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

• ClinicalTrials.gov Identifier: NCT02422082
• Recruitment Status: Completed
• First Posted: April 21, 2015
• Last Update Posted: April 18, 2018
• Sponsor: Sahlgrenska University Hospital, Sweden
• Collaborator: BioGaia AB
• Information provided by (Responsible Party): Mattias Lorentzon, Sahlgrenska University Hospital, Sweden

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Osteopenia	Dietary Supplement: L. reuteri; Dietary Supplement: Placebo	Not Applicable

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effect of Lactobacillus Reuteri ATCC PTA 6475 on Volumetric Bone Mineral Density in Patients With Osteopenia
• Actual Study Start Date: May 8, 2015
• Actual Primary Completion Date: September 15, 2017
• Actual Study Completion Date: December 1, 2017

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: L. reuteri; 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; Dietary supplementation with L. reuteri twice daily for 12 months; Other Name: Lactobacillus reuteri ATCC PTA 6475
Placebo Comparator: Placebo; 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; Dietary supplementation with placebo twice daily for 12 months

Outcome Measures

Primary Outcome Measures :

1. Total tibia volumetric bone mineral density [ Time Frame: 12 months ]
   Change in percent in total tibia volumetric bone mineral density compared to placebo group after 1 year of dietary supplementation with L. reuteri

Secondary Outcome Measures :

1. Trabecular volumetric bone mineral density [ Time Frame: 12 months ]
   Change in percent in trabecular volumetric bone mineral density compared to placebo group after 1 year of dietary supplementation with L. reuteri
2. Cortical volumetric bone mineral density [ Time Frame: 12 months ]
   Change in percent in cortical volumetric bone mineral density compared to placebo group after 1 year of dietary supplementation with L. reuteri
3. Cortical thickness [ Time Frame: 12 months ]
   Change in percent in cortical thickness compared to placebo group after 1 year of dietary supplementation with L. reuteri
4. Cortical porosity [ Time Frame: 12 months ]
   Change in percent in cortical porosity compared to placebo group after 1 year of dietary supplementation with L. reuteri
5. Areal bone mineral density [ Time Frame: 12 months ]
   Change in percent in areal bone mineral density compared to placebo group after 1 year of dietary supplementation with L. reuteri
6. Bone material strength index [ Time Frame: 12 months ]
   Change in percent in bone material strength index compared to placebo group after 1 year of dietary supplementation with L. reuteri
7. Blood pressure [ Time Frame: 12 months ]
   Change in percent in blood pressure compared to placebo group after 1 year of dietary supplementation with L. reuteri
8. Change in gut microbiota composition [ Time Frame: 3-12 months ]
   Change in percent in gut microbiota composition compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
9. Ultrasensitive C-reactive protein [ Time Frame: 3-12 months ]
   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
10. Interleukin-10 [ Time Frame: 3-12 months ]
    Change in percent in interleukin-10 in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
11. Interleukin-17 [ Time Frame: 3-12 months ]
    Change in percent in interleukin-17 in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
12. Tumor-necrosis factor-alpha [ Time Frame: 3-12 months ]
    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
13. Tartrate-resistent alkaline phosphatase 5b [ Time Frame: 3-12 months ]
    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
14. Cross-linked N-terminal telopeptide [ Time Frame: 3-12 months ]
    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
15. Bone-specific alkaline phosphatase [ Time Frame: 3-12 months ]
    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
16. Receptor activator of nuclear factor kappa B (RANK) [ Time Frame: 3-12 months ]
    Change in percent in RANK in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
17. Receptor activator of nuclear factor kappa B ligand (RANK-ligand) [ Time Frame: 3-12 months ]
    Change in percent in RANK-ligand in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
18. Osteocalcin [ Time Frame: 3-12 months ]
    Change in percent in osteocalcin in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
19. Blood glucose [ Time Frame: 3-12 months ]
    Change in percent in blood glucose compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
20. Haemoglobin A1C [ Time Frame: 3-12 months ]
    Change in percent in haemoglobin A1C compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
21. Apolipoprotein A1 (ApoA1) [ Time Frame: 3-12 months ]
    Change in percent in ApoA1 compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
22. Apolipoprotein B (ApoB) [ Time Frame: 3-12 months ]
    Change in percent in ApoB compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
23. Cholesterol [ Time Frame: 3-12 months ]
    Change in percent in cholesterol compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
24. High density lipoprotein (HDL) [ Time Frame: 3-12 months ]
    Change in percent in HDL compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
25. Low density lipoprotein (LDL) [ Time Frame: 3-12 months ]
    Change in percent in LDL compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
26. Triglycerides [ Time Frame: 3-12 months ]
    Change in percent in triglycerides compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
27. Oxytocin [ Time Frame: 3-12 months ]
    Change in percent in oxytocin in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
28. Estradiol [ Time Frame: 3-12 months ]
    Change in percent in estradiol in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
29. Leptin [ Time Frame: 3-12 months ]
    Change in percent in leptin in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
30. Adiponectin [ Time Frame: 3-12 months ]
    Change in percent in adiponectin in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
31. Testosterone [ Time Frame: 3-12 months ]
    Change in percent in testosterone in serum compared to placebo after 3, 6, 9, and 12 months of dietary supplementation with L. reuteri
32. Lean mass [ Time Frame: 12 months ]
    Change in percent in lean mass compared to placebo after 12 months of dietary supplementation with L. reuteri
33. Fat mass [ Time Frame: 12 months ]
    Change in percent in fat mass compared to placebo after 12 months of dietary supplementation with L. reuteri

Eligibility Criteria

• Ages Eligible for Study: 75 Years to 80 Years (Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

Sweden

Geriatric Medicine, Mölndal Hospital

Mölndal, Västra Götaland, Sweden, 43180

Sponsors and Collaborators

Sahlgrenska University Hospital, Sweden

BioGaia AB

Investigators

• Principal Investigator: Mattias Lorentzon, MD, PhD; Dept Geriatrics, Sahlgrenska University Hospital

More Information

Publications:

Adams MR, Marteau P. On the safety of lactic acid bacteria from food. Int J Food Microbiol. 1995 Oct;27(2-3):263-4.

Reid G, Kim SO, Köhler GA. Selecting, testing and understanding probiotic microorganisms. FEMS Immunol Med Microbiol. 2006 Mar;46(2):149-57. Review.

Britton RA, Irwin R, Quach D, Schaefer L, Zhang J, Lee T, Parameswaran N, McCabe LR. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J Cell Physiol. 2014 Nov;229(11):1822-30. doi: 10.1002/jcp.24636.

McCabe LR, Irwin R, Schaefer L, Britton RA. Probiotic use decreases intestinal inflammation and increases bone density in healthy male but not female mice. J Cell Physiol. 2013 Aug;228(8):1793-8. doi: 10.1002/jcp.24340.

Fåk F, Bäckhed F. Lactobacillus reuteri prevents diet-induced obesity, but not atherosclerosis, in a strain dependent fashion in Apoe-/- mice. PLoS One. 2012;7(10):e46837. doi: 10.1371/journal.pone.0046837. Epub 2012 Oct 9.

• Responsible Party: Mattias Lorentzon, Professor, Specialist physician, Sahlgrenska University Hospital, Sweden
• ClinicalTrials.gov Identifier: NCT02422082
• Other Study ID Numbers: LRvBMD
• First Posted: April 21, 2015
• Last Update Posted: April 18, 2018
• Last Verified: April 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mattias Lorentzon, Sahlgrenska University Hospital, Sweden:

Osteopenia; Lactobacillus reuteri; Volumetric bone mineral density

Additional relevant MeSH terms:

Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases