Lipid metabolism in age-related musculoskeletal disorders: insights into sarcopenia and osteoporosis

Abstract

Musculoskeletal disorders (MSDs), notably sarcopenia and osteoporosis, profoundly affect aging individuals. This review explores lipid metabolism's role in age-related MSD pathophysiology, highlighting fatty acid uptake, lipid signaling, and lipotoxicity in muscle deterioration. It further addresses lipid-mediated regulation of osteoclasts, osteoblasts, and bone remodeling, emphasizing age-associated metabolic shifts exacerbating bone loss. Emerging therapeutic strategies targeting lipid pathways for MSD treatment are also discussed. This review integrates recent findings in muscle and bone lipid metabolism to deepen understanding of lipid dysregulation in musculoskeletal disorders and explore potential metabolic intervention strategies.

Introduction

Age-related musculoskeletal disorders, including osteoporosis and sarcopenia, are prevalent conditions that substantially impair physical function and contribute to emotional stress [1]. These conditions can lead to chronic pain, decreased mobility, and an increased risk of bone fractures in affected individuals, impacting their ability to perform daily activities independently [2]. These disorders contribute to a considerable economic burden through increased healthcare costs, lost productivity, and reduced workforce participation [3]. Musculoskeletal conditions are associated with 574 million physician visits and 21 million hospital admissions yearly [3]. In the years 2009–2011, those living with MSDs were responsible for an aggregate economic impact of $796.3 billion [3]. More recently, in 2015, this figure grew to $874 billion when accounted with other disorders such as diabetes and heart disease, almost six percent of the United States’ gross domestic product [4]. Much of the financial burden associated with age-related musculoskeletal disorders is attributable to bone and muscle loss.

Bone loss can be seen as a reduction in bone mineral density and deterioration of bone tissue over time, increasing fracture rates and leading to conditions such as osteoporosis [5]. An estimated 53.6 million individuals had osteoporosis and low bone mass in 2010, and this number is expected to grow 17.2 million by 2030 [6]. The lifetime risk of fracturing associated with osteoporosis is as high as 40%, carrying a 12-month excess mortality of up to 20% [5]. Muscle loss, also known as sarcopenia, is the progressive decline in skeletal muscle mass and strength that occurs with aging [7]. This loss of muscle function can lead to decreased mobility, increased risk of falls, and overall decline in physical performance [8]. The prevalence of sarcopenia ranges from 3 to 24%, increasing with age in individuals over the age of 65 [9]. According to the guidelines placed by the European Working Group on Sarcopenia in Older People (EWGSOP), the prevalence is 7.1% when both loss of muscle mass and loss of muscle function are considered and 11% when only the muscle mass loss criterion is included [9]. The progression of osteoporosis and sarcopenia often develops very slowly. Current data shows that the lean muscle mass of individuals over 30 years-old declines by about 3 to 8% per decade and 10% after age 60 [10].

Understanding the pathophysiology of bone and muscle loss is critical for early diagnosis and identifying therapeutic targets. Dissecting the underlying mechanisms that drive pathophysiological changes will help develop more effective diagnostic tools, interventions, and treatment strategies. Our group is actively involved in understanding nutritional signaling and its impact on age-related musculoskeletal pathology [11–14]. Our group demonstrated that age-related alterations in tryptophan metabolism play a significant role in bone and muscle loss. We established a strong correlation between elevated kynurenine levels, a key metabolite in the tryptophan pathway, and an increased incidence of fractures [15].

Additionally, our recent studies revealed age-related shifts in nutritional metabolites [16] and identified changes in lipid metabolite profiles with age [16]. These findings underscore the critical impact of wider metabolic alterations on skeletal and muscular health in aging populations. Over the past decade, several groups have elucidated the mechanisms underlying lipid metabolism and its association with musculoskeletal disorders (MSDs). Building upon those findings and recent advancements in the field, we have compiled a comprehensive summary of data concerning lipid metabolism and its effects on MSDs. This narrative comprehensive review encompasses the latest developments in bioactive lipid metabolism and its relation to osteoporosis and sarcopenia.

General lipid metabolism

Lipids are vital in maintaining cellular structure, energy storage, physiological functions, growth, and development [17]. Lipid metabolism refers to the complex biochemical processes by which lipids (fats and fat-like substances) are synthesized, broken down, and utilized in the body [17]. This includes the digestion, absorption, transport, and storage of lipids and their conversion into energy and other necessary molecules [17].

To begin, the ingestion of fats from the diet is broken down into micelles, which aid in lipid absorption [18]. Once these micelles have been absorbed, the lipid contents are restructured into triglycerides (TAGs) [18] and are transported via the lymphatic system and bloodstream to target tissues or the liver. The liver plays a key role in lipid metabolism by synthesizing and secreting very low-density lipoproteins (VLDL), which further break down triglycerides, taking up fatty acids for either energy production or storage [19]. Lipids are most commonly stored in adipose tissue, which is crucial for storing and releasing lipids [20]. Once TAGs have reached the peripheral tissues, they undergo lipolysis, in which lipase hydrolyzes triglycerides, yielding fatty acids (FA) and glycerol [20]. Adipocytes, common reservoirs for these molecules, release fatty acids as an energy source for other tissues, such as bone and skeletal muscle. Glycerol and fatty acids also serve as initial compounds to synthesize phospholipids and other vital molecules. After metabolizing lipids into fatty acids, a process known as beta-oxidation can occur, which further metabolizes fatty acids into Acetyl-CoA, allowing for it to enter the tricarboxylic acid (TCA) cycle and be used to generate NADH and FADH2.

To start beta-oxidation, fatty acids must be transported into the mitochondrial matrix. Since fatty acids are negatively charged, they cannot be transported between a biological membrane. Instead, Long-chain-fatty-acid Co-A ligase facilitates a reaction between fatty acids, ATP, and acetyl-CoA, resulting in a fatty acyl-CoA ester. With that, if the fatty acid is short-chained, it can now simply diffuse through the mitochondrial membranes into the matrix. If the fatty acid is long-chained, however, the carnitine shuttle will need to be utilized [21].

In the outer mitochondrial membrane, the carnitine palmitoyltransferase (CPTI) attaches fatty-acyl-CoA ester to carnitine, which is then shuttled into the intermembrane space. Then, through the Carnitine-acylcarnitine translocase (CACT) the fatty acid is transported into the matrix. The carnitine palmitoyl transferase (CPTII) in the inner membrane will break the molecule into fatty-acyl-CoA ester and carnitine [21]. Upon arrival into the matrix, several biochemical processes result in an Acetyl-CoA generation. The first step is dehydration, where acyl CoA dehydrogenase catalyzes the formation of a trans double bond between the alpha and beta carbons on acyl CoA molecules. The next step is hydration, where CoA hydratase adds a hydroxyl (OH-) group to the beta carbon and a proton (H +) to the alpha carbon in the double bond. The third step is oxidation, where beta-hydroxyl acyl CoA dehydrogenase removes electrons and two protons from the hydroxyl group and oxidizes the beta carbon to produce NADH [21].

