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Vitamin D Status in Paget Disease of Bone and Efficacy–Safety Profile of Cholecalciferol Treatment in Pagetic Patients with Hypovitaminosis D

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Abstract

Adequate vitamin D status is essential for skeletal health. Paget’s disease of bone (PDB) is a common metabolic skeletal disorder, but data regarding the vitamin D status in PDB patients are lacking. We performed a case–control study to estimate vitamin D status in 708 PDB patients and in 1803 healthy controls from Italy and an observational prospective study to evaluate the efficacy–safety profile of oral cholecalciferol treatment [400.000 International Units (UI) of cholecalciferol administered in cycles of 8 weeks until 25OHD levels reaches 70 nmol/L as primary therapy and 50.000 UI of cholecalciferol administered every 2 weeks for 52 weeks for the maintenance therapy] in 82 PDB patients with hypovitaminosis D, i.e., 25OHD < 50 nmol/L. The main outcome measures for the prospective study were 25OHD levels, metabolic risk factors (RF) for nephrolithiasis, bone pain score (BPS), and pain medication score (PMS). Over half of PDB patients had hypovitaminosis D. Among PDB patients treated with cholecalciferol, 76 patients reached 25OHD levels ≥ 70 nmol/L after the first cycle of primary therapy and the remaining six patients after a second cycle. The maintenance therapy guaranteed 25OHD levels ≥ 70 nmol/L during the entire follow-up. The increase in 25OHD levels reduced PTH, BPS, and PMS levels, without changes in RF for nephrolithiasis. We can conclude that (i) hypovitaminosis D is frequent in PDB patients, (ii) cholecalciferol significantly increased 25OHD levels in PDB patients, and (iii) the correction of hypovitaminosis D improves the quality of life of PDB patients without inducing significant changes in RF for nephrolithiasis.

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References

  1. Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281

    Article  CAS  PubMed  Google Scholar 

  2. Francis RM, Aspray TJ, Bowring CE, Fraser WD, Gittoes NJ, Javaid MK, Macdonald HM, Patel S, Selby PL, Tanna N (2015) National osteoporosis society practical clinical guideline on vitamin D and bone health. Maturitas 80:119–121

    Article  CAS  PubMed  Google Scholar 

  3. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 96:1911–1930

    Article  CAS  Google Scholar 

  4. Ralston SH (2013) Clinical practice. Paget’s disease of bone. N Engl J Med 368:644–650

    Article  CAS  PubMed  Google Scholar 

  5. Gennari L, Rendina D, Falchetti A, Merlotti D. Paget’s disease of bone. Calcif Tissue Int in press

  6. Seitz S, Priemel M, von Domarus C, Beil FT, Barvencik F, Amling M, Rueger JM (2008) The second most common bone disease: a review on Paget’s disease of bone. Eur J Trauma Emerg Surg 34:549–553

    Article  PubMed  Google Scholar 

  7. Corral-Gudino L, Borao-Cengotita-Bengoa M, Del Pino-Montes J, Ralston S (2013) Epidemiology of Paget’s disease of bone: a systematic review and meta-analysis of secular changes. Bone 55:347–352

    Article  PubMed  Google Scholar 

  8. van Staa TP, Selby P, Leufkens HG, Lyles K, Sprafka JM, Cooper C (2002) Incidence and natural history of Paget’s disease of bone in England and Wales. J Bone Miner Res 17:465–471

    Article  PubMed  Google Scholar 

  9. Rendina D, Gennari L, De Filippo G, Merlotti D, de Campora E, Fazioli F, Scarano G, Nuti R, Strazzullo P, Mossetti G (2006) Evidence for increased clinical severity of familial and sporadic Paget’s disease of bone in Campania, southern Italy. J Bone Miner Res 21:1828–1835

    Article  PubMed  Google Scholar 

  10. Siris ES, Lyles KW, Singer FR, Meunier PJ (2006) Medical management of Paget’s disease of bone: indications for treatment and review of current therapies. J Bone Miner Res 21:P94–P98

    Article  CAS  PubMed  Google Scholar 

  11. Gennari L, Gianfrancesco F, Di Stefano M, Rendina D, Merlotti D, Esposito T, Gallone S, Fusco P, Rainero I, Fenoglio P, Mancini M, Martini G, Bergui S, De Filippo G, Isaia G, Strazzullo P, Nuti R, Mossetti G (2010) SQSTM1 gene analysis and gene-environment interaction in Paget’s disease of bone. J Bone Miner Res 25:1375–1384

