The Impact of Fermented Dairy Products and Probiotics on Bone Health Improvement

Genetic factors are the most significant contributors in bone health determination. BMD, a key determinant of bone health, is varied as high as 60%–90% due to genetic factors (Duncan et al., 2003; Recker and Deng, 2002). Bone health traits like BMD, height and strength are influenced by genes (Krall and Dawson‐Hughes, 1993). Some of the genes like LRP5 and SOST are critical for bone health and remodeling influencing overall bone strength and fracture susceptibility (Duncan and Brown, 2010). Several single nucleotide polymorphisms have been reported to influence an individual’s susceptibility to bone diseases (Mäkitie et al., 2019). Mutations in genes such as CLCN7, TCIRG1, and IKBKG are primarily responsible for various forms of osteopetrosis. These genes regulate the formation, growth, and function of osteoclasts, and mutations in one or more of them can lead to osteoclast dysfunction or loss (Stark and Savarirayan, 2009). Additionally, Paget’s disease of bone (PDB) is largely influenced by genetic factors, with mutations or polymorphisms identified in four key genes: TNFRSF11A, TNFRSF, VCP and SQSTM. All these genes are part of the RANK-NFκB signaling pathway, and their mutations enhance the risk of PDB by disrupting normal signaling eventually leading to osteoclast overactivation (Ralston, 2008). Ongoing research is focused on identifying specific genes that regulate bone mass and affect the risk of bone diseases ^{(Ralston, 2008; Singh et al., 2023). Understanding the genetic basis of bone diseases may enable better screening, treatment, and prevention strategies for conditions like osteoporosis and age-related bone loss (Boskey and Coleman, 2010).}

Aging influences the mechanical properties and composition of bones. Bone growth starts during fetal life and continues until the second decade of life; peak bone mass is reached at about 20 years of age which allows us to withstand mechanical overload (Rizzoli, 2014; Rizzoli and Biver, 2018). While growing old, the reduction in BMD leads to weaker and more brittle bones. Bone composition also shifts with growing age; collagen and other organic compound may degrade, and proportion of minerals increase making bones more brittle. It’s been reported that cortical bones become weaker and more brittle with age (Tommasini et al., 2007). Bone shape changes with age due to processes like cortical drift, where the outer diameter of bones expands, and the cortical walls become thin, leading to a reduction in bone strength. These changes contribute to bones becoming more fragile and prone to fractures (Boskey and Coleman, 2010).

Dietary patterns significantly impact bone health, with certain diets promoting higher BMD and reducing fracture risk, while others contribute to bone fragility (Movassagh Elham and Vatanparast, 2017). Beneficial diets, such as the Mediterranean diet which predominantly consists of fruits, vegetables, whole grains, healthy fats, and dairy-based patterns with low-fat and fermented dairy products, enhance calcium absorption, improve bone turnover biomarkers, and reduce bone resorption thereby improving bone health and reducing fracture risk (Benetou et al., 2013; Chen et al., 2016; Rivas et al., 2013; Zeng et al., 2014). High nutrient-density diets, rich in protein, calcium, and potassium, along with dietary diversity, also support stronger bones and lower osteoporosis risk. Conversely, harmful patterns like the Western diet, high in processed foods, soft drinks, fast food and red meat, as well as high-fat and low-nutrient diets, deplete essential nutrients and increase bone resorption, raising the risk of osteoporosis and fractures (Langsetmo et al., 2010; Langsetmo et al., 2016; Park et al., 2012; Zeng et al., 2013).

Environmental pollutants such as heavy metals, bisphenols, phthalates, and particulate matter can disrupt bone homeostasis by affecting hormonal balance, osteoblast function, and osteoclast activity. These toxins interfere with calcium metabolism by altering the regulation of hormones like calcitonin, PTH and vitamin D resulting in increased calcium release from bones and reduced absorption from dietary sources (Kheirouri et al., 2020; Prada et al., 2020; Zhang et al., 2020). Pollutants can also enhance osteoclast activity, reduce osteoblasts formation, enhance oxidative stress and systemic inflammation, accelerating bone resorption and inhibiting bone formation. Long-term exposure, even at low levels, may cause significant bone disorders, including osteoporosis, due to cumulative damage to bone cells and the extracellular matrix (Rodríguez and Mandalunis, 2018; Singh et al., 2023; Zhang et al., 2020).

