should be considered proof-of-concept, and there is a still a long way to go before firm conclusions can be drawn on this issue. HypoCCS is a post-marketing surveillance study, which has several intrinsic limitations that cannot be overcome by statistical adjustments. First, the study enrolled patients with growth hormone deficiency from many centres, and patients with different ethnic and genetic backgrounds, but without comparison with healthy individuals. Although
comparison with data in the scientific literature for some reference groups might suggest that the fracture rate reported in patients that received growth hormone was similar to the annual incidence of non-vertebral fractures in the general population,6,7 how the fracture rates reported in those that received growth hormone versus those who did not relate to what happens in agematched and sex-matched healthy individuals remains unclear. Without inclusion of healthy individuals, assessment of whether patients with growth hormone deficiency that did not receive growth hormone are at low, medium, or high risk of fractures is not possible. Does growth hormone treatment normalise the risk or even add further protection from fractures? The second limitation is related to the fact that vertebral fractures are at the core of this issue.7 In the study by Mo and colleagues,5 and a previous study,4 patients with growth hormone deficiency that did not receive growth hormone were identified to be at higher risk of this type of fracture; growth hormone treatment seems to mainly exert its protective effect at this level. This finding is consistent with the anabolic effect of growth hormone on trabecular bone—the part of bone with the highest metabolic rate and the most represented at the vertebral level.1 However, the study by Mo and colleagues can only partly deal with this issue for two reasons: first, vertebral fractures were arbitrarily defined in the study by more than a 5 cm loss of height, which might have led to underestimation of clinical vertebral fractures and to uncertainty about the number and severity of fractures in each patient. Second, a further underestimation of the occurrence is due to the fact that about 60% of vertebral fractures in the general population are diagnosed morphometrically (with a spine X-ray)9 and also that growth hormone-deficient patients have been identified to be at increased risk of radiological vertebral fracture.4 Notably, morphometric vertebral fracture is associated with decreased survival and increased risk of future fractures in the general population.7 A third aspect that could not be addressed in the study by Mo and colleagues is whether fracture risk in patients with growth hormone deficiency can be predicted by low bone mineral density. Morphometric fractures might occur in patients with growth hormone deficiency even
www.thelancet.com/diabetes-endocrinology Published online April 13, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00036-4
ISM/Jean-Denis Laredo/Science Photo Library
Growth hormone replacement therapy and fracture risk
Lancet Diabetes Endocrinol 2015 Published Online April 13, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00036-4 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(15)00098-4
1
Comment
when bone mineral density is in the normal range.4 Mo and colleagues report that in patients with growth hormone-deficiency and pre-existing osteoporosis, growth hormone did not reduce the risk of fracture.5 This finding could mean that patients with growth hormonedeficiency with low bone mineral density should not be a target population for growth hormone replacement therapy. This might be an important message that is missed by the scarcity of bone mineral density measurements in the study. Indeed, few patients in the study (8·3–10·7%) were labeled as osteoporotic, whereas in bone mineral density studies of patients with growth hormone deficiency this figure is around 30% (with up to 40% being osteopenic).1 Therefore, debate on the role of bone mineral density in prediction of fracture incidence and the protective effect of growth hormone treatment remains open. Fourth, as expected, many patients in HypoCCS were receiving corticosteroids. Higher fracture risk in patients taking corticosteroids might occur owing to inappropriately increased doses.10 Slightly higher prevalence of corticosteroid use in patients that did not receive growth hormone compared with patients that did receive growth hormone (64% vs 61%; p=0·0444) might have negatively affected fracture risk because only patients receiving growth hormone treatment are protected against morphometric vertebral fractures mediated by glucocorticoid over-replacement.10 In summary, the study by Mo and colleagues opens avenues for further studies that might show that
2
skeletal integrity can be an important endpoint in deciding to use growth hormone replacement therapy in patients with growth hormone deficiency. Andrea Giustina, Gherardo Mazziotti Endocrinology, University of Brescia, 25123 Brescia, Italy [email protected] AG reports personal fees from Ipsen, Novartis, and Pfizer, outside the submitted work. GM reports personal fees from Ipsen and Novartis, outside the submitted work. 1 2
3
4
5
6
7 8 9 10
Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev 2008; 29: 535–59. Gazzaruso C, Gola M, Karamouzis I, Giubbini R, Giustina A. Cardiovascular risk in adult patients with growth hormone (GH) deficiency and following substitution with GH--an update. J Clin Endocrinol Metab 2014; 99: 18–29. Holmer H, Svensson J, Rylander L, et al. Fracture incidence in GH-deficient patients on complete hormone replacement including GH. J Bone Miner Res 2007; 22: 1842–50 Mazziotti G, Bianchi A, Bonadonna S, et al. Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy. J Bone Miner Res 2006; 21: 520–28. Mo D, Fleseriu M, Qi R, et al. Fracture risk in adult patients treated with growth hormone replacement therapy for growth hormone deficiency: a prospective observational cohort study. Lancet Diabetes Endocrinol 2015; published online April 13. http://dx.doi.org/10.1016/S22138587(15)00098-4. Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C; Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group. Meta-analyses of therapies for postmenopausal osteoporosis. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002; 23: 570–78 Mazziotti G, Bilezikian J, Canalis E, Cocchi D, Giustina A. New understanding and treatments for osteoporosis. Endocrine 2012; 41: 58–69. Giustina A. Does growth hormone replacement therapy improve cardiac function? Nat Clin Pract Endocrinol Metab 2007; 3: 614–15. Griffith JF, Genant HK. New advances in imaging osteoporosis and its complications. Endocrine 2012; 42: 39–51. Mazziotti G, Porcelli T, Bianchi A, Cimino V, Patelli I, Mejia C, Fusco A, Giampietro A, De Marinis L, Giustina A. Glucocorticoid replacement therapy and vertebral fractures in hypopituitary adult males with GH deficiency. Eur J Endocrinol 2010; 163: 15–20.
www.thelancet.com/diabetes-endocrinology Published online April 13, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00036-4
Growth hormone deficiency has been associated in crosssectional studies with low bone turnover, osteoporosis, and an increased prevalence of clinical and radiological fractures, in line with the fact that growth hormone is a bone anabolic hormone.1 As for other clinical endpoints,2 few data are available for the bone protective role of growth hormone replacement therapy. Previous studies reported decreased risk of incident clinical fractures in male patients with hypopituitarism receiving growth hormone compared with patients without growth hormone deficiency,3 and a protective effect of early growth hormone treatment in patients with growth hormone deficiency has been reported for prevalent radiological vertebral fractures.4 The Article by Daojun Mo and colleagues5 is one of the first attempts to show potential protection from incidence of fractures by growth hormone replacement therapy in a large population of adults with growth hormone deficiency. In the context of the Hypopituitary Control and Complications Study (HypoCCS), the authors followed-up 8374 patients that received growth hormone and 1267 patients that did not for more than 4 years and identified that the annual incidence of clinical fractures was decreased in patients that received growth hormone compared with those that did not (hazard ratio [HR] 0·69, 95% CI 0·54–0·88), with an effect size similar to that of clinical trials of bone-active drugs in osteoporosis.6 This finding points towards a beneficial effect of growth hormone on bone in growth hormone-deficient patients. In view of the fact that the clinical and social burden of fractures is well known,7 this finding is substantial. Are these findings the end of a long-lasting quest for clinically convincing data to support growth hormone replacement therapy in adults with growth hormone deficiency?8 Unfortunately, not quite: the data of Mo and colleagues should be considered proof-of-concept, and there is a still a long way to go before firm conclusions can be drawn on this issue. HypoCCS is a post-marketing surveillance study, which has several intrinsic limitations that cannot be overcome by statistical adjustments. First, the study enrolled patients with growth hormone deficiency from many centres, and patients with different ethnic and genetic backgrounds, but without comparison with healthy individuals. Although
comparison with data in the scientific literature for some reference groups might suggest that the fracture rate reported in patients that received growth hormone was similar to the annual incidence of non-vertebral fractures in the general population,6,7 how the fracture rates reported in those that received growth hormone versus those who did not relate to what happens in agematched and sex-matched healthy individuals remains unclear. Without inclusion of healthy individuals, assessment of whether patients with growth hormone deficiency that did not receive growth hormone are at low, medium, or high risk of fractures is not possible. Does growth hormone treatment normalise the risk or even add further protection from fractures? The second limitation is related to the fact that vertebral fractures are at the core of this issue.7 In the study by Mo and colleagues,5 and a previous study,4 patients with growth hormone deficiency that did not receive growth hormone were identified to be at higher risk of this type of fracture; growth hormone treatment seems to mainly exert its protective effect at this level. This finding is consistent with the anabolic effect of growth hormone on trabecular bone—the part of bone with the highest metabolic rate and the most represented