Skip to main content

Advertisement

SpringerLink
Log in

Predictors of bone mineral density in patients receiving glucocorticoid replacement for Addison’s disease

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

Patients receiving long-term glucocorticoid (GC) treatment are at risk of osteoporosis, while bone effects of substitution doses in Addison’s disease (AD) remain equivocal. The project was aimed to evaluate serum bone turnover markers (BTMs): osteocalcin, type I procollagen N-terminal propeptide (PINP), collagen C-terminal telopeptide (CTX), sclerostin, DKK-1 protein, and alkaline phosphatase (ALP) in relation to bone mineral density (BMD) during GC replacement.

Methods

Serum BTMs and hormones were assessed in 80 patients with AD (22 males, 25 pre- and 33 postmenopausal females) on hydrocortisone (HC) substitution for ≥3 years. Densitometry with dual-energy X-ray absorptiometry covered the lumbar spine (LS) and femoral neck (FN).

Results

Among BTMs, only PINP levels were altered in AD. BMD Z-scores remained negative except for FN in males. Considering T-scores, osteopenia was found in LS in 45.5% males, 24% young and 42.4% postmenopausal females, while osteoporosis in 9.0%, 4.0% and 21.1%, respectively. Lumbar BMD correlated positively with body mass (p = 0.0001) and serum DHEA-S (p = 9.899 × 10−6). Negative correlation was detected with HC dose/day/kg (p = 0.0320), cumulative HC dose (p = 0.0030), patient’s age (p = 1.038 × 10−5), disease duration (p = 0.0004), ALP activity (p = 0.0041) and CTX level (p = 0.0105). However, only age, body mass, ALP, serum CTX, and sclerostin remained independent predictors of LS BMD.

Conclusion

Standard HC substitution does not considerably accelerate BMD loss in AD patients and their serum BTMs: CTX, osteocalcin, sclerostin, DKK-1, and ALP activity remain within the reference ranges. Independent predictors of low lumbar spine BMD, especially ALP activity, serum CTX and sclerostin, might be monitored during GC substitution.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. E.S. Husebye, B. Allolio, W. Arlt et al. Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J. Intern. Med. 275(2), 104–115 (2014). https://doi.org/10.1111/joim.12162

    Article  CAS  PubMed  Google Scholar 

  2. G. Johannsson, A. Falorni, S. Skrtic et al. Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy. Clin. Endocrinol. (Oxf) 82(1), 2–11 (2015). https://doi.org/10.1111/cen.12603

    Article  CAS  PubMed  Google Scholar 

  3. V. Guarnotta, C. Di Stefano, C. Giordano, Long-term outcomes of conventional and novel steroid replacement therapy on bone health in primary adrenal insufficiency. Sci. Rep. 12(1), 13280 (2022). https://doi.org/10.1038/s41598-022-13506-5

    Article  PubMed  PubMed Central  Google Scholar 

  4. K. Løvås, C.G. Gjesdal, M. Christensen et al. Glucocorticoid replacement therapy and pharmacogenetics in Addison’s disease: effects on bone. Eur. J. Endocrinol. 160(6), 993–1002 (2009). https://doi.org/10.1530/EJE-08-0880

    Article  CAS  PubMed  Google Scholar 

  5. M. Yazidi, C. Danguir, D. Maamer et al. Impact of hydrocortisone replacement on bone mineral density and bone turnover markers in patients with primary adrenal insufficiency. Endocr. Regul. 56(3), 209–215 (2022). https://doi.org/10.2478/enr-2022-0022

    Article  PubMed  Google Scholar 

  6. L. Li, S. Bensing, H. Falhammar, Rate of fracture in patients with glucocorticoid replacement therapy: a systematic review and meta-analysis. Endocrine 74, 29–37 (2021). https://doi.org/10.1007/s12020-021-02723-z

    Article  CAS  PubMed  Google Scholar 

  7. J. Compston, Glucocorticoid-induced osteoporosis: an update. Endocrine 61(1), 7–16 (2018). https://doi.org/10.1007/s12020-018-1588-2

    Article  CAS  PubMed Central  Google Scholar 

  8. Z.E. Belaya, T.A. Grebennikova, G.A. Melnichenko et al. Effects of endogenous hypercortisolism on bone mRNA and microRNA expression in humans. Osteoporos. Int. 29(1), 211–221 (2018). https://doi.org/10.1007/s00198-017-4241-7

    Article  CAS  PubMed  Google Scholar 

  9. T. van Staa, H.G. Leufkens, C. Cooper, The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos. Int. 13(10), 777–787 (2002). https://doi.org/10.1007/s001980200108

