Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Endocrine
Published in: Endocrine 2/2018

01-02-2018 | Original Article

Vertebral fractures assessed with dual-energy X-ray absorptiometry in patients with Addison’s disease on glucocorticoid and mineralocorticoid replacement therapy

Authors: Valentina Camozzi, Corrado Betterle, Anna Chiara Frigo, Veronica Zaccariotto, Martina Zaninotto, Erica De Caneva, Paola Lucato, Walter Gomiero, Silvia Garelli, Chiara Sabbadin, Monica Salvà, Miriam Dalla Costa, Marco Boscaro, Giovanni Luisetto

Published in: Endocrine | Issue 2/2018

Login to get access

Abstract

Purpose

to assess bone damage and metabolic abnormalities in patients with Addison’s disease given replacement doses of glucocorticoids and mineralocorticoids.

Methods

A total of 87 patients and 81 age-matched and sex-matched healthy controls were studied. The following parameters were measured: urinary cortisol, serum calcium, phosphorus, creatinine, 24-h urinary calcium excretion, bone alkaline phosphatase, parathyroid hormone, serum CrossLaps, 25 hydroxyvitamin D, and 1,25 dihydroxyvitamin D. Clear vertebral images were obtained with dual-energy X-ray absorptiometry in 61 Addison’s disease patients and 47 controls and assessed using Genant’s classification.

Results

Nineteen Addison’s disease patients (31.1%) had at least one morphometric vertebral fracture, as opposed to six controls (12.8%, odds ratio 3.09, 95% confidence interval 1.12–8.52). There were no significant differences in bone mineral density parameters at any site between patients and controls. In Addison’s disease patients, there was a positive correlation between urinary cortisol and urinary calcium excretion. Patients with fractures had a longer history of disease than those without fractures. Patients taking fludrocortisone had a higher bone mineral density than untreated patients at all sites except the lumbar spine.

