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Vitamin D, PTH, and calcium in relation to survival following prostate cancer

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Abstract

Purpose

Epidemiological studies suggest that low levels of vitamin D constitute a risk factor for prostate cancer. However, the results are conflicting, perhaps because prostate cancer is a very heterogeneous disease. More recent studies have focused on cancer progression and mortality. Vitamin D is closely related to both calcium metabolism and parathyroid hormone (PTH) levels, and all three factors have been implicated in prostate cancer.

Methods

We examined the associations between pre-diagnostic serum levels of vitamin D (25OHD), PTH, and calcium and mortality among 943 participants within the Malmö Diet and Cancer Study, who were diagnosed with prostate cancer. The mean time from diagnosis until the end of followup was 9.1 years (SD 4.5), and the mean time from inclusion until end of follow-up was 16.6 years (SD 4.9). The analytes were divided into quartiles, and the risk of death from prostate cancer was analyzed using Cox proportional hazard analysis, yielding hazards ratios (HR) with 95 % confidence intervals. The models were adjusted for season and year of inclusion, age at baseline, age at diagnosis, body mass index (BMI), and tumor characteristics (TNM and Gleason score).

Results

We observed a trend toward a lower prostate-specific mortality with 25OHD >85 nmol/L in the unadjusted analysis. This became statistically significantly in the third quartile of 25OHD (85–102 nmol/L) compared to the first (<68 nmol/L), HR 0.54 (0.34–0.85) when adjusting for age, time of inclusion, and BMI. The association was further strengthened when adjusted for age at diagnosis, Gleason score, and TNM classification with a HR in Q3 0.36 (0.22–0.60). p for trend was 0.03. Regarding calcium, there was a significantly lower HR for the second quartile (2.35–2.39 mmol/L) compared to the first (≤2.34 mmol/L) with a HR of 0.54 (0.32–0.86) in the unadjusted analysis. However, this association disappeared when adjusting for tumor characteristics. There were no associations between levels of PTH and prostate cancer mortality.

Conclusion

This study shows that levels of pre-diagnostic vitamin D above 85 nmol/L may improve survival in men with prostate cancer.

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References

  1. Schwartz GG, Hulka BS (1990) Is vitamin D deficiency a risk factor for prostate cancer? (Hypothesis). Anticancer Res 10(5A):1307–1311

    CAS  PubMed  Google Scholar 

  2. Moreno J, Krishnan AV, Peehl DM, Feldman D (2006) Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: inhibition of the prostaglandin pathway. Anticancer Res 26(4A):2525–2530

    CAS  PubMed  Google Scholar 

  3. Krishnan AV, Feldman D (2011) Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annual Rev Pharmacol 51:311–336. doi:10.1146/annurev-pharmtox-010510-100611

    Article  CAS  Google Scholar 

  4. Gandini S, Boniol M, Haukka J, Byrnes G, Cox B, Sneyd MJ, Mullie P, Autier P (2011) Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int J Caner 128(6):1414–1424

    Article  CAS  Google Scholar 

  5. Gilbert R, Martin RM, Beynon R, Harris R, Savovic J, Zuccolo L, Bekkering GE, Fraser WD, Sterne JA, Metcalfe C (2011) Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose-response meta-analysis. Cancer Cause Control 22(3):319–340. doi:10.1007/s10552-010-9706-3

    Article  Google Scholar 

  6. Yin L, Raum E, Haug U, Arndt V, Brenner H (2009) Meta-analysis of longitudinal studies: serum vitamin D and prostate cancer risk. Cancer Epidemiol 33(6):435–445. doi:10.1016/j.canep.2009.10.014

    Article  CAS  PubMed  Google Scholar 

  7. Xu Y, Shao X, Yao Y, Xu L, Chang L, Jiang Z, Lin Z (2014) Positive association between circulating 25-hydroxyvitamin D levels and prostate cancer risk: new findings from an updated meta-analysis. J Cancer Res Clin 140(9):1465–1477. doi:10.1007/s00432-014-1706-3

    Article  CAS  Google Scholar 

  8. Albertsen PC, Hanley JA, Fine J (2005) 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 293(17):2095–2101. doi:10.1001/jama.293.17.2095

