Probiotics and Osteoporosis -What Do We Know Today?

What we know today

Osteoporosis, characterized by progressive loss of bone mass and deterioration of bone tissue structure, particularly microstructure, is a prevalent skeletal disease affecting over 200 million individuals worldwide, posing a significant global public health concern (Picture 1). Fractures associated with osteoporosis stem from increased bone fragility and susceptibility to fractures. The principal pathophysiological mechanism involves an imbalance in bone remodeling, with heightened bone resorption by osteoclasts and decreased bone formation by osteoblasts, resulting in continuous bone loss, typically observed as a decline in bone mineral density (BMD) at a rate of approximately 2-5% per year, along with deterioration in bone microarchitecture.^1-4

Osteoporosis can be classified as primary (type I), occurring as a natural part of aging, particularly in women with estrogen deficiency post-menopause, or secondary (senile) osteoporosis, resulting from medical conditions, diseases, or certain medical treatments. The multifactorial development of primary osteoporosis involves genetic and environmental factors, including diet, lifestyle choices (such as smoking), hygiene practices, and antibiotic use.^5-7

New findings

Given the high incidence and prevalence of osteoporosis and osteopenia worldwide, the scientific community continues its pursuit of effective and safe treatment options.⁸ Presently, therapeutic choices remain limited, with lifestyle modifications showing low compliance rates.⁹ While hormonal estrogen therapy, such as red clover isoflavone supplementation, has demonstrated effectiveness in prevention and treatment, it’s associated with severe adverse events.¹¹ Similarly, antiresorptive agents like bisphosphonates, parathyroid hormone, and calcitonin face limited use due to adverse effects, high costs, and poor compliance.¹² Although calcium and vitamin D offer beneficial effects on bone microarchitecture and overall bone health, they’re insufficient alone for treating menopausal bone loss.¹³ Current treatment methods typically involve a combination of lifestyle adjustments, bone health supplements, drug intervention, and rehabilitation.

The gut microbiome’s role in osteoporosis has emerged as a significant area of research.¹⁴ Studies indicate that the gut microbiome influences osteoclast and osteoblast activity through metabolite secretion, impacting host metabolism and immune response.^15,16 Dysbiosis-induced gastrointestinal inflammation and disturbances in metabolite secretion can lead to potent osteoclastogenic cytokine production, contributing to bone loss. Moreover, the gut microbiome affects the intestinal absorption of minerals crucial for bone health.^17,18 Imbalances in the gut microbiome, along with estrogen deficiency, can increase gut permeability, facilitating the absorption of toxins and pathogens, thus promoting systemic inflammation detrimental to bone turnover.

The complexity and time-dependent nature of the gut microbiome’s effects on bone health are evident in research. This has led to the emergence of the term “osteomicrobiology” to describe research on the gut microbiome’s impact on bone health and metabolic bone diseases.^19,20

Probiotics, live microorganisms with beneficial health effects for the host, offer a promising avenue for osteoporosis treatment.²¹ However, not all probiotics are equally effective due to differences in food processing, strain specificity, and targeted effects. Probiotics likely exert their effects through modulation of gut microbiome metabolite secretion, influencing immune response, and improving gut epithelial barrier function, crucial for normal bone cell functioning.^22,23 While the magnitude of probiotic treatment’s effect may be lower compared to anti-resorptive drugs, it’s comparable to calcium and/or vitamin D treatment.²⁵

The discovery that probiotics can mitigate bone mass loss presents a novel approach to osteoporosis prevention and treatment.²⁶ In vitro studies reveal that different probiotic strains have varying effects on bone health, indicating both cell-specific and strain-specific mechanisms. For instance, Lactobacillus reuteri has been shown to inhibit osteoclast differentiation and reverse TNF-a-induced suppression of Wnt10b expression, potentially through histamine secretion.²⁷ Similarly, Lactobacillus casei 393 and Lactobacillus helveticus have demonstrated effects on bone cell proliferation and osteoblast differentiation, respectively, suggesting strain-specific interactions with bone metabolism.³⁰

Studies in animals have shown probiotic supplementation to improve BMD and have osteoprotective properties in osteoporosis. Results of several studies are shown in Table 1.

In a study by Amdekar et al. in 2012, supplementation with the probiotics Lactobacillus casei and Lactobacillus acidophilus demonstrated an osteoprotective effect, reducing bone loss caused by oxidative stress through their anti-oxidative mechanism of action.³⁷ Additionally, results from Rodrigues et al. showed intriguing findings, indicating that supplementation with Bifidobacterium longum ATCC15707 for 28 days increased the calcium, phosphorus, and magnesium content in the tibias of male rats, along with higher fracture strength compared to controls⁴¹ (Table 1). Furthermore, a study by Parvaneh et al. found that probiotic supplementation with Bifidobacterium longum increased bone density, trabecular thickness, and number, as well as femoral strength. This was achieved by elevating serum osteocalcin levels, promoting osteoblast genesis and bone formation parameters, while simultaneously decreasing osteoclast activity over the bone surface in the femur and reducing C-terminal telopeptide levels between ovariectomized and sham-ovariectomized mice⁴⁸ (Table 1).

