Milk and osteoporosis: A review

Introduction

Jean Lobstein first used the term "osteoporosis" to describe a condition that is thought to be age-related and is characterized by low bone mineral density, deterioration of bone microarchitecture, decreased bone mass, and increased bone fragility. According to the World Health Organization, osteoporosis is a systemic skeletal illness marked by low bone mass and micro-architectural degradation of bone tissue, which increases bone fragility and fracture risk. Osteoporosis is a dangerous bone condition that increases a person's risk of fractures by weakening their bones (NOGG, 2017) [25] . The condition is influenced by several factors including age, hormonal changes, inadequate nutrition, and lifestyle habits. With more than 200 million people affected worldwide, it represents a significant global health burden (Upadhyaya et al., 2020) [36] . The number of hip fractures worldwide is expected to rise sharply, reaching an estimated 21.3 million cases by 2050 (Gullberg et. al., 1997) [9] . Normal bone is undergoing the process called "Remodeling" in which osteoblast and osteoclast both cells play an important role. Osteoblast is the cell which forms the bone whereas Osteoclast is the cells which remove/break the old bone cells. Balance between two cells is most important for bone remodeling. E.g. Osteoclast being more active than Osteoblast results in bone resorption; as a result, osteopenia or osteoporosis may occur (As given in Fig. 1). Osteopenic is a middle condition between normal and osteoporosis bone meaning that bone is porous but not easily breakable. , it has maintained a niche for evaluating bone mineral density. The bone absorbs photons, and the amount of photons that are not absorbed is used to calculate bone mineral density; higher absorption corresponds to higher bone mineral density (Jain & Vokes, 2017) [17] . The results are presented as a "T-score," which shows the difference (standard deviation, SD) between the tested individual and the typical healthy population (IOF, 2023) (see table below). Milk and Osteoporosis: Bones consist of minerals, collagen fibers, and organic matrix that provide strength and flexibility (Iyer, 2019) [16] . [10] . It is absorbed in the intestine through vitamin Ddependent active transport and passive diffusion (Hess et al., 2016) [10] . Approximately 60% of daily calcium should come from dairy foods (Infante and Tormo, 2000) [12] . Calcium absorption decreases with age due to reduced vitamin D activation (Hess et al., 2016) [10] . Calcium intake varies across regions, with many developing nations showing low dietary calcium levels (Balk et. al., 2017) [3] (Refer the Fig. 3). [3] Intestinal calcium absorption efficiency is inversely related to calcium intake, so that a diet low in calcium leads to a compensatory increase in fractional absorption, due to activation of vitamin D. The calcium contents of Milk and Milk Products are as follows: [6] . Three primary hormones control phosphorus homeostasis: osteocytesecreted fibroblast growth factor 23 (FGF23), 1, 25(OH)2 D3, and parathyroid hormone (PTH) (Bergwitz & Jüppner). The dietary Ca/P ratio is necessary for optimal bone development. Bone's Ca/P ratio is thought to be about 2.2 (molar ratio) (Pastore et al., 2012) [27] . Another mechanism regulating the increased bone resorption in response to a diet high in phosphorus is the bone matrix protein osteopontin (OPN) (Koyama et al). The primary regulators of calcium homeostasis, 1, 25(OH) 2 D3, are impacted by magnesium shortage, which has an effect on bones (Astor et al., 2015) [2] . A lack of magnesium causes leukocytes and macrophages to become activated, which leads to the release of inflammatory cytokines and an overabundance of free radicals (Nielsen, 2018) [26] . Osteoclast development and activation are encouraged by interleukin (IL)-6. Another potent inducer of bone resorption that contributes to the increased bone loss seen in postmenopausal osteoporosis is IL-1 (Wei et al., 2005) [38] . The stimulation of the inducible Nitric Oxide synthesis (iNOS) pathway by various cytokines (e.g., IL-1) impairs osteoblast activity in vitro and promotes osteoblast apoptosis (Armour et al., 2001) [1] . In addition to helping in the active transport of calcium across the intestinal lumen, vitamin D is essential for preserving calcium homeostasis (Hess et al., 2016) [10] . A daily intake of 700-1000 IU of vitamin D lowers the incidence of fractures and falls by roughly 20% (Bischoff-Ferrari et al., 2009) [4] . A 25-hydroxyvitamin D test is recommended for individuals with osteoporosis (Dawson-Hughes et al., 2010) [7] . [19] . Vitamin K2 downregulated basal and cytokine-induced NF-κB activation in humans. Osteoclast production requires the activation of the NF-κB signal transduction pathway. (Yamaguchi et al., 2011) [39] . Dietary fat (CLA and omega-3 fatty acids) may influence bone formation and resorption by altering prostaglandin (PG) biosynthesis in bones.

Types of Osteoporosis

Global mean dietary

Prostaglandins (PG) have stimulatory effect at low concentration and inhibitory at high concentration (Li et al.).

