Immunology and Osteoporosis: A New Frontier in Treatment

Abstract

Osteoporosis, a chronic bone disease, alters both the microstructure and macrostructure of bones, endangering bone strength and increasing the susceptibility to fragility fractures. Its consequences on the aging population raise important sociological, healthcare, and economic issues. The relationship between the immune system and osteoporosis can be understood by carefully examining a wide range of immune cells, related cytokines, and their functions. Long-term inflammation, immune cell production of RANKL, and autoimmune illnesses like systemic lupus erythematosus and rheumatoid arthritis all affect bone loss. An overview of the cycle of bone remodeling and the pathophysiology of osteoporosis are covered in this chapter. Important features of osteoporosis for diagnostic purposes are covered, including the formation and resorption markers, potential immunological markers for osteoporosis diagnosis, and new bone metabolic biomarkers. This chapter focuses solely on the roles of innate and adaptive immune cells. It also highlights novel therapeutic strategies that target specific immune pathways and show promise in the management of these challenging bone disorders. As research advances, these findings may pave the way for more specialized and efficient treatments, ultimately enhancing the quality of life for osteoporosis patients.

1. Introduction

Osteoporosis is a chronic bone disease that weakens bone mass and raises the risk of fragility fractures by affecting both the microstructure and macrostructure of bone. The bones typically affected are those in the hip and spine. The condition’s deterioration with age is a significant public health issue with clear social, health, and financial consequences. The most significant way that it lowers people’s quality of life is by causing pain and functional restrictions. People over 50 are typically more likely to develop osteoporosis. Women (16.5%) and males (5.1%) both had significantly higher prevalence rates. By 2025, 121.3 million people would be estimated to have osteoporosis and low bone mass [1]. Prior to the development of osteoporosis, there are no warning indications or symptoms. It silently depletes bone mass up until a fragility fracture occurs. Osteoporosis risk factors include malnutrition-related deficiencies in calcium and vitamin D, sedentary habits or insufficient exercise, and use of tobacco and alcohol. Other secondary causes have been discovered, such as celiac disease, chronic renal failure, monoclonal gammopathy of unknown origin, renal tubular acidosis, and diabetic mellitus [2].

Osteoporosis is diagnosed by dual-energy X-ray absorptiometry (DEXA), which gauges bone mineral density. The WHO suggests utilizing the fracture risk prediction (FRAX) tool to measure the frequency of osteoporotic fractures [3]. The sole foundation for treatment is the pathophysiology of osteoporosis, which is studied at various stages of disease progression. Healthy bone has dynamic and balanced production and resorption. Therefore, drugs that inhibit resorption and promote bone formation are used to treat osteoporosis. To find new target factors for osteoporosis treatment, research approaches now prioritize examining the genomes, proteomes, epigenomes, and metabolomes of human samples. One of the recommended treatments for osteoporosis is prevention. Bone tissue ossifies, grows, and undergoes changes. These processes are necessary for the consistency or strength of the bone, and to maintain them, certain nutrition and exercises are essential. By maintaining a balanced diet that includes the nutrients required for bone synthesis, growth, and maintenance, osteoporosis can be prevented. Recent research in this area has shown that some of the medicines used to treat osteoporosis, such as bisphosphonates, estrogens, mesenchymal stem cell therapies, and vitamin D supplementation, can alter immunological mediators. The term “immunoporosis” emphasizes how immune cells contribute to osteoporosis. One of the main initiators of many bone illnesses is inflammation. Latest study has shown that osteoblast pyroptosis, or inflammatory cell death, is essential for osteoporosis. Acute inflammatory illnesses are brought on by a variety of signals, including exogenous signals PAMPS (Pathogen Associated Molecular Patterns) and endogenous signals DAMPS (Death Associated Molecular Patterns), which cause inflammation in the body and rapidly assault the immune system. In this chapter, the overview of pathophysiology of osteoporosis, immunological markers, and immunotherapy for osteoporosis are described. This chapter will provide in-depth information about the immunology of osteoporosis as a new treatment approach.

