Abstract
The recent recognition of the importance of the intestinal microbiome in host physiology has driven investigations of gut microbiome-directed therapeutics, with probiotics attracting increased attention in the treatment of a diversity of conditions. The application of probiotics has expanded beyond the treatment of intestinal tract disorders. Today, their capacity to treat a vast array of conditions arising also along the gut–bone axis is being studied. Therefore, in this study we have carried out a scoping literature review of the clinical trials evaluating the effect of probiotics in the treatment of bone fracture. In total, six articles were found for review, four randomized placebo-controlled trials on humans and two studies using animal models. Probiotics were found to have positive effects on fracture treatment. Probiotics were shown to improve not only bone regeneration but also decrease systemic inflammation and pain during conservative fracture treatment. However, this is a novel field and due to the limited number of studies only sparse conclusions can be made. Additional clinical trials on the possible role of probiotics in fracture treatment are necessary to fully evaluate their therapeutic potential.
Introduction
Omics technological breakthroughs contributed to the field of intestinal microbiome analysis over the past decade (Ng et al. 2023). The intestinal microbiome is a complex microbial community residing in the gastrointestinal tract which is in continuous interaction with the host regarding not only benefits for host intestinal health but all components of host physiology, the foremost being host metabolism and immunity (Heintz-Buschart & Wilmes 2018). Due to the recently discovered impact of the gut microbiome on host physiology in life sciences, the 21st century is being referred to as ‘the era of gut microbiome’. Recently, a great interest has developed in gut microbiome-directed therapeutics such as probiotics and prebiotics (Cunningham et al. 2021). Nowadays, the focus of potential probiotic application is more and more expanding from exclusively intestinal conditions to extraintestinal conditions (Kiousi et al. 2019). An interesting example of this trend is research on probiotic administration in bone health (McCabe et al. 2015).
Probiotics are defined as live microbial organisms when administered in adequate amounts, conferring a health benefit on the host (Hill et al. 2014). Due to the general safety profile and high tolerability of probiotics (Sanders et al. 2010), probiotic research and application has extended into different aspects of human health, such as bone health (Malmir et al. 2021).
A potential beneficiary effect of probiotics treatment on bone health has been established in clinical studies (Takimoto et al. 2018) but with inconsistent results (Sergeev et al. 2020). Probiotics have been found to increase bone mass density and prevent bone loss through various animal studies (Rizzoli & Biver 2020). Future research on this topic is warranted in the form of high-quality large-scale multicentric studies, since the effect of probiotic administration on bone health seems to be dependent on a plethora of internal and external factors (de Sire et al. 2022).
To the best of our knowledge no reviews on the topic of probiotic application in fracture treatment have been published. Since we detected a gap in knowledge, we decided to review the current literature on probiotic administration in bone fracture treatment. Bone fractures bear a great socioeconomic burden (Nazrun et al. 2014), and probiotics, if found effective, could be of importance as a safer, relatively low-cost support to conventional fracture treatment.
Materials and methods
A formal systematic review of clinical trials published on the electronic bibliographic databases PubMed and Cochrane was conducted. For the identification of relevant studies on the current topic a combination of medical subject headings and keywords was deployed. The search strategy included the following MeSH and non-MeSH terms and keywords: probiotic, probiotics, Lactobacillus, Bifidobacterium, fracture, bone fracture, and fracture treatment, fracture healing (Supplementary materials S1: Search strategy, see section on supplementary materials given at the end of this article). The search criterion was original research articles on animal and human studies (randomized and nonrandomized controlled trials, prospective observational studies, retrospective cohort studies, case–control studies) published in peer-reviewed journals up to August 2022. The search results were limited to English-language publications. To assess the impact of restricting the search string to English-language studies, the search was repeated with the language restriction removed. None of the new search results warranted full-text search based on their title and abstracts. Therefore, restricting the search parameters to English-language publications did not alter the current findings. Only research articles that reported on outcomes related to probiotic administration in fracture treatment in animal or subjects were included. Articles were excluded if the probiotic administration was not associated with fracture treatment but for other bone health conditions (osteoporosis). Full text of all reports were available. Each search result was independently reviewed by all authors. This review was conducted in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines (Page et al. 2021). The results are presented as a narrative review of the available research material assessing the potential effects of probiotic administration in bone fracture treatment. Given that research in this area is in its infancy, only a small number of scientific articles are available, and in addition, because these are rather heterogeneous studies with specificities in experimental design, there are still no meta-analyses available. The quality of the included trials was independently assessed as ‘low’ risk of bias, ‘some concerns’, or ‘high’ risk of bias using the Cochrane Collaboration Revised Risk of Bias tool RoB 2.0 (Sterne et al. 2019).
