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
BMC Endocrine Disorders
Published in: BMC Endocrine Disorders 1/2020

Open Access 01-12-2020 | Glucocorticoid | Research article

The contribution of serum cortisone and glucocorticoid metabolites to detrimental bone health in patients receiving hydrocortisone therapy

Authors: Rosemary Dineen, Lucy-Ann Behan, Grainne Kelleher, Mark J. Hannon, Jennifer J. Brady, Bairbre Rogers, Brian G. Keevil, William Tormey, Diarmuid Smith, Christopher J. Thompson, Malachi J. McKenna, Wiebke Arlt, Paul M. Stewart, Amar Agha, Mark Sherlock

Published in: BMC Endocrine Disorders | Issue 1/2020

Login to get access

Abstract

Background

Glucocorticoid therapy is the most common cause of iatrogenic osteoporosis. Less is known regarding the effect of glucocorticoids when used as replacement therapy on bone remodelling in patients with adrenal insufficiency. Enhanced intracellular conversion of inactive cortisone to active cortisol, by 11 beta-hydroxysteroid dehydrogenase type 1(11β-HSD1) and other enzymes leading to alterations in glucocorticoid metabolism, may contribute to a deleterious effect on bone health in this patient group.

Methods

Study design: An open crossover prospective study randomizing ten hypopituitary men, with severe ACTH deficiency, to three commonly used hydrocortisone dose regimens.
Measurements: Following 6 weeks of each regimen, patients underwent 24-h serum cortisol/cortisone sampling, measurement of bone turnover markers, and a 24-h urine collection for measurement of urinary steroid metabolites by gas chromatography-mass spectrometry (GC-MS). Serum cortisone and cortisol were analysed by liquid chromatography-mass spectrometry (LC-MS).

Results

Dose-related and circadian variations in serum cortisone were seen to parallel those for cortisol, indicating conversion of ingested hydrocortisone to cortisone. The median area under the curve (AUC) of serum cortisone was significantly higher in patients on dose A (20 mg/10 mg) [670.5 (IQR 621–809.2)] compared to those on dose C (10 mg/5 mg) [562.8 (IQR 520.1–619.6), p = 0.01]. A negative correlation was observed between serum cortisone and bone formation markers, OC [1–49] (r = − 0.42, p = 0.03), and PINP (r = − 0.49, p = 0.01). There was a negative correlation between the AUC of night-time serum cortisone levels with the bone formation marker, OC [1–49] (r = − 0.41, p = 0.03) but there were no significant correlations between day-time serum cortisone or cortisol with bone turnover markers. There was a negative correlation between total urinary cortisol metabolites and the bone formation markers, PINP (r = − 0.39, p = 0.04), and OC [1–49] (r = − 0.35, p = 0.06).

Conclusion

Serum cortisol and cortisone and total urinary corticosteroid metabolites are negatively associated with bone turnover markers in patients receiving replacement doses of hydrocortisone, with nocturnal glucocorticoid exposure having a potentially greater influence on bone turnover.