    Article  CAS  PubMed  Google Scholar 

  12. Fillée C, Keller T, Mourad M, Brinkmann T, Ketelslegers JM (2012) Impact of vitamin D-related serum PTH reference values on the diagnosis of mild primary hyperparathyroidism, using bivariate calcium/PTH reference regions. Clin Endocrinol 76:785–789

    Article  CAS  Google Scholar 

  13. Rendina D, Gianfrancesco F, De Filippo G, Merlotti D, Esposito T, Mingione A, Nuti R, Strazzullo P, Mossetti G, Gennari L (2010) FSHR gene polymorphisms influence bone mineral density and bone turnover in postmenopausal women. Eur J Endocrinol 163:165–172

    Article  CAS  PubMed  Google Scholar 

  14. Cooper DS, Biondi B (2012) Subclinical thyroid disease. Lancet 379:1142–1154

    Article  PubMed  Google Scholar 

  15. Gambaro G, Croppi E, Coe F, Lingeman J, Moe O, Worcester E, Buchholz N, Bushinsky D, Curhan GC, Ferraro PM, Fuster D, Goldfarb DS, Heilberg IP, Hess B, Lieske J, Marangella M, Milliner D, Preminger GM, Reis Santos JM, Sakhaee K, Sarica K, Siener R, Strazzullo P, Williams JC; Consensus Conference Group (2016) Metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations: a consensus statement. J Nephrol 29:715–734

    Article  CAS  Google Scholar 

  16. Kaye AD, Cornett EM, Hart B, Patil S, Pham A, Spalitta M, Mancuso KF (2018) Novel pharmacological nonopioid therapies in chronic pain. Curr Pain Headache Rep 22:31

    Article  PubMed  Google Scholar 

  17. Tong D, Gillick L, Hendrickson FR (1982) The palliation of symptomatic osseous metastases. Final results of the study by the radiation therapy oncology group. Cancer 50:893–899

    Article  CAS  PubMed  Google Scholar 

  18. Rendina D, De Filippo G, Postiglione L, Covelli B, Ricciardone M, Guillaume S, Di Spigna G, Selleri C, Merlotti D, Bianciardi S, Materozzi M, Muscariello R, De Pascale F, DʼElia L, Nuti R, Strazzullo P, Gennari L (2018) Interleukin-6 trans-signaling and pathological low back pain in patients with Paget disease of bone. Pain 159:1664–1673

    Article  CAS  PubMed  Google Scholar 

  19. Tiselius HG (2013) A proposed method for approximate estimates of the ion-activity products of calcium oxalate and calcium phosphate in spot-urine samples or in urine samples collected during less well defined periods of time. Urolithiasis 41:105–109

    Article  CAS  PubMed  Google Scholar 

  20. Coe FL, Evan A, Worcester E (2005) Kidney stone disease. J Clin Invest 115:2598–2608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rubenstein L, Robbins A, Josephson K, Schulman B, Osterweil D (1990) The value of assessing falls in an elderly population: a randomised clinical trial. Ann Intern Med 113:308–316

    Article  CAS  PubMed  Google Scholar 

  22. Conley D, Schultz AA, Selvin R (1999) The challenge of predicting patients at risk for falling: development of the Conley Scale. Medsurg Nurs 8:348–354

    CAS  PubMed  Google Scholar 

  23. Rendina D, Mossetti G, Viceconti R, Sorrentino M, Castaldo R, Manno G, Guadagno V, Strazzullo P, Nunziata V (2004) Association between vitamin D receptor gene polymorphisms and fasting idiopathic hypercalciuria in recurrent stone-forming patients. Urology 64:833–838

    Article  PubMed  Google Scholar 

  24. Gennari L, Merlotti D, Valenti R, Ceccarelli E, Ruvio M, Pietrini MG, Capodarca C, Franci MB, Campagna MS, Calabrò A, Cataldo D, Stolakis K, Dotta F, Nuti R (2012) Circulating sclerostin levels and bone turnover in type 1 and type 2 diabetes. J Clin Endocrinol Metab 97:1737–1744

