Osteoporosis is a metabolic bone disease that, on a cellular level, results from osteoclastic bone resorption not compensated by osteoblastic bone formation This causes bones to become weak and fragile, thus increasing the risk of fractures Traditional pathophysiological concepts of osteoporosis focused on endocrine mechanisms such as estrogen or vitamin D deficiency as well as secondary hyperparathyroidism However, research over the last decades provided exiting new insights into mechanisms contributing to the onset of osteoporosis, which go far beyond this Selected mechanisms such as interactions between bone and the immune system, the gut microbiome, and cellular senescence are reviewed in this article Furthermore, an overview on currently available osteoporosis medications including antiresorptive and bone forming drugs is provided and an outlook on potential future treatment options is given

Osteoporosis: Pathophysiology and therapeutic options.

Osteoporosis is a frequently observed complication in patients with chronic liver disease, particularly liver cirrhosis and cholestatic liver diseases. In addition, osteoporosis is critical in patients receiving a liver transplant. Nevertheless, few studies have evaluated bone diseases in patients with more frequently observed chronic liver disease, such as chronic viral hepatitis, nonalcoholic fatty liver disease and alcoholic liver disease. Osteoporosis is a disease caused by an imbalance in the activities of osteoblasts and osteoclasts. Over the last few decades, many advances have improved our knowledge of the pathogenesis of osteoporosis. Importantly, activated immune cells affect the progression of osteoporosis, and chronic inflammation may exert an additional effect on the existing pathophysiology of osteoporosis. The microbiota of the intestinal tract may also affect the progression of bone loss in patients with chronic liver disease. Recently, studies regarding the effects of chronic inflammation on dysbiosis in bone diseases have been conducted. However, mechanisms underlying osteoporosis in patients with chronic liver disease are complex and precise mechanisms remain unknown. The following special considerations in patients with chronic liver disease are reviewed: bone diseases in patients who underwent a liver transplant, the association between chronic hepatitis B virus infection treatment and bone diseases, the association between sarcopenia and bone diseases in patients with chronic liver disease, and the association between chronic liver disease and avascular necrosis of the hip. Few guidelines are currently available for the management of low bone mineral density or bone diseases in patients with chronic liver disease. Due to increased life expectancy and therapeutic advances in chronic liver disease, the importance of managing osteoporosis and other bone diseases in patients with chronic liver disease is expected to increase. Consequently, specific guidelines need to be established in the near future.

https://www.mdpi.com/1422-0067/20/17/4270/pdf

Bone Diseases in Patients with Chronic Liver Disease.

We investigated the relationship between gut microbiota composition and osteoporosis/fracture risk in Japanese postmenopausal women using 16S rRNA gene sequencing, FRAX, bone mineral density, biochemical bone parameters, and a self-administered questionnaire. Variation in abundance of specific microbiota was found to be significantly associated with fracture risk and vitamin K levels. Gut microbiota data with respect to bone metabolism and fracture risk is limited. Vitamin K is produced by certain intestinal bacteria and has been reported to play a role in maintaining bone quality. We investigated relationships among gut microbiota composition, bone metabolism, and fracture risk in postmenopausal Japanese women. Bone mineral density (BMD) was evaluated in 38 postmenopausal women (mean age 62.9 years) using forearm dual-energy X-ray absorptiometry. We collected and analyzed serum bone turnover markers (vitamin K fraction and tartrate-resistant acid phosphatase 5b; TRACP-5b), gut microbiota profiling (16S rRNA gene sequencing), and self-administered questionnaire data, including fracture history and vitamin K intake. Vitamin K2, BMD, and TRACP-5b data were divided into high- and low-level groups using cutoff values of 0.06 ng/mL, 87.05%, and 420 mU/dL, respectively; the proportions of bacteria were analyzed. Fracture incidence and relative risk were investigated for each bacterium. The genus Bacteroides was predominant in the high vitamin K2 group (29.73% vs 21.58%, P = 0.022). Fracture incidence was significantly higher in the low Bacteroides group, with a 5.6-times higher risk ratio of fracture history. The family Rikenellaceae was more abundant in the low BMD group and more abundant in the high TRACP-5b group (2.15% vs 0.82%, P = 0.004; 2.38% vs 1.12%, P = 0.013, respectively). Bacteroides and Rikenellaceae may be involved in bone metabolism and fracture risk. Further investigations of the underlying microbiota-related pathways in bone metabolism may reveal treatment strategies, and facilitate the prevention of osteoporosis.