    Article  CAS  PubMed  Google Scholar 

  9. Shui IM, Mucci LA, Kraft P, Tamimi RM, Lindstrom S, Penney KL, Nimptsch K, Hollis BW, Dupre N, Platz EA, Stampfer MJ, Giovannucci E (2012) Vitamin D-related genetic variation, plasma vitamin D, and risk of lethal prostate cancer: a prospective nested case-control study. J Natl Cancer I 104(9):690–699. doi:10.1093/jnci/djs189

    Article  CAS  Google Scholar 

  10. Fang F, Kasperzyk JL, Shui I, Hendrickson W, Hollis BW, Fall K, Ma J, Gaziano JM, Stampfer MJ, Mucci LA, Giovannucci E (2011) Prediagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer. PLoS ONE 6(4):e18625. doi:10.1371/journal.pone.0018625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tretli S, Hernes E, Berg JP, Hestvik UE, Robsahm TE (2009) Association between serum 25(OH)D and death from prostate cancer. Br J Cancer 100(3):450–454. doi:10.1038/sj.bjc.6604865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mondul AM, Weinstein SJ, Moy KA, Mannisto S, Albanes D (2016) Circulating 25-hydroxyvitamin D and prostate cancer survival. Cancer Epidemiol Biomar. doi:10.1158/1055-9965.EPI-15-0991

    Google Scholar 

  13. Albanes D, Mondul AM, Yu K, Parisi D, Horst RL, Virtamo J, Weinstein SJ (2011) Serum 25-hydroxy vitamin D and prostate cancer risk in a large nested case-control study. Cancer Epidemiol Biomar 20(9):1850–1860. doi:10.1158/1055-9965.EPI-11-0403

    Article  CAS  Google Scholar 

  14. Holt SK, Kolb S, Fu R, Horst R, Feng Z, Stanford JL (2013) Circulating levels of 25-hydroxyvitamin D and prostate cancer prognosis. Cancer Epidemiol 37(5):666–670. doi:10.1016/j.canep.2013.07.005

    Article  CAS  PubMed  Google Scholar 

  15. Shui IM, Mondul AM, Lindstrom S, Tsilidis KK, Travis RC, Gerke T, Albanes D, Mucci LA, Giovannucci E, Kraft P, For the B, Prostate Cancer Cohort Consortium G (2015) Circulating vitamin D, vitamin D-related genetic variation, and risk of fatal prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. Cancer. doi:10.1002/cncr.29320

    Google Scholar 

  16. Ritchie CK, Thomas KG, Andrews LR, Tindall DJ, Fitzpatrick LA (1997) Effects of the calciotrophic peptides calcitonin and parathyroid hormone on prostate cancer growth and chemotaxis. Prostate 30(3):183–187

    Article  CAS  PubMed  Google Scholar 

  17. Iwamura M, Abrahamsson PA, Foss KA, Wu G, Cockett AT, Deftos LJ (1994) Parathyroid hormone-related protein: a potential autocrine growth regulator in human prostate cancer cell lines. Urology 43(5):675–679

    Article  CAS  PubMed  Google Scholar 

  18. Ongkeko WM, Burton D, Kiang A, Abhold E, Kuo SZ, Rahimy E, Yang M, Hoffman RM, Wang-Rodriguez J, Deftos LJ (2014) Parathyroid hormone related-protein promotes epithelial-to-mesenchymal transition in prostate cancer. PLoS ONE 9(1):e85803. doi:10.1371/journal.pone.0085803

    Article  PubMed  PubMed Central  Google Scholar 

  19. Gensure RC, Gardella TJ, Juppner H (2005) Parathyroid hormone and parathyroid hormone-related peptide, and their receptors. Biochem Biophys Res Commun 328(3):666–678. doi:10.1016/j.bbrc.2004.11.069

    Article  CAS  PubMed  Google Scholar 

  20. Giovannucci E, Liu Y, Platz EA, Stampfer MJ, Willett WC (2007) Risk factors for prostate cancer incidence and progression in the health professionals follow-up study. Int J Cancer J 121(7):1571–1578