    Article  CAS  PubMed  Google Scholar 

  25. Thomas L (1997) Retrospective power analysis. Conserv Biol 11:276–280

    Article  Google Scholar 

  26. Battista C, Guarnieri V, Carnevale V, Baorda F, Pileri M, Garrubba M, Salcuni AS, Chiodini I, Minisola S, Romagnoli E, Eller-Vainicher C, Santini SA, Parisi S, Frusciante V, Fontana A, Copetti M, Hendy GN, Scillitani A, Cole DE (2017) Vitamin D status in primary hyperparathyroidism: effect of genetic background. Endocrine 55:266–272

    Article  CAS  PubMed  Google Scholar 

  27. Rendina D, Mossetti G, Viceconti R, Sorrentino M, Nunziata V (2004) Risedronate and pamidronate treatment in the clinical management of patients with severe Paget’s disease of bone and acquired resistance to bisphosphonates. Calcif Tissue Int 75:189–196

    Article  CAS  PubMed  Google Scholar 

  28. Gennari L, Merlotti D, Mossetti G, Rendina D, De Paola V, Martini G, Nuti R (2009) The use of intravenous aminobisphosphonates for the treatment of Paget’s disease of bone. Mini Rev Med Chem 9:1052–1063

    Article  CAS  PubMed  Google Scholar 

  29. Griz L, Bandeira F, Diniz ET, Cabral M, Freese E (2013) Prevalence of vitamin D deficiency is higher in patients with Paget’s disease of bone compared with age-matched controls. Arq Bras Endocrinol Metabol 57:509–512

    Article  PubMed  Google Scholar 

  30. de Deuxchaisnes CN, Rombouts-Lindemans C, Huaux JP, Devogelaer JP, Withofs H, Meersseman F (1981) Relative vitamin D deficiency in Paget’s disease. Lancet 1:833–834

    Article  PubMed  Google Scholar 

  31. Guillard-Cumming DF, Beard DJ, Douglas DL, Johnson SK, Lawson-Matthew PJ, Russell RG, Kanis JA (1985) Abnormal vitamin D metabolism in Paget’s disease of bone. Clin Endocrinol (Oxf) 22:559–566

    Article  CAS  Google Scholar 

  32. Foldes J, Shamir S, Kidroni G, Menczel J (1989) Vitamin D in Paget’s disease of bone. Clin Orthop Relat Res 243:275–279

    Google Scholar 

  33. Nunziata V, Giannattasio R, di Giovanni G, Lettera AM, Nunziata CA (1993) Vitamin D status in Paget’s bone disease. Effects of calcitonin therapy. Clin Orthop Relat Res 293:366–371

    Google Scholar 

  34. Rosen CJ, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Manson JE, Mayne ST, Ross AC, Shapses SA, Taylor CL (2012) IOM committee members respond to endocrine society vitamin D guideline. J Clin Endocrinol Metab 97:1146–1152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM (2012) Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited. J Clin Endocrinol Metab 97:1153–1158

    Article  CAS  PubMed  Google Scholar 

  36. Bettica P, Bevilacqua M, Vago T, Norbiato G (1999) High prevalence of hypovitaminosis D among free-living postmenopausal women referred to an osteoporosis outpatient clinic in northern Italy for initial screening. Osteoporos Int 9:226–229

    Article  CAS  PubMed  Google Scholar 

  37. Isaia G, Giorgino R, Rini GB, Bevilacqua M, Maugeri D, Adami S (2003) Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors. Osteoporos Int 14:577–582

    Article  CAS  PubMed  Google Scholar 

  38. Lips P, Cashman KD, Lamberg-Allardt C, Bischoff-Ferrari HA, Obermayer-Pietsch BR, Bianchi M, Stepan J, El-Hajj Fuleihan G, Bouillon R. MANAGEMENT OF ENDOCRINE DISEASE: Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency; a position statement of the European Calcified Tissue Society. Eur J Endocrinol. in press

  39. Close GL, Leckey J, Patterson M, Bradley W, Owens DJ, Fraser WD, Morton JP (2013) The effects of vitamin D(3) supplementation on serum total 25[OH]D concentration and physical performance: a randomised dose-response study. Br J Sports Med 47:692–696

