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Characterization of vitamin D metabolism in active acromegaly in the setting of bolus (150,000 IU) cholecalciferol treatment

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Abstract

Purpose

To reveal distinctive features of vitamin D metabolism in patients with active acromegaly compared to healthy individuals, particularly in the setting of cholecalciferol treatment.

Methods

The study group included 34 adults with active acromegaly, and the control group included 30 apparently healthy adults with similar age, sex, and BMI. All participants received a single dose (150,000 IU) of cholecalciferol aqueous solution orally. Laboratory assessments including serum vitamin D metabolites (25(OH)D3, 25(OH)D2, 1,25(OH)2D3, 3-epi-25(OH)D3 and 24,25(OH)2D3), free 25(OH)D, vitamin D-binding protein (DBP) and parathyroid hormone (PTH) as well as serum and urine biochemical parameters were performed before the intake and on Days 1, 3, and 7 after the administration. All data were analyzed with nonparametric statistics.

Results

Patients with acromegaly had tendency to lower baseline 25(OH)D3 levels (p = 0.05) and lower 25(OH)D3 levels (p < 0.05) during the follow-up. They were also characterized by PTH suppression (lower baseline PTH levels and lower prevalence of secondary hyperparathyroidism), altered production of main vitamin D metabolites (higher 1,25(OH)2D3 and lower 24,25(OH)2D3 levels with corresponding lower 25(ОН)D3/1,25(ОН)2D3 and higher 25(ОН)D3/24,25(ОН)2D3 ratios) as well as concordant biochemical features (higher levels of serum phosphorus and albumin-adjusted calcium levels) throughout the study (p < 0.05). The acromegaly group showed an increase in DBP levels after cholecalciferol intake as opposed to the control group (p < 0.05) and had lower increase in free 25(OH)D levels (p < 0.05). Δ25(OH)D3 was similar between the groups (p > 0.05), showed a negative correlation with the disease activity markers—both IGF-1 levels (r = −0.44, p < 0.05) and fasting GH levels (r = −0.56, p < 0.05)—and lacked correlation with BMI in the acromegaly group (p > 0.05).

Conclusion

Patients with active acromegaly have dysregulated vitamin D metabolism characterized by higher 1,25(ОН)2D3, lower 24,25(ОН)2D3 and altered DBP production. The response to vitamin D supplementation in acromegaly patients might be influenced by hormonal excess. Obtained results require reproducibility check and further study to develop specific clinical recommendations.

Trial registration

NCT04844164 (release date: April 9, 2021; retrospectively registered).

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. O. Bergeim, F.T. Stewart, P.B. Hawk, A study of the metabolism of calcium, magnesium, sulphur, phosphorus, and nitrogen in acromegaly. J. Exp. Med. 20, 218–224 (1914)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. F. Camanni, F. Massara, O. Losana, G.M. Molinatti, Increased renal tubular reabsorption of phosphorus in acromegaly. J. Clin. Endocrinol. Metab. 28, 999–1005 (1968)

    Article  CAS  PubMed  Google Scholar 

  3. T. Xie et al. Serum phosphate: does it more closely reflect the true state of acromegaly? J. Clin. Neurosci. 71, 26–31 (2020)

    Article  CAS  PubMed  Google Scholar 

  4. G.Y. Yalin et al. Utility of baseline serum phosphorus levels for predicting remission in acromegaly patients. J. Endocrinol. Investig. 40, 867–874 (2017)

    Article  CAS  Google Scholar 

  5. A. Nadarajah, M. Hartog, B. Redfern, N. Thalassinos, A.D. Wright, G.F. Joplin, Calcium metabolism in acromegaly. Br. Med J. 4, 797–801 (1968)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. J. Halse, H.N. Haugen, Calcium and phosphate metabolism in acromegaly. Acta Endocrinol. 94, 459–467 (1980)

    Article  CAS  Google Scholar 

  7. G. Sigurdsson, V. Nunziata, M. Reiner, A. Nadarajah, G.F. Joplin, Calcium absorption and excretion in the gut in acromegaly. Clin. Endocrinol. 7, 187–192 (1973)

    Article  Google Scholar 

  8. J. Brown, F.R. Singer, Calcium metabolism in acromegaly. Br. Med J. 2, 50 (1969)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. A.B. Libório et al. Urinary calcium excretion and insulin resistance in patients with acromegaly. Int. Urol. Nephrol. 44, 1473–1477 (2012)