    Article  CAS  Google Scholar 

  21. Tseng M, Breslow RA, Graubard BI, Ziegler RG (2005) Dairy, calcium, and vitamin D intakes and prostate cancer risk in the National Health and Nutrition Examination Epidemiologic Follow-up Study cohort. Am J Clin Nutr 81(5):1147–1154

    CAS  PubMed  Google Scholar 

  22. Brandstedt J, Almquist M, Manjer J, Malm J (2012) Vitamin D, PTH, and calcium and the risk of prostate cancer: a prospective nested case-control study. Cancer Causes Control 23(8):1377–1385. doi:10.1007/s10552-012-9948-3

    Article  PubMed  Google Scholar 

  23. Brandstedt J, Almquist M, Ulmert D, Manjer J, Malm J (2016) Vitamin D, PTH, and calcium and tumor aggressiveness in prostate cancer: a prospective nested case-control study. Cancer Causes Control 27(1):69–80. doi:10.1007/s10552-015-0684-3

    Article  PubMed  Google Scholar 

  24. Manjer J, Carlsson S, Elmstahl S, Gullberg B, Janzon L, Lindstrom M, Mattisson I, Berglund G (2001) The Malmo Diet and Cancer Study: representativity, cancer incidence and mortality in participants and non-participants. Eur J Cancer Prev 10(6):489–499

    Article  CAS  PubMed  Google Scholar 

  25. Anker P, Wieland E, Ammann D, Dohner RE, Asper R, Simon W (1981) Neutral carrier based ion-selective electrode for the determination of total calcium in blood serum. Anal Chem 53(13):1970–1974

    Article  CAS  PubMed  Google Scholar 

  26. Lagunova Z, Porojnicu AC, Dahlback A, Berg JP, Beer TM, Moan J (2007) Prostate cancer survival is dependent on season of diagnosis. Prostate 67(12):1362–1370. doi:10.1002/pros.20577

    Article  PubMed  Google Scholar 

  27. Peterlik M, Boonen S, Cross HS, Lamberg-Allardt C (2009) Vitamin D and calcium insufficiency-related chronic diseases: an emerging world-wide public health problem. Int J Environ Res Public Health 6(10):2585–2607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Samverkan RCI (2012) Nationell kvalitetsrapport för diagnosår 2012 från Nationella prostatacancerregistret (NPCR)

  29. Andren O, Fall K, Franzen L, Andersson SO, Johansson JE, Rubin MA (2006) How well does the Gleason score predict prostate cancer death? A 20-year followup of a population based cohort in Sweden. J Urol 175(4):1337–1340. doi:10.1016/S0022-5347(05)00734-2

    Article  PubMed  Google Scholar 

  30. Schwartz GG (2013) Vitamin D, sunlight, and the epidemiology of prostate cancer. Anticancer Agents Med Chem 13(1):45–57

    Article  CAS  PubMed  Google Scholar 

  31. Robsahm TE, Tretli S, Dahlback A, Moan J (2004) Vitamin D3 from sunlight may improve the prognosis of breast-, colon- and prostate cancer (Norway). Cancer Causes Control 15(2):149–158. doi:10.1023/B:CACO.0000019494.34403.09

    Article  PubMed  Google Scholar 

  32. Porojnicu AC, Robsahm TE, Ree AH, Moan J (2005) Season of diagnosis is a prognostic factor in Hodgkin’s lymphoma: a possible role of sun-induced vitamin D. Br J Cancer 93(5):571–574. doi:10.1038/sj.bjc.6602722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Moan J, Porojnicu AC, Robsahm TE, Dahlback A, Juzeniene A, Tretli S, Grant W (2005) Solar radiation, vitamin D and survival rate of colon cancer in Norway. J Photochem Photobiol B 78(3):189–193. doi:10.1016/j.jphotobiol.2004.11.004

    Article  CAS  PubMed  Google Scholar 

  34. Zhou W, Heist RS, Liu G, Neuberg DS, Asomaning K, Su L, Wain JC, Lynch TJ, Giovannucci E, Christiani DC (2006) Polymorphisms of vitamin D receptor and survival in early-stage non-small cell lung cancer patients. Cancer Epidemiol Biomar 15(11):2239–2245. doi:10.1158/1055-9965.EPI-06-0023

