LOW-TRAUMATIC FRACTURES IN PATIENTS WITH ENDOGENOUS HYPERCORTISOLISM. PREDICTORS AND RISK FACTORS, THE IMPACT ON QUALITY OF LIFE

The objective of this study was to investigate the prevalence of low traumatic fractures, the factors influencing fractures in endogenous Cushing’s syndrome (CS) of various etiologies and their contributions into functional abilities and quality of life in patients with CS. Materials and methods: the retrospective data of patients, who had received treatment due to endogenous CS, (2001-2011), was evaluated. All enrolled patients underwent standard spinal radiographs in lateral positions of the vertebrae Th4-L4. Recent low traumatic non-vertebral fractures were recorded in the medical cards. Bone mineral density (BMD) was measured by DXA GE Lunar Prodigy. Serum samples on octeocalcin (OC), carboxyterminal cross-linked telopeptide of type I collagen (CTx), latenight cortisol in serum were assayed by electrochemiluminescence (ECLIA). 24h urinary free cortisol (24hUFC) was measured by an immunochemiluminescence assay (extraction with diethyl ether). Functional assessment was performed using «chair rising», «up and go» and «tandem» tests. Universal pain assessment tool (verbal descriptor scale, Wong-Baker facial grimace scale, activity tolerance scale), EQ-5D and ECOS-16 questionnaires were given to patients and they self-reported their conditions. Results: Among 215 patients, 178 were females and 37 males, median age 35 (Q25-Q75 27-48); 88patients (40,9%) had low traumatic fractures, including vertebral fractures in 76 cases (in 60 cases multiple vertebral fractures) and non-vertebral fractures in 27 cases (17 patients had rib fractures, 3 -fractures of metatarsal bones, 2 fractures of radius, 2 fractures of tibia and fibula, 1 humerus, 1 breastbone; 1 hip fracture). Patients with fractures had higher 24hUFC, late-night cortisol in serum, lower OC, Total Hip BMD, but did not differ in age, BMI, CTx or etiology of CS. After applying the logistic regression analysis (adjusted for sex, age, BMI, BMD, OC), the main predictor of fractures was late-night serum cortisol level (p=0,001). Patients with late-night serum cortisol higher than 597 nmol/l were more likely to have low traumatic fractures (Odds ratio 2,86 (95%CI 1,55-5,28) p=0,001). Patients with fractures suffered from more pain and reported worse functional abilities. They had slightly worse results in «tandem» test, but did not differ in other functional tests, which assessed mainly muscle power. Conclusions: Patients with CS have very high risk of low traumatic fractures. The severity of hypercortisolemia is the best predictor of low traumatic fractures in patients with CS. Patients with fractures sufferedfrom more severe pain and because of this they restricted their daily activity even more than patients with CS without fractures. Consequently, patients with higher levels of late-night serum cortisol need earlier preventive treatment for osteoporosis.

эндогенный гиперкортицизм, низкотравматичные переломы, уровень кортизола как предиктор переломов

1. Kalsas G, Makras P.: Skeletal diseases in Cushing’s syndrome: osteoporosis versus arthropathy.// Neuroendocrinology, 2010, Vol. 92 (suppl 1), pp. 60-64.

2. Cushing H.: The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism).// Bull Johns Hopkins Hosp, 1932 Vol. 50, pp. 137-195.

3. Lekamwasam S, Adachi JD, Agnusdei D, Bilezikian J, Boonen S, Borgstrom F, Cooper C, Diez Perez A, Eastell R, Hofbauer LC, Kanis JA, Langdahl BL, Lesnyak O, Lorene R,McCloskey E, Messina OD, Napoli N, Obermayer-Pietsch B, Ralston SH, Sambrook PN,Silverman S, Sosa M, Stepan J, Suppan G, Wahl DA, Compston JE, Joint IOF-ECTS GIO Guidelines Working Group 2012 A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporosis International, 2012, Vol. 23, pp. 2257-2276.

4. Белая Ж.Е., Рожинская Л.Я., Драгунова н.в., солодовников А.г, Ильин А.в., Дзеранова Л.к., мельниченко г.А., Дедов И.И. «сывороточные концентрации белков регуляторов остеобластогенеза и остеокластогенеза у пациентов с эндогенным гиперкортицизмом». Ж. Остеопороз и Остеопатии, 2012, № 2, стр. 3-8.

