#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Introduction: Patients with primary adrenal insufficiency receive long – term glucocorticoid replacement therapy, which may cause osteoporosis


Authors: Peter Vaňuga;  Ivana Ságová
Authors‘ workplace: Národný endokrinologický a diabetologický ústav, Ľubochňa
Published in: Vnitř Lék 2021; 67(5): 264-269
Category: Main Topic

Overview

Aim of the study: The aim of the study was to assess the effect of glucocorticoid replacement therapy in patients with Addison´s disease on bone mineral density (BMD), parameters of calcium – phosphate (Ca-P) metabolism as well as on bone turneover markers.

Patients and methods: The study group consisted of 46 patients with Addison´s disease (12men, 17 pre- and 17 postmenopausal women, the control group consisted of 44 healthy individuals (8 men, 16 prepre- and 16 postmenopausal women). Ca-P metabolism parameters, bone turnover markers and adrenal hormones were examined in all groups. BMD was measured by dual-energy X-ray absorptiometry in the lumbar spine (BMD lumb) and forearm (BMDfore).

Results: We did not confirm an increased prevalence of osteoporosis and osteopenia in patients with Addison´s disease. BMD values did not correlate with hydrocortisone (HCT) doses, HCT doses calculated on body weight and body surface area as well as with duration of substitution treatment. Patients with daily HCT doses > 25 mg had significantly lower BMD in lumbar spine compared with patients with daily HCT doses ≤ 25 mg. In study group we observed decreased levels of adrenal androgens, in women also estradiol. Decreased level of serum calcium and increased level of osteocalcin, bone alkaline phosphatase, 25- hydroxyvitamin D were present in women with Addison´s disease. RANKL/OPG ratio was higher in patients with Addison´s disease compared with controls.

Conclusion: Glucocorticoid replacement therapy is not a significant risk factor for development of osteoporosis in patients with Addison’ disease, because this therapy only physiologically replaces endogenous cortisol deficiency. An increased RANKL / OPG ratio may indicate a relative lack of OPG. It is possible that female patients, despite adequate substitution, have an increased bone turnover and a relatively higher risk of decrease in BMD. Potential risks are higher doses of glucocorticoid replacement therapy (HCT > 25 mg daily) and a typical steroid constellation (decreased adrenocortical androgens DHEA and DHEAS and in women also estradiol).

Keywords:

osteoporosis – bone mineral density – Addison’s disease – glucocorticoid replacement therapy


Sources

1. Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency. J Clin Endocrinol Metab 2009; 94: 1059–1067.

2. Crown A, Lightman S. Why is the management of glucocorticoid deficiency still controversial: a review of the literature. Clin Endocrinol (Oxf) 2005; 63: 483–492.

3. Fichna M, Zurawek M, Fichna P, Fryczynska M et al. Increased serum osteoprotegerin in patients with primary adrenal insufficiency receiving conventional hydrocortisone substitution 2012; 63: 677–682.

4. Chronocort® Phase 3 and Safety Extension Study results published in JCEM | Investor or Media Relations | Diurnal | Dedicated to developing hormone therapeutics, 2021. Dostupné na:www.diurnal.co.uk.

5. Lovas K, Gjesdal CG, Christensen M et al. Glucocorticoid replacement therapy and pharmacogenetics in Addison’s disease: effects on bone. Eur J Endocrinol 2009; 160: 993–1002.

6. Peacey SR, Guo C-Y, Robinson AM et al. Glucocorticoid replacement therapy: are patients over treated and does it matter? Clin Endocrinol 1997; 46: 255–261.

7. Koetz KR, Ventz S, Diederich S, Quinkler M. Bone mineral density is not significantly reduced in adult patients on lowdose glucocorticoid replacement therapy. J Clin Endocrinol Metab 2012; 97: 85–92.

8. Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular disease. JAMA 2004; 292: 490–495.

