Prevention of Early Postmenopausal Bone Loss With Lactobacillus Reuteri

Study Overview
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Brief Summary
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This study evaluates the effect of two different doses of Lactobacillus reuteri ATCC PTA 6475 (L.reuteri 6475) on bone loss in early postmenopausal women. One third of the participants will be randomised to the lower dose, one third to the higher dose and one third to placebo.

Detailed Description
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We have previously shown that daily supplementation of the probiotic Lactobacillus reuteri ATCC PTA 6475 (10E10 colony-forming units (CFU)) was able to reduce bone loss over 12 months in 76-year-old women compared to placebo. It is not known if the probiotic is effective over longer time periods or if the effect is dose-dependent. The aim of this study is to investigate if two different doses of Lactobacillus reuteri ATCC PTA 6475 (total daily dose of either 1x10E9 or 1x10E10 CFU/day) can prevent or reduce bone loss, compared to placebo, in early (1-4 years since last menses) postmenopausal women over 24 months. All women will receive 400 IU of vitamin D (cholecalciferol) per day. Changes in bone mineral density, bone geometry and microstructure will be measured using dual x-ray absorptiometry and high resolution peripheral computed tomography.

Official Title
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Prevention of Early Postmenopausal Bone Loss With Lactobacillus Reuteri - A Randomized, Placebo-Controlled, Single Centre Clinical Trial

Conditions
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Postmenopausal Osteoporosis

Intervention / Treatment
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* Dietary Supplement: Lactobacillus reuteri ATCC PTA 6475 (L. reuteri 6475)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal women, 45 years or older, within 1-4 years from their last menses. Vitamin D levels above 25 nmol/L. Signed informed consent. Stated availability throughout the entire study period. Ability to understand study instructions and willingness to adhere to the protocol. Exclusion Criteria: Bone mineral density of < -2.5 combined with a fracture risk assessment tool (FRAX) score of 20% or higher for major osteoporotic fracture. Severe osteoporosis, defined as bone mineral density of < -3.0 in either the total hip, femur neck or lumbar spine L1-L4. Vertebral fracture (grade II or III) diagnosed using lateral spine imaging with DXA. Untreated hyperthyroidism or hyperthyroidism within the last 5 years. Known untreated hyperparathyroidism. Rheumatoid arthritis. Diagnosed with disease causing secondary osteoporosis, including chronic obstructive pulmonary disease, inflammatory bowel disease, celiac disease, or diabetes mellitus. Recently diagnosed malignancy (within the last 5 years). Oral corticosteroid use. Previous (within the last 5 years) use of antiresorptive therapy, including systemic hormone therapy (estrogen), bisphosphonates, strontium ranelate or denosumab. Systemic skeletal disease (including e.g. Paget's disease and osteogenesis imperfecta). Any systemic disease that could affect bone loss, as judged by the investigator. Use of teriparatide (current or during the last 3 years). Participation in other clinical trials. Current antibiotics treatment or within the last 2 months prior to inclusion. Current and within the past 2 months use of probiotic supplement Vitamin D deficiency (25-OH vitamin D<25 nmol/l) Hypo- or hypercalcemia. Osteosynthesis materials in both lower legs (tibia).

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: L. reuteri Low Dose<br>Capsules of freeze-dried L. reuteri 6475 of 5x10E8 colony-forming units (CFU) mixed with maltodextrin powder and 200 IU of cholecalciferol, taken twice daily for 24 months, yielding a total dose of either 1x10E9 L.reuteri CFU and 400 IU of cholecalciferol per day. | Dietary Supplement: Lactobacillus reuteri ATCC PTA 6475 (L. reuteri 6475)<br>* L.reuteri high or low dose with cholecalciferol compared to cholecalciferol only.<br>|
| Active Comparator: L. reuteri High Dose<br>Capsules of freeze-dried L. reuteri 6475 of 5x10E9 colony-forming units (CFU) mixed with maltodextrin powder and 200 IU of cholecalciferol, taken twice daily for 24 months, yielding a total daily dose of 1x10E10 L.reuteri CFU and 400 IU of cholecalciferol per day. | Dietary Supplement: Lactobacillus reuteri ATCC PTA 6475 (L. reuteri 6475)<br>* L.reuteri high or low dose with cholecalciferol compared to cholecalciferol only.<br>|
| Placebo Comparator: Placebo<br>Placebo product identical to the active product (L. reuteri) in taste and appearance but without the active component, orally twice daily, for 24 months.The placebo product contains 200 IU cholecalciferol per dose, yielding a total dose of cholecalciferol of 400 IU per day. | Dietary Supplement: Lactobacillus reuteri ATCC PTA 6475 (L. reuteri 6475)<br>* L.reuteri high or low dose with cholecalciferol compared to cholecalciferol only.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total tibia volumetric bone mineral density | Measured using high resolution peripheral computed tomography (HRpQCT), relative change 0-24 months | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Areal bone mineral density (aBMD) at the lumbar spine | Measured using dual x-ray absorptiometry (DXA), relative change 0-24 months and 0-12 months | 24 months | 
| Areal BMD of the total hip (DXA) | Measured using DXA, relative change 0-24 months and 0-12 months | 0-24 months and 0-12 months | 
| Tibia trabecular bone volume fraction | Measured using HRpQCT, relative change 0-24 months and 0-12 months | 0-24 months and 0-12 months | 
| Tibia cortical area | Measured using HRpQCT, relative change 0-24 months and 0-12 months | 0-24 months and 0-12 months | 
| Tibia cortical volumetric BMD | Measured using HRpQCT, relative change 0-24 months and 0-12 months | 0-24 months and 0-12 months | 
| Total tibia volumetric bone mineral density | Measured using HRpQCT, relative change 0-12 months | 12 months | 
| Blood bone formation marker procollagen type 1N propeptide (P1NP) | Relative change 0-24 months and 0-12 months | 0-24 months and 0-12 months | 
| Blood bone resorption marker C-terminal cross-linking telopeptide of type I collagen (CTX) | Relative change 0-24 months and 0-12 months | 0-24 months and 0-12 months | 
| Fecal calprotectin | Relative change 0-24 months and 0-12 months | 0-24 months and 0-12 months | 
| Fecal lipocalin-2 | Relative change 0-24 months and 0-12 months | 0-24 months and 0-12 months | 
| Serum butyrate concentration | Relative change 0-24 months and 0-12 months | 0-24 months and 0-12 months | 
| Serum Wnt10b concentration | Relative change 0-24 months and 0-12 months | 0-24 months and 0-12 months |