5. Wang F-S, Lin C-L, Chen Y-J, Wang C-J, Yang KD, Huang Y-T, Sun Y-C, Huang H-C.: Secreted frizzled-related protein 1 modulates glucocorticoid attenuation of osteogenic activities and bone mass. // J. Endocrinology, 2005, Vol. 146, pp. 2415-2423.

6. Wang F-S, Ko J-Y, Yeh D-W, Ke H-C, Wu H-L.: Modulation of dickkopf-1 attenuates glucocorticoid induction of osteoblast apoptosis, adipocytic differentiation and bone mass loss. // Endocrinology, 2008, Vol. 149, pp.1793-1801.

7. Yao W, Cheng Z, Busse C, Pham A, Nakamura MC, Lane NE.: Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis. // Arthritis Rheum, 2008, Vol. 58, pp.1674-1686.

8. Swanson C, Lorentzon M, Conaway HH, Lerner UH.: Glucocorticoid regulation of osteoclast differentiation and expression of receptor activator of nuclear factor-kappaB in mouse calvarial bones.// Endocrinology, 2006, Vol. 147, pp.3613-3622.

9. Canalis E, Mazziotti G, Giustina A, Bilezikian JP.: Glucocorticoid-induced osteoporosis: pathophysiology and therapy. // Osteoporosis International, 2007, Vol. 18, pp. 1319-1328.

10. Van Hogezand RA, Hamdy NA.: Skeletal morbidity in inflammatory bowel disease.// Scand J. Gastroenterology, 2006, Vol. 243: S59-S64.

11. Lekamwasam S, Trivedi DP, Khaw KT. An association between respiratory function and bone mineral density in women from the general community: a cross sectional study. // Osteoporosis Int. 2002, Vol. 13, pp. 710-715.

12. Рожинская Л.Я. «Остеопенический синдром при заболеваниях эндокринной системы и постменопаузальный остеопороз: патогенетические аспекты, диагностика и лечение». Диссертация докторская, Москва 2002.

13. Lukert BP, Higgins JC, Stoskopf MM.: Serum osteocalcin is increased in patients with hyperthyroidism and decreased in patients receiving glucocorticoids.// J. Clin Endocrinol Metab, 1986, Vol. 62, pp. 1056-1058.

14. Szappanos A, Toke J, Lippai D, Patocs A, Igaz P, Szucs N, Futo L, Glaz E, Racz K, Toth M. //Bone turnover in patients with endogenous Cushing’s syndrome before and after successful treatment. Osteoporosis International, 2010, Vol. 21, pp. 637-645.

15. Kristo C, Jemtland R, Ueland T, Godang K, Bollerslev J.: Restoration of the coupling process and normalization of bone mass following successful treatment of endogenous Cushing’s syndrome: a prospective, long-term study// European J. Endocrinology, 2006, Vol. 154, pp.109-118.

16. Sereg M, Toke J, Patocs A, Varga I, Igaz P, Szucs N, Horanyi J, Pusztai P, Czirjak S, Glaz E, Racz K, Toth M.: Diagnostic performance of salivary cortisol and serum osteocalcin measurements in patients with overt and subclinical Cushing’s syndrome// Steroids, 2011, Vol. 76, pp. 38-42.

17. Белая Ж.Е., Рожинская Л.Я., Мельниченко Т.А., Ильин А.В., Драгунова Н.В., колесникова ЕС., Бутрова С.А., Трошина Е.А.: Возможности маркёра костного обмена остеокальцина для диагностики эндогенного гиперкортицизма и вторичного остеопороза.// Ж. Остеопороз и Остеопатии, 2011 № 2, стр. 7-10.

18. Van Staa TP, Leufkens Hg, Abenhaim L, Zhang B, Cooper C.: Use of oral corticoids and risk of fractures.// J. Bone Miner Res, 2000 Vol.15, pp. 933-1000.

19. Kanis JA, Johansson H, Oden A, Johnell O, de Laet C, Melton LJ III, Tenenhouse A, Reeve J, Silman AJ, Pols HA, Eisman JA, McCloskey EV, Mellstrom D.: A meta-analysis of prior corticosteroid use and fracture risk. // J. Bone Miner Res, 2004 Vol. 19, pp. 893-899.

