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Complications of Phosphate and Vitamin D Treatment in X-Linked Hypophosphataemia

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Abstract

Conventional treatment of X-linked hypophosphataemia (XLH) consists in the oral administration of phosphate plus calcitriol supplements. Although this therapy has reduced bone deformities and even achieved adequate patient growth, overtreatment or low adherence could lead to subsequent consequences that may compromise the efficacy of the therapy. Some of the complications associated with phosphate and vitamin D treatment are abdominal discomfort, diarrhoea, hypokalaemia, hyperparathyroidism, hypercalcaemia or hypercalciuria, nephrocalcinosis or nephrolithiasis, and ectopic calcifications. Therefore, constant multidisciplinary monitoring of patients with XLH is necessary to prevent the manifestation of these complications and to deal with them as soon as they appear. The main objective of this article is to review the main complications arising from conventional treatment of XLH and how to deal with them.

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References

  1. Econs MJ. Conventional therapy in adults with XLH improves dental manifestations, but not enthesopathy. J Clin Endocrinol Metab. 2015;100(10):3622–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Linglart A, Biosse-Duplan M, Briot K, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect. 2014;3(1):R13–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res. 2011;26(7):1381–8.

    Article  PubMed  Google Scholar 

  4. Carpenter TO. Primary disorders of phosphate metabolism. In: Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, editors. Endotext. South Dartmouth: MDText.com; 2000.

    Google Scholar 

  5. Makitie O, Doria A, Kooh SW, Cole WG, Daneman A, Sochett E. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab. 2003;88(8):3591–7.

    Article  CAS  PubMed  Google Scholar 

  6. Nielsen LH, Rahbek ET, Beck-Nielsen SS, Christesen HT. Treatment of hypophosphataemic rickets in children remains a challenge. Dan Med J. 2014;61(7):A4874.

    PubMed  Google Scholar 

  7. Albright F, Butler AN, Bloomberg E. Rickets resistant to vitamin D therapy. Am J Dis Child. 1937;54(3):529–47.

    Google Scholar 

  8. Stickler GB. Familial hypophosphatemic vitamin D resistant rickets. The neonatal period and infancy. Acta Paediatr Scand. 1969;58(3):213–9.

    Article  CAS  PubMed  Google Scholar 

  9. Paunier L, Kooh SW, Conen PE, Gibson AA, Fraser D. Renal function and histology after long-term vitamin D therapy of vitamin D refractory rickets. J Pediatr. 1968;73(6):833–44.

    Article  CAS  PubMed  Google Scholar 

  10. Lilly CA, Peirce CB, Grant RL. The effect of phosphates on the bones of rachitic rats: three plates (twelve figures). J Nutr. 1935;9(1):25–35.

    Article  CAS  Google Scholar 

  11. Fraser D, Geiger DW, Munn JD, Slater PE, Jahn R, Liu E. Clinical vitamin-D deficiency and in hypophosphatemic vitamin-D-refractory rickets-the induction of calcium deposition in rachitic cartilage without the administration of vitamin-D. Am J Dis Child. 1958;96(4):460–3.

    Google Scholar 

  12. Marie PJ, Travers R, Glorieux FH. Healing of bone lesions with 1,25-dihydroxyvitamin D3 in the young X-linked hypophosphatemic male mouse. Endocrinology. 1982;111(3):904–11.

    Article  CAS  PubMed  Google Scholar 

  13. Harrell RM, Lyles KW, Harrelson JM, Friedman NE, Drezner MK. Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol. J Clin Invest. 1985;75(6):1858–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Block JE, Piel CF, Selvidge R, Genant HK. Familial hypophosphatemic rickets: bone mass measurements in children following therapy with calcitriol and supplemental phosphate. Calcif Tissue Int. 1989;44(2):86–92.

    Article  CAS  PubMed  Google Scholar 

  15. Haris A, Toth A, Rado JP. High-dose phosphate treatment leads to hypokalemia in hypophosphatemic osteomalacia. Exp Clin Endocrinol Diabetes. 1998;106(5):431–4.

    Article  CAS  PubMed  Google Scholar 

  16. Zivicnjak M, Schnabel D, Billing H, et al. Age-related stature and linear body segments in children with X-linked hypophosphatemic rickets. Pediatr Nephrol. 2011;26(2):223–31.