The fourth and final step of beta-oxidation is thiolysis. Beta-keto thiolase cleaves the bond between the alpha and beta carbon. This entire reaction produces one molecule of acetyl CoA, regulated by malonyl-CoA, and a fatty acyl CoA which is two carbons shorter. The acetyl-CoA is oxidized in the mitochondrial matrix to reduced coenzymes NADH and FADH₂, crucial for oxidative phosphorylation in the electron transport chain (ETC) [21]. Electrons from NADH and FADH₂ are shuttled through the ETC to establish an electrochemical gradient across the inner mitochondrial membrane. The gradient is used by ATP synthase to produce adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate (Pi) [21]. Therefore, the coupling of lipid metabolism with the TCA cycle provides a continuous energy supply that supports numerous cellular processes, including those critical to the function of the musculoskeletal system.

Involvement of lipid metabolism in musculoskeletal disorders

To gain a broader understanding of the involvement of lipid metabolism in bone (osteoporosis) and muscle (sarcopenia) disorders, we leveraged the Lipidisease database. This comprehensive resource provides insights into lipid metabolic alterations linked to various diseases [22]. LipiDisease is a specialized bioinformatics resource that integrates lipid-gene-disease associations by mining large-scale literature data and curated databases. It provides systematic and comprehensive insights into how specific lipid species and their metabolic pathways are implicated in various diseases, including metabolic, musculoskeletal, and degenerative conditions. The strength of LipiDisease lies in its ability to uncover less obvious or underappreciated lipid-gene-disease relationships by integrating experimental data with published associations, making it a valuable complement to conventional literature reviews.

In the context of sarcopenia and osteoporosis, both conditions are increasingly recognized as being influenced by altered lipid metabolism, but much of the available literature remains fragmented. Using LipiDisease allowed us to capture a broader, unbiased network of lipid-related genes and pathways associated with musculoskeletal health and diseases. This approach allowed us to systematically investigate how dysregulation in lipid pathways contributes to the pathophysiology of osteoporosis and sarcopenia. The Lipidisease tool explores the PubMed database and performs full-text mining for various disorders. The tool takes into account 4,270 diseases and 4,798 lipids. The lipid-to-disease analysis offers statistical data on lipid levels, including p-values and False Discovery Rates (FDR), while also providing relevant PubMed IDs for subsequent analysis. While this analysis identifies targets with statistical confidence, it does not reveal the direction of the perturbation. In our analysis of lipid-related metabolic changes across musculoskeletal diseases, we identified 38 lipid-related entities significantly perturbed in muscular diseases, compared to 15 in osteoporosis (Fig. 1).

Fig. 1.

Altered Lipid metabolite composition in musculoskeletal pathogenesis. A 38 lipid-related entities were found to be significantly perturbed in muscular diseases, while only 15 were found to be significantly affected in osteoporosis. B and C showcase broad biological classification of the perturbed entities in muscular diseases and osteoporosis, respectively. Osteoporosis shows a higher number of perturbations in steroid hormones and sterols categories compared to muscular diseases. D KEGG biological pathways related to the perturbed biological pathways

Interestingly, osteoporosis exhibited a more significant number of perturbations in the steroid hormones and sterols categories than muscular diseases. These findings highlight distinct lipid metabolic disruptions between these two disorders. The differential lipid metabolism perturbations observed in muscular diseases and osteoporosis highlight the different roles of lipid species in these disorders. Muscular diseases exhibit widespread lipid intermediates and fatty acid metabolism alterations, contributing to muscle atrophy and inflammation. In contrast, osteoporosis is more affected by steroid hormones and sterols, which regulate bone resorption and formation. Based on these findings, we summarize the recent advancements in understanding bioactive lipid metabolism and its direct connection to the pathogenesis of osteoporosis and sarcopenia. These insights reveal bioactive lipids'significant and complex roles in maintaining musculoskeletal health, shedding light on their potential as therapeutic targets.

Lipid metabolism in muscle cells

Lipid metabolism in muscle cells differs significantly from that in other cell types due to the unique energy demands and specialized functions of muscle tissue. Skeletal muscle cells undergo distinct lipid metabolic processes to support their contractile activity, endurance, and overall physiological functions. These include glucose and lipid uptake, as well as thermogenic function. Skeletal muscle cells differ from the general metabolic pathway in that they exhibit a high degree of metabolic flexibility when faced with acute lipid oversupply that increases fatty acid utilization [22].

Regarding lipid uptake, FAs can move into skeletal muscle cells using FA binding proteins [23] and various transport proteins, upregulated by stimuli classic to skeletal muscle, including contraction [24]. A protein called FA translocase relocates to the plasma membrane from the cytoplasm in response to elevated lipid supply and fatty acid uptake in skeletal muscle (Fig. 2) [25]. In terms of the presence of FA transport proteins (FATPs) [26], FATP1, FATP4, and FATP6 are also commonly expressed skeletal muscle proteins linked to lipid uptake [27]. While their function needs to be more closely studied, FATP1’s overexpression in T-tubules is linked to increased FA oxidation in skeletal muscle [28]. Through contraction and insulin stimulation, FATPs, specifically FATP1 and FATP4, are translocated to T-tubules and increase FA uptake [29]. Once FAs are present in the skeletal muscle tissue, they can be utilized for various muscle activities, depending on the metabolic status of these skeletal muscle cells [30].

Fig. 2.

Schematic figure illustrating the key pathways involved in lipid metabolism within muscle cells, highlighting the uptake, storage, and utilization of lipids for energy production. Diagram abbreviations: TAG (Triglyceride), DAG (Diglyceride), FATP (Fatty Acid Transport Protein), PLIN (Perilipin), ACC (Acetyl-CoA Carboxylase), CPT1 (Carnitine Palmitoyltransferase 1). This image was created with BioRender (https://biorender.com/)

Skeletal muscle cells express three key lipases: monoacylglycerol lipase, adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL), all of which are involved in the breakdown of TAG [31]. Monoacylglycerol lipase is responsible for the breakdown of monoacylglycerol, while ATGL is responsible for the catalysis of the first step of TAG lipolysis [30]. ATGL overexpression has been linked to increased lipolysis and the expression of transcription factor PPARδ. Given its involvement in mitochondrial biogenesis, ATGL is thus associated with increased oxidative capacity in skeletal muscle [32]. As this review will explore later in its alterations of lipid metabolism, findings show that a decrease in ATGL expression characterizes aged muscle and is associated with sarcopenia [33].

In addition to the specialized utilization of lipids in skeletal muscle, their storage plays a critical role in maintaining intracellular lipid homeostasis [30]. In skeletal muscle cells, lipids are stored within lipid droplets (LDs), primarily composed of neutral lipids and sterol esters [34]. The surface of LDs is covered with proteins from the PAT family, a lipid droplet-associated protein family containing peripilins (PLINs) [35]. This family comprises 5 members that control TAG hydrolysis in adipose tissue. PLIN 2 is highly expressed in adipose and skeletal muscle and positively correlates with LD content in skeletal muscle [36]. PLIN4, however, is expressed in skeletal muscle, heart, and adipose tissue and is located in LDs containing cholesterol esters [37]. PLIN5 is expressed on both surfaces of LDs and plays a role in the communication between LDs and the mitochondria, with its overexpression leading to mitochondrial biogenesis and electron transport chain complexes [38].