Trial registration

Irish Medicines Board Clinical Trial Number – CT900/459/1 and EudraCT Number – 2007-005018-37. Registration date: 07-09-2007.
Literature
1.
2.
Howlett TA. An assessment of optimal hydrocortisone replacement therapy. Clin Endocrinol. 1997;46(3):263–8.CrossRef
3.
Mah PM, Jenkins RC, Rostami-Hodjegan A, Newell-Price J, Doane A, Ibbotson V, et al. Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clin Endocrinol. 2004;61(3):367–75.CrossRef
4.
5.
Behan LA, Rogers B, Hannon MJ, O'Kelly P, Tormey W, Smith D, et al. Optimizing glucocorticoid replacement therapy in severely adrenocorticotropin-deficient hypopituitary male patients. Clin Endocrinol. 2011;75(4):505–13.CrossRef
6.
Husebye ES, Allolio B, Arlt W, Badenhoop K, Bensing S, Betterle C, et al. Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J Intern Med. 2014;275(2):104–15.PubMedCrossRef
7.
Grossman A, Johannsson G, Quinkler M, Zelissen P. Therapy of endocrine disease: perspectives on the management of adrenal insufficiency: clinical insights from across Europe. Eur J Endocrinol. 2013;169(6):R165–75.PubMedPubMedCentralCrossRef
8.
Johannsson G, Falorni A, Skrtic S, Lennernas H, Quinkler M, Monson JP, et al. Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy. Clin Endocrinol. 2015;82(1):2–11.CrossRef
9.
Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int. 2007;18(10):1319–28.PubMedCrossRef
10.
Angeli A, Guglielmi G, Dovio A, Capelli G, de Feo D, Giannini S, et al. High prevalence of asymptomatic vertebral fractures in post-menopausal women receiving chronic glucocorticoid therapy: a cross-sectional outpatient study. Bone. 2006;39(2):253–9.PubMedCrossRef
11.
Zelissen PM, Croughs RJ, van Rijk PP, Raymakers JA. Effect of glucocorticoid replacement therapy on bone mineral density in patients with Addison disease. Ann Intern Med. 1994;120(3):207–10.PubMedCrossRef
12.
Heureux F, Maiter D, Boutsen Y, Devogelaer JP, Jamart J, Donckier J. Evaluation of corticosteroid replacement therapy and its effect on bones in Addison's disease. Ann Endocrinol. 2000;61(3):179–83.
13.
Jodar E, Valdepenas MP, Martinez G, Jara A, Hawkins F. Long-term follow-up of bone mineral density in Addison's disease. Clin Endocrinol. 2003;58(5):617–20.CrossRef
14.
Koetz KR, Ventz M, Diederich S, Quinkler M. Bone mineral density is not significantly reduced in adult patients on low-dose glucocorticoid replacement therapy. J Clin Endocrinol Metab. 2012;97(1):85–92.PubMedCrossRef
15.
Lovas K, Gjesdal CG, Christensen M, Wolff AB, Almas B, Svartberg J, et al. Glucocorticoid replacement therapy and pharmacogenetics in Addison's disease: effects on bone. Eur J Endocrinol. 2009;160(6):993–1002.PubMedCrossRef
16.
Valero MA, Leon M, Ruiz Valdepenas MP, Larrodera L, Lopez MB, Papapietro K, et al. Bone density and turnover in Addison’s disease: effect of glucocorticoid treatment. Bone Mineral. 1994;26(1):9–17.PubMedCrossRef
17.
Braatvedt GD, Joyce M, Evans M, Clearwater J, Reid IR. Bone mineral density in patients with treated Addison’s disease. Osteoporos Int. 1999;10(6):435–40.PubMedCrossRef
18.
Peacey SR, Guo CY, Robinson AM, Price A, Giles MA, Eastell R, et al. Glucocorticoid replacement therapy: are patients over treated and does it matter? Clin Endocrinol. 1997;46(3):255–61.CrossRef
19.
Wichers M, Springer W, Bidlingmaier F, Klingmuller D. How hydrocortisone substitution influences the quality of life and the bone metabolism of patients with secondary hypocortisolism. Eur J Clin Investig. 2000;30(Suppl 3):55–7.CrossRef
20.
Behan LA, Kelleher G, Hannon MJ, Brady JJ, Rogers B, Tormey W, et al. Low-dose hydrocortisone replacement therapy is associated with improved bone remodelling balance in hypopituitary male patients. Eur J Endocrinol. 2014;170(1):141–50.PubMedCrossRef
21.
