Persistent improvement of bone mineral density up to 20 years after treatment of Cushing’s syndrome

in European Journal of Endocrinology
View More View Less
  • 1 Department of Internal Medicine, Division of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  • | 2 Department of Internal Medicine, Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands
  • | 3 Department of Internal Medicine, Rijnstate Hospital, Arnhem, The Netherlands

Correspondence should be addressed to Annenienke van de Ven Email annenienke.vandeven@radboudumc.nl
Restricted access

Objective

Cushing’s syndrome (CS) is associated with osteoporosis and high fracture risk. Besides male sex, it is unknown which variables influence bone mineral density (BMD) at diagnosis and it is unclear to what extent BMD normalizes during long-term follow-up after treatment of CS. The aim of this study was to determine factors associated with BMD at diagnosis of CS and to determine the long-term course of BMD and fracture rate after successful treatment of CS.

Design

Retrospective cross-sectional and longitudinal cohort study.

Methods

Data were collected from 231 patients with CS who were treated at the Radboud University Medical Centre between 1968 and 2020.

Results

At diagnosis, male sex was associated with lower Z-scores at the lumbar spine (LS) compared with female sex: −0.97s.d. (−1.45 to −0.49) after correction for possible confounders. Shorter duration of symptoms and younger age were also associated with lower Z-scores at diagnosis, while etiology of CS, urinary cortisol excretion and gonadal status were not associated with Z-scores at diagnosis. Z-scores improved up to 20 years after treatment. Fifteen years after treatment, men showed larger improvements of Z-scores than women; +2.56 (1.82–3.30) increase in LS Z-score vs +1.48 (0.96–2.00) respectively. Fracture incidence was highest during the 2 years before diagnosis and decreased after treatment.

Conclusion

Male sex, younger age and shorter duration of symptoms are associated with lower BMD at diagnosis of CS. BMD continues to improve up to 20 years after treatment of CS. Fracture rate decreases after treatment of CS.

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 1355 1355 137
Full Text Views 65 65 9
PDF Downloads 94 94 16
  • 1

    Lindholm J, Juul S, Jørgensen JOL, Astrup J, Bjerre P, Feldt-Rasmussen U, Hagen C, Jørgensen J, Kosteljanetz M & Kristensen L et al. Incidence and late prognosis of Cushing’s syndrome: a population-based study. Journal of Clinical Endocrinology and Metabolism 2001 86 117123. (https://doi.org/10.1210/jcem.86.1.7093)

    • Search Google Scholar
    • Export Citation
  • 2

    Hardy RS, Zhou H, Seibel MJ, Cooper MS. Glucocorticoids and bone: consequences of endogenous and exogenous excess and replacement therapy. Endocrine Reviews 2018 39 519548. (https://doi.org/10.1210/er.2018-00097)

    • Search Google Scholar
    • Export Citation
  • 3

    Di Somma C, Pivonello R, Loche S, Faggiano A, Klain M, Salvatore M, Lombardi G, Colao A. Effect of 2 years of cortisol normalization on the impaired bone mass and turnover in adolescent and adult patients with Cushing's disease: a prospective study. Clinical Endocrinology 2003 58 302308. (https://doi.org/10.1046/j.1365-2265.2003.01713.x)

    • Search Google Scholar
    • Export Citation
  • 4

    Dos Santos CV, Vieira Neto L, Madeira M, Alves Coelho MC, de Mendonça LM, Paranhos-Neto Fde P, Lima IC, Gadelha MR, Farias ML. Bone density and microarchitecture in endogenous hypercortisolism. Clinical Endocrinology 2015 83 468474. (https://doi.org/10.1111/cen.12812)

    • Search Google Scholar
    • Export Citation
  • 5

    Hermus AR, Smals AG, Swinkels LM, Huysmans DA, Pieters GF, Sweep CF, Corstens FH, Kloppenborg PW. Bone mineral density and bone turnover before and after surgical cure of Cushing’s syndrome. Journal of Clinical Endocrinology and Metabolism 1995 80 28592865. (https://doi.org/10.1210/jcem.80.10.7559865)

    • Search Google Scholar
    • Export Citation
  • 6

    Minetto M, Reimondo G, Osella G, Ventura M, Angeli A, Terzolo M. Bone loss is more severe in primary adrenal than in pituitary-dependent Cushing’s syndrome. Osteoporosis International 2004 15 855861. (https://doi.org/10.1007/s00198-004-1616-3)

    • Search Google Scholar
    • Export Citation
  • 7

    Ohmori N, Nomura K, Ohmori K, Kato Y, Itoh T, Takano K. Osteoporosis is more prevalent in adrenal than in pituitary Cushing’s syndrome. Endocrine Journal 2003 50 17. (https://doi.org/10.1507/endocrj.50.1)