Conclusions

Addison’s disease patients have more fragile bones irrespective of any decrease in bone mineral density. Supra-physiological doses of glucocorticoids and longer-standing disease (with a consequently higher glucocorticoid intake) might be the main causes behind patients’ increased bone fragility. Associated mineralocorticoid treatment seems to have a protective effect on bone mineral density.
Literature
1.
2.
C. Betterle, L. Morlin, Autoimmune Addison’s disease. Endocrine. Development 20, 161–172 (2011)
3.
M. Quinkler, F. Beuschlein, S. Hahner, G. Meyer, C. Schöfl, G.K. Stalla, Adrenal cortical insufficiency - a life threatening illness with multiple etiologies. Dtsch. Arztebl. Int. 110, 882–888 (2013)PubMedPubMedCentral
4.
M.M. Erichsen, K. Lovas, B. Skinningsrud, A.B. Wolff, D.E. Undlien, J. Svartberg, K.J. Fougner, T.J. Berg, J. Bollerslev, B. Mella, J.A. Carlson, H. Erlich, E.S. Husebye, Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. J. Clin. Endocr. Metab. 94, 4882–4890 (2009)CrossRefPubMed
5.
C. Betterle, R. Scarpa, S. Garelli, L. Morlin, F. Lazzarotto, F. Presotto, G. Coco, S. Masiero, A. Parolo, M.P. Albergoni, R. Favero, S. Barollo, M. Salvà, D. Basso, S. Chen, B. Rees Smith, J. Furmaniak, F. Mantero, Addison’s disease: a survey on 633 patients in Padova. Eur. J. Endocrinol. 169, 773–784 (2013)CrossRefPubMed
6.
C. Betterle, C. Dal Pra, F. Mantero, R. Zanchetta, Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr. Rev. 23, 327–364 (2002)CrossRefPubMed
7.
G.S. Eisenbarth, P.A. Gottlieb, Autoimmune polyendocrine syndromes. New Engl. J. Med. 13, 2068–2079 (2004)CrossRef
8.
A. Soderbergh, O. Winqvist, I. Norheim, F. Rorsman, E.S. Husebye, O. Dolva, F.A. Karlsson, O. Kämpe, Adrenal autoantibodies and organ-specific autoimmunity in patients with Addison’s disease. Clin. Endocrinol. 45, 453–460 (1996)CrossRef
9.
M. Fichna, P. Fichna, M. Gryczynska, J. Walkowiak, M. Zurawek, J. Sowinski, Screening for associated autoimmune disorders in Polish patients with Addison’s disease. Endocrine 37, 349–360 (2010)CrossRefPubMed
10.
A. Soderbergh, A.G. Myhre, O. Ekwall, G. Gebre-Medhin, H. Hedstrand, E. Landgren, A. Miettinen, P. Eskelin, M. Halonen, T. Tuomi, J. Gustafsson, E.S. Husebye, J. Perheentupa, M. Gylling, M.P. Manns, F. Rorsman, O. Kämpe, T. Nilsson, Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. J. Clin. Endocr. Metab. 89, 557–562 (2004)CrossRefPubMed
11.
E.S. Husebye, J. Perheentupa, R. Rautemaa, O. Kämpe, Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J. Intern. Med 265, 514–529 (2009)CrossRefPubMed
12.
Ø. Bruserud, B.E. Oftedal, A.B. Wolff, E.S. Husebye, AIRE-mutations and autoimmune disease. Curr. Opin. Immunol. 6, 8–15 (2016)CrossRef
13.
E.S. Husebye, B. Allolio, W. Arlt, K. Badenhoop, S. Bensing, C. Betterle, A. Falorni, E.H. Gan, A.L. Hulting, A. Kasperlik-Zaluska, O. Kämpe, K. Løvås, G. Meyer, S.H. Pearce, Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J. Intern. Med. 275, 104–115 (2014)CrossRefPubMed
14.
A. Grossman, G. Johannsson, M. Quinkler, P. Zelissen, Therapy of endocrine disease. Perspectives on the management of adrenal insufficiency: clinical insights from across Europe. Eur. J. Endocrinol. 21, R165–R175 (2013)CrossRef
15.
A. Falorni, V. Minarelli, S. Morelli, Therapy of adrenal insufficiency: an update. Endocrine 43, 514–528 (2013)CrossRefPubMed
16.
G. Johannsson, iA. Falorn, S. Skrtic, H. Lennernäs, M. Quinkler, J.P. Monson, P.M. Stewart, Adrenal insufficiency: review of clinical outcomes with current GC replacement therapy. Clin. Endocrinol. (Oxf.) 82, 2–11 (2015)CrossRef
17.
J.P. Devogelaer, J. Crabbé; Nagant de Deuxchaisnes, C, Bone mineral density in Addison’s disease: evidence for an effect of adrenal androgens on bone mass. Brit. Med. J. (Clin. Res Ed.) 294, 798–800 (1987)CrossRef
18.
P.M. Zelissen, R.J. Croughs, P.P. van Rijk, J.A. Raymakers, Effect of MC replacement therapy on bone mineral density in patients with Addison disease. Ann. Intern. Med. 120, 207–210 (1994)CrossRefPubMed