    Article  PubMed  Google Scholar 

  17. Kooh SW, Binet A, Daneman A. Nephrocalcinosis in X-linked hypophosphataemic rickets: its relationship to treatment, kidney function, and growth. Clin Invest Med. 1994;17(2):123–30.

    CAS  PubMed  Google Scholar 

  18. Sellarés VL, Martín de Francisco AL, Torregrosa V. Alteraciones del metabolismo mineral en la enfermedad renal crónica. Nefrologia. 2012;7(1):483–503.

    Google Scholar 

  19. Davies M. Hyperparathyroidism in X-linked hypophosphataemic osteomalacia. Clin Endocrinol (Oxf). 1995;42(2):205–6.

    Article  CAS  Google Scholar 

  20. Arnaud C, Glorieux F, Scriver C. Serum parathyroid hormone in X-linked hypophosphatemia. Science. 1971;173(3999):845–7.

    Article  CAS  PubMed  Google Scholar 

  21. Kruse K, Hinkel GK, Griefahn B. Calcium metabolism and growth during early treatment of children with X-linked hypophosphataemic rickets. Eur J Pediatr. 1998;157(11):894–900.

    Article  CAS  PubMed  Google Scholar 

  22. Goodyer PR, Kronick JB, Jequier S, Reade TM, Scriver CR. Nephrocalcinosis and its relationship to treatment of hereditary rickets. J Pediatr. 1987;111(5):700–4.

    Article  CAS  PubMed  Google Scholar 

  23. DeLacey S, Liu Z, Broyles A, et al. Hyperparathyroidism and parathyroidectomy in X-linked hypophosphatemia patients. Bone. 2019;127:386–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Glorieux FH, Marie PJ, Pettifor JM, Delvin EE. Bone response to phosphate salts, ergocalciferol, and calcitriol in hypophosphatemic vitamin D-resistant rickets. N Engl J Med. 1980;303(18):1023–31.

    Article  CAS  PubMed  Google Scholar 

  25. Makitie O, Kooh SW, Sochett E. Prolonged high-dose phosphate treatment: a risk factor for tertiary hyperparathyroidism in X-linked hypophosphatemic rickets. Clin Endocrinol (Oxf). 2003;58(2):163–8.

    Article  CAS  Google Scholar 

  26. Jain N, Reilly RF. Hungry bone syndrome. Curr Opin Nephrol Hypertens. 2017;26(4):250–5.

    Article  PubMed  Google Scholar 

  27. Alon US, Levy-Olomucki R, Moore WV, Stubbs J, Liu S, Quarles LD. Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets. Clin J Am Soc Nephrol. 2008;3(3):658–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chocron S, Lara LE, Madrid A, Muñoz M, Vilalta R, Ariceta G. Cinacalcet allows reduction of oral phosphate dose and PTH control in XLHR. Preliminary data. Pediatr Nephrol. 2014;29:1684 (Abstract O78).

    Google Scholar 

  29. Dong BJ. Cinacalcet: an oral calcimimetic agent for the management of hyperparathyroidism. Clin Ther. 2005;27(11):1725–51.

    Article  CAS  PubMed  Google Scholar 

  30. de Francisco AL. New strategies for the treatment of hyperparathyroidism incorporating calcimimetics. Expert Opin Pharmacother. 2008;9(5):795–811.

    Article  PubMed  Google Scholar 

  31. Alon US, Monzavi R, Lilien M, Rasoulpour M, Geffner ME, Yadin O. Hypertension in hypophosphatemic rickets—role of secondary hyperparathyroidism. Pediatr Nephrol. 2003;18(2):155–8.

    Article  PubMed  Google Scholar 

  32. Colares Neto G, Yamamuchi FI, Baroni RH, et al. Nephrocalcinosis and nephrolithiasis in 36 X-linked hypophosphatemic rickets patients: diagnostic imaging and evaluation of risk factors in a single-center study (Poster 218-P2). In: 51st Annual Meeting European Society of Paediatric Endocrinology (ESPE); 2015 October 1–3; Barcelona, Spain.

  33. Alon U, Brewer WH, Chan JC. Nephrocalcinosis: detection by ultrasonography. Pediatrics. 1983;71(6):970–3.

    CAS  PubMed  Google Scholar 

  34. Keskin M, Savas-Erdeve S, Sagsak E, Cetinkaya S, Aycan Z. Risk factors affecting the development of nephrocalcinosis, the most common complication of hypophosphatemic rickets. J Pediatr Endocrinol Metab. 2015;28(11–12):1333–7.