Results
The literature search on PubMed and Cochrane utilizing the search strategy disclosed earlier yielded a total of 85 articles, of which six eligible studies (Lei et al. 2016, Guo et al. 2018, Lei et al. 2018, Zhang et al. 2019, Liu et al. 2020, Roberts et al. 2020) with accessible full text of the respective article presented data for the application of probiotics in bone fracture treatment. Details of the selection process are shown in the PRISMA flow diagram (Fig. 1).
PRISMA (Page et al. 2021) flow diagram depicting study selection.
Citation: Microbiota and Host 1, 1; 10.1530/MAH-23-0003
Study quality assessment
Risk of bias in randomized trials was applied (RoB-2) to assess study quality (Sterne et al. 2019), and the results were visualized using the robvis visualization tool (Fig. 2). All studies had an overall low risk of bias, with some concerns regarding outcome measurement.
Assesment of the risk of bias of each study using RoB-2.
Citation: Microbiota and Host 1, 1; 10.1530/MAH-23-0003
Probiotic trials for bone fracture treatment
The compounds included in the probiotic trials included the probiotic strains Lactobacillus casei strain Shirota and Bifidobacteriumadolescentis all possessing proven probiotic properties. Duration of probiotic administration ranged from 22 days to 1, 3, and 6 months.
To simplify the display of the results the studies’ characteristics are presented in Table 1.
Summary of the main outcomes of the RCT studies of probiotic intervention.
| Reference | Subjects, n | Females, n | Probiotic | Intervention duration | Type of fracture | Outcome measures | Effect | Bias | ||
|---|---|---|---|---|---|---|---|---|---|---|
| Total | Per study arm | Total, n (%)a | Per study arm | |||||||
| Lei et al. (2018) | 381 | 189/192 | 196 (60.9) | 96/98 | LcS | 6 months | Distal radius | DASH, VAS pain, CRPS, ROM, grip strength | Significant better pain relief, significant fracture healing acceleration in the first 6 months | Allocation bias |
| Lei et al. (2016) | 266 | 133/131 | 122 (66.2) | 61/67 | LcS | 1 month | Single rib | VAS pain, SMI lung volume, VAS sleep quality | More effective pain relief, significant increase in SMI | Allocation bias, reporting bias |
| Guo et al. (2018) | 176 | 87/89 | 77 (43.79) | 39/38 | LcS | 1 month | Single rib | pneumonia incidence, FEV, NIP, FVC, adverse effects | Reduced pneumonia incidence, increased lung function recovery | Reporting bias |
| Zhang et al. (2019) | 266 | 126/121 | 133 (66.3) | 70/63 | LcS | 3 months | Distal radius | MHQ, radiology | Fracture healing acceleration, improved ROM recovery | Allocation bias |
| Liu et al. (2020) | NA | NA | 0 | 0 | AM, LG | 42 days | Femur diaphysis | Radiology, callus strength, cartilage remodeling, inflammatory response, gut permeability, gut microbiome composition | Fracture healing improvement, increased angiogenesis, osteogenesis, decreased gut permeability, lower systemic inflammation | |
| Roberts et al. (2020) | NA | NA | 0 | 0 | BA | 10–22 days | Femur diaphysis | Gut permeability, cartilage remodeling, systemic inflammatory response, tight junction expression, gut microbiome composition, posttraumatic bone loss | Accelerated cartilage remodeling, decreased gut permeability, lower systemic inflammation | |
aPercentage in total study population.