20. Tauchmanova L, Pivonello R, Di Somma C, Rossi R, De Martino MC, Camera L, Klain M, Salvatore M, Lombardi G, Colao A.: Bone Demineralization and vertebral fractures in endogenous cortisol excess: role of disease etiology and gonadal status.// J. Clin Endocrinol. Metab, 2006, Vol. 91, pp. 1779-1784.

21. Vestergaard P, Lindholm J, Jorgensen JOI, Hagen C, Hoeck HC, Laurberg P, Rejnmark L, Brixen K, Kristensen L, Feldt-Rasmussen U, Mosekilde L.: Increased risk of osteoporotic fractures in patients with Cushing’s syndrome. European J. Endocrinology, 2002, Vol. 146, pp. 51-56.

22. Белая Ж.Е., Ильин А.В., Мельниченко Т.А., Рожинская Л.Я., Драгунова Н.В., Дзеранова Л.к., Огнева Н.А., Бутрова С.А., Трошина Е.А, колесникова Т.С., Дедов И.И.: Автоматизированный электрохемилюминисцентный метод определения кортизола в слюне для диагностики эндогенного гиперкортицизма среди пациентов с ожирением.// Ж. Ожирение и метаболизм, 2011, том 27, № 2, стр. 56-63.

23. Nieman LK, Biller BMK, Finding jW, Newell-Price J, Savage MO, Stewart PM, Montori VM.: The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. // J. Clin Endocrinol Metab, 2008, Vol. 93, pp.1526-1540.

24. Genant HK, Wu CY, van Kujik C, Nevitt MC.: Vertebral fracture assessment using a semiquantative technique. J. Bone Miner Res, 1993, Vol. 8, pp. 1137-1148.

25. Runge M, Rehfeld G, Resnicek E.: Balance training and exercise in geriatric patients.// J. Musculoskel Neuronal Interact, 2000, Vol. 1, pp. 54-58.

26. Gill TM, Williams CS, Tinetti ME.: Assessing risk for the onset of functional dependence among older adults: the role of physical performance.// J. American Geriatr Soc, 1995, Vol. 43, pp. 603-609.

27. Podsialdo D, Richardson S.: The timed «Up and go»: a test of basic functional mobility for frail elderly persons // J. Am. Geriatr Soc, 1991, Vol. 39 (2), pp. 142-148.

28. Mathias S, Nayak US, Isaacs B.: Balance in elderly patients: the «get-up and go» test.// Arch Phys Med Rehabil, 1986, Vol. 67, pp. 387-389.

29. Zhu K, Devine A, Prince RL: Timed Up and Go test and BMD as predictors of fractures: a 10-year longitudinal study.// J. Bone Mineral Research, 2008, Vol. 23, s119.

30. Guralnik JM, Ferrucci L, Simonsick EM, Salive ME, Wallace RB.: Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability.// New England J. Medicine, 1995, Vol. 332, pp. 556-561.

31. Rabin R, Oemar M, Oppe M.: EQ-5D-3L User Guide: Basic information on how to use the EQ-5D-3L instrument. Version 4.0 April 2011.

32. Abourzazzak FE, Allali F, Rostom S, Hmamouchi I, Ichchou L, Mansouri LE, Bennani L, Khazzani H, Abouqal R Hajjaj-Hassouni N.: Factors influencing quality of life in Moroccan postmenopausal women with osteoporotic vertebral fracture assessed by ECOS 16 questionnaire// Health and quality of life outcomes, 2009, Vol. 7, pp. 23-31.

33. Badia X, Diez-Perez A, Lahoz R, Lizan L, Nogues X, Iborra J.: The ECOS-16 questionnaire for the evaluation of health related quality of life in post-menopausal women with osteoporosis.// Health and quality of life outcomes, 2004, Vol. 2, pp. 41-52.

34. Salaffi F, Malavolta N, Cimmino MA, Di Matteo L, Scendoni P, Carotti M, Stancati A, Mule R, Fringato M, Gutierrez M, Grassi W, Italian Multicentre Osteoporotic Fracture (MOF) Study Group.: Validity and reliability of the Italian version of the ECOS-16 questionnaire in postmenopausal women with prevalent vertebral fractures due to osteoporosis.// Clin Exp Rheumatol. 2007, Vol. 25, pp. 390-403.

