The Effect of Lactobacillus Reuteri ATCC PTA 6475 on Volumetric Bone Mineral Density in Patients With Osteopenia

Study Overview
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Brief Summary
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Lactobacillus reuteri (L. reuteri) has been widely studied in clinical trials and has probiotic, health-promoting effects in both adults and children, and is safe for human consumption. Animal models indicate that treatment with L. reuteri has positive effects on bone metabolism and bone density. In other animal models of diabetes and the metabolic syndrome, positive effects on blood glucose and weight have been reported. The present double-blind, placebo-controlled, randomized study is designed to investigate if dietary supplementation with L. reuteri twice daily for 12 months has any effect on bone density, body composition, inflammation, or metabolic and endocrine markers in elderly women with osteopenia.

Detailed Description
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The role of the gut microbes for human health has gained considerable interest in recent years. Lactobacillus reuteri (L.reuteri) is a naturally occurring bacterial species in the human gut. L. reuteri has been widely studied in clinical trials of adults and children and treatment with L. reuteri is safe and is associated with health-promoting effects in humans. In animal models, L. reuteri has anti-inflammatory effects and in ovariectomized mice supplementation with L. reuteri partly prevented the bone loss induced by estrogen deficiency. Furthermore, both bone density and bone formation increased in male mice in another mice model. In mice with medically induced diabetes mellitus, L. reuteri reduced blood glucose and in a mouse model mimicking the metabolic syndrome, L. reuteri prevented diet-induced obesity. The present study is a double-blind, placebo-controlled, randomized, study in 90 elderly women with osteopenia recruited from the population. These women will be treated with L. reuteri or placebo orally twice daily for 12 months. The effects on bone will be investigated with dual energy x-ray absorptiometry, high-resolution peripheral quantitative computed tomography, and bone turnover markers. Hormones and markers of inflammation and metabolism will be followed as well as changes in the gut microbiota composition.

Official Title
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The Effect of Lactobacillus Reuteri ATCC PTA 6475 on Volumetric Bone Mineral Density in Patients With Osteopenia

Conditions
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Osteopenia

Intervention / Treatment
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* Dietary Supplement: L. reuteri
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: bone mineral density T-score less than -1 but more than -2.5 in the total hip or femoral neck or lumbar spine (L1-L4) by dual energy x-ray absorptiometry signed informed consent stated availability throughout the entire study period mental ability to understand and willingness to fulfill all the details of the protocol Exclusion Criteria: untreated hyperthyroidism rheumatoid arthritis diagnosed with disease causing secondary osteoporosis within the last year, including primary hyperparathyroidism, chronic obstructive pulmonary disease, inflammatory bowel disease, celiac disease, or diabetes recently diagnosed malignancy (within the last 5 years) per oral corticosteroid use use of antiresorptive therapy, including systemic hormone replacement therapy, bisphosphonates, strontium ran elate use of teriparatide (current or during the last 3 years) participation in other clinical interventional trials use of antibiotics within 2 months preceding the inclusion

Ages Eligible for Study
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Minimum Age: 75 Years
Maximum Age: 80 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<br>Lactobacillus reuteri (L. reuteri) ATCC PTA 6475 at a dose of 5 000 000 000 CFU as a powder in a stick-pack, orally twice daily (morning and evening) yielding a total daily dose of 10 000 000 000 CFU per day, for 12 months. | Dietary Supplement: L. reuteri<br>* Dietary supplementation with L. reuteri twice daily for 12 months<br>* Other names: Lactobacillus reuteri ATCC PTA 6475;|
| 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 12 months. | Dietary Supplement: Placebo<br>* Dietary supplementation with placebo twice daily for 12 months<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 | Change in percent in total tibia volumetric bone mineral density compared to placebo group after 1 year of dietary supplementation with L. reuteri | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trabecular volumetric bone mineral density | Change in percent in trabecular volumetric bone mineral density compared to placebo group after 1 year of dietary supplementation with L. reuteri | 12 months | 
| Cortical volumetric bone mineral density | Change in percent in cortical volumetric bone mineral density compared to placebo group after 1 year of dietary supplementation with L. reuteri | 12 months | 
| Cortical thickness | Change in percent in cortical thickness compared to placebo group after 1 year of dietary supplementation with L. reuteri | 12 months | 
| Cortical porosity | Change in percent in cortical porosity compared to placebo group after 1 year of dietary supplementation with L. reuteri | 12 months | 
| Areal bone mineral density | Change in percent in areal bone mineral density compared to placebo group after 1 year of dietary supplementation with L. reuteri | 12 months | 
| Bone material strength index | Change in percent in bone material strength index compared to placebo group after 1 year of dietary supplementation with L. reuteri | 12 months | 
| Blood pressure | Change in percent in blood pressure compared to placebo group after 1 year of dietary supplementation with L. reuteri | 12 months | 
| Change in gut microbiota composition | Change in percent in gut microbiota composition compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Ultrasensitive C-reactive protein | Change in percent in ultrasensitive C-reactive protein in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Interleukin-10 | Change in percent in interleukin-10 in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Interleukin-17 | Change in percent in interleukin-17 in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Tumor-necrosis factor-alpha | Change in percent in tumor-necrosis factor-alpha in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Tartrate-resistent alkaline phosphatase 5b | Change in percent in tartrate-resistent alkaline phosphatase 5b in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Cross-linked N-terminal telopeptide | Change in percent in cross-linked N-terminal telopeptide in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Bone-specific alkaline phosphatase | Change in percent in bone-specific alkaline phosphatase in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Receptor activator of nuclear factor kappa B (RANK) | Change in percent in RANK in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Receptor activator of nuclear factor kappa B ligand (RANK-ligand) | Change in percent in RANK-ligand in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Osteocalcin | Change in percent in osteocalcin in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Blood glucose | Change in percent in blood glucose compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Haemoglobin A1C | Change in percent in haemoglobin A1C compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Apolipoprotein A1 (ApoA1) | Change in percent in ApoA1 compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Apolipoprotein B (ApoB) | Change in percent in ApoB compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Cholesterol | Change in percent in cholesterol compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| High density lipoprotein (HDL) | Change in percent in HDL compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Low density lipoprotein (LDL) | Change in percent in LDL compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Triglycerides | Change in percent in triglycerides compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Oxytocin | Change in percent in oxytocin in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Estradiol | Change in percent in estradiol in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Leptin | Change in percent in leptin in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Adiponectin | Change in percent in adiponectin in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Testosterone | Change in percent in testosterone in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri | 3-12 months | 
| Lean mass | Change in percent in lean mass compared to placebo after 12 months of dietary supplementation with L. reuteri | 12 months | 
| Fat mass | Change in percent in fat mass compared to placebo after 12 months of dietary supplementation with L. reuteri | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lactobacillus reuteri, Osteopenia, Volumetric bone mineral density