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Bone loss is more severe in primary adrenal than in pituitary-dependent Cushing’s syndrome

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Abstract

Either exogenous or endogenous glucocorticoid excess is an established cause of osteoporosis and fractures. Glucocorticoids exert their negative effects on bone through mechanisms that are not yet completely elucidated; however, as many as 50% of patients with Cushing’s syndrome suffer from osteoporosis. Bone loss induced by glucocorticoids is potentially reversible after resolution of glucocorticoid excess. It is presently unknown if Cushing’s disease (CD) sustained by a pituitary ACTH-producing adenoma and adrenal-dependent Cushing’s syndrome (ACS) sustained by an adrenocortical adenoma have a different potential of inducing osteopenia. The aim of the present study was to retrospectively analyze bone mineral density (BMD) in 26 patients with CD (4 men, 22 women, aged 14–79 years), 12 patients with ACS (4 men, 8 women, aged 32–79 years) and 38 healthy subjects carefully matched for sex, age and body mass index (BMI). Measurement of BMD was performed by dual-energy X-ray absorptiometry (DXA) using the Hologic QDR 4500 W instrument. Data were analyzed using absolute BMD values (g/cm2), T-score and Z-score referred to the manufacturer’s normative data for the lumbar spine and to the NHANES III dataset for the hip. The patients with CD and ACS were comparable for age, BMI, estimated duration of disease, urinary free cortisol (UFC) levels, midnight serum cortisol and gonadal function. The analysis of variance demonstrated that lumbar bone densitometric parameters were significantly different among the three groups. They were more reduced in patients with ACS (BMD, 0.76±0.03 g/cm2; T-score, –2.78±0.28; Z-score, –2.25±0.30) while patients with CD (BMD, 0.87±0.02 g/cm2; T-score, –1.74±0.24; Z-score, –0.99±0.32) showed DXA values between the first group and controls (BMD, 1.02±0.02 g/cm2; T-score, –0.35±0.19; Z-score, 0.33±0.16). The difference in BMD at the spine remained statistically significant (P=0.04) after adjustment for the non-significant differences in age, UFC and fat mass between CD and ACS. Conversely, femoral bone densitometric parameters were not significantly different between patients with ACS and CD, even if they were more reduced than in controls. In patients with ACS, we observed a reduction of DHEA-S levels, expressed as standard score (Z-score) values referred to a group of 180 healthy subjects stratified by sex and different age groups (<40 years, between 40 and 60 years, >60 years) to circumvent the pronounced effect of gender and age on such hormone (ACS DHEA-S Z-score -0.88±1.4 versus CD DHEA-S Z-score 2.25±2.35, P=0.0001). DHEA-S Z-score values were significantly correlated with lumbar BMD (r=0.41, P=0.02) and femoral BMD (r=0.43, P=0.01). DHEA-S Z-score values were also significantly correlated with osteocalcin levels (r=0.45, P=0.01). Our data suggest that bone loss is greater in ACS than in CD. A plausible explanation comes from the reduced DHEA-S level in ACS since DHEA-S has well known anabolic actions on bone. However, this hypothesis needs to be confirmed in large, prospective series of patients with Cushing’s syndrome of different etiology.

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References

  1. Cushing H (1932) The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 50:137–195

    Google Scholar 

  2. Chiodini I, Carnevale V, Torlontano M, Fusilli S, Guglielmi G, Pileri M, Modoni S, Di Giorgio A, Liuzzi A, Minisola S, Cammisa M, Trischitta V, Scillitani A (1998) Alterations of bone turnover and bone mass at different skeletal sites due to pure glucocorticoid excess: study in eumenorrheic patients with Cushing’s syndrome. J Clin Endocrinol Metab 83:1863–1867

    Article  CAS  PubMed  Google Scholar 

  3. Godang K, Ueland T, Bollerslev J (1999) Decreased bone area, bone mineral content, formative markers, and increased bone resorptive markers in endogenous Cushing’s syndrome. Eur J Endocrinol 141:126–31

