Determination of maintenance Jarlsberg® cheese dose to keep the obtained serum osteocalcin level; a response surface pathway designed de-escalation dose study with individual starting values

Helge Einar Lundberg, Helge Holo, Trond Holand, Hans E. Fagertun, Stig Larsen

Abstract

Background: Daily maximum effective dose (MED) of Jarlsberg® increased the serum osteocalcin (tOC) level, vitamin K2 and affected the lipid pattern positively. The aim of the study was to estimate and verify a daily maintenance dose.

Methods: 12 healthy female volunteers (HV) were included in a de-escalation study after a six week run-in period on the daily MED of 57 g Jarlsberg® cheese. A 3-level within-patient response surface pathway (RSP) design with individual starting values was developed. Another 12 HVs were included in a new study with a six week run-in period on MED followed with six weeks on the estimated maintenance dose. All HVs were premenopausal female between 20 and 52 years of age. The main variable in the studies was the tOC level.

Results: tOC, cOC and the vitamin K2 variants increases significantly (p<0.01) during the run-in period on daily MED of Jarlsberg® in both studies. The maintenance daily dose was estimated to 45 g (95% CI: 38-52 g/day) and used in the new study. The tOC level was reduced from 19.8 ng/ml (95% CI: 12.0-27.6) obtained in the run-in period to 18.5 ng/ml (95% CI: 11.7-25.3) during the maintenance part. This represents a reduction of 6.6%. The sum of vitamin K2 variants changed from 0.58 ng/ml on MED of Jarlsberg® to 0.59 ng/ml (95% CI: 0.37-0.82) during the maintenance period.

Conclusions: Daily MED of Jarlsberg® cheese increases tOC, cOC and the vitamin K2 level. The maintenance Jarlsberg® dose was estimated to 45 g/day and verified as sufficient.

Keywords

Dose de-escalation, Increased osteocalcin level, Jarlsberg® cheese, Osteocalcin ratio, RSP-design, Vitamin K2

Full Text:

PDF

References

EFSA Panel on Dietetic Products, Nutrition and Allergies. Scientific Opinion on the substantiation of health claims related to vitamin K and maintenance of bone (ID 123, 127, 128, and 2879), blood coagulation (ID 124 and 126), and function of the heart and blood vessels (ID 124, 125 and 2880) pursuant to Article 13(1) of Regulation (EC) No 1924/2006. EFSA J. 2009;7(10):1228-47.

Gröber U, Reichrath J, Holick M, Kisters K. Vitamin K: an old vitamin in a new perspective. Dermato Endocrinol. 2014;6(1):968490.

Sato T, Schurgers LJ, Uenishi K. Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women. Nutrition J. 2012;11(1):93.

Schurgers LJ, Teunissen KJ, Hamulyak K, Knapen MH, Vik H, Vermeer C. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood. 2007;109(8):3279-83.

Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MHJ, Meer IMVD, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam study. J Nutr. 2004;134(11):3100-5.

Nimptsch K, Rohrmann S, Kaaks R, Linseisen J. Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg). Am J Clinic Nutr 2010;91(5):1348-58.

Manoury E, Jourdon K, Boyaval P, Fourcassie P. Quantitative measurement of vitamin K2 (menaquinones) in various fermented dairy products using a reliable high- performance liquid chromatography method. J Dairy Sci. 2013;96(3):1335-46.

Hojo K, Watanabe R, Mori T, Taketomo NJ. Quantitative measurement of tetrahydromena-quinone-9 in cheese fermented by Propioni-bacterium. J Dairy Sci. 2007;90(9):4078-83.

Dewi S, Kristiansen VM, Lindkær-Jensen S, Larsen S. Between a within-patient response surface pathway designs in dose-finding studies. Open Access J Clin Trials. 2014;6:63-74.

Holand T, Ellingsen K, Dewi S, Larsen S. Randomized response surface pathway design with odd response outcomes in a Latin Square designed study. Open Access J Clin Trials. 2017;9:1-10.

Larsen S, Holand T, Bjornaes K, Glomsrod E, Kaufmann J, Garberg TH, et al. randomized two-dimensional between-patient response surface pathway design with two interventional-and one response variable in estimating minimum efficacy dose. Int J Clin Trials. 2018;6(3):75-83.

Lundberg HE, Holand T, Holo H, Larsen S. Increased serum osteocalcin level and vitamin K status by daily cheese intake. Int J Clin Trials. 2020;7(2):55-65.

Holand T, Evensen Ø, Dewi S, Larsen S. Randomized response surface pathway design with skewed starting point and stochastic dose window. Int J Clin Trials. 2020;7(1):18-27.

Manoury E, Jourdon K, Boyaval P, Fourcassie P. Quantitative measurement of vitamin K2 (menaquinones) in various fermented dairy products using a reliable high- performance liquid chromatography method. J Dairy Sci. 2013;96(3):1335-46.

Altman DG. Practical statistics for medical research. London: Chapman and Hall. Wiley Online Lib. 1991;10(10):1635-6.

Agresti A. Categorical Data Analysis. 3rd ed. New Jersey: John Wiley and Sons; 2002.

Kleinbaum DG, Kupper LL, Muller KE, Nizam A. Applied regression analysis and other multivariable methods. CA: Duxbury Press Belmont; 1988.

Stylianou M, Flournoy N. Dose finding using the biased coin up‐and‐down design and isotonic regression. Biometrics. 2002;58(1):171-7.

Balley S, Karsenty G, Gundberg C, Vashishth D. Osteocalcin and osteopontin influence bone morphplogy and mechanical properties. Ann NY Acad Sci. 2017;1409(1):79-84.

Sokoll LJ, Sadowski JA. Comparison of biochemical indexes for assessing vitamin K nutritional status in a healthy adult population. Am J Clin Nutr. 1996;63:566-73.

Lees JS, Chapman FA, Witham MD, Jardine AG, Mark PB. Vitamin K status, supplementation and vascular disease: a systematic review and meta-analysis. Heart. 2019;105(12):938-45.

Halder M, Petsophonsakul P, Akbulut AC, Pavlic A, Bohan F, Anderson E, et al. Vitamin K: double bonds beyond coagulation insights into differences between Vitamin K1 and K2 in health and disease. Int J Mol Sci. 2019;20:896.

Azuma K, Ouchi Y, Inoue S. Vitamin K: Novel molecular mechanisms of action and its roles in Osteoporosis. 2014;14(1):1-7.

Atkins GJ, Welldon KJ, Wijenayaka AR, Bonewald LF, Findlay DM. Vitamin K promotes mineralization, osteoblast-to-osteocyte transition, and an anticatabolic phenotype by {gamma}-carboxylation-dependent and independent mechanisms Am J Physiol Cell Physiol, 2009;297:1358-67.

Liu X, Liu Y, Mathers J, Cameron M, Levinger I, Yeap BB, et al. Osteocalcin and measures of adiposity: a systematic review and meta-analysis of observational studies. Archiv Osteoporosis. 2020;15(1):145.

DiRenzo L, Gualtieri P, Pivari F, Soldati L, Attinà A, Cinelli G, et al. Eating habits and lifestyle changes during COVID-19 lockdown: an Italian survey. J Transl Med. 2020;18(1):229.