2. Pathophysiology and alterations of bone structure

Bone is a distinctive, multifaceted connective tissue that contains both organic and inorganic elements. Bone has constant turnover throughout adulthood. As a result, bone tissue is renewed, keeping the skeleton’s biomechanical characteristics. A wide variety of non-collagenous proteins as well as collagenous proteins make up the osteoid, organic bone matrix. The numerous non-collagenous proteins control the deposition, mineralization, and turnover of bones, among other aspects of bone metabolism. The inorganic component, which makes up between 50 and 70 percent of the total bone mass, is mostly composed of calcium and phosphorus in the form of hydroxyapatite and gives the bone its mechanical firmness. Osteocytes, osteoblasts, and osteoclasts make up most of the cells that make up bone’s cellular structure. Osteocytes play a mechano-sensory role in bone formation and are in the matrix’s lacunae. While osteoclasts enzymatically resorb bone, osteoblasts produce osteoid [4].

A delicate balance between the actions of osteoclasts and osteoblasts is required for bone remodeling to maintain skeletal structure, repair microdamage, and maintain serum calcium and phosphate homeostasis. A specific sequence of cellular activities taking place at a specific location on the trabecular bone surfaces or in cortical bone make up the process of bone remodeling. The five steps of the remodeling cycle on the surface of the resting bone are activation, resorption, reversal, formation, and termination (Figure 1). The first stage is activation, which causes the lining cells to retract back from the surface of the bone. Osteoclast precursors multiply and develop into adult osteoclasts in the bone marrow. Osteoclasts destroy the old bone by secreting hydrogen ions and lysosomal enzymes from beneath the cell, which causes acidification and proteolysis. This particular area of the bone surface is where these active osteoclasts are drawn to. The nuclear factor NF- kB ligand amino acid peptide receptor activator, which binds to the kB ligand receptor on osteoclast precursors and may drive development into multinucleated osteoclasts, is expressed by osteoocytes. The expression of M-CSF (macrophage colony-stimulating factor) by osteoblasts promotes the survival and growth of osteoclast precursors. Osteoblasts create matrix metalloproteinase to degrade our calcified osteoid and expose adhesion sites for osteoclast attachment. Osteoblasts create chemokines to entice potential osteoclast precursors [4].

Figure 1.

The phases of bone remodeling cycle.

The second step is the phase of bone resorption by osteoclasts which will excavate an erosion cavity. Osteoprotegerin (OPG) prevents the interaction between kB-kB, which lowers resorption by preventing osteoclast development and raising their death [4]. The next stage, known as the reversal phase, involves the preparation of the bone lacuna by mononuclear cells. The critical connection of osteoclastic and osteoblastic activity found at remodeling sites is caused by the reversal phase, which starts with osteoclastic signaling [5]. They promote osteoblast differentiation and proliferative growth. To entirely replace the tunnel of resorbed bone, osteoblasts deposit un-mineralized osteoid, which results in a limited net change in bone volume during remodeling. As osteoid gradually mineralizes by incorporating hydroxyapatite, bone formation is finished. The remodeling cycle is complete when the tunnel of resorbed bone has been completely restored [6].

3. Osteoimmunology

Osteoporosis is traditionally thought of as the result of an estrogen-driven dysregulation of the bone remodeling process. However, new developments in the field have now firmly proven the immune system’s crucial role in regulating inflammatory bone loss in osteoporotic disorders, or “Immunoporosis,” i.e., osteoporosis. We emphasize the distinct functions of diverse innate and adaptive immune cells and their plasticity, and we uncover fresh therapeutic prospects for clinical interventions as well as their applicability in various pathological states of the bone, including osteoporosis (Figures 2 and 3).

Figure 2.

Schematic diagram representing the role of immune cells and their cytokines in the pathophysiology of osteoporosis.

Figure 3.

Schematic diagram representing the role of lymphoid lineage and their cytokines in the pathophysiology of osteoporosis.

3.1 Role of innate immune cells in osteoporosis

The term “myeloid lineage” refers to the type of bone marrow cell development pathway that gives rise to different types of immune cells (Table 1). As the first line of defense against any invasive pathogens within the host, innate immune cells are also the main makers of pro-inflammatory mediators, which serve as triggers for the emergence of a number of bone diseases, including osteoporosis. According to a study, Macrophages, OC’s, and DC’s are all clinically significant cells because they all originate from the same progenitor [9]. In addition to these cells, the production of numerous inflammatory mediators by granulocytes, innate lymphoid cells (ILCs), and natural killer (NK) cells further promotes the development of osteoporosis. The body’s fight against illnesses and infections depends heavily on these cells. TNF-α, IL-1β, ROS, and IFN-γ are a few of the main pro-inflammatory mediators that are released by innate immune cells (Table 2) [18].