    CAS  PubMed  Google Scholar 

  4. Osella G, Terzolo M, Reimondo A (1997) Serum markers of bone and collagen turnover in patients with Cushing’s syndrome and in subjects with adrenal incidentalomas. J Clin Endocrinol Metab 82:3303–3307

    Article  CAS  PubMed  Google Scholar 

  5. Kimberg DV, Baerg RD, Gershon E, Graudusius RT (1971) Effect of cortisone treatment on the active transport of calcium by the small intestine. J Clin Invest 50:1309–1321

    CAS  PubMed  Google Scholar 

  6. Gennari C, Imbimbo B, Montagnani M, Bernini M, Nardi P, Avioli LV (1984) Effects of prednisone and deflazacort on mineral metabolism and parathyroid hormone activity in humans. Calcif Tissue Int 6:245–252

    Google Scholar 

  7. Lukert BP (1999) Glucocorticoid and drug-induced osteoporosis. In: Favus MJ (eds) (1999) Primer on the metabolic bone diseases and disorders of mineral metabolism, 3rd edn. Lippincott-Raven, New York, pp 292–296

  8. Rubin MR, Bilezikian JP (2002) The role of parathyroid hormone in the pathogenesis of glucocorticoid-induced osteoporosis: a re-examination of the evidence. J Clin Endocrinol Metab 87:4033–4041

    Article  CAS  PubMed  Google Scholar 

  9. Boscaro M, Barzon L, Fallo F, Sonino N (2001) Cushing’s syndrome. Lancet 357:783–791

    Article  CAS  PubMed  Google Scholar 

  10. Canalis E (1996) Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis. J Clin Endocrinol Metab 81:3441–3447

    CAS  PubMed  Google Scholar 

  11. Lane NE, Lukert B (1998) The science and therapy of glucocorticoid-induced bone loss. Endocrinol Metab Clin N Am 27:465–483

    CAS  Google Scholar 

  12. Frost HM (1987) The mechanostat: a proposed pathogenic mechanism of osteoporoses and the bone mass effects of mechanical and nonmechanical agents. Bone Miner 2:73–85

    CAS  PubMed  Google Scholar 

  13. Peck WA (1984) Effects of glucocorticoids on bone cell metabolism and function. Adv Exp Med Biol 171:111–119

    CAS  PubMed  Google Scholar 

  14. Angeli A, Dovio A, Sartori ML, Masera RG, Ceoloni B, Prolo P, Racca S, Chiappelli F (2002) Interactions between glucocorticoids and cytokines in the bone microenvironment. Ann N Y Acad Sci 966:97–107

    CAS  PubMed  Google Scholar 

  15. Kristo C, Godano K, Ueland T, Lien E, Aukrust P, Froland SS, Bollerslev J (2002) Raised serum levels of Interleukin (IL)-8 and IL-18 in relation to bone metabolism in endogenous Cushing syndrome. Eur J Endocrinol 146:389–395

    CAS  PubMed  Google Scholar 

  16. Hofbauer LC, Gori F, Riggs BL, Lacey DL, Dunstan CR, Spelsberg TC, Khosla S (1999) Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 140:4382–4389

    CAS  PubMed  Google Scholar 

  17. Ross EJ, Linch DC (1982) Cushing’s syndrome-killing disease: discriminatory value of signs and symptoms aiding early diagnosis. Lancet 2:646–649

    Article  CAS  PubMed  Google Scholar 

  18. Lufkin EG, Wahner HW, Bergstralh EJ (1988) Reversibility of steroid-induced osteoporosis. Am J Med 85:887–888

    CAS  Google Scholar 

  19. Hermus AR, Smals AG, Swinkels LM, Huysmans DA, Pieters GF, Sweep CF, Corstens FH, Kloppenborg PW (1995) Bone mineral density and bone turnover before and after surgical cure of Cushing’s syndrome. J Clin Endocrinol Metab 80:2859–2865

    Article  CAS  PubMed  Google Scholar 

  20. Kaplan FS, Leone VJ, Fallon MD, Haddad JG, Brighton CT, Steinberg ME (1987) Multiple pathologic fractures of the appendicular skeleton in a patient with Cushing’s disease. Clin Orthop 216:171–175