    Article  CAS  Google Scholar 

  35. Skinner HG, Schwartz GG (2008) Serum calcium and incident and fatal prostate cancer in the National Health and Nutrition Examination Survey. Cancer Epidemiol Biomar 17(9):2302–2305. doi:10.1158/1055-9965.EPI-08-0365

    Article  CAS  Google Scholar 

  36. Skinner HG, Schwartz GG (2009) A prospective study of total and ionized serum calcium and fatal prostate cancer. Cancer Epidemiol Biomar 18(2):575–578

    Article  CAS  Google Scholar 

  37. Van Hemelrijck M, Hermans R, Michaelsson K, Melvin J, Garmo H, Hammar N, Jungner I, Walldius G, Holmberg L (2012) Serum calcium and incident and fatal prostate cancer in the Swedish AMORIS study. Cancer Causes Control 23(8):1349–1358. doi:10.1007/s10552-012-0015-x

    Article  PubMed  Google Scholar 

  38. Halthur C, Johansson AL, Almquist M, Malm J, Gronberg H, Manjer J, Dickman PW (2009) Serum calcium and the risk of prostate cancer. Cancer Causes Control 20(7):1205–1214

    Article  CAS  PubMed  Google Scholar 

  39. Kristal AR, Cohen JH, Qu P, Stanford JL (2002) Associations of energy, fat, calcium, and vitamin D with prostate cancer risk. Cancer Epidemiol Biomar 11(8):719–725

    CAS  Google Scholar 

  40. Gao X, LaValley MP, Tucker KL (2005) Prospective studies of dairy product and calcium intakes and prostate cancer risk: a meta-analysis. J Natl Cancer I 97(23):1768–1777. doi:10.1093/jnci/dji402

    Article  CAS  Google Scholar 

  41. Giovannucci E, Liu Y, Stampfer MJ, Willett WC (2006) A prospective study of calcium intake and incident and fatal prostate cancer. Cancer Epidemiol Biomar 15(2):203–210. doi:10.1158/1055-9965.EPI-05-0586

    Article  CAS  Google Scholar 

  42. Snowdon DA, Phillips RL, Choi W (1984) Diet, obesity, and risk of fatal prostate cancer. Am J Epidemiol 120(2):244–250

    CAS  PubMed  Google Scholar 

  43. Cole DE, Peltekova VD, Rubin LA, Hawker GA, Vieth R, Liew CC, Hwang DM, Evrovski J, Hendy GN (1999) A986S polymorphism of the calcium-sensing receptor and circulating calcium concentrations. Lancet 353(9147):112–115

    Article  CAS  PubMed  Google Scholar 

  44. Murray RM, Grill V, Crinis N, Ho PW, Davison J, Pitt P (2001) Hypocalcemic and normocalcemic hyperparathyroidism in patients with advanced prostatic cancer. J Clin Endocrinol Metab 86(9):4133–4138

    Article  CAS  PubMed  Google Scholar 

  45. Age JL (2010) Dödsorsaksstatistik. http://www.socialstyrelsen.se/publikationer2010/2010-4-33

  46. Barlow L, Westergren K, Holmberg L, Talback M (2009) The completeness of the Swedish Cancer Register: a sample survey for year 1998. Acta Oncol 48(1):27–33

    Article  PubMed  Google Scholar 

  47. Johansson LA, Bjorkenstam C, Westerling R (2009) Unexplained differences between hospital and mortality data indicated mistakes in death certification: an investigation of 1,094 deaths in Sweden during 1995. J Clin Epidemiol 62(11):1202–1209. doi:10.1016/j.jclinepi.2009.01.010

    Article  PubMed  Google Scholar 

  48. Hofmann JN, Yu K, Horst RL, Hayes RB, Purdue MP (2010) Long-term variation in serum 25-hydroxyvitamin D concentration among participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cancer Epidemiol Biomar 19(4):927–931. doi:10.1158/1055-9965.EPI-09-1121

    Article  CAS  Google Scholar 

  49. van Schoor NM, Knol DL, Deeg DJ, Peters FP, Heijboer AC, Lips P (2014) Longitudinal changes and seasonal variations in serum 25-hydroxyvitamin D levels in different age groups: results of the Longitudinal Aging Study Amsterdam. Osteoporos Int 25(5):1483–1491. doi:10.1007/s00198-014-2651-3