Cooper MS, Syddall HE, Fall CH, Wood PJ, Stewart PM, Cooper C, et al. Circulating cortisone levels are associated with biochemical markers of bone formation and lumbar spine BMD: the Hertfordshire cohort study. Clin Endocrinol. 2005;62(6):692–7.CrossRef
22.
Reynolds RM, Dennison EM, Walker BR, Syddall HE, Wood PJ, Andrew R, et al. Cortisol secretion and rate of bone loss in a population-based cohort of elderly men and women. Calcif Tissue Int. 2005;77(3):134–8.PubMedCrossRef
23.
Raff H, Raff JL, Duthie EH, Wilson CR, Sasse EA, Rudman I, et al. Elevated salivary cortisol in the evening in healthy elderly men and women: correlation with bone mineral density. J Gerontol A Biol Sci Med Sci. 1999;54(9):M479–83.PubMedCrossRef
24.
Brooke-Wavell K, Clow A, Ghazi-Noori S, Evans P, Hucklebridge F. Ultrasound measures of bone and the diurnal free cortisol cycle: a positive association with the awakening cortisol response in healthy premenopausal women. Calcif Tissue Int. 2002;70(6):463–8.PubMedCrossRef
25.
Osella G, Ventura M, Ardito A, Allasino B, Termine A, Saba L, et al. Cortisol secretion, bone health, and bone loss: a cross-sectional and prospective study in normal non-osteoporotic women in the early postmenopausal period. Eur J Endocrinol. 2012;166(5):855–60.PubMedCrossRef
26.
Nielsen HK, Brixen K, Kassem M, Charles P, Mosekilde L. Inhibition of the morning cortisol peak abolishes the expected morning decrease in serum osteocalcin in normal males: evidence of a controlling effect of serum cortisol on the circadian rhythm in serum osteocalcin. J Clin Endocrinol Metab. 1992;74(6):1410–4.PubMed
27.
Schlemmer A, Hassager C, Alexandersen P, Fledelius C, Pedersen BJ, Kristensen IO, et al. Circadian variation in bone resorption is not related to serum cortisol. Bone. 1997;21(1):83–8.PubMedCrossRef
28.
Heshmati HM, Riggs BL, Burritt MF, McAlister CA, Wollan PC, Khosla S. Effects of the circadian variation in serum cortisol on markers of bone turnover and calcium homeostasis in normal postmenopausal women. J Clin Endocrinol Metab. 1998;83(3):751–6.PubMed
29.
Hardy RS, Fenton C, Croft AP, Naylor AJ, Begum R, Desanti G, et al. 11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis. J Autoimmun. 2018;92:104–13.PubMedPubMedCentralCrossRef
30.
Cooper MS, Walker EA, Bland R, Fraser WD, Hewison M, Stewart PM. Expression and functional consequences of 11beta-hydroxysteroid dehydrogenase activity in human bone. Bone. 2000;27(3):375–81.PubMedCrossRef
31.
Bland R, Worker CA, Noble BS, Eyre LJ, Bujalska IJ, Sheppard MC, et al. Characterization of 11beta-hydroxysteroid dehydrogenase activity and corticosteroid receptor expression in human osteosarcoma cell lines. J Endocrinol. 1999;161(3):455–64.PubMedCrossRef
32.
Hwang JY, Lee SH, Kim GS, Koh JM, Go MJ, Kim YJ, et al. HSD11B1 polymorphisms predicted bone mineral density and fracture risk in postmenopausal women without a clinically apparent hypercortisolemia. Bone. 2009;45(6):1098–103.PubMedCrossRef
33.
Pierotti S, Gandini L, Lenzi A, Isidori AM. Pre-receptorial regulation of steroid hormones in bone cells: insights on glucocorticoid-induced osteoporosis. J Steroid Biochem Mol Biol. 2008;108(3–5):292–9.PubMedCrossRef
34.
Behan LA, Carmody D, Rogers B, Hannon MJ, Davenport C, Tormey W, et al. Low-dose hydrocortisone replacement is associated with improved arterial stiffness index and blood pressure dynamics in severely adrenocorticotrophin-deficient hypopituitary male patients. Eur J Endocrinol. 2016;174(6):791–9.PubMedCrossRef
35.
Sherlock M, Behan LA, Hannon MJ, Alonso AA, Thompson CJ, Murray RD, et al. The modulation of corticosteroid metabolism by hydrocortisone therapy in patients with hypopituitarism increases tissue glucocorticoid exposure. Eur J Endocrinol. 2015;173(5):583–93.PubMedCrossRef
36.