Recent studies also have shown that lipid droplet (LD) formation plays a regulatory role in muscle stem cell biology. Particularly, satellite cell activation, which is responsible for muscle degeneration and early differentiation is heavily influenced by LD formation [39]. LDs are unequally distributed in newly divided muscle stem cells, where the LD (Low) cell self-renews while the LD (High) cell commits to differentiation. Pharmacological inhibition of LD biogenesis impairs both the regenerative potential and homeostatic maintenance of muscle stem cells. These findings establish a functional link between LD formation and the regulation of muscle stem cell fate and function [39]. LDs are distributed either as ‘intramyofibrillar’ (IMF), or just below the surface membrane or ‘subsarcolemmal’ (SS) [40]. The IMF and SS LDs are the presumed fuel source their respective mitochondria, which provides energy for muscle contraction. These LDs also appear to buffer excess fatty acids and regulate signaling through mitochondrial pathways, influencing oxidative metabolism and the progression toward myogenic lineage. Impairment of LD formation or function can impair muscle regeneration, indicating that the proper handling of lipid intermediates during this early phase is essential for satellite cell function and muscle repair [40].

Alterations in lipid composition in skeletal muscle

As mentioned above, muscle tissue contains various lipids, including phospholipids, sphingolipids, and neutral lipids. These lipids are crucial for maintaining membrane integrity, signaling, and energy production [41]. The balance between these lipids in healthy muscle tissue supports optimal muscle function and adaptation. Muscle tissue, known for its abundance of specialized mitochondria with lipid membranes, typically contains high levels of phosphatidylethanolamine and phosphatidylcholine, while having low levels of sterols and sphingolipids under healthy conditions [42]. Dyslipidemia and oxidative damage can cause changes to this muscle lipidome with age. This section will highlight the most notable changes in lipid composition within skeletal muscle mitochondria associated with aging.

Pollard et al. [42] analyzed the lipid composition of enriched mitochondrial fractions of the skeletal muscle ranging from 4 to 78 weeks old mice tissue. They found that two of the top five lipids increased in abundance with age [42]. These lipids are responsible for interacting with inner mitochondrial membrane lipids and are vital for oxidative phosphorylation, mitochondrial dynamics, and apoptosis. In terms of the top five lipids found to decrease in abundance with skeletal muscle aging, several of these were classified as lysophosphatidylcholines and docosatetraenoic acid. The study also found that triglycerides increase in aged skeletal muscle mitochondria while general phosphatidylethanolamines decrease [42]. They reported elevated levels of ceramides, cardiolipin, and phosphatidylcholine with age, whereas reduced levels of lysophosphatidylcholine, phosphatidylethanolamine, and docosatetraenoic acid with age [42]. These changes are important to note, given that increased TGs in the cytosolic space have been associated with mitochondrial dysfunction. In contrast, decreased levels of PE have been associated with abnormal mitochondrial morphology and reduced respiratory capacity.

Preuss et al. [43] have recently performed a lipidomic approach to elucidate the composition of lipid droplets in various tissues, including skeletal muscle. They performed lipidomic on 22-week-old transgenic mice with NAFLD. They were able to quantify twelve DAG subtypes and eight ceramide subtypes in skeletal muscle and other tissue. In their mouse skeletal muscle lipid analysis, there was a statistically significant increase in unsaturated DAG 16:0/18:1 and oleic acid containing DAG 18:1/18:1 in both cytosolic and membrane subcellular fractions [43]. They found a 5–tenfold increase in DAG species in the LD fraction [43]. The study also noted that there was an increase in CER d18:1/18:0 in LD fractions [43]. They reported that increased DAGs and CERs lead to increased localization and spatial restriction of bioactive lipids. Another study by Rivas et al. performed lipidomic analysis on ceramide subtypes C14:0 to C24:1. Samples from the vastus lateralis muscle at the midthigh level in both young and aged males. This study measured the baseline concentrations of these most abundant ceramides in young and aged skeletal muscle. The study found that the skeletal muscle from the aged phenotype had a 156% high concentration of C16:0 ceramide compared with the young skeletal muscle sample at baseline [44]. There was also a 30% increase in C20:0 concentration in the aged phenotype compared to the young and a higher concentration of C18:0-dihydroceramide [44]. Overall, they found that the aged phenotype had more saturated ceramide, while the two groups had no differences in unsaturated or total ceramide [44]. This data helps prove the significance of ceramide subtypes in impairing contractile-induced muscle growth.

Alterations in lipid metabolism with sarcopenia

A recent study by Yang et al. has elucidated novel lipid signatures associated with sarcopenia in human studies. The study consisted of 40 sarcopenic and 40 control patients, the plasma lipids of which were quantified, and relevant lipid markers correlated with sarcopenia's clinical manifestations. In their analysis, the authors detected 34 lipid subclasses and a total of 1,446 lipid molecules. Eighty lipids were identified as differentially expressed between the sarcopenic and control groups. The differential lipids comprised 38 phospholipids, 21 ceramides and glycosylceramides, 20 triglycerides, and 9 other lipid species. 53 of these differential lipids were upregulated in the sarcopenic group compared to the control group, while 27 were downregulated. Notably, most of these differential markers were phospholipids, closely correlated with sarcopenia's clinical manifestations. To further investigate these associations linked to clinical traits. PG lipids with unsaturated fatty acids were found to be positively correlated with SMI, maximum grip strength, and daily walking steps. Lipids consisting of PC, SM, and PS showed positive correlations with TG, LDL-C, and HDL-C levels but were negatively correlated with maximum grip strength and SMI. This correlation suggests that these triglycerides and lipoproteins may induce lipid alteration in sarcopenia lipid metabolism. Furthermore, the significance of these findings is supported by a meta-analysis that reported an odds ratio (OR) of 1.47 for dyslipidemia as a risk factor for sarcopenia, with OR values of 1.27 for HDL-C and 1.95 for LDL-C, confirming a strong correlation between dyslipidemia and sarcopenia. Therefore, triglycerides and lipoproteins may serve as lipid biomarkers for muscle pathology [45].

Understanding age-related alterations in lipid metabolism in bone and muscle cells is crucial for unraveling the pathological mechanisms underlying sarcopenia and osteoporosis. This knowledge can aid in identifying therapeutic targets to prevent or delay the onset of musculoskeletal disorders (MSDs). In sarcopenic muscle, increased adipocyte infiltration is linked to impaired activation of adipose triglyceride lipase (ATGL) and disrupted lipid signaling through PPARα [33]. This disruption leads to elevated levels of proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which contribute to muscle degeneration [46]. The decreased expression of ATGL in sarcopenia may impair lipid metabolism and reduce the muscle's capacity to counteract age-related inflammation, exacerbating muscle loss. These insights could provide a foundation for developing interventions aimed at mitigating sarcopenia.