19.
M.A. Valero, M. Leon, M.P. Ruiz Valdepeñas, L. Larrodera, M.B. Lopez, K. Papapietro, A. Jara, F. Hawkins, Bone density and turnover in Addison’s disease: effect of glucocorticoid treatment. Bone Miner. 26, 9–17 (1994)CrossRefPubMed
20.
F. Heureux, D. Maiter, Y. Boutsen, J.P. Devogelaer, J. Jamart, J. Donckier, Evaluation of corticosteroid replacement therapy and its effect on bones in Addison’s disease. Ann. Endocrinol. (Paris) 61, 179–183 (2000)
21.
E. Jódar, M.P. Valdepeñas, G. Martinez, A. Jara, F. Hawkins, Long-term follow-up of bone mineral density in Addison’s disease. Clin. Endocrinol. (Oxf.) 58, 617–620 (2003)CrossRef
22.
K.R. Koetz, M. Ventz, S. Diederich, M. Quinkler, Bone mineral density is not significantly reduced in adult patients on low-dose glucocorticoid replacement therapy. J. Clin. Endocr. Metab. 97, 85–92 (2012)CrossRefPubMed
23.
D.D. Chandy, E. Bhatia, Bone mineral density in patients with Addison disease on replacement therapy with prednisolone. Endocr. Pract. 22, 434–439 (2016)CrossRefPubMed
24.
G. Mazziotti, T. Porcelli, A. Bianchi, V. Cimino, I. Patelli, C. Mejia, A. Fusco, A. Giampietro, L. De Marinis, A. Giustina, Glucocorticoid replacement therapy and vertebral fractures in hypopituitary adult males with GH deficiency. Eur. J. Endocrinol. 163, 15–20 (2010)CrossRefPubMed
25.
R.D. Mosteller, Simplified calculation of body surface area. N. Engl. J. Med. 317, 1098 (1987)PubMed
26.
H.K. Genant, M. Jergas, L. Palermo, M. Nevitt, R.S. Valentin, D. Black, S.R. Cummings, Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis. The study of osteoporotic fractures research group. J. Bone Miner. Res. 11, 984–996 (1996)CrossRefPubMed
27.
N. Binkley, D. Krueger, R. Gangnon, H.K. Genant, M.K. Drezner, Lateral vertebral assessment: a valuable technique to detect clinically significant vertebral fractures. Osteoporos. Int. 16, 1513–8 (2005)CrossRefPubMed
28.
I.C. Hospers, J.G. van der Laan, C.J. Zeebregts, P. Nieboer, B.H. Wolffenbuttel, R.A. Dierckx, H.G. Kreeftenberg, P.L. Jager, R.H. Slart, Vertebral fracture assessment in supine position: comparison by using conventional semiquantitative radiography and visual radiography. Radiology 251, 822–828 (2009)CrossRefPubMed
29.
T. Fuerst, C. Wu, H.K. Genant, G. von Ingersleben, Y. Chen, C. Johnston, M.J. Econs, N. Binkley, T.J. Vokes, G. Crans, B.H. Mitlak, Evaluation of vertebral fracture assessment by dual X-ray absorptiometry in a multicenter setting. Osteoporos. Int. 20, 1199–1205 (2009)CrossRefPubMed
30.
P.L. Jager, S. Jonkman, W. Koolhaas, A. Stiekema, B.H. Wolffenbuttel, R.H. Slart, Combined vertebral fracture assessment and bone mineral density measurement: a new standard in the diagnosis of osteoporosis in academic populations. Osteoporos. Int. 22, 1059–1068 (2011)CrossRefPubMed
31.
K. Løvås, C.G. Gjesdal, M. Christensen, A.B. Wolff, B. Almås, J. Svartberg, K.J. Fougner, U. Syversen, J. Bollerslev, J.A. Falch, P.J. Hunt, V.K. Chatterjee, E.S. Husebye, Glucocorticoid replacement therapy and pharmacogenetics in Addison’s disease: effects on bone. Eur. J. Endocrinol. 160, 993–1002 (2009)CrossRefPubMed
32.
S. Björnsdottir, M. Sääf, S. Bensing, O. Kämpe, K. Michaëlsson, J.F. Ludvigsson, Risk of hip fracture in Addison’s disease: a population-based cohort study. J. Intern. Med 270, 187–195 (2011)CrossRefPubMed
33.
F. Heureux, D. Maiter, Y. Boutsen, J.P. Devogelaer, Jamar,t J., Donckier J.: evaluation of corticosteroid replacement therapy and its effect on bones in Addison’s disease. Ann. Endocrinol. (Paris) 61, 179–183 (2000)
34.
E. Jódar, M.P. Valdepeñas, G. Martinez, A. Jara, F. Hawkins, Long-term follow-up of bone mineral density in Addison’s disease. Clin. Endocrinol. (Oxf.) 58, 617–620 (2003)CrossRef
35.
G.D. Braatvedt, M. Joyce, M. Evans, J. Clearwater, I.R. Reid, Bone mineral density in patients with treated Addison’s disease. Osteoporos. Int 10, 435–440 (1999)CrossRefPubMed