Murray RD, Ekman B, Uddin S, Marelli C, Quinkler M, Zelissen PM. Management of glucocorticoid replacement in adrenal insufficiency shows notable heterogeneity - data from the EU-AIR. Clin Endocrinol. 2017;86(3):340–6.CrossRef
37.
Trainer PJ, Besser GM. The Bart's endocrine protocols: Churchill Livingstone; 1995.
38.
Owen LJ, Adaway JE, Davies S, Neale S, El-Farhan N, Ducroq D, et al. Development of a rapid assay for the analysis of serum cortisol and its implementation into a routine service laboratory. Ann Clin Biochem. 2013;50(Pt 4):345–52.PubMedCrossRef
39.
Palermo M, Shackleton CH, Mantero F, Stewart PM. Urinary free cortisone and the assessment of 11 beta-hydroxysteroid dehydrogenase activity in man. Clin Endocrinol. 1996;45(5):605–11.CrossRef
40.
Arlt W, Biehl M, Taylor AE, Hahner S, Libe R, Hughes BA, et al. Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors. J Clin Endocrinol Metab. 2011;96(12):3775–84.PubMedPubMedCentralCrossRef
41.
Vassiliadi DA, Barber TM, Hughes BA, McCarthy MI, Wass JA, Franks S, et al. Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2009;94(9):3558–66.PubMedCrossRef
42.
Michelsen J, Wallaschofski H, Friedrich N, Spielhagen C, Rettig R, Ittermann T, et al. Reference intervals for serum concentrations of three bone turnover markers for men and women. Bone. 2013;57(2):399–404.PubMedCrossRef
43.
Few JD, Cashmore GC. Plasma cortisone in man: its determination, physiological variation, and significance. Ann Clin Biochem. 1980;17(5):227–32.PubMedCrossRef
44.
Morineau G, Boudi A, Barka A, Gourmelen M, Degeilh F, Hardy N, et al. Radioimmunoassay of cortisone in serum, urine, and saliva to assess the status of the cortisol-cortisone shuttle. Clin Chem. 1997;43(8 Pt 1):1397–407.PubMedCrossRef
45.
Keevil BG. LC-MS/MS analysis of steroids in the clinical laboratory. Clin Biochem. 2016;49(13–14):989–97.PubMedCrossRef
46.
Lee S, Lim HS, Shin HJ, Kim SA, Park J, Kim HC, et al. Simultaneous determination of cortisol and cortisone from human serum by liquid chromatography-tandem mass spectrometry. J Anal Methods Chem. 2014;2014:787483.PubMedPubMedCentral
47.
Angeli A, Bisbocci D, Melo F, Frairia R, Gaidano GP. Relative competition of corticosterone, cortisol, cortisone, 11-dexycortisol and prednisolone with (1,2-3H)-cortisol in various protein-binding radioassay systems. Clin Chimica Acta. 1975;61(3):279–86.CrossRef
48.
Debono M, Harrison RF, Whitaker MJ, Eckland D, Arlt W, Keevil BG, et al. Salivary cortisone reflects cortisol exposure under physiological conditions and after hydrocortisone. J Clin Endocrinol Metab. 2016;101(4):1469–77.PubMedCrossRef
49.
Brennan-Speranza TC, Henneicke H, Gasparini SJ, Blankenstein KI, Heinevetter U, Cogger VC, et al. Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism. J Clin Invest. 2012;122(11):4172–89.PubMedPubMedCentralCrossRef
50.
Meyer T, Gustafsson JA, Carlstedt-Duke J. Glucocorticoid-dependent transcriptional repression of the osteocalcin gene by competitive binding at the TATA box. DNA Cell Biol. 1997;16(8):919–27.PubMedCrossRef
51.
Prummel MF, Wiersinga WM, Lips P, Sanders GT, Sauerwein HP. The course of biochemical parameters of bone turnover during treatment with corticosteroids. J Clin Endocrinol Metab. 1991;72(2):382–6.PubMedCrossRef
52.
Reid IR, Chapman GE, Fraser TR, Davies AD, Surus AS, Meyer J, et al. Low serum osteocalcin levels in glucocorticoid-treated asthmatics. J Clin Endocrinol Metab. 1986;62(2):379–83.PubMedCrossRef
53.
Eastell R, Calvo MS, Burritt MF, Offord KP, Russell RG, Riggs BL. Abnormalities in circadian patterns of bone resorption and renal calcium conservation in type I osteoporosis. J Clin Endocrinol Metab. 1992;74(3):487–94.PubMed
54.
Gundberg CM, Markowitz ME, Mizruchi M, Rosen JF. Osteocalcin in human serum: a circadian rhythm. J Clin Endocrinol Metab. 1985;60(4):736–9.PubMedCrossRef
55.