    Article  PubMed  Google Scholar 

  40. Wagner D, Hanwell HE, Schnabl K, Yazdanpanah M, Kimball S, Fu L, Sidhom G, Rousseau D, Cole DE, Vieth R (2011) The ratio of serum 24,25-dihydroxyvitamin D(3) to 25-hydroxyvitamin D(3) is predictive of 25-hydroxyvitamin D(3) response to vitamin D(3) supplementation. J Steroid Biochem Mol Biol 126:72–77

    Article  CAS  PubMed  Google Scholar 

  41. Singer FR, Bone HG 3rd, Hosking DJ, Lyles KW, Murad MH, Reid IR, Siris ES; Endocrine Society (2014) Paget’s disease of bone: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 99:4408–4422

    Article  CAS  Google Scholar 

  42. Mossetti G, Vuotto P, Rendina D, Numis FG, Viceconti R, Giordano F, Cioffi M, Scopacasa F, Nunziata V (2003) Association between vitamin D receptor gene polymorphisms and tubular citrate handling in calcium nephrolithiasis. J Intern Med 253:194–200

    Article  CAS  PubMed  Google Scholar 

  43. Rendina D, De Filippo G, Gianfrancesco F, Muscariello R, Schiano di Cola M, Strazzullo P, Esposito T (2017) Evidence for epistatic interaction between VDR and SLC13A2 genes in the pathogenesis of hypocitraturia in recurrent calcium oxalate stone formers. J Nephrol 30:411–418

    Article  CAS  PubMed  Google Scholar 

  44. Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C (2014) Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev 10:007470

    Google Scholar 

  45. Brandi ML, Falchetti A (2006) What is the relationship between Paget’s disease of bone and hyperparathyroidism? J Bone Miner Res 21:P69–P74

    Article  CAS  PubMed  Google Scholar 

  46. Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, Nicholson GC (2010) Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 303:1815–1822

    Article  CAS  PubMed  Google Scholar 

  47. Sanders KM, Nicholson GC, Ebeling PR (2013) Is high dose vitamin D harmful? Calcif Tissue Int 92:191–206

    Article  CAS  PubMed  Google Scholar 

  48. Mackenzie L, Byles J, D’Este C (2006) Validation of self-reported fall events in intervention studies. Clin Rehabil 20:331–339

    Article  PubMed  Google Scholar 

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Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

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Authors and Affiliations

  1. Department of Medicine and Surgery, Federico II University, 5, via Pansini, 80131, Naples, Italy

    Domenico Rendina, Lanfranco D’Elia & Pasquale Strazzullo

  2. Service de Médecine des Adolescents, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France

    Gianpaolo De Filippo

  3. Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy

    Daniela Merlotti, Simone Bianciardi, Ranuccio Nuti & Luigi Gennari

  4. Department of Medical Science, Gerontology and Bone Metabolic Diseases, University of Torino, Turin, Italy

    Marco Di Stefano & Eleonora Coppo

  5. Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy

    Mariangela Succoio, Simona Maria Muggianu & Raffaella Faraonio

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  1. Domenico Rendina
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Contributions

DR designed the study and prepared the first draft of the paper. He is guarantor. GDF, DM, MDS, MS, SMM, SB, EC, RF, RN, PS, and LG contributed to the experimental work. LD’E was responsible for statistical analysis of the data.

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Correspondence to Domenico Rendina.

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Conflict of interest

Domenico Rendina, Gianpaolo De Filippo, Daniela Merlotti, Marco Di Stefano, Mariangela Succoio, Simona Maria Muggianu, Simone Bianciardi, Lanfranco D’Elia, Eleonora Coppo, Raffaella Faraonio, Ranuccio Nuti, Pasquale Strazzullo, and Luigi Gennari declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

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All procedures performed in this study, which involves human participants, were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Human and Animal Rights and Informed Consent

Written informed consent has been obtained from each patient or subject after full explanation of the purpose and nature of all used procedures. The study protocol was approved by the Federico II University Ethical Committee.

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Rendina, D., De Filippo, G., Merlotti, D. et al. Vitamin D Status in Paget Disease of Bone and Efficacy–Safety Profile of Cholecalciferol Treatment in Pagetic Patients with Hypovitaminosis D. Calcif Tissue Int 105, 412–422 (2019). https://doi.org/10.1007/s00223-019-00578-1

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