    • Search Google Scholar
    • Export Citation
  • 8

    Randazzo ME, Grossrubatscher E, Ciaramella PD, Vanzulli A, Loli P. Spontaneous recovery of bone mass after cure of endogenous hypercortisolism. Pituitary 2012 15 193201. (https://doi.org/10.1007/s11102-011-0306-3)

    • Search Google Scholar
    • Export Citation
  • 9

    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. Journal of Clinical Endocrinology and Metabolism 2006 91 17791784. (https://doi.org/10.1210/jc.2005-0582)

    • Search Google Scholar
    • Export Citation
  • 10

    Valassi E, Santos A, Yaneva M, Tóth M, Strasburger CJ, Chanson P, Wass JA, Chabre O, Pfeifer M & Feelders RA et al. The European Registry on Cushing's syndrome: 2-year experience. Baseline demographic and clinical characteristics. European Journal of Endocrinology 2011 165 383–392. (https://doi.org/10.1530/EJE-11-0272)

    • Search Google Scholar
    • Export Citation
  • 11

    Trementino L, Appolloni G, Ceccoli L, Marcelli G, Concettoni C, Boscaro M, Arnaldi G. Bone complications in patients with Cushing’s syndrome: looking for clinical, biochemical, and genetic determinants. Osteoporosis International 2014 25 913921. (https://doi.org/10.1007/s00198-013-2520-5)

    • Search Google Scholar
    • Export Citation
  • 12

    Van der Eerden AW, Den Heijer M, Oyen WJ, Hermus AR. Cushing’s syndrome and bone mineral density: lowest Z scores in young patients. Netherlands Journal of Medicine 2007 65 137141.

    • Search Google Scholar
    • Export Citation
  • 13

    Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BM, Colao A. Complications of Cushing's syndrome: state of the art. Lancet. Diabetes and Endocrinology 2016 4 611629 (https://doi.org/10.1016/S2213-8587(1600086-3)

    • Search Google Scholar
    • Export Citation
  • 14

    Jia J, Yao W, Guan M, Dai W, Shahnazari M, Kar R, Bonewald L, Jiang JX, Lane NE. Glucocorticoid dose determines osteocyte cell fate. FASEB Journal 2011 25 33663376. (https://doi.org/10.1096/fj.11-182519)

    • Search Google Scholar
    • Export Citation
  • 15

    Shi C, Huang P, Kang H, Hu B, Qi J, Jiang M, Zhou H, Guo L, Deng L. Glucocorticoid inhibits cell proliferation in differentiating osteoblasts by microRNA-199a targeting of WNT signaling. Journal of Molecular Endocrinology 2015 54 325337. (https://doi.org/10.1530/JME-14-0314)

    • Search Google Scholar
    • Export Citation
  • 16

    Jia D, O’brien CA, Stewart SA, Manolagas SC, Weinstein RS. Glucocorticoids act directly on osteoclasts to increase their life span and reduce bone density. Endocrinology 2006 147 55925599. (https://doi.org/10.1210/en.2006-0459)

    • Search Google Scholar
    • Export Citation
  • 17

    Swanson C, Lorentzon M, Conaway HH, Lerner UH. Glucocorticoid regulation of osteoclast differentiation and expression of receptor activator of nuclear factor-κB (NF-κB) ligand, osteoprotegerin, and receptor activator of NF-κB in mouse calvarial bones. Endocrinology 2006 147 36133622. (https://doi.org/10.1210/en.2005-0717)

    • Search Google Scholar
    • Export Citation
  • 18

    Weinstein RS, Chen JR, Powers CC, Stewart SA, Landes RD, Bellido T, Jilka RL, Parfitt AM, Manolagas SC. Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. Journal of Clinical Investigation 2002 109 10411048. (https://doi.org/10.1172/JCI14538)

    • Search Google Scholar
    • Export Citation
  • 19

    Buckley LM, Leib ES, Cartularo KS, Vacek PM, Cooper SM. Calcium and vitamin D3 supplementation prevents bone loss in the spine secondary to low-dose corticosteroids in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine 1996 125 961968. (https://doi.org/10.7326/0003-4819-125-12-199612150-00004)

    • Search Google Scholar
    • Export Citation
  • 20

    Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporosis International 2007 18 13191328. (https://doi.org/10.1007/s00198-007-0394-0)

    • Search Google Scholar
    • Export Citation
  • 21

    Reid IR Glucocorticoid-induced osteoporosis. Best Practice and Research Clinical Endocrinology and Metabolism 2000 14 279298. (https://doi.org/10.1053/beem.2000.0074)