AM, Akkermansia muciniphila; BA, Bifidobacterium adolescentis; CRPS, complex regional pain syndrome; DASH, Disabilities of the Arm, Shoulder, and Hand; MHQ, Michigan Hand Questionnaire; LcS, Lactobacillus casei strain Shirota; LG, Lactobacillus gasseri; NA, not applicable; ROM, range of motion; SMI, sustained maximal inspiration; VAS, visual analog scale.
Four studies were performed on human participants, while two studies were based on an animal model. The mean age of the participants in the human studies was 44, 56, and 65 years, respectively.
In four studies probiotics were found to accelerate fracture healing and in three studies to provide additional pain relief. Additional outcome measures that were found to be affected by probiotic administration were intestinal permeability, systemic inflammation, lung recovery in rib fractures, wrist function in radius fractures, and overall quality of life.
Discussion
Recent developments in microbiome research suggest that the gut microbiome even impacts bone health. Although only few studies have addressed the link between the intestinal microbiome and bone health, they have paved the way for the development of the novel concept of the gut–bone axis, which refers to the interactions of the intestinal microbiome and skeletal system (Sjögren et al. 2012, Weaver 2015, Zaiss et al. 2019). Studies on this topic have been conducted in different murine microbiome models, including germ-free, antibiotic-treated, or monocolonized mice. They found discrepancies in the results, possibly because of different experimental conditions such as mouse strain used, type of feeding, microbial reconstitution, and exposure time. However, the composition of the gut microbiome is hypothetically linked to bone health and its cellular metabolism in the form of bone formation and resorption directly through metabolites and indirectly through immunomodulation (Yan et al. 2022). Specific intestinal microbiome composition profiles and their respective metabolites are suggested to impact the bone loss, i.e. occurrence of bone diseases such as osteoporosis. The application of probiotics or specific substrates, such as prebiotics, may exert beneficial effects on intestinal microbiome composition in a way to prevent or reverse bone loss. Within the aspect of the gut–bone axis, the connection with host immunity must be considered. Intestinal microbiome affects the immunity of the host but also various metabolic–endocrine processes in health; therefore, it is a potential immunoregulator of the physiological processes of bone remodeling in adults (Novince et al. 2017).
The number of plausible mechanisms responsible for the impact of the gut microbiome on bone metabolism surpasses the scope of this review and has evolved into a completely new scientific discipline – ‘osteomicrobiology’ (Bhardwaj et al. 2022).
The molecular mechanisms by which probiotic bacteria exert their beneficial effects, particularly those on bone, in vivo, are complex and have yet to be elucidated. The underlying molecular mechanisms are likely triggered by different bacterial cell components including a cascade of pathways within the host (Novak et al. 2021). Furthermore, certain probiotic strains synthesize vitamins C, D, K, folate, or enzymes necessary for matrix formation and bone growth (Collins et al. 2017).
However, the main most promising mechanism whereby probiotics elicit health-promoting effects upon entry into the gut is its interactions with the host intestinal microbiome and thereby the metabolites accumulated in the intestinal lumen (Fig. 3). This impacts the increase in the relative abundances of certain bacterial genera such as Bacteroides and thus increases local concentrations of specific metabolites, particularly intestinal short-chain fatty acids (SCFAs), with an impact on gut health and host physiology (Zaiss et al. 2019), Namely, SCFAs are the main metabolites produced by microbial fermentation of dietary fiber in the intestine. According to Lucas et al. (Lucas et al. 2018), SCFAs such as propionate and butyrate are regulators of osteoclast metabolism and bone mass, through inhibition of osteoclast differentiation and bone resorption, as shown in an experimental model of inflammatory arthritis in C57BL/6J mice. As reported by Lucas et al. (2018), propionate and butyrate directly impact the cellular metabolism in osteoclasts by shifting toward glycolysis at the expense of oxidative phosphorylation, thereby downregulating specific osteoclast genes such as TRAF6 and NFATc1 that suppress osteoclastogenesis.