In addition to an altered ATGL profile, sarcopenic patients typically have elevated levels of LDs, fewer mitochondria, and live a more sedentary lifestyle [47]. As such, several metabolic pathways have been studied to determine the cause of lipid accumulation in the muscle, including the accumulation of sphingolipid ceramide, myosteatosis through fibro/adipogenic progenitors (FAPs), and general inflammation [47]. Lipid accumulation in skeletal muscle can cause lipotoxicity and is responsible for organelle damage involved in metabolism. These lipid intermediates include lipid-derived DAGs and ceramides [48]. More specifically, lipotoxicity alters insulin-stimulated glucose uptake by activating serine/threonine kinases [49]. These kinases impair insulin receptors and reduce their ability to activate downstream targets such as IRS-1, which ultimately decreases the concentration of glucose transporter 4 (GLUT4) in the plasma membrane and reduces glucose uptake in skeletal muscle [50]. This insulin resistance may be further aggravated by lipid intermediate over-flux of the mitochondria through the increased production of reactive oxygen species (ROS) [51]. In this over-flux, lipid accumulation drives intrinsic protein kinase activity that alters insulin pathways [47].

In addition to the accumulation of ceramides and their impact on insulin signaling, LDs play an important role in skeletal muscle homeostasis. As explored previously, LD family members, including perilipins (PLINs), are responsible for lipolysis and TAG hydrolysis in adipose tissue. It has been shown that PLIN2 specifically plays a role in muscle lipotoxicity, as its overexpression has been linked to increased myocellular fat storage and TAG accumulation in LDs [52]. It has also been found that PLIN2 overexpression increases palmitate-induced debilitation of insulin signaling in skeletal muscle [52]. PLIN2 overexpression also results in GLUT4 inhibition by retaining SNARE proteins responsible for vesicle fusion. PLIN2 is paramount in regulating the skeletal muscle insulin response, and changes in its concentration may cause significant impairment in lipid signaling.

Lipid metabolism in bone cells

Bone consists of specialized cells that play crucial roles in forming, maintaining, and remodeling bone tissue. They mainly consist of osteoclasts, osteocytes, and osteoblasts [53]. Although these cells share many characteristics with the general lipid pathway, they also have unique processes that warrant further exploration. More studies are still necessary to understand lipid-mediated regulation in these cell types. It is known that 10% of the human skeleton undergoes remodeling annually [54]. As such, lipids play an essential role in controlling the differentiation of these bone cells. In bone cells, lipids form membranes, store energy and transduce critical signals for activity and function, composing 28–84% of neutral lipids in the bone marrow [54].

Cholesterol, an essential lipid, plays a vital role in osteoclastogenesis. It is crucial for the formation and function of lipid rafts, which are specialized microdomains within the plasma membrane (Fig. 3). These lipid rafts are important in regulating RANK-RANKL signaling pathways, essential for osteoclast differentiation. Cholesterol's role in maintaining lipid raft integrity thus directly impacts the efficiency and regulation of osteoclast formation and function. Cholesterol also impacts bone turnover, with excess accumulation leading to decreased bone mass [54]. However, too little cholesterol can also lead to the induction of osteoclast apoptosis. In addition to cholesterol, lipoproteins are also crucial to bone cells in that they determine osteoclast viability by regulating cholesterol importation. Previous studies have even found that cells cultured in LDL-depleted serum had lower levels of osteoclast differentiation [54]. More broadly, fatty acids also have a unique impact on osteoclast function. Long-chain polyunsaturated fatty acids (LCPUFAs) have been seen to suppress osteoclast formation in CD14-positive monocytes, reducing bone resorption [55]. Thus, LCPUFAs have been found in many studies to exhibit a protective effect from pathological bone destruction [54]. More specifically, ⍵−3 LCPUFAs positively correlate with BMD in humans [56]. Supplementation of these specific LCPUFAs has been found to reduce bone resorption in rats and enhance bone formation in periapical areas [57]. Another class of fatty acids, unsaturated fatty acids (UFAs), has also been shown to inhibit osteoclastogenesis in CD14-positive monocytes [54]. In bone cells, peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors, play a crucial role in suppressing osteoclastogenesis. UFAs, particularly monounsaturated (MUFAs) and polyunsaturated fatty acids (PUFAs), act as ligands for these receptors, resulting in PPAR activation, which exerts protective effects on bone, as demonstrated with long-chain polyunsaturated fatty acids (LCPUFAs) [58]. While the impact of lipid metabolism on bone physiology is well-documented, other lipid classes, such as saturated fatty acids (SFAs), short-chain fatty acids (SCFAs), and medium-chain fatty acids (MCFAs), also influence osteoclast differentiation and bone function [54].

Fig. 3.

Schematic diagram showing the crucial role of lipid metabolism in maintaining bone homeostasis. Diagram abbreviations: HSC (Hematopoietic Stem Cell), SPT (Serine Palmitoyltransferase), ⍵−3LCPUFA (Omega-3 Long Chain Polyunsaturated Fatty Acid), PPAR (Peroxisome Proliferator-activated Receptors (PPAR), MSC (Mesenchymal Stem Cell), SFA (Saturated Fatty Acid). This image was created with BioRender (https://biorender.com/)

Bioactive lipids such as ceramides also play important roles in bone biology [59, 60]. Ceramide biosynthesis takes place with the help of the rate-limiting enzyme serine palmitoyl transferase (SPT). SPT involves various cellular processes, including cell growth, differentiation, and inflammation [59]. Elevated ceramide levels have been linked to mitochondrial dysfunction and increased cellular stress in bone cells [59, 61]. Ceramides may disrupt bone remodeling processes by affecting osteoblast and osteoclast function, leading to bone loss and osteoporosis [62]. Inhibiting SPT can reduce ceramide levels, restore mitochondrial function [57], and improve bone health. However, the precise molecular mechanisms by which these lipids modulate bone signaling remain underexplored, necessitating further investigation. A deeper understanding of these mechanisms could help develop therapeutic strategies.

The involvement of lipid metabolism in osteocytes and osteoblasts is an emerging area of research and remains less explored than its established role in osteoclasts. It is important to note that lipids can both positively and negatively regulate osteocyte function. Saturated fatty acids have been found to induce apoptosis in osteocytes [63]. However, for the most part, studies have found that fatty acids are utilized primarily for catabolic processes [64]. The expression of carnitine palmitoyltransferase-2 (CPT2), the enzyme essential for fatty acid oxidation, affects bone density [64]. A study in mice found that female mice had low bone mass when CPT2 expression was ablated [65]. CPT2 is important for the β-oxidation of long-chain fatty acids in osteocytes and all cells, it makes sense that a deletion of the gene for osteocytes would result in changes to body adiposity [65].

Osteoblasts, the primary bone-forming cells, exhibit a distinct lipid metabolism profile compared to other cell types, such as adipocytes, which store significant amounts of energy in lipid droplets. While lipid droplets in many cells serve as reservoirs for ATP production, osteoblasts rely predominantly on extracellular lipid sources [66]. This is crucial because osteoblasts are highly active cells that require energy for bone formation, mineralization, and overall maintenance of skeletal health. In a study, the expression of adipose triglyceride lipase (ATGL) was ablated in calvarial and mature osteoblasts, which normally would inhibit lipolysis and normal usage of fatty acids [65]. However, the study found no effects on osteoblast function or bone structure itself [65], suggesting the use of extracellular lipid sources. These findings suggest osteoblasts preferentially utilize circulating fatty acids and lipoproteins rather than relying on intracellular lipid stores. Further research is necessary to elucidate the mechanisms by which osteoblasts regulate fatty acid metabolism and how extracellular lipid clearance contributes to bone health.