36.
C.M. Florkowski, S.J. Holmes, J.R. Elliot, R.A. Donald, E.A. Espiner, Bone mineral density is reduced in female but not male subjects with Addison’s disease. N. Z. Med. J. 107, 52–53 (1994)PubMed
37.
D.D. Chandy, E. Bhatia, Bone mineral density in patients with Addison’s disease on replacement therapy with prednisolone. Endocr. Pract. 22, 434–439 (2016)CrossRefPubMed
38.
P.M. Zelissen, R.J. Croughs, P.P. van Rijk, J.A. Raymakers, Effect of glucocorticoid replacement therapy on bone mineral density in patients with Addison disease. Ann. Intern. Med. 120, 207–210 (1994)CrossRefPubMed
39.
N. Chikada, T. Imaki, M. Hotta, K. Sato, K. Takano, An assessment of bone mineral density in patients with Addison’s disease and isolated ACTH deficiency treated with glucocorticoid. Endocr. J. 51, 355–360 (2004)CrossRefPubMed
40.
M.A. Valero, M. Leon, M.P. Ruiz Valdepeñas, L. Larrodera, M.B. Lopez, K. Papapietro, A. Jara, F. Hawkins, Bone density and turnover in Addison’s disease: effect of glucocorticoid treatment. Bone Miner. 26, 9–17 (1994)CrossRefPubMed
41.
L.A. Behan, G. Kelleher, M.J. Hannon, J.J. Brady, B. Rogers, W. Tormey, D. Smith, C.J. Thompson, M.J. McKenna, A. Agha, Low-dose hydrocortisone replacement therapy is associated with improved bone remodelling balance in hypopituitary male patients. Eur. J. Endocrinol. 170, 141–150 (2013)CrossRefPubMed
42.
J. Schulz, K.R. Frey, M.S. Cooper, K. Zopf, M. Ventz, S. Diederich, M. Quinkler, Reduction in daily hydrocortisone dose improves bone health in primary adrenal insufficiency. Eur. J. Endocrinol. 174, 531–538 (2016)CrossRefPubMed
43.
G. Mazziotti, A. Angeli, J.P. Bilezikian, E. Canalis, A. Giustina, Glucocorticoid-induced osteoporosis: an update. Trends Endocrinol. Metab. 7, 144–149 (2006)CrossRef
44.
F.P. Cappuccio, N.D. Markandu, G.A. MacGregor, Renal handling of calcium and phosphate during mineralocorticoid administration in normal subjects. Nephron 48, 280–283 (1988)CrossRefPubMed
45.
W.N. Suki, R.S. Schwettmann, F.C. Rector Jr, D.W. Seldin, Effect of chronic mineralocorticoid administration on calcium excretion in the rat. Am. J. Physiol. 215, 71–74 (1968)PubMed
46.
E. Rossi, C. Sani, F. Perazzoli, M.C. Casoli, A. Negro, C. Dotti, Alterations of calcium metabolism and of parathyroid function in primary aldosteronism, and their reversal by spironolactone or by surgical removal of aldosterone-producing adenomas. Am. J. Hypertens. 8, 884–893 (1995)CrossRefPubMed
47.
L. Ceccoli, V. Ronconi, L. Giovannini, M. Marcheggiani, F. Turchi, M. Boscaro, G. Giacchetti, Bone health and aldosterone excess. Osteoporos. Int. 24, 2801–2807 (2013)CrossRefPubMed
48.
L.Petramala, L.Zinnamosca, A.Settevendemmie, C.Marinelli, M.Nardi, A.Concistrè, F.Corpaci, G.Tonnarini, G.De Toma, C.Letizia Bone and Mineral metabolism in patients with primary aldosteronism.Int. J. Endocrinol (2014). doi:10.1155/2014/836529PubMedPubMedCentral
49.
Y. Zhang, B. Feng, Association of serum parathyrine and calcium levels with primary aldosteronism: a meta-analysis. Int. J. Clin. Exp. Med. 8, 14625–14633 (2015)PubMedPubMedCentral
50.
S. Beavan, A. Horner, S. Bord, D. Ireland, J. Compston, Colocalization of glucocorticoid and mineralocorticoid receptors in human bone. J. Bone Miner. Res. 16, 1496–1504 (2001)CrossRefPubMed
51.
N.Z. Lu, J.B. Collins, S.F. Grissom, J.A. Cidlowski, Selective regulation of bone cell apoptosis by translational isoforms of the glucocorticoid receptor. Mol. Cell Biol. 27, 7143–7160 (2007)CrossRefPubMedPubMedCentral
52.
R. La Corte, F. Trotta, S. Adami, Glucocorticoid receptors and bone. Curr. Pharm. Des. 16, 3586–3592 (2010)CrossRefPubMed
53.
C.M. Jewell, A.B. Scoltock, B.L. Hamel, M.R. Yudt, J.A. Cidlowski, Complex human glucocorticoid receptor dim mutations define glucocorticoid-induced apoptotic resistance in bone cells. Mol. Endocrinol. 26, 244–256 (2012)CrossRefPubMed
54.
P. Moutsatsou, E. Kassi, A.G. Papavassiliou, Glucocorticoid receptor signaling in bone cells. Trends Mol. Med. 18, 348–359 (2012)CrossRefPubMed