    Article  PubMed  Google Scholar 

  10. 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. Endocrinol. Metab. 97(1), 85–92 (2012). https://doi.org/10.1210/jc.2011-2036

    Article  CAS  PubMed  Google Scholar 

  11. D.D. Chandy, E. Bhatia, Bone mineral density in patients with Addison’s disease on replacement therapy with prednisolone. Endocr. Pract. 22(4), 434–439 (2016). https://doi.org/10.4158/EP151014.OR

    Article  PubMed  Google Scholar 

  12. K.R. Frey, T. Kienitz, J. Schulz et al. Prednisolone is associated with a worse bone mineral density in primary adrenal insufficiency. Endocr. Connect. 7(6), 811–818 (2018). https://doi.org/10.1530/EC-18-0160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. N. Esteban, T. Loughlin, A.L. Yergey et al. Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J. Clin. Endocrinol. Metab. 72(1), 39–45 (1991). https://doi.org/10.1210/jcem-72-1-39

    Article  CAS  PubMed  Google Scholar 

  14. W. Arlt, C. Rosenthal, S. Hahner, B. Allolio, Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol measurements. Clin. Endocrinol. (Oxf) 64(4), 384–389 (2006). https://doi.org/10.1111/j.1365-2265.2006.02473.x

    Article  CAS  PubMed  Google Scholar 

  15. M. Fichna, M. Gryczyńska, A. Sowińska, J.Sowiński, Ocena metaboliczna terapii substytucyjnej hydrokortyzonem u pacjentów z pierwotna niedoczynnościa kory nadnerczy [Metabolic assessment of hydrocortisone replacement therapy in patients with primary adrenocortical insufficiency]. Przegl. Lek. 68(2), 96–102 (2011)

    PubMed  Google Scholar 

  16. V. Camozzi, C. Betterle, A.C. Frigo et al. Vertebral fractures assessed with dual-energy X-ray absorptiometry in patients with Addison’s disease on glucocorticoid and mineralocorticoid replacement therapy. Endocrine 59(2), 319–329 (2018). https://doi.org/10.1007/s12020-017-1380-8

    Article  CAS  PubMed  Google Scholar 

  17. F. Heureux, D. Maiter, Y. Boutsen, J.P. Devogelaer, J. Jamart, J. Donckier, Evaluation de la substitution par corticostéroïdes et de ses répercussions osseuses dans la maladie d’Addison [Evaluation of corticosteroid replacement therapy and its effect on bones in Addison’s disease]. Ann. Endocrinol. (Paris) 61(3), 179–183 (2000)

    CAS  PubMed  Google Scholar 

  18. S. Kaptoge, L.I. Benevolenskaya, A.K. Bhalla et al. Low BMD is less predictive than reported falls for future limb fractures in women across Europe: results from the European Prospective Osteoporosis Study. Bone 36(3), 387–398 (2005). https://doi.org/10.1016/j.bone.2004.11.012

    Article  CAS  PubMed  Google Scholar 

  19. P.D. Delmas, R. Eastell, P. Garnero, M.J. Seibel, J. Stepan; Committee of Scientific Advisors of the International Osteoporosis Foundation, The use of biochemical markers of bone turnover in osteoporosis. Committee of Scientific Advisors of the International Osteoporosis Foundation. Osteoporos. Int. 6, S2–S17 (2000). https://doi.org/10.1007/s001980070002

    Article  Google Scholar 

  20. S. Vasikaran, R. Eastell, O. Bruyère et al. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos. Int. 22(2), 391–420 (2011). https://doi.org/10.1007/s00198-010-1501-1

    Article  CAS  PubMed  Google Scholar 

  21. J. Delgado-Calle, A.Y. Sato, T. Bellido, Role and mechanism of action of sclerostin in bone. Bone 96, 29–37 (2017). https://doi.org/10.1016/j.bone.2016.10.007

    Article  CAS  PubMed  Google Scholar 

  22. P. Garnero, E. Sornay-Rendu, B. Claustrat, P.D. Delmas, Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J. Bone Miner. Res. 15(8), 1526–1536 (2000). https://doi.org/10.1359/jbmr.2000.15.8.1526

    Article  CAS  PubMed  Google Scholar 

  23. L. Gifre, S. Ruiz-Gaspà, A. Monegal et al. Effect of glucocorticoid treatment on Wnt signalling antagonists (sclerostin and Dkk-1) and their relationship with bone turnover. Bone 57(1), 272–276 (2013). https://doi.org/10.1016/j.bone.2013.08.016

