Diğer

Serum IGF-1 and IGFBP-3 Levels in Middle Aged Turkish Males: Relationships with Bone Mineral Density and Markers of Bone Turnover (Male Osteoporosis & IGF-1, IGFBP-3) - Original Investigation

  • Melek Sezgin
  • Burak Çimen
  • Arzu Kanik
  • Ismet As
  • Neslihan Erçetin
  • Nurgül Arinci Incel
  • Günsah Sahin

Turk J Osteoporos 2007;13(2):-

SummaryAim: The aim of this study was to determine whether circulating levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) were associated with bone mineral density (BMD) and bone turnover markers in middle aged Turkish males.Patients and Methods: At the beginning, a total of 160 Turkish men aged between 35 and 65 years were included to this study. The final sample comprised of 112 men because 48 men were excluded from the study. BMD of the spine and the hip was measured with dual energy x-ray absorptiometry. After an overnight fasting, serum IGF-1, IGFBP-3, intact parathyroid hormone, 25-hydroxy vitamin D, osteocalcin, C-terminal telopeptide, calcium, phosphorous and alkaline phosphatase levels were measured. Urinary concentrations of calcium, phosphorous and creatinine were also estimated. Results: Twenty-one men (18.8%) had a bone mineral density of ≤ -2.5 SD (T score). There was a significant difference in IGF-1 levels between men with normal BMD and men with reduced BMD (132.5 ± 38.1 and 116.1 ± 40.6 respectively and p: 0.04). Serum IGF-1 levels were positively correlated with BMD of the lumbar spine (r: 0.28, p:0.006), but there was no correlation between IGFBP-3 and BMD of any sites tested. IGF-1, IGFBP-3 and BMD were not correlated with bone turnover markers except serum alkaline phosphatase level.Conclusion: Serum IGF-1 levels were lower in men with reduced BMD and positively correlated with BMD of the lumbar spine. Neither IGF-1 nor IGFBP-3 was correlated with bone turnover markers. Further studies of these factors in skeletal cells are needed to explain their role in the pathophysiology of idiopathic male osteoporosis.(From the World of Osteoporosis 2007;13:37-43)Key words: Idiopathic male osteoporosis, insulin-like growth factor-1, insulin-like growth factor binding protein-3, and bone turnover markersÖzetAmaç: Bu çalismanin amaci orta yasli Türk erkeklerinde serum insulin benzeri büyüme faktörü-1 (IGF-1) ve insulin benzeri büyüme faktörü baglayici protein-3 (IGFBP-3)’ün kemik mineral yogunlugu ve kemik yapim yikim belirteçleri ile iliskili olup olmadigini göstermekti.Hastalar ve Yöntem: Baslangiçta bu çalismaya 35 ile 65 yaslari arasinda 160 Türk erkegi dahil edildi. Daha sonra 48 hasta çalisma disi birakildigi için son örneklem 112 erkegi içerdi. Omurga ve kalçanin kemik mineral yogunlugu (KMY) dual enerji x-ray absorptiometri ile ölçüldü. Bir gecelik açlik sonrasi, serum IGF-1, IGFBP-3, intakt parathormon, 25-OH vitamin D, osteokalsin, C-terminal telopeptid, kalsiyum, fosfor, ve alkalen fosfataz seviyeleri ölçüldü. Kalsiyum, fosfor ve kreatininnin idrar konsantrasyonlari da tesbit edildi.Bulgular: Yirmi bir erkekde (% 18.8) kemik mineral yogunlugu T skoru -2.5 SD’a esit veya altinda idi. Normal  ve azalmis KMY’si olan hastalar arasinda IGF-1 düzeylerinde anlamli farklilik vardi (sirasiyla 132.5 ± 38.1 ve 116.1 ± 40.6, p: 0.04). Serum IGF-1 düzeyleri  lomber omurganin KMY’si ile pozitif korele idi. Fakat, IGFBP-3 ve test edilen yerlerin hiçbirinin KMY’si arasinda korelasyon yoktu. IGF-1, IGFBP-3 ve KMY serum alkalen fosfatazi hariç kemik yapim yikim belirteçleri korele degildi.Sonuçlar: Serum IGF-1 seviyeleri  KMY’si azalmis olan erkelerde daha düsüktü ve lomber omurganin KMY’si ile pozitif olarak korele idi. Ne IGF-1 ne de IGFBP-3 kemik yapim yikim belirteçleri ile korele degildi. Iskelet hücrelerindeki bu faktörlerin, idiopatik erkek osteoporozunun patofizyolojisindeki rolünü açiklamak için ek çalismalara gereksinim vardir. (Osteoporoz Dünyasindan 2007;13:37-43)Anahtar kelimeler: Geçici osteoporoz, kalça agrisi, manyetik rezonans görüntüleme