Positive results were seen in studies on humans too. The list of human studies on probiotics and osteoporosis are summarized in Table 2.

In a study by Narva et al., probiotic supplementation was found to decrease serum parathyroid hormone (PTH) levels while increasing serum calcium levels. Notably, this effect was observed only when the probiotic itself was administered, not when solely peptides secreted by the probiotic were applied⁵³ (Table 2). Conversely, research by Jafarnejad et al. demonstrated that probiotic supplementation led to a decrease in bone-specific alkaline phosphatase levels, parathyroid hormone, tumor necrosis factor TNF-a, and collagen type 1 cross-linked C-telopeptide. However, spine and hip bone mineral density (BMD) remained unaffected by probiotic supplementation⁵⁴ (Table 2).

Mechanisms of action

Probiotics exert their influence on bone health through various mechanisms.

The primary mechanism involves the positive alteration of gut microbiota composition by probiotics, leading to an optimal profile of gut microbiome metabolite secretion with systemic benefits to the host, including bone metabolism.^62,63,64

Probiotics can enhance the utilization of calcium, phosphorus, and iron, as well as the absorption of iron and vitamin D, through the secretion of metabolites such as lactic, butyric, and acetic acid.⁶⁵

Certain probiotics have been found to increase the expression of the vitamin D receptor (VDR) in both humans and animal studies, thereby increasing circulating vitamin D levels, which suggests that probiotics can enhance the positive effect of vitamin D on bone health through multiple pathways.⁶⁶

Additionally, probiotic administration can lead to altered hormone levels, such as estrogen, which plays a crucial role in the pathophysiology of osteoporosis.⁶⁷

By influencing gut microbiome metabolite secretion, probiotics can reduce intestinal pH, leading to increased calcium solubility and absorption in the intestinal lumen, ultimately resulting in increased bone mineral content and density. This mechanism is particularly important in the elderly population where intestinal absorption is often diminished.

Another significant mechanism of probiotics in osteoporosis involves their anti-inflammatory effects. Probiotics can mitigate the inflammatory cascade impacting bone turnover by calming gastrointestinal and systemic inflammation and producing anti-inflammatory metabolites, such as arginine deiminase in the case of Lactobacillus brevis CD2. Probiotics may also reduce the expression of proinflammatory and osteolytic cytokines, including tumor necrosis factor-alpha (TNF-α), interferon 17 (IL-17), and receptor activator of nuclear factor-kappa ligand (RANKL), resulting in reduced osteoclast formation and enhanced osteoblastic activity. Furthermore, the anti-inflammatory effect of probiotics improves calcium transport across the intestinal barrier.^68,69

Moreover, probiotics can influence the expression of genes crucial for bone metabolism, rendering them as antioxidants by enhancing bone cell response to oxidative stress, which is heightened in estrogen deficiency and leads to increased osteoclast over osteoblast differentiation.³⁹

Probiotic trials for osteoporosis

Research on the effects of probiotic supplementation on bone health has yielded promising results, indicating potential benefits for individuals at risk of osteoporosis. Clinical trials involving both humans and animals have highlighted the positive impact of certain probiotic strains such as L. reuteri, L. casei, L. paracasei, L. bulgaricus, L. acidophilus, and B. subtilis.⁷⁰ For instance, in a study involving osteopenic postmenopausal women, a 12-week regimen of multispecies probiotics was found to potentially slow the increase in serum bone resorption marker CTX, suggesting a mechanism for reducing osteoclast-induced bone resorption without adverse effects.⁷¹ Another study observed that supplementation with probiotics containing L. reuteri 6475 over the course of a year led to a significant reduction in bone loss (osteoporosis) in women.⁷² This indicates a potential long-term benefit in preserving bone health. Animal studies have also provided insights, showing that strains like Lactobacillus casei, L. reuteri, L. gasseri, and B. longum (ATCC 15707) can enhance bone mineral density, calcium absorption, and fracture strength.^{73, 74}

These findings collectively suggest that probiotic supplementation could offer a natural approach to support bone health, potentially reducing the risk of osteoporosis. However, further research, particularly randomized controlled trials with larger cohorts, is necessary to validate these findings and establish optimal dosage and duration for probiotic interventions targeting bone health.

Conclusions

The gut microbiome and the host immune response play critical roles in the pathophysiology of osteoporosis. Probiotics offer osteoprotective benefits by positively influencing the gut microbiome and modulating the host immune response through various direct and indirect mechanisms. Research across in vitro, animal, and human studies has demonstrated the beneficial effects of probiotic administration on bone health and osteoporosis. However, further investigation is warranted to delve into the strain-specific mechanisms of action, particularly concerning the gut microbiome and metabolite secretion. This emphasizes the potential of probiotics as adjunctive therapeutic agents in the prevention and management of osteoporosis, while underscoring the need for continued research to elucidate their precise mechanisms of action.

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