35. Hoskisson EC.: Measurement of pain.// J. Rheumatology, 1982, Vol. 9, pp. 768-769.

36. Glas AS, Lijmer JG, Prins MH, Bonsel GJ, Bossuyt PMM.: The diagnostic odds ratio: a single indicator of test performance. Journal of Clinical Epidemiology, 2003, Vol.56, pp. 1129-113.

37. Белая Ж.Е., Рожинская Л.Я., Драгунова Н.В., Дзеранова Л.К., Марова Е.И., Арапова С.Д., Молитвословова Н.Н., Зенкова Т.С., Мельниченко Г.А., Дедов И.И.: «Метаболические осложнения эндогенного гиперкортицизма. Выбор пациентов для скрининга». Ж. Ожирение и Метаболизм, 2013, Том 34. № 1, стр 29-34.

38. Рожинская Л.Я. «Системный остеопороз». Практическое руководство для врачей, 2-ое издание (переработанное и дополненное). Издатель Мокеев, Москва 2000г, 195 стр.

39. Minne HW, Leidig G, Wuster C, Siromachhkostov L, Baldauf G, Bickel R, Sauer P, Lojen M, Ziegler R.: A newly defined spine deformity index (SDI) to quantitative vertebral crush fractures in patients with osteoporosis. Bone Miner J, 1988, Vol. 3, pp. 335-349.

40. Chiodini I, Viti R Coletti F et al. Eugonadal male patients with adrenal incidentalomas and subclinical hypercortisolism have increate rate of vertebral fractures//Clin Endocrinol (Oxf.), 2009, Vol. 70, pp. 208-213.

41. Morelli V, Eller-Vainicher C, Salcuni AS, Coletti F, Iorio L, Muscogiuri G, Della Casa S, Arosio M, Ambrosi B, Beck-Peccoz P, Chiodini I.: Risk of new vertebral fractures in patients with adrenal incidentaloma with and without subclinical hypercortisolism: a multicenter longitudinal study. J. Bone Mineral Research, 2011, Vol. 26, pp. 1816-1821.

42. Feelders RA, Pulgar SJ, Kempel A, Pereira AM.: The burden of Cushing’s disease: clinical and health-related quality of life aspects. European J. Endocrinology, 2012, Vol. 167, pp. 311-326.

43. Johnson MD, Woodburn CJ, Vance ML.: Quality of life in patients with a pituitary adenoma. Pituitary, 2003, Vol. 6, pp. 81-87.

44. van Aken MO, Pereira AM, Biermasz Nr, van Thiel SW, Hoftijzer HC, Smit JW, Roelfsema F, Lamberts SW, Romijn JA.: Quality of life in patients after long-term biochemical cure of Cushing’s disease. J. Clinical Endocrinology and Metabolism, 2005, Vol. 90, pp. 3279-3286.

45. Lindsay JR, Nansel T, Baid S, Gumowski J, Nieman LK.: Long-term impaired quality of life in Cushing’s syndrome despite initial improvement after surgical remission. J Clinical Endocrinology and Metabolism, 2006, Vol. 91, pp. 447-453.

46. Webb SM, Badia X, Barahona MJ, Colao A, Strasburger CJ, Tabarin A, van Aken MO, Pivonello R Stalla G, Lamberts SW, Glusman JE.: Evaluation of health-related quality of life in patients with Cushing’s syndrome with a new questionnaire. European J. Endocrinology, 2008, Vol. 158, pp. 623-630.

47. Heald AH, Ghosh S, Bray S, Gibson C, Anderson SG, Buckler H, Fowler HL.: Long-term negative impact on quality of life in patients with successfully treated Cushing’s disease. Clinical Endocrinology, 2004, Vol. 61, pp. 458-465.

48. van Aken MO, Pivonello R, Stalla G, Lamberts SW, Glusman JE.: Evaluation of health-related quality of life in patients with Cushing’s syndrome with a new questionnaire. European J. Endocrinology, 2008, Vol. 158, pp. 623-630.