    PubMed  Google Scholar 

  21. Reid IR, Grey AB (1993) Corticosteroid osteoporosis. Bailliere’s Clin Rheumatol 7:573–587

  22. Bertagna C, Orth DN (1981) Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951 to 1978). Am J Med 71:855–875

    CAS  PubMed  Google Scholar 

  23. Morio H, Terano T, Yamamoto K, Tomizuka T, Oeda T, Saito Y, Tamura Y, Sasano H (1996) Serum levels of dehydroepiandrosterone sulfate in patients with asymptomatic cortisol producing adrenal adenoma: comparison with adrenal Cushing’s syndrome and non-functional adrenal tumor. Endocr J 43:387–396

    CAS  PubMed  Google Scholar 

  24. Vestergaard P, Lindholm J, Jorgensen JOL, Hagen C, Hoech HC, Laurberg P, Rejnmark L, Brixen K, Kristensen LO, Feldt-Rasmussen U, Mosekilde L (2002) Increased risk of osteoporotic fractures in patients with Cushing’s syndrome. Eur J Endocrinol 146:51–56

    CAS  PubMed  Google Scholar 

  25. Oldfield EH, Doppman JL, Nieman LK, Chrousos GP, Miller DL, Katz DA, Cutler GB, Loriaux DL (1991) Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med 26:897–905

    Google Scholar 

  26. Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro B (1995) Incidentally discovered adrenal masses. Endocr Rev 16:460–484

    CAS  PubMed  Google Scholar 

  27. Korobkin M, Brodeur FJ, Yutzy GG, Francis IR, Quint LE, Dunnick NR, Kazerooni EA (1996) Differentiation of adrenal adenomas from nonadenomas using CT attenuation values. Am J Roentgenol 166:531–536

    CAS  Google Scholar 

  28. Korobkin M, Brodeur FJ, Francis IR, Quint LE, Dunnick NR, Goodsitt M (1996) Delayed enhanced CT for differentiation of benign from malignant adrenal masses. Radiology 200:737–742

    CAS  PubMed  Google Scholar 

  29. Belanger A, Candas B, Dupont A, Cusan L, Diamond P, Gomez JL, Labrie F (1994) Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men. J Clin Endocrinol Metab 79:1086–1090

    Article  CAS  PubMed  Google Scholar 

  30. Vermeulen A (1991) Clinical review 24: androgens in the aging male. J Clin Endocrinol Metab 73:221–224

    CAS  PubMed  Google Scholar 

  31. Christenson RH (1997) Biochemical markers of bone metabolism: an overview. Clin Biochem 30:573–593

    Article  CAS  PubMed  Google Scholar 

  32. Terzolo M, Osella G, Ali A, Borretta G, Cesario F, Paccotti P, Angeli A (1998) Subclinical Cushing’s syndrome in adrenal incidentaloma. Clin Endocrinol (Oxf) 48:89–97

    Google Scholar 

  33. Looker AC, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse SP, Johnston CC Jr, Lindsay RL (1995) Proximal femur bone mineral levels of US adults. Osteoporos Int 5:389–409

    CAS  PubMed  Google Scholar 

  34. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis (1994) WHO Tech Rep Ser 843, Geneva

  35. Melton LJ, Orwoll ES, Wasnich RD (2001) Does bone density predict fractures comparably in men and women? Osteoporos Int 12:707–709

    Article  PubMed  Google Scholar 

  36. Francucci CM, Pantanetti P, Garrapa G, Massi F, Arnaldi G, Mantero M (2002) Bone metabolism and mass in women with Cushing’s syndrome and adrenal incidentaloma. Clin Endocrinol 2002;57:587–593

    Google Scholar 

  37. Miller J, Crapo L (1994) The biochemical analysis of hypercortisolism. Endocrinologist 4:7–16

    Google Scholar 

  38. Schmidt M, Kreutz M, Loffler G, Scholmerich J, Straub RH (2000) Conversion of dehydroepiandrosterone to downstream steroid hormones in macrophages. J Endocrinol 164:161–169