Cell type	Physiological role	Function
Macrophage	Inflammation, tissue repair	M1 macrophage promotes bone resorption, M2 macrophage majorly promotes bone formation by stimulating differentiation of precursor cells into mature osteoblasts [7, 8].
Monocyte	Inflammation	Serves as precursor to osteoclasts, macrophages and DCs [9].
Dendritic Cells (DCs)	Inflammation, antigen presentation	Can transdifferentiate to osteoclasts in the inflammatory milieu [10].
Neutrophils	Inflammation, Phagosytosis	Promotes bone resorption by increased expression of mRANKL [11].
Mast Cells	Allergic Response, Inflammation	Triggers osteoclastogenesis by producing pro-inflammatory mediators [12].
NK Cells	Cellular cytotoxicity, AdCC, Inflammation	Promotes osteoclastogenesis by producing RANKL and MCSF [13].

Table 1.

Innate immune cell types and their role in osteoimmunology.

Pro-inflammatory cytokines	Cellular sources	Functions
TNF-α	T-cells, NK cells, B cells, Neutrophils, Monocytes, Macrophages.	promotes RANK expression on macrophages and stromal cell production of RANKL, limiting osteoblast development, proliferation, and activity [14].
IFN- γ	T-cells, NK cells, B-cells, Neutrophils, Monocytes, Macrophages.	T-cell activation and osteoclast fusion [15].
IL-6	Osteoblasts, Osteoclasts, Dendritic cells, Macrophages.	Osteoclast activation and migration are mediated by RANK-L [16, 17].

Table 2.

Role of pro-inflammatory cytokines in osteoimmunology.

3.1.1 Macrophages

The most powerful inflammatory cells, macrophages, serve as the main sentinel cells. They exist in the tissues and are capable of quickly detecting pathogen infection caused by bacteria, viruses, parasites, etc. They also operate as a host system’s first line of defense. They have the capacity to trigger inflammatory reactions as well as phagocytosis. This capability results from the presence of a wide variety of pattern recognition receptors (PRRs), including scavenger receptors (SRs), toll receptors (TLRs), nod-like receptors (NLRs), etc. Bone marrow macrophages (BMMs), OCs, and osteal macrophages are among the several macrophage populations found in the bone [7]. Osteal macrophages aid in the effective mineralization of osteoblasts and the production of bone. Bone mineral density (BMD) is shown to decline in the presence of osteal macrophages. In addition to causing inflammation, macrophages support tissue homeostasis and assist in tissue healing after injury [8, 9]. They have a high degree of flexibility to support these functions and can switch between an M1 and M2 phenotype depending on the surroundings. Both M1 and M2 are alternatively activated macrophages; M1 is a classically activated macrophage. Bone remodeling processes are driven by macrophage polarization. Anti-inflammatory cytokines like IL-4 and IL-13 can induce M2 polarization, which is typically linked to bone catabolic and anabolic activities, whereas pro-inflammatory cytokines like TNF-α and IL-6 can stimulate M1 polarization [19].

M2 macrophages have been implicated in osteogenesis in numerous studies. An osteoclast’s precursor is the M1 macrophage. By generating pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6, which can promote osteoclastogenesis and bone resorption, macrophages are widely acknowledged to play a crucial part in the pathogenesis of the inflammatory disease rheumatoid arthritis (RA). In osteoarthritis (OA) and peri-implant osteolysis, macrophages were also seen to contribute in similar ways [9].

3.1.2 Monocytes

Monocytes make up 10% of all leukocytes in humans and 2–4% in mice. Similar to macrophages, different subsets of monocytes exist, and each has particular traits and functions [20]. Monocytes can participate directly in the inflammatory process in addition to acting only as precursors. As a result of serving as precursors for osteoclasts and producing cytokines, circulating monocytes have a big impact on bone remodeling. Monocytes may also play a significant role in bone issues, as evidenced by the fact that intermediate monocytes take the initiative to transform into high bone-absorbing osteoclasts and may result in bone degeneration [9].

3.1.3 Dendritic cells

Antigen-presenting cells (APCs) with the capacity to elicit an adaptive immune response make up the majority of dendritic cells (DC). The process of bone resorption, osteoclastogenesis, which is mediated by inflammation, can be aided by DCs. T-cells that have been stimulated by DCs can also release cytokines and soluble substances that promote bone remodeling. Furthermore, DCs and T-cells can work together directly to create aggregates that are involved in bone diseases. TGF-, a strong anti-osteoporotic molecule, is known to be produced by DCs. This suggests an alternative function for DCs in osteoporosis [21].