    Article  CAS  PubMed  Google Scholar 

  24. A.L. Burshell, R. Möricke, R. Correa-Rotter et al. Correlations between biochemical markers of bone turnover and bone density responses in patients with glucocorticoid-induced osteoporosis treated with teriparatide or alendronate. Bone 46(4), 935–939 (2010). https://doi.org/10.1016/j.bone.2009.12.032

    Article  CAS  PubMed  Google Scholar 

  25. M. Tóth, A. Grossman, A. Glucocorticoid-induced osteoporosis: lessons from Cushing’s syndrome. Clin. Endocrinol. (Oxf) 79(1), 1–11 (2013). https://doi.org/10.1111/cen.12189

    Article  CAS  PubMed  Google Scholar 

  26. M.A. Valero, M. Leon, M.P. Ruiz Valdepeñas et al. Bone density and turnover in Addison’s disease: effect of glucocorticoid treatment. Bone Miner 26(1), 9–17 (1994). https://doi.org/10.1016/s0169-6009(08)80158-4

    Article  CAS  PubMed  Google Scholar 

  27. S.R. Peacey, C.Y. Guo, A.M. Robinson et al. Glucocorticoid replacement therapy: are patients over treated and does it matter? Clin. Endocrinol. (Oxf) 46(3), 255–261 (1997). https://doi.org/10.1046/j.1365-2265.1997.780907.x

    Article  CAS  PubMed  Google Scholar 

  28. M. Wichers, W. Springer, F. Bidlingmaier, D. Klingmüller, The influence of hydrocortisone substitution on the quality of life and parameters of bone metabolism in patients with secondary hypocortisolism. Clin. Endocrinol. (Oxf) 50(6), 759–765 (1999). https://doi.org/10.1046/j.1365-2265.1999.00723.x

    Article  CAS  PubMed  Google Scholar 

  29. A. Zdrojowy-Wełna, J. Halupczok-Żyła, N. Słoka, J. Syrycka, Ł. Gojny, M. Bolanowski, Bolanowski Trabecular bone score and sclerostin concentrations in patients with primary adrenal insufficiency. Front. Endocrinol. (Lausanne) 13, 996157 (2022). https://doi.org/10.3389/fendo.2022.996157

    Article  PubMed  Google Scholar 

  30. J.A. Kanis, L.J. Melton 3rd, C. Christiansen, C.C. Johnston, N. Khaltaev, The diagnosis of osteoporosis. J. Bone. Miner. Res. 9(8), 1137–1141 (1994). https://doi.org/10.1002/jbmr.5650090802

    Article  CAS  PubMed  Google Scholar 

  31. P. Głuszko, E. Sewerynek, W. Misiorowski et al. Guidelines for the diagnosis and management of osteoporosis in Poland. Update 2022. Endokrynol. Pol. 74(1), 5–15 (2023). https://doi.org/10.5603/EP.a2023.0012

    Article  PubMed  Google Scholar 

  32. M. Penna-Martinez, G. Meyer, A.B. Wolff et al. Vitamin D status and pathway genes in five European autoimmune Addison’s disease cohorts. Eur. J. Endocrinol. 184(3), 373–381 (2021). https://doi.org/10.1530/EJE-20-0956

    Article  PubMed  Google Scholar 

  33. W. Guo, F. Li, C. Zhu et al. Effect of hypercortisolism on bone mineral density and bone metabolism: A potential protective effect of adrenocorticotropic hormone in patients with Cushing’s disease. J. Int. Med. Res. 46(1), 492–503 (2018). https://doi.org/10.1177/0300060517725660

    Article  CAS  PubMed  Google Scholar 

  34. F.N. Ton, S.C. Gunawardene, H. Lee, R.M. Neer, Effects of low-dose prednisone on bone metabolism. J. Bone Miner. Res. 20(3), 464–470 (2005). https://doi.org/10.1359/JBMR.041125

    Article  CAS  PubMed  Google Scholar 

  35. A.M. Suliman, R. Freaney, T.P. Smith, Y. McBrinn, B. Murray, T.J. McKenna, The impact of different glucocorticoid replacement schedules on bone turnover and insulin sensitivity in patients with adrenal insufficiency. Clin. Endocrinol. (Oxf) 59(3), 380–387 (2003). https://doi.org/10.1046/j.1365-2265.2003.01860.x

