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

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.

Study Overview

• Status: Completed
• Conditions: Osteopenia
• Intervention / Treatment: Dietary supplement: L. reuteri; Dietary supplement: Placebo

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 Type: Interventional
• Enrollment (Actual): 90
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Sweden
  • Västra Götaland
    • Mölndal, Västra Götaland, Sweden, 43180
      • Geriatric Medicine, Mölndal Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 75 years to 80 years (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sahlgrenska University Hospital, Sweden
• Collaborators: BioGaia AB
• Investigators: Principal Investigator: Mattias Lorentzon, MD, PhD, Dept Geriatrics, Sahlgrenska University Hospital

Publications and helpful links

General 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. doi: 10.1016/0168-1605(95)00067-t. No abstract available.
• Reid G, Kim SO, Kohler GA. Selecting, testing and understanding probiotic microorganisms. FEMS Immunol Med Microbiol. 2006 Mar;46(2):149-57. doi: 10.1111/j.1574-695X.2005.00026.x.
• 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.
• Fak F, Backhed 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2015
• Primary Completion (Actual): September 15, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: April 10, 2015
• First Submitted That Met QC Criteria: April 16, 2015
• First Posted (Estimate): April 21, 2015

Study Record Updates

• Last Update Posted (Actual): April 18, 2018
• Last Update Submitted That Met QC Criteria: April 17, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Osteopenia; Lactobacillus reuteri; Volumetric bone mineral density
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic
• Other Study ID Numbers: LRvBMD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No