3.1.4 Neutrophils

Additionally, neutrophils can cause osteoporosis by secreting substances that promote osteoclastogenesis and increased bone resorption. Neutrophils have the ability to make chemokines and draw in osteoporotic cells like Th17. Neutrophils can increase bone loss, but they can prevent it by keeping the body’s homeostasis in check [22].

3.1.5 Eosinophils & mast cells

Eosinophils are responsible for allergic reactions and the production of pro-inflammatory cytokines including IL-31, which plays a role in controlling transcription factors and cytokines linked to osteoporosis. Mast cells play a role in both physiological processes and the pathophysiology of many diseases, including problems with the bones. They release inflammatory mediators that control bone homeostasis and trigger osteoclastogenesis, such as histamine and TNF-α [9].

3.1.6 Natural killer cells

Natural killer cells (NK) are crucial for maintaining homesostasis and immunoregulation because they regulate the activity of T-cells. They aid in the development of inflammatory illnesses by triggering inflammatory processes and cytotoxicity. NK cells have been observed in synovial regions that are inflamed at an early stage of RA, according to certain publications. Both M-CSF and factor-kB ligand (RANKL), which are potent osteoclastogenesis activators, are produced by these NK cells [13].

3.1.7 Innate lymphoid cells (ILCs)

A boom in study led to the discovery of the innate lymphoid cells (ILCs), a newly emerging component of the innate immune system. ILCs were categorized into three groups; Group 1, Group 2, and Group 3 ILCs. ILC1 and NK cells are in Group 1. T-box transcription factor (T-bet) and IFN- cytokine are essential for the growth and operation of these cells. ILC2 is a member of Group 2 and secretes IL-4, IL-5, IL-9, and IL-13 cytokines. ILC2 depends on the transcription factors GATA binding protein-3 (GATA-3) and retinoic acid receptor-related orphan receptor alpha (ROR) for its development. ILC3 and lymphoid tissue inducer cells (LTi), which depend on the transcription factor RORt for their growth and release the cytokines IL-17 and IL-22, are members of group 3. The expression of either the CC chemokine receptor-6 (CCR-6) or the natural cytotoxicity receptor (NCR), which consists of NKp30, NKp44, and NKp46, further categorizes ILC3s into subsets. ILCs are a new class of lymphocytes that mimic the appearance and capabilities of T helper cells. ILC1, ILC2, and ILC3 are analogous to the Th1, Th2, and Th17 CD4+ T helper cells of the adaptive immune system, respectively, in terms of origin and function. ILCs have been identified to have a role in tissue remodeling, defense against infections, and tissue homeostasis. They are primarily concentrated at barrier surfaces. The pathophysiology of inflammatory and autoimmune disorders such multiple sclerosis (MS), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and anti-neutrophil cytoplasmic antibody (ANCA) linked vasculitis has been linked to dysregulation in the activation of ILCs, according to several studies [23, 24].

3.1.8 ILC1

Similar to Th1, ILC1 relies on T-bet for development and generates large amounts of the hallmark cytokine IFN- to defend against inflammatory diseases and intracellular infections. ILC1s activate conventional macrophages in response to the intracellular pathogen by using IFN-. ILC1 cells, which share similarities with Th1-cell type, have the potential to reduce bone loss in a mouse model of osteoporosis by producing IFN-. ILCs have been found to release RANKL, which has the potential to improve the differentiation of OCs [24].

3.1.9 ILC2 & ILC3

ILC2s can be considered as the innate equivalent of Th2 cells. According to a study, ILC2s reduced osteoclastogenesis both in vivo and in vitro by releasing IL-4 and IL-13 cytokines. The generation of IL-4/IL-13 cytokines and STAT6 activation in OCs progenitors were linked to ILC2’s anti-osteoclastogenic and anti-osteoporotic properties. The innate counterparts of Th17 cells are ILC3s. ILC3s are dependent on the production of reactive oxygen species and a metabolic pathway that integrates glycolysis and mitochondrial lipid oxidation [24].