In addition to their reliance on extracellular lipids, osteoblasts exhibit unique lipid uptake mechanisms. Lipoprotein receptor-related protein-1 (LRP1) has been implicated in the endocytosis of chylomicron remnants containing triglycerides and cholesterol [67]. Knockout of the LRP1 gene results in an osteopenic phenotype without affecting systemic lipoprotein clearance or osteoblast fatty acid retention [68]. Similarly, when other members of the LRP receptor family, such as LRP5, were knocked out, osteoblasts retained their ability to uptake low-density lipoproteins (LDLs) [69]. These findings suggest that osteoblasts may rely on alternative pathways for lipoprotein uptake, and ongoing genetic studies [66] aim to further characterize the role of LRP receptors in osteoblast lipid metabolism.

Regarding high-density lipoproteins (HDLs), osteoblasts express scavenger receptor class B type 1 (Scarb1) as a primary receptor [66]. However, the functional role of Scarb1 in osteoblast biology remains debated. One group reports that Scarb1 null mice have displayed increased HDL-associated cholesterol, resulting in increased osteoblast surface and bone formation, which is detrimental to skeletal homeostasis [70]. However, this increased bone formation rate may be due to increased adrenocorticotropin [71]. Contrarily, other studies have reported that Scarb1 knockout results in osteopenia, characterized by reduced bone formation and resorption markers, and impaired osteoblast differentiation [72]. Additionally, impaired HDL synthesis in mice has been linked to reduced osteoblast differentiation and bone mass, suggesting a critical role for HDL in osteoblast function and differentiation [73]. The distinct interactions between osteoblasts and various lipoproteins, including their genetic regulation, require further investigation to better understand their contribution to skeletal energetics. Understanding these metabolic distinctions could provide valuable insights into conditions characterized by impaired bone formation or excessive bone loss.

Alterations in lipid composition in bone-forming cells

Like the changes in lipid metabolism found in skeletal muscle, significant shifts in lipid metabolism have also been seen in bone-forming cells in pathological conditions. These metabolic alterations significantly impact bone health and contribute to bone loss. Hyperlipidemia and oxidized lipids significantly affect osteoblasts and overall skeletal health, impacting normal bone formation, osteoblast function, and maintenance of strength and bone mass [74]. Like sarcopenia, lipid accumulation is potent in its association with dyslipidemia in osteoporotic individuals. The National Health and Nutritional Examination Survey (NHANES III) reports that 63% of osteoporotic patients suffer from hyperlipidemia [74].

To most accurately reflect the effects of dyslipidemia on bone structure, researchers have used high-fat diet (HFD) and hyperlipidemic mouse models that commonly exhibit developments in hypertriglyceridemia [66]. Though more metabolic defects have been found in the mice used in these studies, the common consensus is that a diet high in fat decreases trabecular bone mass throughout the axial and appendicular skeleton [66]. In addition to the HFD and hyperlipidemic mouse models, studies have created in vitro culture systems whereby osteoblast cell lines are treated with exogenous lipids [66]. The osteoblast cell lines treated with cholesterol and palmitate reduce proliferation and impair osteoblast differentiation [66]. In addition, exposure to these lipids also encourages the expression of RANKL and results in increased osteoclastic differentiation [75].

The precise mechanisms through which lipid accumulation influences osteoblast function remain to be fully elucidated. One potential explanation involves the elevated inflammation associated with these metabolites [66]. Omega-6 fatty acids have been found to exhibit a proinflammatory profile [76], which can lead to bone fractures in osteoporotic patients. Inflammation is not the only aspect influenced by dyslipidemia; it has also been suggested that dyslipidemia may cause osteoblasts to become desensitized to anabolic stimuli, further exacerbating the imbalance between anabolic and catabolic processes in bone tissue [66].

Dyslipidemia is a metabolic disorder also characterized by abnormal levels of lipids that alter the expression of several genes in Wnt signaling pathways [66]. For example, obese patients show elevated levels of Dkk-1 and secreted Frizzled-related proteins, which may reduce osteoblast differentiation and inhibit bone formation [77]. Additionally, HFD-fed mice have been observed to have lower levels of osteoblast progenitors and LRP6, a co-receptor involved in Wnt signaling [78]. In parathyroid hormone signaling, an overabundance of lipids has been found to attenuate PTH-induced bone formation in hyperlipidemic mouse lines [66]. Studies have also found that oxidized lipids play a role in PTH resistance, possibly even mediated by internalization of LRP6 [79] seen in Wnt signaling. Lastly, studies in insulin signaling have found that HFD-fed mice have reduced levels of IRS1/2 phosphorylation in osteoblasts after insulin stimulation [66]. Like insulin signaling in sarcopenic conditions, dyslipidemia increases osteoblast insulin resistance and contributes to bone loss [79].

Changes in lipid metabolism are also responsible for increased secretion of cytokines by osteocytes, which stimulate osteoclast differentiation (Fig. 4) [80]. Looking more closely at these processes, higher oxidized lipids levels caused by lipid metabolism changes can lead to increased fat cell formation (adipocyte) from mesenchymal stem cells. This happens through the activation of a protein called PPARγ2 [81]. Doing so increases terminal adipocyte differentiation, leading to increased fat accumulation, while osteoblast differentiation and bone formation are inhibited by EGF/MAPK pathway activation [82]. In addition, oxidized lipids increase osteoblast secretion of RANKL, which induces increased osteoclastogenic differentiation. To do so, oxidized lipids act on EP1/TP receptors on osteoblasts to activate the cAMP/PKA pathway, which increases IL-6/RANKL release and promotes more osteoclast differentiation [82]. In addition, oxidized lipids may act on EP2/DP receptors on osteoclasts to activate the cAMP/PKA pathway, increasing osteoclast differentiation [82].

Fig. 4.

Lipid Metabolism Alterations in Osteoporosis and Sarcopenia. This image was created with BioRender (https://biorender.com/)

Increased plasma cholesterol levels also affect the microenvironment of the bone by suppressing Wnt signaling, impairing the differentiation of mesenchymal stem cells into osteoblasts [82]. Cholesterol increases BMP/TGF-β pathway activation and sclerostin levels, downregulating the Wnt/β-catenin pathway [82]. Low Wnt activation leads to decreased Runx2 expression, inhibiting osteogenic differentiation [82]. Plasma cholesterol may also bind with Smoothened protein, activating Hedgehog signaling and inhibiting osteoblast formation [83]. 27-hydroxycholesterol, an intermediate of cholesterol, may act on liver X receptors, increasing the RANKL/OPG ratio [82]. By doing so, it can increase osteoclast differentiation. Through lipid dysregulation and elevated levels of oxidized lipids and plasma cholesterol, there is an increase in bone resorption and a decrease in bone formation that contributes to osteoporosis. These lipid metabolites may also interfere with the inflammatory response of macrophages [84], which may lead to dysregulated bone remodeling, as seen in osteoporosis. Focusing on macrophages, the M1 inflammatory subtype induces osteoclastogenesis and bone resorption [85]. A study published by Liu et al. has shown that decreased macrophage autophagic flux may impair the autophagic process. They noted that inhibition of autophagy-related 5 expression increased the prevalence of the M1 phenotype, leading to further systemic inflammation [86]. By inhibition of important autophagic regulation via macrophages, dysregulated lipid metabolites may give rise to an inflammatory bone microenvironment that disrupts bone remodeling seen in osteoporosis [82]. In summary, dyslipidemia, oxidized lipids and altered cholestrol levels disrupts multiple signaling pathways, including Wnt, parathyroid hormone, and insulin signaling, leading to impaired osteoblast function and increased bone loss.