at the vertebral level.1 However, the study by Mo and colleagues can only partly deal with this issue for two reasons: first, vertebral fractures were arbitrarily defined in the study by more than a 5 cm loss of height, which might have led to underestimation of clinical vertebral fractures and to uncertainty about the number and severity of fractures in each patient. Second, a further underestimation of the occurrence is due to the fact that about 60% of vertebral fractures in the general population are diagnosed morphometrically (with a spine X-ray)9 and also that growth hormone-deficient patients have been identified to be at increased risk of radiological vertebral fracture.4 Notably, morphometric vertebral fracture is associated with decreased survival and increased risk of future fractures in the general population.7 A third aspect that could not be addressed in the study by Mo and colleagues is whether fracture risk in patients with growth hormone deficiency can be predicted by low bone mineral density. Morphometric fractures might occur in patients with growth hormone deficiency even
www.thelancet.com/diabetes-endocrinology Published online April 13, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00036-4
ISM/Jean-Denis Laredo/Science Photo Library
Growth hormone replacement therapy and fracture risk
Lancet Diabetes Endocrinol 2015 Published Online April 13, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00036-4 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(15)00098-4
1
Comment
when bone mineral density is in the normal range.4 Mo and colleagues report that in patients with growth hormone-deficiency and pre-existing osteoporosis, growth hormone did not reduce the risk of fracture.5 This finding could mean that patients with growth hormonedeficiency with low bone mineral density should not be a target population for growth hormone replacement therapy. This might be an important message that is missed by the scarcity of bone mineral density measurements in the study. Indeed, few patients in the study (8·3–10·7%) were labeled as osteoporotic, whereas in bone mineral density studies of patients with growth hormone deficiency this figure is around 30% (with up to 40% being osteopenic).1 Therefore, debate on the role of bone mineral density in prediction of fracture incidence and the protective effect of growth hormone treatment remains open. Fourth, as expected, many patients in HypoCCS were receiving corticosteroids. Higher fracture risk in patients taking corticosteroids might occur owing to inappropriately increased doses.10 Slightly higher prevalence of corticosteroid use in patients that did not receive growth hormone compared with patients that did receive growth hormone (64% vs 61%; p=0·0444) might have negatively affected fracture risk because only patients receiving growth hormone treatment are protected against morphometric vertebral fractures mediated by glucocorticoid over-replacement.10 In summary, the study by Mo and colleagues opens avenues for further studies that might show that
2
skeletal integrity can be an important endpoint in deciding to use growth hormone replacement therapy in patients with growth hormone deficiency. Andrea Giustina, Gherardo Mazziotti Endocrinology, University of Brescia, 25123 Brescia, Italy [email protected] AG reports personal fees from Ipsen, Novartis, and Pfizer, outside the submitted work. GM reports personal fees from Ipsen and Novartis, outside the submitted work. 1 2
3
4
5
6
7 8 9 10
Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev 2008; 29: 535–59. Gazzaruso C, Gola M, Karamouzis I, Giubbini R, Giustina A. Cardiovascular risk in adult patients with growth hormone (GH) deficiency and following substitution with GH--an update. J Clin Endocrinol Metab 2014; 99: 18–29. Holmer H, Svensson J, Rylander L, et al. Fracture incidence in GH-deficient patients on complete hormone replacement including GH. J Bone Miner Res 2007; 22: 1842–50 Mazziotti G, Bianchi A, Bonadonna S, et al. Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy. J Bone Miner Res 2006; 21: 520–28. Mo D, Fleseriu M, Qi R, et al. Fracture risk in adult patients treated with growth hormone replacement therapy for growth hormone deficiency: a prospective observational cohort study. Lancet Diabetes Endocrinol 2015; published online April 13. http://dx.doi.org/10.1016/S22138587(15)00098-4. Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C; Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group. Meta-analyses of therapies for postmenopausal osteoporosis. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002; 23: 570–78 Mazziotti G, Bilezikian J, Canalis E, Cocchi D, Giustina A. New understanding and treatments for osteoporosis. Endocrine 2012; 41: 58–69. Giustina A. Does growth hormone replacement therapy improve cardiac function? Nat Clin Pract Endocrinol Metab 2007; 3: 614–15. Griffith JF, Genant HK. New advances in imaging osteoporosis and its complications. Endocrine 2012; 42: 39–51. Mazziotti G, Porcelli T, Bianchi A, Cimino V, Patelli I, Mejia C, Fusco A, Giampietro A, De Marinis L, Giustina A. Glucocorticoid replacement therapy and vertebral fractures in hypopituitary adult males with GH deficiency. Eur J Endocrinol 2010; 163: 15–20.
www.thelancet.com/diabetes-endocrinology Published online April 13, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00036-4