3.1.10 ILCregs

ILCregs are a type of innate lymphoid cells that have a distinct genetic identity from other ILC subpopulations and regulatory T cells. They are present in the gastrointestinal tracts of both humans and mice and are responsible for regulating immune responses. These cells can reduce the activation of ILC1 and ILC3 by secreting IL-10, which supports the resolution of intestinal inflammation. The discovery of ILCregs’ immunosuppressive activities through the secretion of IL-10 could lead to new research avenues and suggest their potential role in controlling osteoporosis [25].

3.2 Role of adaptive immune cells in osteoporosis

The adaptive immune system is crucial in preventing reinfection from pathogens by providing various resistance strategies and memory responses. B and T cells are significant elements of the adaptive immune system, and they have the potential to impact bone health in osteoporosis. In this section, we will delve into the role of these lymphocytes in osteoporosis.

3.2.1 T cells

The T cells of the adaptive immune system play a crucial role in maintaining bone health. When T cells are at rest, they can prevent osteoclasts (OCs) from breaking down bone. However, when activated, they can increase bone resorption by promoting the production of OCs through the production of RANKL. Studies have shown that interferon-gamma (IFN-γ) has a negative correlation with T cell activation and the process of bone resorption. IFN-γ interferes with RANKL-RANK signaling, leading to the degradation of the RANK adaptor protein (TRAF6) and inhibiting osteoclastogenesis [26].

3.2.2 Tregs/Th17 cells

The balance between regulatory T cells (Tregs) and inflammatory T cells (Th17) is crucial for maintaining immunological homeostasis, and research into these cells has experienced an unprecedented boom. Pathogenesis of bone-related illnesses, including osteoporosis, is heavily influenced by an imbalance between these immune cells. Th17 cells are T effector cells, but pTregs and tTregs, which are generated from the thymus, are both members of the regulatory cell lineage. According to a study, pTregs are locally involved in regulating effector activities of T cells at the site of inflammation, whereas tTregs are involved in the maintenance of immunological homeostasis and broad-spectrum autoimmune disorders [24].

3.2.3 Memory T cells

After the initial antigenic exposure, memory T cells are produced, and they are essential for maintaining robust immune responses against these antigens. BM is where memory T cells often reside since it offers a suitable environment for their self-renewal. DCs have been seen to live longer and express more IL-7 and IL-15 cytokines in estrogen-deficient environments. Together, these cytokines cause memory T cells to produce IL-17A and TNF- without the need for an antigen [27].

3.2.4 B cells & regulatory B cells (Bregs)

The potential of B cells in osteo-immunological regulation is being highlighted by new research, which is further validated by the physiological and anatomical coexistence of B cells and bone cells in BM. According to a paper, RANKL not only improves OC development but also boosts the amount of B cells, which serve as an additional OC supporting cell. Numerous studies have shown that B cells have “non-humoral” functions, or immunomodulatory qualities that are independent of secreting antibodies [24].

The immunosuppressive subset of B cells in the B cell lineage known as regulatory B cells (Bregs) is known to inhibit inflammation in a variety of autoimmune and inflammatory disorders. Bregs have been found to inhibit the progression of arthritis by releasing the cytokine IL-10 in the arthritic model. The subpopulation of Bregs, CD19 + CD1dhiCD5+, which is highly enriched for IL-10, has characteristics that can inhibit osteoclastogenesis. In bone fracture patients, the frequencies of IL-10-producing Bregs (IgM + CD27+) were significantly increased during the early healing state (6 weeks after surgery), indicating the role of Bregs in mediating the fracture healing process [24].

4. Immune dysfunction and osteoporosis

Immune cells and inflammatory chemicals are essential for bone remodeling, and immune system dysregulation can cause bone loss and the onset of osteoporosis.

1. Inflammatory cytokines: Chronic inflammation, which is characterized by increased production of pro-inflammatory cytokines like interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha), has been associated with accelerated bone loss and osteoporosis. These cytokines can increase the activity of osteoclasts, which are bone-degrading cells. There will be further bone resorption consequently [28].

2. RANKL and immune cells: The receptor activator of the nuclear factor-kB ligand (RANKL) molecule is necessary for both osteoclast formation and bone resorption. Immune cells such as T cells and B cells can create RANKL, which promotes osteoclast activity. Immune system imbalances may cause an excessive amount of RANKL to be produced, which can lead to bone loss [28].