Physical activity significantly enhances bone health by stimulating osteocytes through mechanical forces from muscle contractions and gravitational loading (Hong and Kim, 2018). Weight-bearing and resistance exercises, particularly high-impact activities like running and jumping, increase BMD, bone size, and strength, especially at weight-bearing sites like the hip and spine. These mechanical forces lead to adaptive changes in bone structure, promoting bone formation (Benedetti et al., 2018; Ishikawa et al., 2013). Physical inactivity, on the other hand, accelerates bone loss, while lifelong exercise helps preserve BMD and reduces fracture risk. Targeted resistance training also benefits non-weight-bearing sites, emphasizing that both muscle contraction and gravitational loading are crucial for maintaining bone health and preventing osteoporosis (Carter and Hinton, 2014).

Inflammation impairs bone health by tipping the balance towards bone resorption through inflammatory mediators like tumor necrosis factor-α (TNF-α), IL-6, IL-1, and prostaglandins (PGEs). These mediators alter the RANK/RANKL signaling pathway, stimulating osteoclast formation and activity (Singh et al., 2023). TNF-α induces RANKL production, while IL-1 and IL-6 increase PGE2 levels, promoting bone breakdown (Epsley et al., 2021). Mast cells and immune cells also release inflammatory signals, accelerating resorption. Bradykinin and neuropeptides like substance P contribute indirectly by affecting vascular permeability and prostaglandin synthesis (Dobigny and Saffar, 1997; Konttinen et al., 1996). Chronic inflammation in aging, or “inflammaging,” leads to oxidative stress and the buildup of advanced glycation end products, disrupting bone remodeling and reducing bone mass (Sanguineti et al., 2014). Despite known pathways, treatments targeting inflammation-induced bone loss are limited, highlighting the need for more research.

As a systemic skeletal disease, osteoporosis is characterized by decreased bone mass. An imbalance between bone resorption and production causes osteoporosis, where osteoclast activity surpasses that of osteoblasts, resulting in decreased bone mass and elevated fracture risk (Föger-Samwald et al., 2020). Estrogen deficiency, particularly post-menopause, is a key driver, as estrogen regulates osteoblast activity, suppresses osteoclast differentiation via the RANKL/OPG system, and lowers pro-inflammatory cytokines like IL-6 and TNF-α that would otherwise encourage bone resorption (Weitzmann, 2013). Estrogen loss also activates T-cells, especially Th17 cells, which secrete IL-17, further increasing osteoclastogenesis (Bhadricha et al., 2021). Osteoimmunology reveals that immune cells, such as memory T-cells and dendritic cells as well as proinflammatory cytokines, promote osteoclast activity through RANKL signaling, with chronic low-grade inflammation worsening bone loss (Yang and Zhu, 2024). Oxidative stress from reactive oxygen species hinders osteoblasts and promotes osteoclasts, and estrogen deficiency further reduces antioxidant enzymes like superoxide dismutase (Marcucci et al., 2023). Epigenetic changes, such as abnormal DNA methylation of osteogenic genes like RUNX2, suppress osteoblast differentiation, while hypomethylation increases osteoclast activity. Histone modifications and sirtuin 1 activity also influence bone cell function, with aging contributing to decreased bone formation. The gut microbiome affects bone health indirectly by influencing nutrient absorption and immune responses, and modulating osteoclast activity through the process of producing SCFAs (Xu et al., 2021). Fermented dairy and its probiotic content improve the BMD as well as BMC via several mechanisms e.g. i) enhanced supply and bioavailability of essential minerals ii) reduction in pro-inflammatory mediators, iii) modulation in pro-inflammatory Th17 cells and anti-inflammatory Treg cells balance, thus contributing towards improvement in osteoporosis condition thereby reducing fracture risk (Lyu et al., 2023).

Rickets in children and osteomalacia in adults is a condition marked by the softening of bones due to insufficient bone mineralization from deficiencies in vitamin D, calcium, or phosphate. Vitamin D, derived from UV-B exposure or diet, is converted in the liver to calcidiol and then to active calcitriol in the kidneys. Calcitriol enhances calcium and phosphate absorption, essential to the mineralization of bone. Calcium or low vitamin D reduces serum calcium, triggering increased PTH secretion, which boosts calcitriol production and bone resorption to maintain calcium levels, but increases phosphate excretion. Prolonged phosphate loss leads to hypophosphatemia, impairing bone growth and mineralization (Sahay and Sahay, 2012). Dairy restricted diet and high phytates are significant contributors in this regard, therefore intake of dairy products enriched with vitamin D can be a good strategy to improve this condition. Fermented dairy with its probiotic content (having phytase enzyme) can enhance the bioavailability of calcium depressed by phytate (Parvaneh et al., 2014; Uday and Högler, 2020).