    CAS  PubMed  Google Scholar 

  35. Karaplis AC, Bai X, Falet JP, Macica CM. Mineralizing enthesopathy is a common feature of renal phosphate-wasting disorders attributed to FGF23 and is exacerbated by standard therapy in hyp mice. Endocrinology. 2012;153(12):5906–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Polisson RP, Martínez S, Khoury M, et al. Calcification of entheses associated with X-linked hypophosphatemic osteomalacia. N Engl J Med. 1985;313(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  37. Moltz KC, Friedman AH, Nehgme RA, Kleinman CS, Carpenter TO. Ectopic cardiac calcification associated with hyperparathyroidism in a boy with hypophosphatemic rickets. Curr Opin Pediatr. 2001;13(4):373–5.

    Article  CAS  PubMed  Google Scholar 

  38. Seikaly MG, Brown R, Baum M. The effect of recombinant human growth hormone in children with X-linked hypophosphatemia. Pediatrics. 1997;100(5):879–84.

    Article  CAS  PubMed  Google Scholar 

  39. Makitie O, Toiviainen-Salo S, Marttinen E, Kaitila I, Sochett E, Sipila I. Metabolic control and growth during exclusive growth hormone treatment in X-linked hypophosphatemic rickets. Horm Res. 2008;69(4):212–20.

    PubMed  Google Scholar 

  40. Schütt SM, Schumacher M, Holterhus PM, Felgenhauer S, Hiort O. Effect of GH replacement therapy in two male siblings with combined X-linked hypophosphatemia and partial GH deficiency. Eur J Endocrinol. 2003;149(4):317–21.

    Article  PubMed  Google Scholar 

  41. Mirza MA, Alsio J, Hammarstedt A, et al. Circulating fibroblast growth factor-23 is associated with fat mass and dyslipidemia in two independent cohorts of elderly individuals. Arterioscler Thromb Vasc Biol. 2011;31(1):219–27.

    Article  CAS  PubMed  Google Scholar 

  42. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121(11):4393–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Carpenter TO, Insogna KL, Zhang JH, et al. Circulating levels of soluble klotho and FGF23 in X-linked hypophosphatemia: circadian variance, effects of treatment, and relationship to parathyroid status. J Clin Endocrinol Metab. 2010;95(11):E352–7.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Yamazaki Y, Tamada T, Kasai N, et al. Anti-FGF23 neutralizing antibodies show the physiological role and structural features of FGF23. J Bone Miner Res. 2008;23(9):1509–18.

    Article  CAS  PubMed  Google Scholar 

  45. Aono Y, Yamazaki Y, Yasutake J, et al. Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res. 2009;24(11):1879–88.

    Article  CAS  PubMed  Google Scholar 

  46. Carpenter TO, Imel EA, Ruppe MD, et al. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest. 2014;124(4):1587–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Carpenter TO, Whyte MP, Imel EA, et al. Burosumab therapy in children with X-linked hypophosphatemia. N Engl J Med. 2018;378(21):1987–98.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This supplement has been funded by Kyowa Kirin.

Funding

Kyowa Kirin organized the scientific meeting and contributed to the financing of the publication of the opinion of the speakers presented at that meeting (Madrid, November 2018).

Medical Writing, Editorial, and Other Assistance

The author would like to thank Fernando Sánchez Barbero, PhD for providing medical writing assistance on behalf of Springer Healthcare. Kyowa Kirin funded the writing assistance provided by Springer Healthcare Ibérica S.L. Ruth Blaikie provided the copy editing of this manuscript.

Authorship

The named author meets the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, takes responsibility for the integrity of the work as a whole, and has given his approval for this version to be published.

Disclosures

Pedro Arango Sancho declares having received speaker honoraria fees for training talks organized by Kyowa Kirin.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by the author.

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  1. Servicio de Nefrología Pediátrica y Trasplante Renal, Hospital Sant Joan de Déu, Barcelona, Spain

    Pedro Arango Sancho

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  1. Pedro Arango Sancho
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Correspondence to Pedro Arango Sancho.

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Arango Sancho, P. Complications of Phosphate and Vitamin D Treatment in X-Linked Hypophosphataemia. Adv Ther 37 (Suppl 2), 105–112 (2020). https://doi.org/10.1007/s12325-019-01170-7

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