    Article  PubMed  CAS  Google Scholar 

  10. A. Pines, D. Olchovsky, Urolithiasis in acromegaly. Urology 26, 240–242 (1985)

    Article  CAS  PubMed  Google Scholar 

  11. E. van der Valk, T. Tobe, A. Stades, A. Muller, Vanishing hypercalciuric kidney stones after treating underlying acromegaly. Endocrinol. Diabetes Metab. Case Rep. 2013, 130001 (2013)

    PubMed  PubMed Central  Google Scholar 

  12. P. Kamenický et al. Pathophysiology of renal calcium handling in acromegaly: What lies behind hypercalciuria? J. Clin. Endocrinol. Metab. 97, 2124–2133 (2012)

    Article  PubMed  CAS  Google Scholar 

  13. L. Sze et al. Excessively high soluble Klotho in patients with acromegaly. J. Intern. Med. 272, 93–97 (2012)

    Article  CAS  PubMed  Google Scholar 

  14. C. Schmid, M.C. Neidert, O. Tschopp, L. Sze, R.L. Bernays, Growth hormone and Klotho. J. Endocrinol. 219, R37–57 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. J.A. Neyra, M.C. Hu, O.W. Moe, Klotho in clinical nephrology: diagnostic and therapeutic implications. Clin. J. Am. Soc. Nephrol. 16, 162–176 (2021)

    Article  CAS  Google Scholar 

  16. T. Constantin et al. Calcium and bone turnover markers in acromegaly: a prospective, controlled study. J. Clin. Endocrinol. Metab. 102, 2416–2424 (2017)

    Article  PubMed  Google Scholar 

  17. C. Parkinson, M. Kassem, L. Heickendorff, A. Flyvbjerg, P.J. Trainer, Pegvisomant-induced serum insulin-like growth factor-I normalization in patients with acromegaly returns elevated markers of bone turnover to normal. J. Clin. Endocrinol. Metab. 88, 5650–5655 (2003)

    Article  CAS  PubMed  Google Scholar 

  18. P.C. Eskildsen et al. Acromegaly and vitamin D metabolism: effect of bromocriptine treatment. J. Clin. Endocrinol. Metab. 49, 484–486 (1979)

    Article  CAS  PubMed  Google Scholar 

  19. D.J. Brown, E. Spanos, I. MacIntyre, Role of pituitary hormones in regulating renal vitamin D metabolism in man. Br. Med. J. 280, 277–278 (1980)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. O. Fontaine, H. Pavlovitch, S. Balsan, 25-hydroxycholecalciferol metabolism in hypophysectomized rats. Endocrinology 102, 1822–1826 (1978)

    Article  CAS  PubMed  Google Scholar 

  21. N. Wongsurawat, H.J. Armbrecht, T.V. Zenser, L.R. Forte, B.B. Davis, Effects of hypophysectomy and growth hormone treatment on renal hydroxylation of 25-hydroxycholecalciferol in rats. J. Endocr. 101, 333–338 (1983)

    Article  Google Scholar 

  22. K. Brixen, H.K. Nielsen, R. Bouillon, A. Flyvbjerg, L. Mosekilde, Effects of short-term growth hormone treatment on PTH, calcitriol, thyroid hormones, insulin and glucagon. Acta Endocrinol. 127, 331–336 (1992)

    Article  CAS  Google Scholar 

  23. T. Bianda et al. Effects of short-term insulin-like growth factor-I or growth hormone treatment on bone turnover, renal phosphate reabsorption and 1,25 dihydroxyvitamin D3 production in healthy man. J. Intern. Med. 241, 143–150 (1997)

    Article  CAS  PubMed  Google Scholar 

  24. L. Condamine et al. Local action of phosphate depletion and insulin-like growth factor 1 on in vitro production of 1,25-dihydroxyvitamin D by cultured mammalian kidney cells. J. Clin. Investig. 94, 1673–1679 (1994)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. S. Wei, H. Tanaka, Y. Seino, Local action of exogenous growth hormone and insulin-like growth factor-I on dihydroxyvitamin D production in LLC-PK1 cells. Eur. J. Endocrinol. 139, 454–460 (1998)