55.
H.H. Conaway, P. Henning, A. Lie, J. Tuckermann, U.H. Lerner, Activation of dimeric glucocorticoid receptors in osteoclast progenitors potentiates RANKL-induced mature osteoclast bone resorbing activity. Bone 93, 43–54 (2016)CrossRefPubMed
56.
M.K. Agarwal, F. Mirshahi, M. Mirshahi, S. Bracq, J. Chentoufi, M. Hott, A. Jullienne, P.J. Marie, Evidence for receptor-mediated mineralocorticoid action in rat osteoblastic cells. Am. J. Physiol. 270, C1088–C1095 (1996)CrossRefPubMed
57.
T. Fumoto, K.A. Ishii, M. Ito, S. Berger, G. Schütz, K. Ikeda, Mineralocorticoid receptor function in bone metabolism and its role in glucocorticoid-induced osteopenia. Biochem. Biophys. Res. Commun. 447, 407–412 (2014)CrossRefPubMed
58.
K.K. Miller, B.M. Biller, J. Hier, E. Arena, A. Klibanski, Androgens and bone density in women with hypopituitarism. J. Clin. Endocr. Metab. 87, 2770–2776 (2002)CrossRefPubMed
59.
L.J. Dominguez, M. Barbagallo, L. Moro, Collagen overglycosylation: a biochemical feature that may contribute to bone quality. Biochem. Biophys. Res. Commun. 330, 1–4 (2005)CrossRefPubMed
60.
E. Seeman, P.D. Delmas, Bone quality - the material and structural basis of bone strength and fragility. N. Engl. J. Med. 354, 2250–2261 (2006)CrossRefPubMed
61.
E. Canalis, G. Mazziotti, A. Giustina, J.P. Bilezikian, Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos. Int. 18, 1319–1328 (2007)CrossRefPubMed
62.
G. Mazziotti, A. Giustina, Glucocorticoids and the regulation of growth hormone secretion. Nat. Rev. Endocrinol. 9, 265–276 (2013)CrossRefPubMed
63.
O. Svejme, H.G. Ahlborg, J.Å. Nilsson, M.K. Karlsson, Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. Br. J. Obstet. Gynaecol. 119, 810–816 (2012)CrossRef
64.
V.N. Shah, C.S. Shah, J.K. Snell-Bergeon, Type 1 diabetes and risk of fracture: meta-analysis and review of the literature. Diabet. Med. 32, 1134–1142 (2015)CrossRefPubMedPubMedCentral
65.
W. Rathmann, K. Kostev, Fracture risk in patients with newly diagnosed type 2 diabetes: a retrospective database analysis in primary care. J. Diabetes Complicat. 29, 766–770 (2015)CrossRefPubMed
66.
D.L. Kamen, J.D. Alele, Skeletal manifestations of systemic autoimmune diseases. Curr. Opin. Endocrinol. Diabetes Obes. 17, 540–545 (2010)CrossRefPubMed
67.
F. Lombardi, A. Franzese, D. Iafusco, A. del Puente, A. Esposito, F. Prisco, R. Troncone, G. Valerio, Bone involvement in clusters of autoimmune diseases: just a complication? Bone 46, 551–555 (2010)CrossRefPubMed
Metadata
Title
Vertebral fractures assessed with dual-energy X-ray absorptiometry in patients with Addison’s disease on glucocorticoid and mineralocorticoid replacement therapy
Authors
Valentina Camozzi
Corrado Betterle
Anna Chiara Frigo
Veronica Zaccariotto
Martina Zaninotto
Erica De Caneva
Paola Lucato
Walter Gomiero
Silvia Garelli
Chiara Sabbadin
Monica Salvà
Miriam Dalla Costa
Marco Boscaro
Giovanni Luisetto
Publication date
01-02-2018
Publisher
Springer US
Published in
Endocrine / Issue 2/2018
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-017-1380-8

Other articles of this Issue 2/2018

Endocrine 2/2018 Go to the issue

Original Article

Tyrosine kinase inhibitors in iodine-refractory differentiated thyroid cancer: experience in clinical practice

Original Article

Synergistic cytotoxicity of the dipeptidyl peptidase-IV inhibitor gemigliptin with metformin in thyroid carcinoma cells

Research Letter

Pasireotide versus pituitary surgery: a retrospective analysis of 12 months of treatment in patients with Cushing’s disease

Endocrine Genetics/Epigenetics

Analysis of circulating extracellular vesicle-associated microRNAs in cortisol-producing adrenocortical tumors

Review

Irisin in metabolic diseases

Original Article

Metformin, beta-cell development, and novel processes following beta-cell ablation in zebrafish
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits