Supplementation With Lactobacillus Reuteri Reduces Bone Loss in Older Women With Low Bone Mineral Density


Osteoporosis is characterized by deteriorating bone microstructure and a loss of bone density that result in increased fracture risk and reduced bone strength. Inflammation may further complicate osteoporosis as it leads to accelerated bone loss due to osteoclastogenesis stimulation and increased bone resorption.1

Fractures resulting from osteoporosis are quite common in women and men 50 years and older and are usually caused by low-energy trauma. The risk of osteoporotic fractures can be reduced through pharmacologic intervention; however, adherence rates to medication remain low, potentially due to fear of rare adverse effects.1

The human gastrointestinal (GI) tract is colonized with several trillion microbial cells that have been shown to play an important role in a multitude of physiologic functions. Disruption in GI microbial flora homeostasis has been implicated in a variety of diseases such as obesity, diabetes mellitus, and certain autoimmune diseases. It has been demonstrated that in mice, the gut microbiome modulates bone homeostasis via the regulation of osteoclast formation and immune system function. These results suggest that modulating the microbiome and inflammatory tone may provide a way to regulate bone mass and prevent osteoporosis.1

Lactobacillus reuteri ATCC PTA 6475 (L. reuteri 6475) is an indigenous microbe within the human GI tract; it may have several beneficial effects, including anti-inflammatory properties. In female mice with active inflammation, L. reuteri 6475 supplementation was associated with increases in trabecular bone density, and supplementation has also been shown to reduce ovariectomy-induced bone loss in mice. The effect of L. reuteri 6475 supplementation on the human skeleton is not known.1

The Effects of Lactobacillus reuteri on Bone in Older Women (ELBOW) study was designed to evaluate whether daily supplementation with L. reuteri 6475 reduced bone loss in older women with low bone mineral density (BMD).1

Study Design

ELBOW was a 12-month, randomized, double-blind, placebo-controlled trial conducted at a single health center in Mölndal, Sweden. Eligible patients were recruited from a larger population-based study, were 75 to 80 years of age, and had a T-score of —1 standard deviation or less for BMD at the spine, hip, or femoral neck. Patients were excluded from participation if they had osteoporosis (defined as T-score <–2.5 at the spine or total hip); certain comorbidities, including untreated hyperthyroidism, rheumatoid arthritis, inflammatory bowel disease, celiac disease, or diabetes; or received antiresorptive therapy, glucocorticoids, or teriparatide within the last 3 years or antibiotics within the last 2 months.1

Eligible participants were randomized 1:1 to receive either placebo or L. reuteri 6475 at a dose of 5x109 colony-forming units (CFU) twice daily, yielding a total daily dose of 1x1010 CFU per day. Study participants were assessed every third month for the duration of the study.1

Bone microstructure and volumetric BMD (vBMD) in the distal tibia were analyzed at baseline and after 12 months using high-resolution peripheral quantitative computed tomography.1

The primary outcome in the ELBOW study was the relative change in tibia total vBMD after 12 months. Secondary outcomes included relative changes after 12 months in the following: areal BMD (measured at the hip and spine); trabecular bone volume fraction; cortical vBMD; cortical thickness; serum markers for bone turnover (N-terminal telopeptide and bone-specific alkaline phosphatase); serum markers for inflammation (C-reactive protein and tumor necrosis factor-alpha); serum glycated hemoglobin; and body composition (total fat and lean mass). Primary and secondary outcomes were analyzed for both the intent-to-treat (ITT; ie, all randomized subjects) and per protocol (PP; ie, all those who completed the study as instructed) populations.1


A total of 90 women were enrolled and randomized in the ELBOW study. Baseline demographics, general health characteristics, and BMD scores were well balanced between the study groups. Seventy patients completed the study (34 and 36 patients randomized to receive L. reuteri 6475 and placebo, respectively).1

As illustrated in the Table, supplementation with L. reuteri 6475 for 12 months resulted in reduced bone loss as evidenced by the mean relative change in tibia total vBMD.1 After 12 months, the mean relative change in tibia total vBMD was —0.83% (95% CI, –1.47% to –0.19%) among patients given L. reuteri 6475; it was —1.85% (95% CI, –2.64% to –1.07%) among those given placebo in the ITT population. The mean difference between the groups was 1.02% (95% CI, 0.02%-2.03%; adjusted P = .047). Similar results were observed in the PP population.1

There were no significant differences in the secondary outcomes in the ITT population. In the PP population, there was a significant reduction in trabecular bone volume fraction among patients in the L. reuteri 6475 group compared with those in the placebo group (—0.49% vs –1.29%; mean difference of 0.80%; adjusted P = .02). There were no other significant differences in secondary outcomes among the PP population.1

The occurrence of adverse events (AEs) was similar between the 2 groups, with 80% and 87% of patients randomized to L. reuteri 6475 and placebo, respectively, reporting AEs. The most common AEs reported in those given L. reuteri 6475 and placebo were changes in bowel habit (20% and 18%, respectively) and flatulence (11% in both groups). Treatment-related AEs occurred at a similar rate among the 2 study groups (40% vs 44% in the L. reuteri 6475 and placebo groups, respectively).1


In this trial, supplementation with L. reuteri 6475 for 12 months resulted in reduced bone loss in women 75 to 80 years of age with low bone density. Women given L. reuteri 6475 showed a reduction in total vBMD in the distal tibia that was nearly half as large as that observed in those given placebo. Additionally, the AE profiles were similar among the L. reuteri 6475 and placebo groups. Further studies are needed to evaluate the clinical usefulness of L. reuteri 6475 supplementation and to better understand the underlying mechanism of its benefit in reducing bone loss in older women with low BMD.1


1. Nilsson AG, Sundh D, Bäckhed F, Lorentzon M. Lactobacillus reuteri reduces bone loss in older women with low bone mineral density: a randomized, placebo-controlled, double-blind, clinical trial [published online June 21, 2018]. J Intern Med. doi: 10.1111/joim.12805.

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