    Article  CAS  PubMed  Google Scholar 

  36. J.T. Schousboe, J.A. Shepherd, J.P. Bilezikian, S. Baim, Executive summary of the 2013 International Society for Clinical Densitometry Position Development Conference on bone densitometry. J. Clin. Densitom. 16(4), 455–466 (2013). https://doi.org/10.1016/j.jocd.2013.08.004

    Article  PubMed  Google Scholar 

  37. J.P. Devogelaer, J. Crabbé, C. Nagant de Deuxchaisnes, Bone mineral density in Addison’s disease: evidence for an effect of adrenal androgens on bone mass. Br. Med. J. (Clin Res Ed 294(6575), 798–800 (1987). https://doi.org/10.1136/bmj.294.6575.798

  38. 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(6), 435–440 (1999). https://doi.org/10.1007/s001980050251

    Article  CAS  PubMed  Google Scholar 

  39. E.M. Gurnell, P.J. Hunt, S.E. Curran et al. Long-term DHEA replacement in primary adrenal insufficiency: a randomized, controlled trial. J. Clin. Endocrinol. Metab. 93(2), 400–409 (2008). https://doi.org/10.1210/jc.2007-1134

    Article  CAS  PubMed  Google Scholar 

  40. K. Mukaiyama, M. Kamimura, S. Uchiyama, S. Ikegami, Y. Nakamura, H. Kato, Elevation of serum alkaline phosphatase (ALP) level in postmenopausal women is caused by high bone turnover. Aging Clin. Exp. Res. 27(4), 413–418 (2015). https://doi.org/10.1007/s40520-014-0296-x

    Article  PubMed  Google Scholar 

  41. A.H. van Lierop, A.W. van der Eerden, N.A. Hamdy, A.R. Hermus, M. den Heijer, S.E. Papapoulos, Circulating sclerostin levels are decreased in patients with endogenous hypercortisolism and increase after treatment. J. Clin. Endocrinol. Metab. 97(10), E1953–E1957 (2012). https://doi.org/10.1210/jc.2012-2218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. C. Fernández-Roldán, F. Genre, R. López-Mejías et al. Sclerostin serum levels in patients with systemic autoimmune diseases. Bonekey Rep. 5, 775 (2016). https://doi.org/10.1038/bonekey.2016.2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. E. Shevroja, J.Y. Reginster, O. Lamy et al. Update on the clinical use of trabecular bone score (TBS) in the management of osteoporosis: results of an expert group meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), and the International Osteoporosis Foundation (IOF) under the auspices of WHO Collaborating Center for Epidemiology of Musculoskeletal Health and Aging. Osteoporos. Int. 34(9), 1501–1529 (2023). https://doi.org/10.1007/s00198-023-06817-4

    Article  PubMed  PubMed Central  Google Scholar 

  44. F. Bioletto, M. Barale, M. Parasiliti-Caprino et al. Bone safety of dual-release hydrocortisone in patients with autoimmune primary adrenal insufficiency. Front. Endocrinol (Lausanne). 11(14), 1234237 (2023). https://doi.org/10.3389/fendo.2023.1234237

    Article  Google Scholar 

Download references

Acknowledgements

We express our gratitude to all our patients with Addison’s disease for their participation and comprehension.

Author contributions

All authors contributed to the study conception. K.F., P.G. and M.F. were involved in study design. Material preparation was performed by P.G., M.R. and M.F. Data collection and analysis was done by K.F., A.S. and M.F. The first draft of the manuscript was written by K.F. and all authors commented and provided feedback to the final version. All authors read and approved the final manuscript.

Author information

Authors and Affiliations

  1. Department of Endocrinology, Metabolism and Internal Medicine, Poznań University of Medical Sciences, Poznań, Poland

    Katarzyna Furman, Paweł Gut, Marek Ruchała & Marta Fichna

  2. Ludwik Perzyna Regional Hospital, Kalisz, Poland

    Katarzyna Furman

  3. Department of Computer Science and Statistics, Poznan University of Medical Sciences, Poznan, Poland

    Anna Sowińska

Authors
  1. Katarzyna Furman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paweł Gut
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Sowińska
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marek Ruchała
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marta Fichna
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marta Fichna.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethics approval

This study was performed in accordance with the principles of the Declaration of Helsinki. Its protocol was approved by the local Ethics Committee of Poznan University of Medical Sciences (decision 68/19). Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Furman, K., Gut, P., Sowińska, A. et al. Predictors of bone mineral density in patients receiving glucocorticoid replacement for Addison’s disease. Endocrine 84, 711–719 (2024). https://doi.org/10.1007/s12020-024-03709-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-024-03709-3

Keywords

Search

Navigation