Introduction

Osteoporosis is one of the commonest metabolic bone diseases, and its prevalence is expected to rise as the population grows older. Although osteoporosis is less prevelant in men than in women, the morbidity and mortality due to male osteoporosis is higher (1,2). The major causes of osteoporosis in men are hypogonadism, hypercortisolism and excessive alcohol intake. Other abnormalities such as hyperthyroidism and malignancy are less commonly responsible for osteoporosis. All above mentioned disorders account for osteoporosis in approximately 60% of men (3,4). The remaining subset of men with idiopathic osteoporosis has been poorly characterized. With no readily identifiable causes of reduced bone density in men with idiopathic osteoporosis, it is attractive to consider the possibility that this disorder is the result of fundamental abnormalities of bone cell function or of the hormonal or paracrine pathways that regulate the bone cell metabolism (5,6). Growth hormone (GH) and its major mediator insulin like growth factor 1 (IGF-1) are thought to be important both in attainning peak bone mass and maintaining adult bone mass (7,8). The synthesis of circulating IGF-1 occurs principally in the liver; osteoblasts also contribute to IGF-1 production (9). Invitro and invivo studies have shown IGF-1 to enhance type 1 collagen production and bone matrix apposition rates and decrease degradation of bone collagen (10,11). A major portion of IGF-1 is bound to IGFBP-3 which is a quantitatively predominant IGFBP in the circulation. Serum IGFBP-3 level is thought to be positively regulated by GH and / or IGF-1 (12,13). It has been suggested that IGFBP-3 might augment the effect of IGF-1 on the bone (14).Recent studies have focused on the role of GH and IGF-1 in the regulation of bone metabolism in men. In elderly men, bone mineral density (BMD) is not correlated with IGF-1 concentrations. In contrast, studies including younger men suggested a weak possitive correlation between serum IGF-1 and BMD at some skeletal sites (15-20). However, these studies are not easily comparable because they were performed in mixed cohorts composed of men and women or in small samples of different age groups and based on different statistical approaches. There have also been reports indicating an association between low IGFBP-3 and BMD in both men and postmenopausal women. Others have shown only a weak association between IGFBP-3 and BMD in men and no association in women (18). Therefore, we attempted to evaluate the effects of serum IGF-1 and IGFBP-3 levels on BMD at various skeletal sites in Turkish adult men. In addition, we investigated the relationship between IGF-1, IGFBP-3 and bone turnover markers.


Statistical Analyses

Descriptive characteristics of the study population were expressed in numbers and percentages (Table 1). Mean and standard deviations of baseline measurements were used to determine. These statistics are given in Table 2 and 3. Multivariate analyses were used to explain the relation between dependent variables (serum IGF-1, IGFBP-3 and BMD) and independent variables (age, BMI, daily calcium intake, smoking, alcohol intake, chronic diseases, medications, history of fracture, back pain and exercise habits). Partial correlation analyses were made to adjust for age and BMI and Pearson correlation analysis to determine the relationship between IGF-1, IGFBP-3, BMD and bone turnover markers. The results of these analyses are given in Tables 4. In addition, the subjects were assigned into two new groups: those with ‘low BMI’ and those with ‘normal BMI’. Independent samples t test was used to compare these groups in terms of serum IGF-1 and IGFBP-3 (Figures 1 - 2). The scatter plot and regression fit line plotted were used to show the relationship between age and serum IGF-1 and IGFBP-3 in each subgroupAll statistical analysis were performed with SPSS software, version 12. P< 0.05 was considered significant.