Overview of mechanisms of action of probiotics in fracture healing.
Citation: Microbiota and Host 1, 1; 10.1530/MAH-23-0003
Probiotics, widely applied as microbial based therapeutics, may impact intestinal microbiome composition and thus appear to be beneficiary for skeletal conditions, such as osteoporosis (Collins et al. 2017). The review has shown that probiotic administration might be beneficiary in bone fracture treatment. The probiotic strains that have been investigated in this regard, Lactobacillus casei strain Shirota, Lactobacillus gasseri, Akkermansiamuciniphila, and Bifidobacteriumadolescentis, had several positive effects when applied in fracture treatment. Positive effects were demonstrated in osseous metabolism itself and other outcomes essential for solid fracture treatment: pain reduction and increased functional recovery.
In the four human studies included in this review, the investigated probiotic strain was Lactobacillus casei strain Shirota,which is a well-known, widely available probiotic approved by various authorities internationally owing to its good safety profile (Kato-Kataoka et al. 2016). This probiotic strain is proven to be effective for various conditions through its beneficiary effects on gut microbiome composition (Matsumoto et al. 2010) and metabolism (Aoki et al. 2014) as well as its immunomodulatory effects on T cells, natural killer cells and cytokine production (Dong et al. 2010).
In one animal study, the probiotic B.adolescentis was deployed. This probiotic strain, common in scientific and clinical practice, has been shown to alter the host gut microbiome’s taxonomic and functional profile (Wang et al. 2021), to have immunomodulatory effects by stimulation of regulatory T and Th2 cells and regulation of cytokine production (Fan et al. 2021), as well as to have a role in strengthening the intestinal barrier function (Krumbeck et al. 2018). In the Roberts et al. (2020) study included in this review, the beneficiary effect of the probiotic in fracture healing was shown to be a result of the strengthening of the intestinal barrier function and decrease in systemic inflammation associated with probiotic administration.
The next-generation probiotic A.muciniphila, investigated in the study by Liu et al. (2020), also can reduce intestinal permeability and attenuate pro-inflammatory immune responses (Derrien et al. 2017).
The reviewed studies and literature suggest that probiotics exert their positive effects in bone fracture healing and fracture treatment respectively by one or several of the following processes.
The administration of probiotic strains, which mainly belong to Lactobacillus and Bifidobacterium spp., such as the two investigated strains, favorably modulates the host’s gut microbiome composition. Furthermore, the findings of Roberts and his colleagues (Roberts et al. 2020) show that probiotics such as B.adolescentis transiently affect the intestinal microbiota composition and thereby influence bone healing and limit the systemic pathologies induced by fracture (Qian et al. 2022). The results of their study showed that femur fractures cause increases in gut permeability for 7 days after trauma. Supplementation with B. adolescentis enhanced the intestinal barrier function, reduced the posttraumatic systemic inflammatory response, stimulated cartilage remodeling in the fracture callus, and improved protection of the intact skeleton after fracture. Changes in the microbial composition of the intestinal microbiota result in a change in the profile of the produced microbial metabolites. These changes regarding microbial metabolites affect the colonic epithelial cells and the immune cells in the colonic epithelium. The animal studies included in this review indicate that exactly those two mechanisms of action, namely, the increased gut barrier function and reduced systemic inflammation, are crucial for the beneficiary effect of probiotic treatment (Liu et al. 2020, Roberts et al. 2020), which seem to be present in various probiotic strains such as A.muciniphila, B.adolescentis, and Lactobacillus gasseri.