1. Human clinical studies demonstrating altered Lipid Metabolism with Osteoporosis

Few studies have examined the relationship between altered lipid metabolism and osteoporosis in clinical samples and animal models. Lipidomic profiling has recently been performed by Aleidi et al. [87] in patients with low bone mineral density (LBMD) [87]. In this cohort study, 69 participants were recruited, including individuals with osteoporosis, osteopenia, and healthy controls. The results demonstrated a clear distinction in lipid profiles between the LBMD participants and the control group, revealing significant dysregulation in lipid composition. A total of 322 lipids were identified to be dysregulated, with 163 of those being upregulated and 159 being downregulated. The most significantly differentiated lipids came from classes including PCs followed by TGs, and then PEs. TGs were found to be the majority of downregulated lipids. Glycerophospholipid metabolism was also identified to be dysregulated, with changes in LPC, LPE, and PI. The data showed 36 lipids were significantly dysregulated between the osteopenic (ON) and osteoporotic (OP) groups, with 18 being upregulated and 18 being downregulated. Changes were strongly noted in PC, TG, and PE dysregulation. The main distinctions between these groups were significantly upregulated lipids from the PC subclass and significantly downregulated lipids in the TG subclass [87].

Another study highlighting the correlation between postmenopausal women and osteoporosis was performed by Lee et al., which utilized an asymmetrical flow field-flow fractionation (AF4) to sort various high-density and low-density lipoproteins [88]. Lipids in each lipoprotein were analyzed using mass spectrometry to investigate changes in the plasma lipoproteins of patients with postmenopausal osteoporosis (PMOp) compared to healthy controls.The study identified significant differences in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) fractions, characterized primarily by increased lipid concentrations in patients with PMOp. Specifically, phosphatidylcholine (PC), including PC 34:1, PC 36:2, and PC 38:4, and lysophosphatidic acid (LPA) levels were notably elevated in HDL fractions from osteoporotic patients. Ceramides, hexosylceramides, diacylglycerols, and triacylglycerols showed significant increases in LDL fractions. Additionally, antioxidative phosphatidylethanolamine plasmalogen (PEp) species (P-16:0/20:4, P-18:0/20:4, P-18:1/20:4) increased in both lipoprotein fractions, potentially reflecting an adaptive response to oxidative stress. Further evaluation revealed increased oxidized phospholipids (Ox-PLs) in LDL, particularly those derived from highly unsaturated acyl chains such as PC 38:5 and PA 18:1/22:6, suggesting enhanced lipid oxidation associated with osteoporosis. These lipidomic changes underline the potential importance of altered lipid metabolism and oxidative stress in the pathogenesis of osteoporosis, especially in postmenopausal women, and emphasize the importance of tools like AF4 to profile oxidized phospholipids in LDLs in PMOp patients.

With an increasing correlation between postmenopausal status and osteoporosis, it is crucial to explore the pathogenic mechanisms leading to reduced bone mineral density (BMD). Cabrera et al. recently employed an untargeted metabolomic approach to investigate plasma lipid profiles in 95 menopausal Singaporean-Chinese women, identifying several lipid species potentially associated with femoral neck BMD via multivariate analysis [89]. Although their orthogonal partial least squares (OPLS) model suggested potential associations between low BMD and reduced plasma levels of certain glycerophospholipids, glycerolipids, and sphingolipids, direct statistical comparisons using adjusted univariate analyses did not show significant differences (all p-values > 0.05). The observed correlation coefficients (r) between lipid species such as phosphatidylserines (PS 36:1, PS 33:6, PS 29:6), diacylglycerol (DG 42:4), and plasmenylphosphatidylethanolamine (plasmenyl-PE 38:4) and BMD were very weak (r ranging from −0.010 to −0.086), indicating limited practical significance. Nevertheless, these exploratory findings suggest a potential involvement of lipid metabolism in osteoporosis pathology, possibly mediated by chronic inflammation following estrogen withdrawal.

Gender plays a critical role in the onset and progression of musculoskeletal disorders, particularly sarcopenia and osteoporosis. Postmenopausal women experience an accelerated decline in bone mineral density due to estrogen deficiency, leading to increased bone resorption, decreased osteoblast activity, and a shift toward bone marrow adiposity [90]. These changes impair lipid metabolism in bone tissue and contribute to the heightened risk of osteoporosis observed in older women. In contrast, men tend to experience greater reductions in muscle mass and strength due to aging, making sarcopenia severe in male populations as well [91]. Hormonal differences, especially in estrogen and testosterone, affect mitochondrial function, lipid oxidation, and substrate utilization in bone and muscle cells, resulting in gender-specific trajectories of musculoskeletal aging [92]. Understanding these sex-based metabolic differences is critical to developing targeted prevention and treatment strategies for both osteoporosis and sarcopenia. Overall, the above studies provide novel insights into the alterations in lipid composition in osteoprotic patients, and these findings may pave the way for the development of future therapeutic targets for bone loss.

• (b)Animal Osteoporosis models demonstrating altered Lipid Metabolism

Recent studies on animal models of osteoporosis have increasingly focused on the alterations in lipid metabolism and their contribution to bone loss. Zhong et al. [89, 90] conducted a comparative analysis of lipid metabolites in bone marrow cells from osteoporotic mice (ovariectomized, OVX group) and control mice (sham-operated, Sham group) [89]. In a study involving female mice with postmenopausal osteoporosis (PMOP), 400 lipids were identified in the bone marrow, of which nine were classified as phospholipids and six as sphingolipids. Approximately 79% of the identified lipids were categorized as phospholipids, while the remaining 21% were sphingolipids. Lipidomic profiling of osteoporotic mice (ovariectomized, OVX) revealed downregulation of most phospholipid levels compared to the control group, including phosphatidylinositol (PI), phosphatidylglycerol (PG), lysophosphatidylserine (lysoPS), phosphatidic acid, and phosphatidylethanolamine (PE). Within the sphingolipid category, hexosylceramide and sphingosine levels were found to be upregulated in OVX mice, while sphingomyelin levels were downregulated. PE and PS were significantly downregulated in OVX mice, with PE 35:5 being the most downregulated and hexosylceramide and sphingosine being the most upregulated [89].

Same group [89, 93] employed a targeted lipidomic approach to investigate sex-related differences in bone marrow lipid profiles in mice, revealing a distinct lipidomic profile in females [93]. Theys identified 184 lipid species across multiple lipid classes in bone marrow samples from male and female mice. The study revealed that most lipid species, including phospholipids (PC, PE, and PS), sphingolipids (notably lactosylceramide and ceramides), and polyunsaturated fatty acids (PUFAs, particularly DHA derivatives), were significantly elevated in female mice compared to males. Specifically, lactosylceramide (d18:0/16:0) showed the highest fold increase in female mice, whereas its precursor lipid, glucosylceramide, was significantly elevated in males. Furthermore, higher levels of pro-inflammatory and osteoclastogenesis-promoting lipids, such as sphingomyelin and arachidonic acid metabolites, were noted in female mice. These findings suggest that sex-related differences in bone marrow lipid metabolism could contribute to the higher incidence of osteoporosis observed in females, likely via mechanisms involving enhanced osteoclastogenesis and inflammatory signaling. This study provides novel insights into sex-specific lipid metabolism, highlighting sex-specific risks of osteoporosis.