References

1. Jackson JA, Kleerekoper M. Osteoporosis in men: diagnosis, pathophysiology and prevention. Medicine 1990;69:137-52.2. Orwoll ES, Klein RF. Osteoporosis in men. Endocr Rev 1995;16:87-115.3. Khosla S, Lufkin EG, Hodgson SF, Fitzpatrick LA, Melton LJ. Epidemiology and clinical features of osteoporosis in young individuals. Bone 1994;15:551-5.4. Seeman E. The dilemma of osteoporosis in men. Am J Med 1995;98 (Supp) 2A:76-88. 5. Kelepouris N, Harper K, Gannon F, Kaplan F, Haddad JG. Severe osteoporosis in men. Ann Intern Med 1995;123:452-60.6. Kurland ES, Rosen CF, Comsan F, Mcmahon D, Chan F, Shane E, et al. Insulin like growth factor-1 in men with idiopathic osteoporosis. Journal of Clinical Endocrinology and Metabolism 1997;82:2799-805. 7. Ohlsson C, Bengtsson BA, Isaksson OG, Andreassen TT, Slootweg MC. Growth hormone and bone. Endocrine Reviews 1998;19:55-79.8. Russell-Aulet M, Shapiro B, Jaffe CA, Gross MD, Barkan AL. Peak bone mass in young healthy men is correlated with the magnitude of endogenous growth hormone secretion. Journal of Clinical Endocrinology and Metabolism 1998;83:3463-8.9. Krasik D, Rosen CJ, Hannan MT, Broe KE, Dawson Hughes D, Gagnon DR, et al. Insulin like growth factor binding proteins 4 and 5 and bone mineral density in elderly men and women. Calcif Tissue Int 2002;71:323-8.10. Hock JM, Centrella M, Canalis E. Insulin- like growth factor 1 has independent effects on bone matrix formation and cell replication. Endocrinology 1988;122:254-60.11. Marcelli C, Yates AJ, Mundy GR. In vivo effects of human recombinant transforming growth factor beta on bone turnover in normal mice. Journal of Bone Mineral Research 1990;5:1087-96.12. Baxter RC. Circulating binding proteins for the insulin-like growth factors. Trends Endocrinol Metab 1993;4:91-6.13. Corpas E, Harman SM, Blackman MR. Serum IGF-binding protein-3 is related to IGF-1, but not to spontaneous GH release, in healthy old men. Horm Metab Res 1992;24:543-5.14. Conover CA. Glycosylation of insulin-like growth factor binding protein-3 (IGFBP-3) is not required for potentiation of IGF-1 action: Evidence for processing of cell-bound IGFBP-3. Endocrinology 1992;129:3259-68. 15. Barrett-Connor E, Goodman-Gruen D. Gender differences in insulin like growth factor and bone mineral density association in old age: the Rancho Bernardo study. J Bone Miner Res 1998;13:1343-9.16. Langlois JA, Rosen CJ, Visser M, Hannan MT, Harris T, Wilson PWF, et al. Association between insulin-like growth factor 1 and bone mineral density in older women and men: the Framingham Heart Study. J Clin Endocrinol Metab 1998;83:4257-62.17. Center JR, Nguyen TV, Sambrook PN, Eisman JA. Hormonal and biochemical parameters in the determination of osteoporosis in elderly men. J Clin Endocrinol Metab 1999;84:3626-35. 18. Johansson AG, Forslund A, Hambraeus L, Blum WF, Ljunghall S. Growth hormone dependent insulin- like growth factor binding protein is a major determinant of bone mineral density in healthy men. J Bone Miner Res 1994;9:915-21.19. Gillberg P, Olofsson H, Mallmin H, Blum WF, Ljunghall S, Nilsson AG. Bone mineral density in femoral neck is positively correlated to circulating insulin-like growth factor (IGF-1) and IGF-binding protein (IGFBP)-3 in Swedish men. Calcif Tissue Int 2002;70:22-9.20. Szulc P, Joly Pharaboz MO, Marchand F, Delmas PD. Insulin like growth factor 1 is a determinant of hip bone mineral density in men less than 60 years of age: MINOS study. Calcif Tissue Int 2004:74:322-9.21. Sugimoto T, Nishiyama K, Kuribayashi F, Chihara K. Serum levels of insulin-like growth factor (IGF) 1, IGF-binding protein (IGFBP)-2, and IGFBP-3 in osteoporotic patients with and without spinal fractures. J Bone Miner Res 1997;12:1272-9.22. Pfeilschifter J, Scheidt-Nave C, Leidig-Bruckner G, Woitge HW, Blum WF, Wuster C, et al. Relationship between circulating insulin like growth factor components and sex hormones in a population-based sample of 50 to 80 year old men and women. J Clin Endocrinol Metab 1996;81:2534-40. 23. Amin S, Lawrence Riggs B, Atkinson EJ, Oberg AL, Melton LJ, Khosla S. A potentially deleterious role of IGFBP-2 on bone density in aging men and women. Journal of Bone and Mineral Research 2004;19:1075-83.24. Bilezikian JP. Osteoporosis in men. J Clin Endocrinol Metab 1999;84:3431-4. 25. Kanis JL, Melton LS, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res 1994;9:1137-41. 26. Reed BY, Zerwekh JE, Sakhaee K, Breslau NA, Gottschalk F, Pak CYC. Serum IGF-1 is low and correlated with osteoblastic surface in idiopathic osteoporosis. J Bone Miner Res 1995; 10:1218-24.27. Ljunghall S, Johansson AG, Burnan P, Kampe O, Lindh E, Karlsson FA. Low plasma levels of insulin like growth factor 1 (IGF) in male patients with idiopathic osteoporosis. J Intern Med 1992;232:5928. Janssen JA, Burger H, Stolk RP, Grobbee DE, de Jong FH, Lamberts SW, et al. Gender –specific relationship between serum free and total IGF-1 and bone mineral density in elderly men and women. Eur J Endocrinol 1998;138:627-32.29. Krassas GE, Papadopoulou PH, Koliakos G. Growth hormone, insulin growth factor-1, and IGF binding protein-3 axis relationship with bone mineral density among healthy men. Archives of Andrology 2003;49:191-9.30. Gürlek A, Gedik O. Endogenous sex steroid, GH and IGF-1 levels in normal elderly men: Relationship with bone mineral density and markers of bone tornover. J Endocrinol Invest 2001;24:408-14. 31. Johansson AG, Eriksen EF, Lindh E, Langdahl B, Blum WF, Lindahl A, et al. Reduced serum levels of the growth hormone-dependent insulin like growth factor binding protein and a negative bone balance at the level of individual remodeling units in idiopathic osteoporosis in men. J Clin Endocrinol Metab 1997;82:2795-8.32. Rucker D, Ezzat S, Diamandi A, Khosravi J, Hanley DA. IGF-1 and testosterone levels as predictors of bone mineral density in healthy, community-dwelling men. Clinical Endocrinology 2004;60:491-9.


1. Jackson JA, Kleerekoper M, Osteoporosis in men: diagnosis, pathophysiology and prevention. Medicine 1990,69:52-137

2. Orwoll ES, Klein RF, Osteoporosis in men. Endocr Rev 1995,16:87-115

3. Khosla S, Lufkin EG, Hodgson SF, Fitzpatrick LA, Melton LJ, Epidemiology and clinical features of osteoporosis in young individuals. Bone 1994,15:5-551

4. Seeman E, The dilemma of osteoporosis in men. Am J Med 1995,98:76-88

5. Kelepouris N, Harper K, Gannon F, Kaplan F, Haddad JG, Severe osteoporosis in men. Ann Intern Med 1995,123:60-452

6. Kurland ES, Rosen CF, Comsan F, Mcmahon D, Chan F, Shane E, et al, Insulin like growth factor-1 in men with idiopathic osteoporosis. Journal of Clinical Endocrinology and Metabolism 1997,82:805-2799

7. Ohlsson C, Bengtsson BA, Isaksson OG, Andreassen TT, Slootweg MC, Growth hormone and bone. Endocrine Reviews 1998,19:55-79

8. Russell-Aulet M, Shapiro B, Jaffe CA, Gross MD, Barkan AL, Peak bone mass in young healthy men is correlated with the magnitude of endogenous growth hormone secretion. Journal of Clinical Endocrinology and Metabolism 1998,83:8-3463

9. Krasik D, Rosen CJ, Hannan MT, Broe KE, Dawson Hughes D, Gagnon DR, et al, Insulin like growth factor binding proteins 4 and 5 and bone mineral density in elderly men and women. Calcif Tissue Int 2002,71:8-323

10. Hock JM, Centrella M, Canalis E, Insulin- like growth factor 1 has independent effects on bone matrix formation and cell replication. Endocrinology 1988,122:60-254

11. Marcelli C, Yates AJ, Mundy GR, In vivo effects of human recombinant transforming growth factor beta on bone turnover in normal mice. Journal of Bone Mineral Research 1990,5:96-1087

12. Baxter RC, Circulating binding proteins for the insulin-like growth factors. Trends Endocrinol Metab 1993,4:6-91

13. Corpas E, Harman SM, Blackman MR, Serum IGF-binding protein-3 is related to IGF-1, but not to spontaneous GH release, in healthy old men. Horm Metab Res 1992,24:5-543

14. Conover CA, Glycosylation of insulin-like growth factor binding protein-3 (IGFBP-3) is not required for potentiation of IGF-1 action: Evidence for processing of cell-bound IGFBP-3. Endocrinology 1992,129:68-3259