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Association between gut microbiota, bone metabolism, and fracture risk in postmenopausal Japanese women

Gut microbiota is a complex ecosystem seen as an extension of human genome. It represents a major metabolic interface of interaction with food components and xenobiotics in the gastrointestinal (GI...

Metabolic and functional interplay between gut microbiota and fat-soluble vitamins

The gastrointestinal tract is colonized by trillions of microorganisms, consisting of bacteria, fungi, and viruses, known as the "second gene pool" of the human body. In recent years, the microbiota-gut-bone axis has attracted increasing attention in the field of skeletal health/disorders. The involvement of gut microbial dysbiosis in multiple bone disorders has been recognized. The gut microbiota regulates skeletal homeostasis through its effects on host metabolism, immune function, and hormonal secretion. Owing to the essential role of the gut microbiota in skeletal homeostasis, novel gut microbiota-targeting therapeutics, such as probiotics and prebiotics, have been proven effective in preventing bone loss. However, more well-controlled clinical trials are still needed to evaluate the long-term efficacy and safety of these ecologic modulators in the treatment of bone disorders.

The microbiota-gut-bone axis and bone health.

The microbial metagenome and bone tissue composition in mice with microbiome-induced reductions in bone strength.

The genetic components of microbial species that inhabit the body are known collectively as the microbiome. Modifications to the microbiome have been implicated in disease processes throughout the body and have recently been shown to influence bone. Prior work has associated changes in the microbial taxonomy (phyla, class, species, etc.) in the gut with bone phenotypes but has provided limited information regarding mechanisms. With the goal of achieving a more mechanistic understanding of the effects of the microbiome on bone, we perform a metagenomic analysis of the gut microbiome that provides information on the functional capacity of the microbes (all microbial genes present) rather than only characterizing the microbial taxa. Male C57Bl/6 mice were subjected to disruption of the gut microbiota ({Delta}Microbiome) using oral antibiotics (from 4-16 weeks of age) or remained untreated (n=6-7/group). Disruption of the gut microbiome in this manner has been shown to lead to reductions in tissue mechanical properties and whole bone strength in adulthood with only minor changes in bone geometry and density. {Delta}Microbiome led to modifications in the abundance of microbial genes responsible for the synthesis of the bacterial cell wall and capsule; bacterially synthesized carbohydrates; and bacterially synthesized vitamins (B and K) (p <0.01). Follow up analysis focused on vitamin K, a factor that has previously been associated with bone health. The vitamin K content of the cecum, liver and kidneys was primarily microbe-derived forms of vitamin K (menaquinones) and was decreased by 32-66% in {Delta}Microbiome mice compared to untreated animals (p < 0.01). Bone mineral crystallinity was decreased (p=0.01) was decreased in {Delta}Microbiome mice (p < 0.001) and matrix carbonate-phosphoate ratio was increased. This study illustrates the use of metagenomic analysis to link the microbiome to bone phenotypes and implicates microbially synthesized vitamin-K as a regulator of bone matrix quality.

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Zach Rouse

Papers

The microbial metagenome and bone tissue composition in mice with microbiome-induced reductions in bone strength.

The Microbial Metagenome and Tissue Composition in Mice with Microbiome-Induced Reductions in Bone Strength

Engineering solvation in initiated chemical vapour deposition for control over polymerization kinetics and material properties