In the context of probiotic administration in fracture treatment, the metabolomic aspect of the gut microbiome and probiotics is crucial. SCFAs, the main products resulting from the fiber fermentation by the specific representatives of the gut microbiome and by the ingested probiotic strains, are essential compounds in the gut–bone axis (Zaiss et al. 2019). SCFAs affect posttraumatic bone healing by either acting directly on cells involved in reparative bone metabolism or indirectly by regulating the systemic immune response in favor of anti-inflammatory pathways (Wallimann et al. 2021). By modulating gut microbiome composition and increasing abundance of fiber-degrading SCFA producers as well as producing SCFAs by themselves (Markowiak-Kopeć & Śliżewska 2020), probiotics enhance fracture healing. Besides SCFAs, probiotics can produce specific metabolites with osteogenic effects. The probiotic Lactobacillus helveticus LBK-16H produces valyl-prolyl-proline (VPP), a bioactive peptide that promotes bone formation in vitro (Narva et al. 2007). Probiotics apparently not only change the composition but also the functionality of the gut microbiome.
Minerals are key substrates for bone formation after fractures. Although not monitored in the reviewed studies, the literature shows that probiotics successfully increase the bioavailability of minerals (Parvaneh et al. 2014) by the production of vitamins (D and K), phytase, SCFAs, bioactive peptides (VPP, isoleucyl-prolyl-proline, caseinophosphopeptides (CPP)) and through decrease in intraluminal pH.
The analgesic properties of probiotics in fracture treatment were shown in several of the studies included in this review (Lei et al. 2018, Zhang et al. 2019). This is consistent with literature data that probiotics can reduce pain levels through their immunomodulatory effects (Nazemian et al. 2016) but also production of specific analgesic bioactive peptides (Pérez-Berezo et al. 2017). Pain relief is key in fracture treatment because it leads to better functional recovery, as shown in the studies included in this review (Lei et al. 2018, Zhang et al. 2019).
As with all therapeutic agents, the therapeutic safety of probiotic administration must be addressed (Merenstein et al. 2023). In most cases, the available evidence does not indicate an increased risk, and probiotics are considered safe for use, even in critically ill pediatric patients (Srinivasan et al. 2006). But anecdotal reports indicate that probiotics may worsen outcomes in certain patient populations such as critically ill (Lestin et al. 2003, Kara et al. 2018) and immunosuppressed (Mehta et al. 2013, Karime et al. 2022) patients. Currently, scientific literature cannot confirm with certainty the safety of probiotic administration in all the specific groups of patients, since there is a lack of systematic reporting of side effects related to the probiotics administration (Gwee et al. 2018). Therefore, caution is advised when recommending probiotics to patients with bone fractures who are either critically ill or immunocompromised.
This present study possesses certain strengths and limitations. This is the first study to attempt to review the possible role of probiotic administration in fracture treatment. Additionally, a comprehensive search strategy was repeatedly performed with a minimal number of limitations. All types of studies were considered, and great efforts were undertaken to clarify the potential mechanisms behind the effects of probiotics on fracture healing together with an extensive literature review on associated topics. The main limitation of our study is the scarcity of study materials. The number of animal and human studies on the topic of probiotics in fracture treatment is insufficient to draw clinically relevant conclusions. The consequent heterogeneity regarding the investigated probiotic strain, the outcome measures, and the treated fracture sites renders too great of an incoherence to perform a qualitative review. Nevertheless, our findings can be regarded as primary findings that could serve as an orientation in the design of future studies on this topic. This review supported the potential for the application of specific probiotic strains in fracture treatment. Further future research in the form of animal and human studies on this topic, focusing on causality, is warranted to draw consistent conclusions with insights into a more mechanistic basis of the effect.
Conclusions
Due to the limited number of studies, at this stage, it can only be hypothesized that probiotics could have a positive effect on the treatment of bone fractures. Probiotic administration in fracture healing has been investigated in mice and humans with overall positive effects. Probiotics were found to accelerate bone healing and improve patient’s general well-being and quality of life during treatment. Several putative mechanisms of action were described: gut microbiome composition, increased gut barrier function, decreased systemic inflammatory response, production of microbial metabolites, increased mineral bioavailability, and pain relief. Further in-depth functional studies are needed to clarify the role of probiotics in fracture treatment.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/MAH-23-0003.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
AK conceived and wrote the review, and JN and AI reviewed the manuscript.
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