9. Karssen AM, Meijer OC, Van Der Sandt IC, Lucassen PJ, De Lange EC, De Boer AG & De Kloet ER. Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain. Endocrinology 2001; 142: 2686–2694.

10. Yates CR, Chang C, Kearbey JD, Yasuda K, Schuetz EG, Miller DD, Dalton JT & Swaan PW. Structural determinants of P-glycoproteinmediated transport of glucocorticoids. Pharmaceutical Research 2003; 20: 1794–1803.

11. Pariante CM. The role of multi-drug resistance P-glycoprotein in glucocorticoid function: studies in animals and relevance in humans. European Journal of Pharmacology 2008; 583: 263–271.

12. Marzolini C, Paus E, Buclin T, Kim RB. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clinical Pharmacology and Therapeutics 2004; 75: 13–33.

13. Sakaeda T. MDR1 genotype-related pharmacokinetics: fact or fiction? Drug Metabolism and Pharmacokinetics 2005; 20: 391–414.

14. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV & Gottesman MM. A ‘silent’ polymorphism in the MDR1 gene changes substrate specificity. Science 2007; 315: 525–528.

15. Salama NN, Yang Z, Bui T & Ho RJ. MDR1 haplotypes significantly minimize intracellular uptake and transcellular P-gp substrate transport in recombinant LLC-PK1 cells. Journal of Pharmaceutical Sciences 2006; 95: 2293–2308.

16. Guo CY, Weetman AP, Eastell RBone turnover and bone mineral density in patients with congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 1996; 45: 535–541.

17. Stikkelbroeck NM, Oyen WJ, van der Wilt GJ, Hermus AR, Otten BJ. Normal bone mineral density and lean body mass, but increased fat mass, in young adult patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2003; 88: 1036–1042.

18. Girgis R, Winter JS. The effects of glucocorticoid replacement therapy on growth, bone mineral density, and bone turnover markers in children with congenital adrenal hyperplasia. J Clin Endocrnol Metab 1997; 82: 3926–3929.

19. Christiansen P, Mølgaard C, Muller J. Normal bone mineral content in young adults with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res2004; 61: 133–136.

20. Hagenfeldt K, Martin Ritze´n E, Ringertz H, Helleday J, Carlstrom K. Bone mass and body composition of adult women with J Clin Endocrinol Metab 2012; 97(1): 85–92.

21. Valero MA, Leon M, Ruiz Valdepenas MP et al. Bone density and turnover in Addison’s disease: effect of glucocorticoid treatment. Bone Miner 1994; 26: 9–17.

22. Sasaki N, Kusano E, Ando Y, Tsuda E, Asano Y. Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis. Nephrol Dial Transplant 2001; 16: 479–482.

23. Ueland T, Bollerslev J, Godang K, Muller F, Froland SS, Aukrust P. Increased serum osteoprotegerin in disorders characterized by persistent immune activation or glucocorticoid excess – possible role in bone homeostasis. Eur J Endocrinol 2001; 145: 685–690.

24. Abdallah BM, Stilgren LS, Nissen N, Kassem M, Jorgensen HR, Abrahamsen B. Increased RANKL/OPG mRNA ratio in iliac bone biopsies from women with hip fractures. Calcif Tissue Int 2005; 76: 90–97.

25. Hofbauer LC, Hicok KC, Chen D, Khosla S. Regulation of osteoprotegerin production by androgens and anti-androgens in human osteoblastic lineage cells. Eur J Endocrinol 2001; 147: 269–273.

26. 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 (Paris) 2000; 61: 179–183.

27. Devogelaer JP, Crabbe´ J, Nagant de Deuxchaisnes C. Bone mineral density in Addison’s disease: evidence for an effect of adrenal androgens on bone mass. BrMed J (Clin Res Ed) 1987; 294: 798–800.

