Profylactic Treatment for Patients in Risk Osteoporosis

Aim

• To estimate the effect of daily optimal efficacy dose (OED) of Jarlsberg cheese on BMD and bone markers to patients with Osteopeni (OP).
• To compare daily intake of Calsium (Ca) and vitamin D with and without OED of Jarlsberg on BMD and bone markers to OP patients.
• To compare daily intake of Ca and vitamin D with and without OED of Jarlsberg on Time-to-Osteoporotic (TTO) treatment is recommended.

Study population consists of OP-patients of post-menopausal women and men above 55 years of age. OP patients are defined as patients with a T-score below 0.0, but larger than -2.5.

Women in post-menopausal age have a daily OED Jarlsberg of 45 gram and men in the same age interval have a daily OED of 55 gram.

The cheese will be delivered in package of 250 gram with slices of 15.625gram. 45 gram represents 3 slices; 55 gram 4 slices. All the included patients will receive 20µg vitamin D and 1000 mg Ca. Half of the patients will receive vitamin D and Ca-tablets plus Jarlsberg cheese (Treatment group I) and other half only vitamin D and Ca-tablets (Treatment group II).

Design: The study will be performed as a randomized, single-blinded Norwegian multicentre trial with stratified semi-cross-over design with gender and site as stratification factors.

Patients included in the study will be allocated to one of the two treatment groups by block randomization with random block size between 2 and 6.

Main variables: The main response variable will be the change in Bone Mineral Density (BMD).The secondary variables will be total Osteocalcin (tOC), carboxylated osteocalcin (cOC), the osteocalcin ratio and different bone markers (BM). Additionally, the K2 vitamers MK-7, MK-8, MK-9, and MK-9(4H) will be used as explanatory variable together with the Interleukins IL-1β, IL6, IL8, IL10 and the Cytokines TNF-α, NF-ƙβ (RANK-L), OPG and TGF-β . Diet registration as controlling variables and HbA1C, Lipids, biochemical variables will be used as supporting variables. The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) will be used for registration of Adverse Events (AE) and toxicity score at every investigation visit.

Study procedure: Participants, who fulfil the inclusion criteria, do not meet any of the exclusion criteria and willing to give informed consent to participate will be included in a screening period of one week. During this screening week, all the possible participants will receive 40µg vitamin D and 500 mg Ca tablets per day, but asked not to eat Jarlsberg cheese.

BMD measurements will be taken at the start of the screening week. Patients with a negative BMD T-score >-2.5 will be included in the study. All demographic data, social factors, history of disease and vital signs will be recorded at baseline. The participating patients will be given a Diet-App on the web or mobile phone for registration of the daily food intake during four first consecutively days after baseline. Blood samples for measurements of Osteocalcin, BM and vitamin K will be taken fastening in the morning. Additionally, blood samples for measuring biochemical variables, HbA1C, Lipids, Interleukins and Cytokines, will be recorded. The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 used for measuring and classifying the tolerability and toxicity will be recorded as well. The patients will be given a compliance \& activity form and asked to write down the daily intake of treatment medicine, Jarlsberg cheese and hours of physical activities.

Clinical part: The patients will be allocated (1:1) to vitamin D + Ca-tablets ± OED of Jarlsberg cheese. All the participants will get new delivery of vitamin D and Ca-tablets every four weeks. The patients allocated to Jarlsberg will additionally receive Jarlsberg cheese. The patients will receive a compliance \& activity form and asked to fill in every day. All the patients meet for new visits at week4, week 16, and week 32. Patients allocated to only vitamin D + Ca tablets at baseline well additionally meet for visits at week 20 and week 48. At all these visits blood samples for measurement of Osteocalcin, BM and PTH will be drawn fasting in the morning, and concomitant medication and treatment compliance recorded.

The main visit will be performed every 16 weeks. New DXA screening will be performed. Patients obtaining a BMD T-score ≤ -2.5 will discontinue the study and switched to antiresorptive treatment plus daily OED of Jarlsberg cheese. The daily food intake during four consecutively days will be recorded on the Diet-App. Blood samples for measurements of Osteocalcin, CTX-1, PINP, BALB and PTH will be drawn fastening in the morning at every visits. Furthermore, blood samples for measuring and biochemical variables, HbA1C and Lipids, will be recorded. The CTCAE will be recorded as well.After the first 16 weeks, the patients allocated to only Ca + vitamin D will additionally receive OED of Jarlsberg cheese out the study. The visit at Week 32 and Week 48 will be the last observation for the patients initially allocated to Jarlsberg and controls, respectively. In addition to the mentioned variables, blood samples for measurement of Interleukins and Cytokines will be performed. All the patients completed the study will be offered to continue the daily intake of OED Jarlsberg cheese. These patients will be followed up one year after the last visit with a new DXA and a blood sampling for measurements of Osteocalcin level and BM.

Sample size:

With a significance level of 5%, a power of 90% and a Clinically Relevant Difference (CRD) of one time the Standard Deviation in change of BMD, at least 24 patients in each group must finalize the study. With an expected drop-out rate of 25%, 30 patients in each group must be included.