Although genetics does have a significant influence on bone growth, dietary factors have their own significance since a healthy diet ensures the expression of these traits. Bone health depends on nutrients such as calcium, proteins, vitamin D, and other minerals, and deficiencies in these can lead to bone disorders, even if there is genetic predisposition for strong bone development.

Dairy products intake affects positively on bone health by focusing on fracture risk, BMC, and BMD. Dairy products provide 50%–60% of daily calcium and 20%–30% of protein, essential for bone growth and maintenance, aiding in achieving maximal bone mass during development and lowering adult bone turnover (Rizzoli, 2022). Intervention trials indicate that children avoiding dairy have a higher fracture risk, while adults consuming dairy, particularly fermented products like yogurt, show a lower risk of hip fractures due to the combined benefits of calcium, protein, and probiotics that support bone metabolism. Attaining high peak bone mass through dairy consumption reduces fracture risk later in life, with modest BMD increases linked to significant reductions in fracture risk, especially in postmenopausal women. Furthermore, short-term trials demonstrate that dairy products can lower markers of bone resorption, such as CTX and PTH levels, benefiting both young and older adults.

Calcium is the most significant mineral in achieving healthy BMD, preventing bone loss and fractures (Rizzoli, 2014). ^{Calcium intake is important to develop and maintain a healthy bone mass and composition. Increased bone mass density and skeletal growth were observed in the 6 and 9 years old offsprings of expecting mothers who took calcium supplements (Cole et al., 2009; Ganpule et al., 2006). Due to their high calcium content and efficient absorption rate, dairy products are thought to be the best dietary source of calcium and low cost. In addition, dairy products have higher levels of protein, magnesium, potassium, calcium, zinc, and phosphorus per calorie as compared to other foods (Caroli et al., 2011; Heaney, 2000). For example, 170 g of yogurt, on average, provides 231 mg of calcium. In this way, 3–4 servings of the yogurt in a day will satisfy Recommended Daily Intake (RDI). For comparison, one serving of yogurt provides calcium amount which is provided by 5–6 servings of vegetables or 10–12 servings of grain food. Thus, 20%–28% of RDI of protein and 52%–65% that of calcium is satisfied via dairy products (Fulgoni et al., 2004; U.S. Department of Agriculture, 2010). Dairy products have been considered as essential components of a healthy diet both in the West and Asia (Ge, 2011; Lee and Cho, 2017).}

Protein intake in diet provides the body with amino acids that are crucial for stimulating IGF-I an osteotrophic hormone for bone formation, and making bone matrix (Heaney, 2009). Positive correlation has been reported between BMD/BMC and spontaneous protein intake in pubertal boys. Additionally, dairy products are a significant source of protein. One liter of milk have about 35 grams of proteins including whey and casein proteins (Rizzoli, 2008). Long term low milk intake can lead to smaller stature, increased fracture risk by a factor of 2.7 folds (Goulding et al., 2004; Konstantynowicz et al., 2007). Intuitively, protein intake has been associated with the reduced hip fracture risk in an observational study (Wengreen et al., 2004). Table 1 enlists the amount of different bone-related nutrients in 100 g servings of various dairy products.

Probiotic-based dairy products contain live beneficial microorganisms, mainly lactic acid bacteria like Lactobacillus and Bifidobacterium (Table 2), which provide health benefits when consumed in sufficient amounts (Jang et al., 2024a; Saez-Lara et al., 2015).