    Article  CAS  PubMed  Google Scholar 

  26. R. Shah, A. Licata, N.M. Oyesiku, A.G. Ioachimescu, Acromegaly as a cause of 1,25-dihydroxyvitamin D-dependent hypercalcemia: case reports and review of the literature. Pituitary 12, S17–S22 (2012)

    Article  Google Scholar 

  27. M. Ueda et al. Hypercalcemia in a patient with primary hyperparathyroidism and acromegaly: distinct roles of growth hormone and parathyroid hormone in the development of hypercalcemia. Intern. Med. 44, 307–310 (2005)

    Article  PubMed  Google Scholar 

  28. P. Manroa, S. Kannan, B. Hatipoglu, A. Licata, Hypercalcemia and acromegaly-clarifying the connections. A case report and review of the literature. Endocr. Pract. 20, e86–e90 (2014)

    Article  PubMed  Google Scholar 

  29. H. Tsuchiya et al. Acromegalic patient with recurrent urolithiasis. Endocrinol. Jpn. 32, 851–861 (1985)

    Article  CAS  PubMed  Google Scholar 

  30. B. Lund, P.C. Eskildsen, B. Lund, A.W. Norman, O.H. Sorensen, Calcium and vitamin D metabolism in acromegaly. Acta Endocrinol. 96, 444–450 (1981)

    Article  CAS  Google Scholar 

  31. J. Halupczok-Zyła, A. Jawiarczyk-Przybyłowska, M. Bolanowski, Patients with active acromegaly are at high risk of 25 (OH) D deficiency. Front. Endocrinol. 6, 1–7 (2015)

    Google Scholar 

  32. M. Ilhan, et al. Investigation of the vitamin D receptor polymorphisms in acromegaly patients. Biomed Res. Int. 2015, 625981 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. M.M. Uygur, D.D. Yazıcı, O. Buğdaycı, D.G. Yavuz, Prevalence of vertebral fractures and serum sclerostin levels in acromegaly. Endocrine 73, 667–673 (2021)

    Article  CAS  PubMed  Google Scholar 

  34. A.E. Altinova, C. Ozkan, M. Akturk, O. Gulbahar, E. Al, Vitamin D-binding protein and free vitamin D concentrations in acromegaly. Endocrine 52, 374–379 (2016)

    Article  CAS  PubMed  Google Scholar 

  35. S. Takamoto et al. Changes in calcium homeostasis in acromegaly treated by pituitary adenomectomy. J. Clin. Endocrinol. Metab. 61, 7–11 (1985)

    Article  CAS  PubMed  Google Scholar 

  36. C. Cappelli et al. Long-term treatment of acromegaly with lanreotide: evidence of increased serum parathormone concentration. Endocr. J. 51, 517–520 (2004)

    Article  CAS  PubMed  Google Scholar 

  37. J.W.J. Bijlsma et al. Changes in bone metabolism during treatment of acromegaly. Acta Endocrinol. 104, 153–159 (1983)

    Article  CAS  Google Scholar 

  38. H.D. White et al. Effect of active acromegaly and its treatment on parathyroid circadian rhythmicity and parathyroid target-organ sensitivity. J. Clin. Endocrinol. Metab. 91, 913–919 (2006)

    Article  CAS  PubMed  Google Scholar 

  39. P.J. Ho, L.M. Fig, A.L. Barkan, B. Shapiro, Bone mineral density of the axial skeleton in acromegaly. J. Nucl. Med. 33, 1608–1612 (1992)

    CAS  PubMed  Google Scholar 

  40. L. Fredstorp, Y. Pernow, S. Werner, The short and long-term effects of octreotide on calcium homeostasis in patients with acromegaly. Clin. Endocrinol. 39, 331–336 (1993)

    Article  CAS  Google Scholar 

  41. C.T. Sempos, H.W. Vesper, K.W. Phinney, L.M. Thienpont, P.M. Coates, Vitamin D status as an international issue: National surveys and the problem of standardization. Scand. J. Clin. Lab. Investig. 72, 32–40 (2012)

    CAS  Google Scholar 

  42. G. Mazziotti et al. Bone turnover, bone mineral density, and fracture risk in acromegaly: a meta-analysis. J. Clin. Endocrinol. Metab. 100, 384–394 (2015)