Nielsen HK, Charles P, Mosekilde L. The effect of single oral doses of prednisone on the circadian rhythm of serum osteocalcin in normal subjects. J Clin Endocrinol Metab. 1988;67(5):1025–30.PubMedCrossRef
56.
Riehl G, Reisch N, Roehle R, vander Grinten HC, Falhammar H, Quinkler M. Bone mineral density and fractures in congenital adrenal hyperplasia: findings from the dsd-LIFE study. Clin Endocrinol. 2019;92(4):284.CrossRef
57.
Cooper MS, Blumsohn A, Goddard PE, Bartlett WA, Shackleton CH, Eastell R, et al. 11beta-hydroxysteroid dehydrogenase type 1 activity predicts the effects of glucocorticoids on bone. J Clin Endocrinol Metab. 2003;88(8):3874–7.PubMedCrossRef
58.
Tomlinson JW, Finney J, Gay C, Hughes BA, Hughes SV, Stewart PM. Impaired glucose tolerance and insulin resistance are associated with increased adipose 11beta-hydroxysteroid dehydrogenase type 1 expression and elevated hepatic 5alpha-reductase activity. Diabetes. 2008;57(10):2652–60.PubMedPubMedCentralCrossRef
59.
Shimodaira K, Fujikawa H, Okura F, Shimizu Y, Saito H, Yanaihara T. Osteoblast cells (MG-63 and HOS) have aromatase and 5 alpha-reductase activities. Biochem Mol Biol Int. 1996;39(1):109–16.PubMed
60.
Robinson D, Garmo H, Stattin P, Michaelsson K. Risk of fractures and falls during and after 5-alpha Reductase inhibitor use: a Nationwide cohort study. PLoS One. 2015;10(10):e0140598.PubMedPubMedCentralCrossRef
61.
Souverein PC, Van Staa TP, Egberts AC, De la Rosette JJ, Cooper C, Leufkens HG. Use of alpha-blockers and the risk of hip/femur fractures. J Intern Med. 2003;254(6):548–54.PubMedCrossRef
62.
Lin WL, Hsieh YW, Lin CL, Sung FC, Wu CH, Kao CH. A population-based nested case-control study: the use of 5-alpha-reductase inhibitors and the increased risk of osteoporosis diagnosis in patients with benign prostate hyperplasia. Clin Endocrinol. 2015;82(4):503–8.CrossRef
63.
Jacobsen SJ, Cheetham TC, Haque R, Shi JM, Loo RK. Association between 5-alpha reductase inhibition and risk of hip fracture. JAMA. 2008;300(14):1660–4.PubMedCrossRef
Metadata
Title
The contribution of serum cortisone and glucocorticoid metabolites to detrimental bone health in patients receiving hydrocortisone therapy
Authors
Rosemary Dineen
Lucy-Ann Behan
Grainne Kelleher
Mark J. Hannon
Jennifer J. Brady
Bairbre Rogers
Brian G. Keevil
William Tormey
Diarmuid Smith
Christopher J. Thompson
Malachi J. McKenna
Wiebke Arlt
Paul M. Stewart
Amar Agha
Mark Sherlock
Publication date
01-12-2020
Publisher
BioMed Central
Keyword
Glucocorticoid
Published in
BMC Endocrine Disorders / Issue 1/2020
Electronic ISSN: 1472-6823
DOI
https://doi.org/10.1186/s12902-020-00633-1

Other articles of this Issue 1/2020

BMC Endocrine Disorders 1/2020 Go to the issue

Correction

Correction to: Cross-sectional study of associations between normal body weight with central obesity and hyperuricemia in Japan

Research article

Piperine ameliorates insulin resistance via inhibiting metabolic inflammation in monosodium glutamate-treated obese mice

Research article

Relationships between menstrual status and obesity phenotypes in women: a cross-sectional study in northern China

Research article

Associations between alcohol intake and diabetic retinopathy risk: a systematic review and meta-analysis

Research article

Effect of sodium–glucose cotransporter-2 inhibitors on aldosterone-to-renin ratio in diabetic patients with hypertension: a retrospective observational study

Case report

Extraordinarily long-inactive solitary fibrous tumor transformed to produce big insulin-like growth factor-2, leading to hypoglycemia and rapid liposarcoma growth: a case report
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 discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

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

Watch now

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