Enhanced nutrient uptake: Several probiotics have been found to enhance bone growth, mineralization, and bone structure in animal models like rodents. Lactobacillus and Bifidobacterium species are the most common species of probiotics obtained from dairy products and they can improve bone health through different mechanisms which remain the subject of ongoing research, but some researchers suggest that they exert beneficial effect on bones through nutrient uptake, they enhance the absorption of vitamin D and other minerals by human and mouse epithelial cells (Wu et al., 2015). The possible mechanism involves further steps (a) probiotics and their secreted factors interact with the intestinal epithelial barrier and the cells located within the lamina propria. Within the lamina propria, probiotics and their secreted factors interact with antigen-presenting cells, including dendritic cells, to modulate the immune response. This interaction leads to a decrease in inflammatory cytokines, which in turn improves the absorption of minerals from the intestinal lumen. The factors secreted by bacteria subsequently enter the bloodstream and are transported to the bone, where they can interact with osteoclasts, osteoblasts, and immune cells. This may result in a reduction of pro-inflammatory and pro-osteoclastogenic cytokines, along with decreased oxidative stress, while simultaneously promoting mineral apposition and enhancing Wnt10b expression. This modulation reduces the formation of osteoclasts, which subsequently contributes to increased bone density (Collins et al., 2017). Probiotics are capable of digesting complex carbohydrates and producing oligosaccharides that can be further metabolized by other bacteria. This process promotes the proliferation of these bacteria and alters the composition of the microbiota.

Antimicrobial compounds and other peptides secretion: probiotic bacteria also produce antimicrobial agents that can target and eliminate specific bacterial strains in the gastrointestinal tract responsible for dysbiosis. For instance, lactobacilli strains produce lactic acid, bacteriocins (antimicrobial peptides) and hydrogen peroxide (Lebeer et al., 2008) and specifically, Lactobacillus helveticus synthesizes proline-rich peptides, namely isoleucyl-prolyl-proline (IPP) and valyl-prolyl-proline (VPP), which may enhance the bioavailability of minerals. Additionally, some peptides may not be directly absorbed but can aid in releasing minerals from insoluble compounds, thereby enhancing their absorption. Furthermore, the peptides IPP and VPP may function by inhibiting the conversion of Angiotensin I (Ang I) to Angiotensin II (Ang II; Parvaneh et al., 2014).

Immune modulation: It is well established that osteoclasts, which originate from monocytic precursors in the bone marrow, can interact with and be regulated by immune cells, such as B and T cells, as well as immune-stimulating factors like RANKL, TNF-α, IL-1, and IL-6 (Lorenzo et al., 2008). Probiotics seem to play a role in promoting bone health by influencing intestinal conditions by immunoregulation. In a study involving healthy male mice, treatment with Lactobacillus reuteri ATCC 6475, a candidate probiotic known for its anti-TNF-α activity, led to increased bone density. This enhancement was linked to lower levels of intestinal TNF-α, suggesting that probiotics can help prevent bone loss caused by inflammation (McCabe et al., 2013). However, it’s important to note that these positive effects on reducing inflammation and boosting bone density were only observed in male mice, indicating that the impact of probiotics may differ between genders. Another study showed that Lactobacillus plantarum A41 and Lactobacillusfermentum SRK414 exhibited significant antioxidant activity and a strong adhesion rate to intestinal cells. Furthermore, both L. plantarum A41 and L. fermentum SRK414 were found to reduce the mRNA expression levels of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-8. Furthermore, these strains were found to have the potential to mitigate diseases associated with bone loss by enhancing the mRNA expression of markers related to bone metabolism (Lee and Kim, 2020).

Production of SCFAs: Emerging research indicates that probiotics influence bone health through various mechanisms, including the production of SCFAs. Preclinical studies suggest that SCFAs, including butyrate and propionate, help prevent bone loss in osteoporosis models by inhibiting osteoclastogenesis and modulating the immune response (Chang et al., 2021; Feng et al., 2024). Administering SCFAs to mice, along with a high-fiber diet, significantly enhanced bone mass and prevented bone loss associated with postmenopausal conditions and inflammation. The protective effects of SCFAs on bone mass are linked to the inhibition of osteoclast differentiation and bone resorption both in vitro and in vivo, while bone formation remains unaffected (Lucas et al., 2018).