    CAS  PubMed  Google Scholar 

  39. Straub RH, Lehle K, Herfarth H, Weber M, Falk W, Preuner J, Scholmerich J (2002) Dehydroepiandrosterone in relation to other adrenal hormones during an acute inflammatory stressful disease state compared with chronic inflammatory disease: role of interleukin-6 and tumour necrosis factor. Eur J Endocrinol 146:365–374

    CAS  PubMed  Google Scholar 

  40. Arlt W, Allolio B (2001) Dehydroepiandrosterone replacement therapy. Curr Opin Endocrinol Diabet 8:130–139

    Article  CAS  Google Scholar 

  41. Labrie F, Diamond P, Cusan L, Gomez JL, Belanger A, Candas B (1997) Effect of 12-month dehydroepiandrosterone replacement therapy on bone, vagina, and endometrium in postmenopausal women. J Clin Endocrinol Metab 82:3498–3505

    CAS  PubMed  Google Scholar 

  42. Riggs BL, Khosla S, Melton LJ 3rd (2002) Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23:279–302

    CAS  PubMed  Google Scholar 

  43. Arlt W, Justl HG, Callies F, Reincke M, Hubler D, Oettel M, Ernst M, Schulte HM, Allolio B (1998) Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression. J Clin Endocrinol Metab 83:1928–1934

    CAS  PubMed  Google Scholar 

  44. Fujikawa H, Okura F, Kuwano Y, Sekizawa A, Chiba H, Shimodaira K, Saito H, Yanaihara T (1997) Steroid sulfatase activity in osteoblast cells. Biochem Biophys Res Commun 231:42–47

    Article  CAS  PubMed  Google Scholar 

  45. Nawata H, Tanaka S, Tanaka S, Takayanagi R, Sakai Y, Yanase T, Ikuyama S, Haji M (1995) Aromatase in bone cell: association with osteoporosis in postmenopausal women. J Steroid Biochem Mol Biol 53:165–174

    Article  CAS  PubMed  Google Scholar 

  46. Martel C, Sourla A, Pelletier G, Labrie C, Fournier M, Picard S, Li S, Stojanovic M, Labrie F (1998) Predominant androgenic component in the stimulatory effect of dehydroepiandrosterone on bone mineral density in the rat. J Endocrinol 157:433–442

    CAS  PubMed  Google Scholar 

  47. Scheven BA, Milne JS (1998) Dehydroepiandrosterone (DHEA) and DHEA-S interact with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) to stimulate human osteoblastic cell differentiation. Life Sci 62:59–68

    Article  CAS  PubMed  Google Scholar 

  48. Reid IR (1998) Glucocorticoid effects on bone. J Clin Endocrinol Metab 83:1860–1862

    Article  CAS  PubMed  Google Scholar 

  49. Piovesan A, Terzolo M, Reimondo G, Pia A, Codegone A, Osella G, Boccuzzi A, Paccotti P, Angeli A (1994) Biochemical markers of bone and collagen turnover in acromegaly or Cushing’s syndrome. Horm Metab Res 26:234–237

    CAS  PubMed  Google Scholar 

  50. Sartorio A, Ambrosi B, Colombo P, Morabito F, Faglia G (1988) Osteocalcin level in Cushing’s disease before and after treatment. Horm Metab Res 20:70

    CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge the excellent technical skill of Mrs. Angela Termine, who performed hormone measurements. This work was partially supported by grants of the University of Turin (fondi “ex-60%”) and of MURST (PRIN n. 2001062719_004).

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  1. Dipartimento di Scienze Cliniche e Biologiche, Clinica Medica Generale, AO San Luigi, Regione Gonzole 10, 10043, Orbassano (TO), Italia

    M. Minetto, G. Reimondo, G. Osella, M. Ventura, A. Angeli & M. Terzolo

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  1. M. Minetto
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Correspondence to M. Minetto.

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Minetto, M., Reimondo, G., Osella, G. et al. Bone loss is more severe in primary adrenal than in pituitary-dependent Cushing’s syndrome. Osteoporos Int 15, 855–861 (2004). https://doi.org/10.1007/s00198-004-1616-3

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  • DOI: https://doi.org/10.1007/s00198-004-1616-3

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