    • Search Google Scholar
    • Export Citation
  • 22

    Weinstein RS Clinical practice. Glucocorticoid-induced bone disease. New England Journal of Medicine 2011 365 6270. (https://doi.org/10.1056/NEJMcp1012926)

    • Search Google Scholar
    • Export Citation
  • 23

    Seibel MJ, Cooper MS, Zhou H. Glucocorticoid-induced osteoporosis: mechanisms, management, and future perspectives. Lancet: Diabetes and Endocrinology 2013 1 5970. (https://doi.org/10.1016/S2213-8587(1370045-7)

    • Search Google Scholar
    • Export Citation
  • 24

    Borelli A, Leite MO, Correa PH, Jorgetti V, Marcondes JA, Batalha JR, Cintra AB, Wajchenberg BL. Bone histomorphometry in Cushing’s syndrome. Journal of Endocrinological Investigation 1992 15 783787. (https://doi.org/10.1007/BF03348804)

    • Search Google Scholar
    • Export Citation
  • 25

    Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Annals of Internal Medicine 1990 112 352364. (https://doi.org/10.7326/0003-4819-112-5-352)

    • Search Google Scholar
    • Export Citation
  • 26

    Mirza F, Canalis E. Management of endocrine disease: Secondary osteoporosis: pathophysiology and management. European Journal of Endocrinology 2015 173 R131R151. (https://doi.org/10.1530/EJE-15-0118)

    • Search Google Scholar
    • Export Citation
  • 27

    Fütő L, Tőke J, Patócs A, Szappanos A, Varga I, Gláz E, Tulassay Z, Rácz K, Tóth M. Skeletal differences in bone mineral area and content before and after cure of endogenous Cushing’s syndrome. Osteoporosis International 2008 19 941949. (https://doi.org/10.1007/s00198-007-0514-x)

    • Search Google Scholar
    • Export Citation
  • 28

    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 Journal of Endocrinology 2006 154 109118. (https://doi.org/10.1530/eje.1.02067)

    • Search Google Scholar
    • Export Citation
  • 29

    Vestergaard P, Lindholm J, Jorgensen JO, Hagen C, Hoeck HC, Laurberg P, Rejnmark L, Brixen K, Kristensen & Feldt-Rasmussen U et al.Increased risk of osteoporotic fractures in patients with Cushing's syndrome. European Journal of Endocrinology 2002 146 5156. (https://doi.org/10.1530/eje.0.1460051)

    • Search Google Scholar
    • Export Citation
  • 30

    Kawamata A, Iihara M, Okamoto T, Obara T. Bone mineral density before and after surgical cure of Cushing’s syndrome due to adrenocortical adenoma: prospective study. World Journal of Surgery 2008 32 890896. (https://doi.org/10.1007/s00268-007-9394-7)

    • Search Google Scholar
    • Export Citation
  • 31

    Zilio M, Barbot M, Ceccato F, Camozzi V, Bilora F, Casonato A, Frigo AC, Albiger N, Daidone V & Mazzai L et al.Diagnosis and complications of Cushing’s disease: gender‐related differences. Clinical Endocrinology 2014 80 403410. (https://doi.org/10.1111/cen.12299)

    • Search Google Scholar
    • Export Citation
  • 32

    Broersen LHA, Van Haalen FM, Kienitz T, Biermasz NR, Strasburger CJ, Dekkers OM, Pereira AM. Sex differences in presentation but not in outcome for ACTH-dependent Cushing’s syndrome. Frontiers in Endocrinology 2019 10 580. (https://doi.org/10.3389/fendo.2019.00580)

    • Search Google Scholar
    • Export Citation
  • 33

    Giraldi FP, Moro M, Cavagnini F & Study Group on the Hypothalamo-Pituitary-Adrenal Axis of the Italian Society of Endocrinology. Gender-related differences in the presentation and course of Cushing’s disease. Journal of Clinical Endocrinology and Metabolism 2003 88 15541558. (https://doi.org/10.1210/jc.2002-021518)

    • Search Google Scholar
    • Export Citation
  • 34

    Huan C, Qu Y, Ren Z. Gender differences in presentation and outcome of patients with Cushing’s disease in Han Chinese. Bio-Medical Materials and Engineering 2014 24 34393446. (https://doi.org/10.3233/BME-141168)

    • Search Google Scholar
    • Export Citation
  • 35

    Manning PJ, Evans MC, Reid IR. Normal bone mineral density following cure of Cushing’s syndrome. Clinical Endocrinology 1992 36 229234. (https://doi.org/10.1111/j.1365-2265.1992.tb01437.x)

    • Search Google Scholar
    • Export Citation
  • 36

    Catargi B, Tabarin A, Basse-Cathalinat B, Ducassou D, Roger P. Development of bone mineral density after cure of Cushing's syndrome. Annales d'endocrinologie 1996 57 203208.