28. ValeroMA, LeonM, Ruiz Valdepen˜ asMP, Larrodera L, LopezMB, Papapietro K, Jara A, Hawkins F. Bone density and turnover in Addison’s disease: effect of glucocorticoid treatment. Bone Miner 1994; 26: 9–17.

29. 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: 207–210.

30. Braatvedt GD, Joyce M, Evans M, Clearwater J, Reid IR.Bone mineral density in patients with treated Addison’s disease. Osteoporos Int 1999; 10: 435–440.

31. Jo´ dar E, Valdepen˜ as MP, Martinez G, Jara A, Hawkins F.Long-term follow-up of bone mineral density in Addison’s disease. Clin Endocrinol (Oxf) 2003; 58: 617–620.

32. Arlt W, Rosenthal C, Hahner S, Allolio B. Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol measurements. Clin Endocrinol (Oxf) 2006; 64: 384–389.

33. 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: 207–210.

34. Chikada N, Imaki T, Hotta M, Sato K, Takano K. An assessment of bone mineral density in patient with Addison’s disease and isolated ACTH deficiency treated with glucocorticoid. Endocr J 2004; 51: 355–360.

35. Hofbauer LC, Gori F, Riggs BL et al. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoidinduced osteoporosis. Endocrinology 1999; 140: 4382–438.

36. Sasaki N, Kusano E, Ando Y, Tsuda E, Asano Y. Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis. Nephrol Dial Transplant 2001; 16: 479–482.

37. Ueland T, Bollerslev J, Godang K, Muller F, Froland SS, Aukrust P. Increased serum osteoprotegerin in disorders characterized by persistent immune activation or glucocorticoid excess – possible role in bone homeostasis. Eur J Endocrinol 2001; 145: 685–690.

38. Dovio A, Allasino B, Palmas E, et al. Increased osteoprotegerin levels in Cushing’s syndrome are associated with an adverse cardiovascular risk profile. J Clin Endocrinol Metab 2007; 92: 1803–1808.

39. Camozzi V, Sanguin F, Albigier N et al. Persistent increase of osteoprotegerin levels after cortisol normalization in patients with Cushing’s syndrome. Eur J Endocrinol 2010; 162: 85–90.

40. LoCascio V, Bonucci E, Imbimbo B et al. Bone loss in response to long-term glucocorticoid therapy. Bone Miner 1990; 8: 39–51.

41. Devogelaer JP, Crabbe J, Nagant de Deuxchaisnes C. Bone mineral density in Addison’s disease: evidence for an effect of adrenal androgens on bone mass. Br Med J (Clin Res Ed) 1987; 294: 798–800.

42. Arlt W, Callies F, van Vlijmen JC et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 1999; 341: 1013–1020.

43. Lovas K, Gebre-Medhin G, Trovik TS et al. Replacement of dehydroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9-month, randomized, parallel group clinical trial. J Clin Endocrinol Metab 2003; 88: 1112–1118.

44. Miller KK, Biller BM, Hier J, Arena E, Klibanski A. Androgens and bone density in women with hypopituitarism. J Clin Endocrinol Metab2002; 87: 2770–2776.

45. Osmanagaoglu MA, Okumus B, Osmanagaoglu T, Bozkaya H. The relationship between serum dehydroepiandrosterone sulfate concentration and bone mineral density, lipids, and hormone replacement therapy in premenopausal and postmenopausal women. JWomens Health(Larchmt) 2004; 13: 993–999.

46. Hampson G, Bhargava N, Cheung J, Vaja S, Seed PT, Fogelman I. Low circulating estradiol and adrenal androgens concentrations in men on glucocorticoids: a potential contributory factor in steroid-induced osteoporosis.Metabolism 2002; 51: 1458–1462.

47. Gurnell EM, Hunt PJ, Curran SE et al. Long-term DHEA replacemen in primary adrenal insufficiency: a randomized, controlled trial. J Clin Endocrinol Metab 2008; 93: 400–409.

Labels
Diabetology Endocrinology Internal medicine
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#