3. Autoimmune diseases: Numerous autoimmune conditions that impair the immune system and are connected to an elevated risk of osteoporosis include systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These conditions are brought on by the immune system attacking the body’s own tissues specially the joints in the wrong way, which weakens the bones and leads to chronic inflammation [28].

4. Osteoporosis by glucocorticoids: It is well-recognized that long-term use of glucocorticoids, such as prednisone, causes bone loss and increases the risk of developing osteoporosis. Glucocorticoids can affect the immune system, which can lead to aberrant bone remodeling, by reducing immune cell function and suppressing the production of pro-inflammatory cytokines [29].

5. Lack of estrogen: Osteoporosis is a major cause of estrogen loss after menopause since estrogen is necessary for maintaining bone health. Furthermore, estrogen has immunomodulatory effects, and immune system modifications brought on by estrogen deficiency may contribute to bone loss.

5. Potential immunological markers for osteoporosis diagnosis and prognosis

Numerous indicators may be able to predict the risk of fracture in osteoporosis. These include sphingosine-1-phosphate, sclerostin, periostin, macrophage migration inhibitory factor, and indicators of bone turnover. Additionally, it has been demonstrated that bone alkaline phosphatase and collagen-I-N-terminal propeptide can be used to predict the risk of fracture in older women.

5.1 Sphongosine-1-phosphate

Sphongosine-1-phosphate (S1P), a highly bioactive lysophospholipid that has been linked to a variety of biological processes including cell migration, localization, apoptosis, proliferation, and differentiation, has been shown to play a role in both extracellular and intracellular communication. S1P receptors (S1PRs) are expressed by osteoblasts as well as osteoclasts. Osteoblast survival, proliferation, and motility are stimulated by S1P, which osteoclasts release. The fascinating thing about S1P is that it is abundant in the bloodstream but is degraded irreversibly by S1P phosphatase and/or S1P lyase, leaving it low in other tissues. This assumes that S1P would be a viable biomarker predictive of phenotypes associated with osteoporosis because of this easily measured blood characteristic [30, 31].

5.2 Leucine-rich repeat-containing 17

A 37 kDa protein called leucine-rich repeat-containing 17 (LRRc17) has a secretary feature and five putative LRR domains. LRRc17, which is abundantly expressed in osteoblasts, inhibited NFATc1 signaling from RANKL-mediated activated T-cells, which therefore attenuated osteoclast genesis from BM precursors [32, 33].

5.3 Macrophage migration inhibitory factor

Macrophage migration inhibitory factor (MIF) is a 37.5 kDa cytokine that interacts with CD74 to have a variety of biological effects. Along with playing a role in the control of immunological and inflammatory processes. MIF has become a significant figure in bone metabolism [31, 33].

5.4 Sclerostin

Sclerostin is a protein that is secreted, largely by osteocytes, and whose concentration rises with aging. Sclerostin is a dual action molecule that negatively affects skeletal homeostasis by increasing bone resorption and decreasing bone formation. It also increases the development of osteocyte-derived RANKL. In order to support the notion that sclerostin is the perfect biomarker of human bone metabolism, various epidemiologic investigations have been conducted [31].

5.5 RANKL

RANKL plays essential roles at every stage of osteoclastogenesis and bone resorption. Although RANKL is expressed in various cell types, including osteoblasts, conditional genetic deletion indicates that osteocytes are the major source of RANKL needed for osteoclast formation [33].

5.6 Periostin

The extracellular matrix protein periostin, which contains glutamate, was first discovered in mouse pre-osteoblast MC3T3-E1 cells. It was given the name osteoblast-specific factor 2 at that time. Periostin is advantageous for bone metabolism, according to studies done on genetically modified mice [33].

6. Current treatment approaches for osteoporosis

The most popular treatments right now are anti-resorptive ones, which concentrate on stopping or slowing down the process of bone resorption. These medications include monoclonal antibodies, bisphosphonates, selective estrogen receptor modulators (SERMs), and estrogens.

Bisphosphonates are drugs that slow the loss and disintegration of bone (also known as resorption). They are frequently utilized in the management of osteoporosis. Alendronate, risedronate, ibandronate, and zoledronic acid are a few of the bisphosphonates that are commonly prescribed.