15. Barrett-Connor E, Goodman-Gruen D, Gender differences in insulin like growth factor and bone mineral density association in old age: the Rancho Bernardo study. J Bone Miner Res 1998,13:9-1343

16. Langlois JA, Rosen CJ, Visser M, Hannan MT, Harris T, Wilson PWF, et al, Association between insulin-like growth factor 1 and bone mineral density in older women and men: the Framingham Heart Study. J Clin Endocrinol Metab 1998,83:62-4257

17. Center JR, Nguyen TV, Sambrook PN, Eisman JA, Hormonal and biochemical parameters in the determination of osteoporosis in elderly men. J Clin Endocrinol Metab 1999,84:35-3626

18. Johansson AG, Forslund A, Hambraeus L, Blum WF, Ljunghall S, Growth hormone dependent insulin- like growth factor binding protein is a major determinant of bone mineral density in healthy men. J Bone Miner Res 1994,9:21-915

19. Gillberg P, Olofsson H, Mallmin H, Blum WF, Ljunghall S, Nilsson AG, Bone mineral density in femoral neck is positively correlated to circulating insulin-like growth factor (IGF-1) and IGF-binding protein (IGFBP)-3 in Swedish men. Calcif Tissue Int 2002,70:9-22

20. , 20. Szulc P, Joly Pharaboz MO, Marchand F, Delmas PD. Insulin like growth factor 1 is a determinant of hip bone mineral density in men less than 60 years of age: MINOS study. Calcif Tissue Int 2004:74::9-322

21. Sugimoto T, Nishiyama K, Kuribayashi F, Chihara K, Serum levels of insulin-like growth factor (IGF) 1, IGF-binding protein (IGFBP)-2, and IGFBP-3 in osteoporotic patients with and without spinal fractures. J Bone Miner Res 1997,12:9-1272

22. Pfeilschifter J, Scheidt-Nave C, Leidig-Bruckner G, Woitge HW, Blum WF, Wuster C, et al, Relationship between circulating insulin like growth factor components and sex hormones in a population-based sample of 50 to 80 year old men and women. J Clin Endocrinol Metab 1996,81:40-2534

23. Amin S, Lawrence Riggs B, Atkinson EJ, Oberg AL, Melton LJ, Khosla S, A potentially deleterious role of IGFBP-2 on bone density in aging men and women. Journal of Bone and Mineral Research 2004,19:83-1075

24. Bilezikian JP, Osteoporosis in men. J Clin Endocrinol Metab 1999,84:4-3431

25. Kanis JL, Melton LS, Christiansen C, Johnston CC, Khaltaev N, The diagnosis of osteoporosis. J Bone Miner Res 1994,9:41-1137

26. Reed BY, Zerwekh JE, Sakhaee K, Breslau NA, Gottschalk F, Pak CYC, Serum IGF-1 is low and correlated with osteoblastic surface in idiopathic osteoporosis. J Bone Miner Res 1995,10:24-1218

27. Ljunghall S, Johansson AG, Burnan P, Kampe O, Lindh E, Karlsson FA, Low plasma levels of insulin like growth factor 1 (IGF) in male patients with idiopathic osteoporosis. J Intern Med 1992,232

28. Janssen JA, Burger H, Stolk RP, Grobbee DE, de Jong FH, Lamberts SW, et al, Gender –specific relationship between serum free and total IGF-1 and bone mineral density in elderly men and women. Eur J Endocrinol 1998,138:32-627

29. Krassas GE, Papadopoulou PH, Koliakos G, Growth hormone, insulin growth factor-1, and IGF binding protein-3 axis relationship with bone mineral density among healthy men. Archives of Andrology 2003,49:9-191

30. Gürlek A, Gedik O, Endogenous sex steroid, GH and IGF-1 levels in normal elderly men: Relationship with bone mineral density and markers of bone tornover. J Endocrinol Invest 2001,24:14-408

31. Johansson AG, Eriksen EF, Lindh E, Langdahl B, Blum WF, Lindahl A, et al, Reduced serum levels of the growth hormone-dependent insulin like growth factor binding protein and a negative bone balance at the level of individual remodeling units in idiopathic osteoporosis in men. J Clin Endocrinol Metab 1997,82:8-2795

32. Rucker D, Ezzat S, Diamandi A, Khosravi J, Hanley DA, IGF-1 and testosterone levels as predictors of bone mineral density in healthy, community-dwelling men. Clinical Endocrinology 2004,60-491