Hormone modulation: Estrogen and androgen, which are types of gonadal steroids, are essential in regulating bone metabolism by influencing bone mass and turnover (Xu et al., 2017). The decline in estrogen levels is a key factor contributing to the risk of postmenopausal osteoporosis. During menopause, the reduction in circulating estrogen can lead to various negative health outcomes, most notably a rapid loss of bone mass (Freedman, 2002). In the human body, estrogens are found in the bloodstream either in a free form or bound to proteins, where they exert a range of biological effects. Only the free form of estrogen is biologically active, whereas conjugated estrogens are inactivated and ultimately excreted in urine or feces. On the other hand, conjugated estrogen could be deconjugated by gut microbiome and probiotics (Kwa et al., 2016). It is well recognized that gut microbiota influences the absorption and metabolism of phytoestrogens, including isoflavones and lignans. Numerous phytoestrogens are hydrolyzed by intestinal microbes, such as Lactobacillus and Bifidobacterium species, resulting in the production of active compounds that improve their bioavailability (Xu et al., 1995). Recent studies have also investigated the potential effects of probiotic treatment in osteoporosis, particularly using the estrogen deficiency ovariectomized model. Previous studies indicated that healthy female mice did not show significant changes when supplemented with L. reuteri. However, L. reuteri was found to prevent bone loss induced by ovariectomy (OVX) in female mice, indicating its potential for preventing estrogen-deficiency-related osteoporosis in postmenopausal women (McCabe et al., 2013). Similar findings have been confirmed by other studies using comparable probiotic strains. Additionally, Lactobacillus paracasei has been demonstrated to prevent cortical bone loss induced by OVX and to reduce bone resorption (Chen et al., 2023; Collins et al., 2017; Ohlsson et al., 2014). Longitudinal bone growth is controlled by growth hormones (GH) and IGFs. These factors are crucial for cell survival, proliferation, and differentiation, and IGF-1 is considered a significant player in osteoblastogenesis. The bone quality is directly linked to serum IGF-1 level (Delagrange et al., 2021; Wong et al., 2016). Probiotics have been shown to impact the secretion of GH from the endocrine system, thereby contributing to the regulation of growth (Tu et al., 2023). Studies on germ-free mice revealed significantly lower levels of GH and IGF-1 compared to wild-type mice, but supplementation with L. plantarum restored IGF-1 levels to those of wild-type mice (Schwarzer et al., 2016). Probiotics secreted bacterial extracellular vesicles are an emerging new promising platform in bone health therapeutics along with their other biomedical applications. One such example is Akkermansia muciniphila derived EV which showed promising bone health improvement results as reported by Liu and colleagues (Liu et al., 2021). Fig. 2 summarizes the key ways through which probiotics improve bone health.

Fig. 2. Probiotics impact bone health through multiple ways. PTH, parathyroid hormone; CTX, C-terminal telopeptides of type I Collagen; BALP, bone alkaline phosphatase; BMD, bone mineral density; BMC, bone mineral content.

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Probiotic strains, which have been extensively studied for their potential to enhance bone health, vary significantly in origin and functionality. Several common probiotics, along with their respective effects on bone health across different animal models, are summarized in Table 3. In addition, several studies have reported encouraging results of probiotics treatment on humans also as probiotics treatment reduced the bone resorption biomarkers and improved BMD in specific bone types (Table 4). One recent study, however, reported no significant bone health improvement after probiotics treatment (Sergeev et al., 2020). This disparity emphasizes the complexity of bone health regulation and the demand for more thorough research. Thus, Future research should concentrate on elucidating the mechanisms by which probiotics affect bone remodeling, considering differences in strain-specific effectiveness, and assessing the impact of host variables including dietary consumption, microbiome composition, and baseline bone health. Furthermore, to demonstrate the consistency and generalizability of the observed results, extended study periods and standardized procedures along with the use of better techniques are essential to translate the therapeutic potential of probiotics into reality.

The probiotic adjuvant therapies in bone diseases show positive effect on patients. Recent study revealed that, supplementation with a multispecies probiotic for 12 weeks in osteopenic postmenopausal women may slow the rise in the serum bone resorption marker CTX by downregulating osteoclast-mediated bone resorption, without causing significant adverse effects (Vanitchanont et al., 2024). Probiotics and isoflavones are also believed to support bone health by influencing calcium absorption, gut microbiota, and various metabolic pathways linked to osteoblast activity and bone formation (Harahap and Suliburska, 2021). Overall, there is some evidence from human randomized controlled tests that probiotic supplementation can improve antioxidant defenses, disease activity and the inflammatory status of rheumatoid arthritis along with conventional medicines. Since probiotics have been shown to positively impact bone health, it suggests that combining them, such as using multispecies probiotics along with food and conventional medicines, could be a highly effective approach for addressing bone-related issues.