    PubMed  Google Scholar 

  50. Ricos C, Alvarez V, Cava F, Garcia-Lario JV, Hernandez A, Jimenez CV, Minchinela J, Perich C, Simon M (1999) Current databases on biological variation: pros, cons and progress. Scand J Clin Lab Investig 59(7):491–500

    Article  CAS  Google Scholar 

  51. Gallagher SK, Johnson LK, Milne DB (1989) Short-term and long-term variability of indices related to nutritional status. I: Ca, Cu, Fe, Mg, and Zn. Clin Chem 35(3):369–373

    CAS  PubMed  Google Scholar 

  52. Ankrah-Tetteh T, Wijeratne S, Swaminathan R (2008) Intraindividual variation in serum thyroid hormones, parathyroid hormone and insulin-like growth factor-1. Ann Clin Biochem 45(Pt 2):167–169

    Article  CAS  PubMed  Google Scholar 

  53. Viljoen A, Singh DK, Twomey PJ, Farrington K (2008) Analytical quality goals for parathyroid hormone based on biological variation. Clin Chem Lab Med 46(10):1438–1442

    Article  CAS  PubMed  Google Scholar 

  54. Cantarutti A, Bonn SE, Adami HO, Gronberg H, Bellocco R, Balter K (2015) Body mass index and mortality in men with prostate cancer. Prostate 75(11):1129–1136. doi:10.1002/pros.23001

    Article  PubMed  Google Scholar 

  55. Brock K, Huang WY, Fraser DR, Ke L, Tseng M, Stolzenberg-Solomon R, Peters U, Ahn J, Purdue M, Mason RS, McCarty C, Ziegler RG, Graubard B (2010) Low vitamin D status is associated with physical inactivity, obesity and low vitamin D intake in a large US sample of healthy middle-aged men and women. J Steroid Biochem 121(1–2):462–466. doi:10.1016/j.jsbmb.2010.03.091

    Article  CAS  Google Scholar 

  56. Gerdhem P, Ringsberg KA, Obrant KJ, Akesson K (2005) Association between 25-hydroxy vitamin D levels, physical activity, muscle strength and fractures in the prospective population-based OPRA Study of Elderly Women. Osteoporosis Int 16(11):1425–1431. doi:10.1007/s00198-005-1860-1

    Article  CAS  Google Scholar 

  57. Palacios C, Gonzalez L (2014) Is vitamin D deficiency a major global public health problem? J Steroid Biochem 144(Pt A):138–145. doi:10.1016/j.jsbmb.2013.11.003

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the Swedish Research Council (K2007-69X-20487-01-3), the Ernhold Lundström Foundation, the Einar and Inga Nilsson Foundation, Malmö University Hospital Cancer Research Fund, Malmö University Hospital Funds and Donations, the Crafoord Foundation, Region Skåne, the Mossfelt Foundation, Fundacion Federico S.A, the Swedish Cancer Society (CAN 2006/1554), and the Gunnar Nilsson Cancer Foundation.

Authors contribution

JB participated in the design of the study, collected the data, performed the statistical analysis, and drafted the manuscript. MA participated in the design of the study and helped to draft the manuscript. Jonas M participated in the design of the study and helped to draft the manuscript. Johan M participated in the design of the study and helped to draft the manuscript. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Urology, Skåne University Hospital Malmö, Lund University, 205 02, Malmö, Sweden

    Johan Brändstedt

  2. Department of Surgery, Skåne University Hospital Lund, Lund University, Malmö, Sweden

    Martin Almquist

  3. Department of Plastic Surgery, Skåne University Hospital Malmö, Lund University, Malmö, Sweden

    Jonas Manjer

  4. Department of Translational Medicine, Section for Clinical Chemistry, Skåne University Hospital, Lund University, Malmö, Sweden

    Johan Malm

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  1. Johan Brändstedt
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Correspondence to Johan Brändstedt.

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Brändstedt, J., Almquist, M., Manjer, J. et al. Vitamin D, PTH, and calcium in relation to survival following prostate cancer. Cancer Causes Control 27, 669–677 (2016). https://doi.org/10.1007/s10552-016-0740-7

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