Hormone levels, particularly those of estrogens, play a significant role in bone resorption. SERMs have improved in their ability to lessen the adverse effects of estrogens. Although they can maintain bone mineral density (BMD) and show selectivity toward estrogen receptors in the bone, they are not as effective as conventional estrogens. Numerous clinical studies with postmenopausal osteoporotic women utilizing various SERMs have demonstrated that their value for fracture prevention is physically limited (present certain restrictions in preventing non-vertebral fractures). As well as having negative extra-skeletal effects, SERMs are also linked to related side effects such thromboembolic events and, in certain circumstances, carcinogenesis. These effects include a higher risk of cardiovascular events and endometrial cancer. The most popular anti-resorptive medications are bisphosphonates. Because of its affinity for hydroxyapatite, pyrophosphate analogues known as bisphosphonates attach to hard bone. They are absorbed by osteoclasts and integrated into the bone matrix, which inhibits their activity in bone remodeling. In this manner, bone density rises, but the quality of the bone is compromised since the aged bone is more likely to experience microfractures that impair its functionality. Additionally, long-term usage of bisphosphonates might result in unfavorable effects such as musculoskeletal discomfort, atrial fibrillation, osteonecrosis of the jaw, and gastrointestinal issues [34].

Denosumab is a monoclonal antibody that binds to the receptor activator of nuclear factor kappa-B ligand (RANKL) with a high affinity. By limiting the interaction of RANKL and RANK, the osteoclasts’ ability to differentiate and function is inhibited. Regular adherence to Denosumab medication is a major worry because the patient’s fracture risk could go up after the dose wears off. Another monoclonal antibody, Romosozumab, was just given the go-ahead by the US Food and Drug Administration to treat osteoporosis in postmenopausal women. It is the first humanized anti-sclerostin monoclonal antibody that has been demonstrated to increase bone formation with a dual effect. It does so by increasing bone formation while also, albeit to a lesser extent, reducing bone resorption (or bone loss), which lowers the risk of fracture [34, 35].

The existing osteoporosis treatments do not work completely in all individuals and have a number of adverse effects that substantially jeopardize their long-term efficacy. Thus, with a population that is aging and living longer, there is a need for the creation of novel therapeutic approaches for osteoporosis. However, there are some of the emerging therapies for osteoporosis.

Romozumab: A humanized monoclonal antibody called romozumab suppresses sclerostin. Sclerostin, a protein released by osteoclasts in the skeletal tissue, prevents osteoblasts from proliferating and functioning normally, hence reducing bone production [36]. Odanacatib: Odanacatib is a protease that selectively inhibits CatK, a protease that osteoclasts produce to hasten the breakdown of collagen in bones. It is hypothesized that inhibiting CatK will reduce bone resorption without reducing bone growth.

Lasofoxifene: A third generation SERM is lasofoxifene (Sermonix) [37, 38].

7. Conclusions and future directions

The primary goal of this book chapter is to deliver about the fragility fractures, which cause significant morbidity and impairment. In summary, osteoporosis is a complicated, chronic bone disease that has a big impact on health, finances, and society. Osteoporosis affects quality of life mostly through pain and functional limits, and it is predicted that in the coming years, its prevalence will increase dramatically. The delicate balancing act between bone formation and resorption that underlies the pathophysiology of osteoporosis is controlled by a number of immune cells, cytokines, and communication pathways. Osteoimmunology, a new subject, emphasizes the delicate relationship between bone health and the immune system. Both lymphoid and myeloid immune cells have a role in bone maintenance and remodeling. In the maintenance of bone homeostasis, specific functions are played by macrophages, dendritic cells, neutrophils, NK cells, ILCs, T cells, B cells, and regulatory B cells. The development of osteoporosis and bone loss can result from the dysregulation of these immune cells and inflammatory chemicals. To enhance the management of osteoporosis, new therapeutic modalities are being investigated. Monoclonal antibodies that target particular molecules, such as RANKL and sclerostin, have the potential to change the dynamics of bone remodeling. Protease inhibitors and third generation SERMs are further possible substitutes for traditional treatments. Future study into the immunological systems underlying osteoporosis is essential for creating cutting-edge therapeutic approaches. More individualized methods might result from the discovery of specific immunological markers for early diagnosis and prognosis. Immunotherapy, which focuses on controlling immune responses to improve bone health, has promise as a novel treatment option.

As our knowledge of the interaction between the immune system and bones grows, novel therapeutic approaches may be developed that will change the treatment of osteoporosis and enhance the lives of millions of people who are impacted by the disease.