Another study done to correlate postmenopause and osteoporosis was done by Zhao et al., where an ovariectomized (OVX) mouse model was used to mimic postmenopausal osteoporosis, followed by a lipid panel to characterize alterations in lipid metabolism associated with osteoporosis [94]. Their analysis identified significant changes in 93 lipid metabolites in femur tissues of osteoporotic mice, highlighting pronounced disturbances in fatty acyls, glycerophospholipids, glycerolipids, sphingolipids, and sterols. Specifically, the OVX mice showed notable elevations in triglycerides (TGs), multiple fatty acid species, and ceramides, suggesting enhanced lipid accumulation and disrupted lipid homeostasis in osteoporotic bones due to decreased hormone levels in OVX mice. Quantitatively, out of the altered lipids, 84 were significantly increased, while only nine were reduced compared to the sham group, underscoring a distinct metabolic shift toward lipid accumulation. Furthermore, the study also revealed a marked decrease in critical glycerophosphocholines (PC) and sphingomyelins (SM), lipids integral to cell membrane integrity and signaling pathways. These lipidomic alterations are hypothesized to exacerbate bone loss through increased oxidative stress, inflammation, and altered cellular differentiation pathways favoring osteoclastogenesis. Such lipid profiling in a controlled mouse model reinforces the role of lipid dysregulation in osteoporosis pathogenesis.

Lastly, Cabrera et al. utilized an ovariectomized (OVX) sheep model to investigate lipidomic alterations induced by short and long-term glucocorticoid treatment, providing insights into lipid dysregulation associated with osteoporosis [95]. The study found significant alterations in 15 identified plasma lipids belonging predominantly to phospholipids, lysophospholipids, and ceramides, indicative of substantial lipid metabolic perturbations. In the short term, OVX combined with glucocorticoid administration reduced lipid concentrations, particularly cardiolipin (CL 76:7) and phosphatidylinositol (PI 14:0), with fold-changes less than 1.0 compared to OVX alone. In contrast, long-term treatment (five months) led to distinct lipidomic shifts, including elevated levels of ceramide phosphate (CerP 39:1) and several cardiolipin species, particularly CL (72:5, 76:7, 76:8), with fold increases up to 1.26 relative to controls. Thus, the alterations identified by Cabrera et al. highlight critical lipid pathways affected during glucocorticoid-induced osteoporosis, furthering their work from previous studies to identify lipid biomarkers that can be the targets of therapeutic intervention. Both human and murine models of osteoporosis have demonstrated alterations in lipid metabolism, providing valuable insights into the pathophysiological mechanisms underlying bone loss and offering potential therapeutic targets for the prevention and treatment of osteoporosis.

Osteosarcopenic Adiposity (OSA)

With advancing age, there is a concurrent manifestation of osteoporosis, sarcopenia, and increased adiposity, collectively termed osteosarcopenic adiposity (OSA). In individuals affected by OSA, ectopic fat accumulation extends beyond conventional adipose depots to include intramuscular (myosteatosis) and bone marrow (marrow adiposity) fat infiltration, thereby impairing musculoskeletal tissue's structural integrity and regenerative capacity [96]. The combined degenerative effects of reduced bone density and muscle mass, alongside adipose tissue dysfunction, result in heightened vulnerability to frailty, increased risk of falls and fractures, metabolic disturbances, and overall decline in functional status and quality of life [96].

The musculoskeletal system comprises bone, muscle, and adipose tissue, all metabolically interconnected. Each of these tissues produces hormones and molecules that can act on the other, influencing their function. Without these mechanisms, the body systems will lack the coordination needed to maintain metabolic homeostasis. In addition, metabolic disorders, increased risk of injury, and impaired mobility can result from a connection gap between bone, muscle, and adipose tissue. Aging disrupts this triad, leading to bone loss (osteopenia/osteoporosis), muscle wasting (sarcopenia), and increased adiposity. This condition represents a breakdown in tissue homeostasis, driven by dysregulated lipid metabolism and systemic inflammation [96].

Excess adipose tissue, especially visceral and ectopic fat, seen in obesity, can exacerbate OSA by introducing additional metabolic challenges. Excessive adipose tissue also leads to chronic low-grade inflammation by secretion of cytokines such as TNF-α and IL-1 [97]. These cytokines suppress muscle protein synthesis, leading to conditions like sarcopenia. These cytokines also play a role in bone degradation as they promote osteoclastogenesis and impair osteoblast function, leading to osteoporosis or osteopenia [97]. In addition, intramuscular fat infiltration reduces contractility and regenerative potential of the muscle, while marrow fat expansion is associated with reduced bone mineral density and fracture risk. Both of these can later lead to degenerative disorders such as sarcopenia and osteoporosis. These lipid-driven effects are both a cause and consequence of musculoskeletal degeneration, particularly in older adults with obesity [98].

The presence of obesity with sarcopenia and osteoporosis has led to the classification of a more severe and metabolically active syndrome called osteosarcopenic obesity (OSO). Individuals with OSO are characterized by loss of muscle mass, strength, and function and demonstrate an increased risk of falls compared to those with any single condition alone [90]. Osteosarcopenic obesity presents a complex challenge in clinical settings for treatment as notable differences in functionality have been found between individuals with sarcopenic obesity compared to those with sarcopenia alone. This emphasizes the importance of these conditions for patient health and the importance of tailored therapeutic strategies.

Therapeutic targets of lipid metabolism in musculoskeletal disorders

Considering explorations into altered lipid metabolism and the classification of an osteosarcopenic adiposity, studies have been to traverse therapeutic avenues that may help restore metabolic function in sarcopenic and osteoporotic conditions. It has been revealed that changes in ceramide biosynthesis have correlated with a diverse range of muscle disorders, including sarcopenia and osteoporosis. Ceramide biosynthesis is responsible for the decline in mitochondrial and protein homeostasis during muscle aging and loss. Possible targets of ceramide biosynthesis include serine palmitoyltransferase (SPT), the rate-limiting enzyme of ceramide synthesis. By inhibiting SPT through gene silencing or treatment with myriocin (inhibitor of SPT), mitochondrial function was restored in human myoblasts and improved muscle health [61]. These findings imply that genetic suppression or pharmacological intervention of ceramide biosynthesis can be potential therapeutic targets of sarcopenia or osteoporosis.

In addition to the inhibition of de novo ceramide synthesis, there is a potential therapeutic avenue to be explored in the PLINs discussed earlier, specifically PLIN5. While PLIN2 is damaging in its overexpressed state, increased expression of PLIN5 may increase LD size and richness of TAGs without impairing insulin sensitivity [91]. Furthermore, PLIN5 can protect against the effects of lipotoxicity by converting esterified lipid chains into LDs [92]. Diacylglycerol (DAG) accumulation disrupts insulin signaling and contributes to insulin resistance in muscle. However, the DAG accumulation was reduced in myotubes overexpressing PLIN5 and exposed to palmitate (which elevates DAG levels) [92]. Given the strong association between increased DAG concentrations and the development of sarcopenia, targeting PLIN5 to regulate DAG levels represents a promising therapeutic strategy for mitigating muscle degeneration and insulin resistance in sarcopenia.