    • Search Google Scholar
    • Export Citation
  • 37

    Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2008 93 15261540. (https://doi.org/10.1210/jc.2008-0125)

    • Search Google Scholar
    • Export Citation
  • 38

    Kanis JA Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO Study Group. Osteoporosis International 1994 4 368381. (https://doi.org/10.1007/BF01622200)

    • Search Google Scholar
    • Export Citation
  • 39

    Genant HK, Wu CY, Van Kuijk C, Nevitt MC. Vertebral fracture assessment using a semiquantitative technique. Journal of Bone and Mineral Research 1993 8 11371148. (https://doi.org/10.1002/jbmr.5650080915)

    • Search Google Scholar
    • Export Citation
  • 40

    Fernandez-Rodriguez E, Stewart PM, Cooper MS. The pituitary–adrenal axis and body composition. Pituitary 2009 12 105115. (https://doi.org/10.1007/s11102-008-0098-2)

    • Search Google Scholar
    • Export Citation
  • 41

    Malgo F, Hamdy NAT, Ticheler CHJM, Smit F, Kroon HM, Rabelink TJ, Dekkers OM, Appelman-Dijkstra NM. Value and potential limitations of vertebral fracture assessment (VFA) compared to conventional spine radiography: experience from a fracture liaison service (FLS) and a meta-analysis. Osteoporosis International 2017 28 29552965. (https://doi.org/10.1007/s00198-017-4137-6)

    • Search Google Scholar
    • Export Citation
  • 42

    Morin S, Tsang JF, Leslie WD. Weight and body mass index predict bone mineral density and fractures in women aged 40 to 59 years. Osteoporosis International 2009 20 363370. (https://doi.org/10.1007/s00198-008-0688-x)

    • Search Google Scholar
    • Export Citation
  • 43

    Warming L, Hassager C, Christiansen C. Changes in bone mineral density with age in men and women: a longitudinal study. Osteoporosis International 2002 13 105112. (https://doi.org/10.1007/s001980200001)

    • Search Google Scholar
    • Export Citation
  • 44

    De Laet C, Kanis JA, Odén A, Johanson H, Johnell O, Delmas P, Eisman JA, Kroger H, Fujiwara S & Garnero P et al.Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporosis International 2005 16 13301338. (https://doi.org/10.1007/s00198-005-1863-y)

    • Search Google Scholar
    • Export Citation
  • 45

    Looker AC, Flegal KM, Melton LJ. Impact of increased overweight on the projected prevalence of osteoporosis in older women. Osteoporosis International 2007 18 307313. (https://doi.org/10.1007/s00198-006-0241-8)

    • Search Google Scholar
    • Export Citation
  • 46

    Van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporosis International 2002 13 777787. (https://doi.org/10.1007/s001980200108)

    • Search Google Scholar
    • Export Citation
  • 47

    Koetz KR, Van Rossum EF, Ventz M, Diederich S, Quinkler M. BclI polymorphism of the glucocorticoid receptor gene is associated with increased bone resorption in patients on glucocorticoid replacement therapy. Clinical Endocrinology 2013 78 831837. (https://doi.org/10.1111/cen.12096)

    • Search Google Scholar
    • Export Citation
  • 48

    Szappanos A, Patócs A, Tõke J, Boyle B, Sereg M, Majnik J, Borgulya G, Varga I, Likó I & Rácz K et al. BclI polymorphism of the glucocorticoid receptor gene is associated with decreased bone mineral density in patients with endogenous hypercortisolism. Clinical Endocrinology 2009 71 636643. (https://doi.org/10.1111/j.1365-2265.2009.03528.x)

    • Search Google Scholar
    • Export Citation
  • 49

    Dekkers OM, Horváth-Puhó E, Jørgensen JOL, Cannegieter SC, Ehrenstein V, Vandenbroucke JP, Pereira AM, Sørensen HT. Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. Journal of Clinical Endocrinology and Metabolism 2013 98 22772284. (https://doi.org/10.1210/jc.2012-3582)

    • Search Google Scholar
    • Export Citation
  • 50

    Bergh C, Wennergren D, Möller M, Brisby H. Fracture incidence in adults in relation to age and gender: a study of 27,169 fractures in the Swedish Fracture Register in a well-defined catchment area. PLoS ONE 2020 15 e0244291. (https://doi.org/10.1371/journal.pone.0244291)

    • Search Google Scholar
    • Export Citation