    Article  CAS  PubMed  Google Scholar 

  43. I.I. Dedov, N.N. Molitvoslovova, L.Y. Rozhinskaya, G.A. Mel’nichenko, Russian association of endocrinologists national practice guidelines (clinical signs, diagnosis, differential diagnosis, treatment). Acromegaly Probl. Endocrinol. 59, 4–18 (2013)

    Article  Google Scholar 

  44. A. Povaliaeva et al. Evaluation of vitamin D metabolism in patients with type 1 diabetes mellitus in the setting of cholecalciferol treatment. Nutrients 12, 1–14 (2020)

    Article  CAS  Google Scholar 

  45. J. Thode et al. Comparison of serum total calcium, albumin-corrected total calcium, and ionized calcium in 1213 patients with suspected calcium disorders. Scand. J. Clin. Lab. Investig. 49, 217–223 (1989)

    Article  CAS  Google Scholar 

  46. D.D. Bikle, P.K. Siiteri, E. Ryzen, J.G. Haddad, E. Gee, Serum protein binding of 1, 25-Dihydroxyvitamin D: a reevaluation by direct measurement of free metabolite levels. J. Clin. Endocrinol. Metab. 61, 969–975 (1985)

    Article  CAS  PubMed  Google Scholar 

  47. D.D. Bikle et al. Assessment of the free fraction of 25-Hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein. J. Clin. Endocrinol. Metab. 63, 954–959 (1986)

    Article  CAS  PubMed  Google Scholar 

  48. Sealed Envelope Ltd. Power calculator for continuous outcome superiority trial. https://www.sealedenvelope.com/power/continuous-superiority (2012). Accessed 17 Sep 2021

  49. M.F. Holick et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 96, 1911–1930 (2011)

    Article  CAS  PubMed  Google Scholar 

  50. E.A. Pigarova et al. Russian association of endocrinologists recommendations for diagnosis, treatment and prevention of vitamin D deficiency in adults. Probl. Endocrinol. 62, 60–84 (2016)

    Article  Google Scholar 

  51. J.C.Y. Tang et al. The dynamic relationships between the active and catabolic vitamin D metabolites, their ratios, and associations with PTH. Sci. Rep. 9, 1–10 (2019)

    Google Scholar 

  52. X. Guo et al. Pre- and postoperative body composition and metabolic characteristics in patients with acromegaly: a prospective study. Int. J. Endocrinol. 2018, 4125013 (2018)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. G. Mazziotti, F. Maffezzoni, A. Giustina, Vitamin D-binding protein: one more piece in the puzzle of acromegalic osteopathy? Endocrine 52, 183–186 (2016)

    Article  CAS  PubMed  Google Scholar 

  54. J. Arnaud, J. Constans, Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP). Hum. Genet. 92, 183–188 (1993)

    Article  CAS  PubMed  Google Scholar 

  55. N.F. Dirks et al. Determination of human reference values for serum total 1,25-dihydroxyvitamin D using an extensively validated 2D ID-UPLC–MS/MS method. J. Steroid Biochem. Mol. Biol. 164, 127–133 (2016)

    Article  CAS  PubMed  Google Scholar 

  56. J.C.Y. Tang et al. Reference intervals for serum 24,25-dihydroxyvitamin D and the ratio with 25-hydroxyvitamin D established using a newly developed LC–MS/MS method. J. Nutr. Biochem. 46, 21–29 (2017)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We express our deep gratitude to our colleagues: Zhanna Y. Belaya for the help in recruiting patients, Natalya M. Malysheva, Vitaliy A. Ioutsi, and Larisa V. Nikankina for the help with the laboratory research.

Funding

This research was funded by the Russian Science Foundation, grant number 19-15-00243.

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Correspondence to Alexandra A. Povaliaeva.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Endocrinology Research Center, Moscow, Russia on April 10, 2019 (abstract of record No. 6). Informed consent was obtained from all individual participants included in the study.

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Povaliaeva, A.A., Bogdanov, V.P., Zhukov, A.Y. et al. Characterization of vitamin D metabolism in active acromegaly in the setting of bolus (150,000 IU) cholecalciferol treatment. Endocrine 76, 407–418 (2022). https://doi.org/10.1007/s12020-022-02994-0

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  • DOI: https://doi.org/10.1007/s12020-022-02994-0

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