On the osteoporotic front, various therapies are being studied and exercised to target bone loss by altering bone cell metabolism and bioenergetics. One anti-resorptive therapy of interest is bisphosphonates, which exhibit anti-osteoclastogenic potential [99]. Amino-bisphosphonates, zoledronic acid (ZA) specifically, suppress farnesyl-diphosphonate synthase production in the mevalonate pathway, which is known to control cholesterol homeostasis [99]. One cohort study showed that intravenous infusion of ZA reduced atherogenic lipids in patients with metabolic bone pathologies [100]. As such, the study suggests that ZA can reduce lipid deposition, which may prevent the effects of dyslipidemia on metabolic pathways discussed previously.

Lipid metabolism can also be targeted to improve bone quality. For example, statins, typically used for treating dyslipidemia, have shown potential in bone health by promoting osteoblast activity (bone formation cells) [101]. Statins may increase bone mineral density by upregulating bone morphogenetic protein-2 (BMP-2) and enhancing the differentiation of mesenchymal stem cells (MSCs) into osteoblasts [102]. This makes statins a promising candidate for osteoporosis treatment, although their long-term effects on bone are still under investigation [103]. Omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have anti-inflammatory properties that may protect against bone loss [104]. These fatty acids reduce the production of proinflammatory cytokines such as TNF-α and IL-6, which are known to promote bone resorption by osteoclasts. By reducing inflammation, omega-3 fatty acids may help maintain bone homeostasis and prevent osteoporosis. Certain bioactive lipids, like lysophosphatidic acid (LPA) and prostaglandins, influence bone remodeling by modulating osteoblast and osteoclast activity [105–107]. Targeting these molecules or their receptors could offer a novel approach to enhancing bone formation or reducing bone resorption, offering new avenues for osteoporosis treatment. Adipokines, such as leptin and adiponectin, are hormones secreted by adipose tissue that affect bone metabolism [108]. Leptin has a dual effect on bones, promoting bone formation via central nervous system pathways and inhibiting it through local mechanisms [109, 110]. Conversely, Adiponectin has been shown to enhance osteoblast differentiation [111]. Modulating these adipokines'levels could help manage osteoporosis by shifting the balance towards bone formation. Therapies that target lipid metabolism, whether through modulating PPARs, statins, or bioactive lipids like sphingolipids and omega-3 fatty acids, represent a promising approach to treating MSDs. These strategies can potentially improve bone health by reducing inflammation, promoting osteoblast activity, and inhibiting bone resorption.

Recent advances in osteoporosis treatment have also introduced anabolic agents and monoclonal antibodies that offer novel mechanisms to improve bone density and reduce fracture risk. These drugs directly or indirectly also regulates lipid metabolism in bone forming cells. Currently, the only treatment to increase bone density is injections of parathyroid hormone or analogs of parathyroid hormones, such as teriparatide and abaloparatide, analogs. These stimulate osteoblast activity, enhancing bone formation and strength [112]. Beyond bone, PTH signaling has been implicated in modulating lipid metabolism by enhancing lipolysis, regulating adipocyte function, and shifting mesenchymal stem cell fate away from adipogenesis toward osteogenesis [113]. Studies have shown that PTH can promote browning of white adipose tissue and improve lipid utilization, potentially contributing to improved systemic lipid profiles [114].

Romosozumab, a monoclonal antibody targeting sclerostin, is a protein that inhibits Wnt signaling and promotes bone formation. It also reduces resorption by activating the Wnt/β-catenin signaling pathway, significantly improving bone mineral density, especially in postmenopausal women with osteoporosis [115]. Sclerostin has been shown to influence Wnt signaling pathways that regulate lipid metabolism, adipocyte differentiation, and mitochondrial biogenesis. Clinical and experimental data suggest that sclerostin inhibition can improve lipid profiles, reduce ectopic fat deposition, and enhance muscle function, although further validation is required [116]. Another antibody, denosumab, inhibits RANKL, a key regulator of osteoclast activity, which reduces bone resorption and increases bone strength [117]. Interestingly, RANKL-RANK signaling is also involved in lipid metabolism, as RANKL can promote adipogenesis, and its inhibition has been associated with reduced adipose tissue inflammation and improved insulin sensitivity [118, 119].

Emerging evidence suggests that above mentioned therapies have systemic metabolic effects beyond their direct actions on bone remodeling, including modulation of lipid metabolism, inflammation, and energy balance. These targeted biologic therapies represent a new generation of treatment that complements traditional antiresorptive agents and offers new hope for patients with severe or treatment-resistant osteoporosis.

Conclusion

Lipid metabolism plays a pivotal role in maintaining musculoskeletal health, with its altered regulation with age contributing to the development of pathological conditions such as sarcopenia and osteoporosis. In muscle, efficient fatty acid uptake, utilization, and lipid droplet regulation are essential for preserving muscle function and preventing lipotoxicity, while in bone, lipid signaling influences bone remodeling and cellular function. Alterations in lipid profiles, including shifts in ceramides, cardiolipins, and triglycerides, are linked to both muscle and bone degeneration and offer potential biomarkers for early detection and treatment of these conditions. In bone biology, cholesterol plays a significant role in osteoclast formation and function through lipid rafts and RANK-RANKL signaling mechanisms. In contrast, long-chain polyunsaturated fatty acids (LCPUFAs) and unsaturated fatty acids (UFAs) offer protective effects on bone health, indicating potential therapeutic applications in osteoporosis management. Osteoblasts rely on extracellular lipid sources, with receptors such as LRP1 and Scarb1 being essential for lipid uptake, highlighting the need for further research into lipid energetics in osteocytes and their role in bone homeostasis. Therapies targeting lipid metabolism, such as bisphosphonates, statins, and omega-3 fatty acids, offer potential avenues for improving bone quality and preventing osteoporosis by modulating osteoclast activity, enhancing osteoblast function, and reducing inflammation. Furthermore, bioactive lipids and adipokines, such as leptin and adiponectin, are emerging as important regulators of bone metabolism and may serve as novel therapeutic targets. Understanding the connections between lipid metabolism and musculoskeletal disorders provides new opportunities for therapeutic strategies to restore metabolic balance and improve overall musculoskeletal health. Future research should focus on developing targeted lipid-based therapies. By advancing research in this area, we can develop more effective, targeted interventions to prevent or treat age-related musculoskeletal disorders, potentially alleviating these conditions'significant economic and healthcare burdens.

Authors’ contributions

SV: Initial Draft. SG: figure development. PA: Data analysis,. RK: data analysis and editing. WB: editing and search. WDH: Funding and editing. MEM: Funding, Literature search and editing. CMI: Funding and editing. SF: funding, Original idea, writing and editing

Funding

This publication is based upon work supported in part by the National Institutes of Health, National Institute on Aging: 3P01AG036675-13S1 (SF, MEM and CMI) and VA Research Career Scientist Award #IK6 BX005691 (W.B.B). The above-mentioned funding did not lead to any conflict of interest regarding the publication of this manuscript.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Competing interests

The authors declare no competing interests.