Dietary beef fat and a CLA supplement were able to maintain synthetic activity of osteoblastic cells and CLA was even able to reduce bone formation rate in rats given a diet high in omega-6 fatty acids (Watkins et al., 2003) [37] . An increase in cytokines increases bone loss, and CLA appears to counter the effect of cytokines (Watkins et al., 1997) [37] . Whey protein has been shown to increase the level of organic material in bone, especially collagen-specific amino acids such as proline and hydroxyproline. Whey protein reduces the formation of osteoclasts and activates the osteoblasts (Takada et al., 1997) [34] . Active compound of milk basic protein (cystatin C) inhibits osteoclast activity by decreasing the secretion of collagen-digesting cathepsin (Matsuoka et al., 2002) [35] . Higher protein intake increases blood levels of Insulin-like Growth Factor-1 (IGF-1), which promotes bone and muscle formation, and facilitates the transformation of vitamin D into its active form. (1, 25dihydroxyvitamin D) (Bonjour et al., 2013) [5] . Increased the expression of osteocalcin and collagen (type I).

Reddi et al., 2016 [44] VLPVPQK Treatment of calvarial osteoblast cells with antioxidative peptide at a dose of 50-200 ng/ml for 7, 14, and 21 days.

Increases osteoblast cell viability and decreases inflammatory cytokines expression.

Mada et al., 2017 [41] Casein phosphopeptides (CPP)

Treatment of OVX rats with Ca-bound and Ca-free CPP for 17 weeks provided 62.5 and 100% of dietary phosphorus.

Increases bone mineral density (BMD) in OVX rats.

Tsuchita et al., 1996 [46] Lactobacillus helveticus fermented milk containing peptides IPP and VPP Treatment of postmenopausal women with fermented milk containing 14.5 mg/100 g milk of IPP and VPP.

Fermented milk containing IPP and VPP reduces serum PTH level and increases serum calcium level.

Narva et al., 2004 [43] VLPVPQK Treatment of OVX rats with peptide at a dose of 50 and 100 µg/kg/day for 8 weeks.

Increases bone mineral density (BMD) and improved trabecular microarchitecture of femur in OVX rats.

Mada et al., 2018 [42] NAVPITTL Feeding of OVX rats with peptide at a dose of 100 µg/kg/day for 8 weeks.

Enhanced femur BMD and microarchitecture. Suppressed RANKL gene expression in OVX rats.

Reddi et al., 2019 [45] It is important to remember that lactose increases children's absorption of calcium (Hodges et al., 2019) [11] . The MCM6 gene's single polymorphism nucleotide in 13910CC and 22018GG is linked to lactose intolerance, which is genetically conditioned (Ratajczak et al., 2021) [28] . Lactosetolerant individuals with genotypes LCT-13910 TT and LCT-13910 CT had higher bone mineral density than lactose-intolerant individuals with genotype LCT-13910 CC (Mnich et al., 2018). Patients with lactose intolerance should eat fermented dairy products, lactose-free milk, and calcium-rich non-dairy products to avoid osteoporosis (Ratajczak et al., 2021) [28] .

Gut Microbiota-Modulation of Bone Mineral Density

Production of biologically active compounds by Gut microbiota such as short-chain fatty acids and polyamines affects intestinal cells resulting in altered bone turnover and Bone Mineral Density. Galactooligosaccharides (GOS) and other human milk oligosaccharides (HMO) are essential for healthy gut microbial colonization. (2013) [29] Sakurama et al. Short-chain fatty acids are produced by the fermentation of GOS by Bifidobacterium species. Lacto-N-biosidase, which is present in Bifidobacterium species, aids in the absorption of GOS (Sakurama et al., 2013) [29] . In healthy individuals, Lactobacillus reuteri raised serum levels of 25(OH) D, which impacts calcium absorption and may have an impact on the increasing activity of liver 25 hydroxylase (Jones et al., 2013) [18] . Additionally, there is breakdown of molecule-binding minerals (such as phytic acid and oxalates) and enhancement of calcium-binding protein expression (Scholz-Ahrens et al., 2007) [31] . The gut microbiome, which produces serotonin, decreases the activity of duodenal enterochromaffin cells (Yano et al., 2015) [40] . Serotonin inhibits the growth of osteoblasts by activating 5-HT1B receptors in preosteoblasts (Kode et al., 2012) [20] .

Conclusion

For bone health throughout life, a healthy diet is essential. The building blocks for bone structure are found in dairy products. Because milk and dairy products provide highavailability protein, vitamin D, calcium, and phosphorusall of which are crucial for preventing osteoporosis-elderly people shouldn't avoid them. Fermented dairy products (kefir, yoghurt) and lactose-free milk are the best options for patients with lactose sensitivity. Dairy products' beneficial effects on gut microbiota may boost calcium absorption, short-chain fatty acid synthesis, and serotonin productionall of which have a direct impact on bone metabolism.

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