Although our study indicates a potential causal relationship between osteoporosis and chronic tendinopathy, the underlying biological mechanisms driving this association require further investigation.Chronic tendinopathy occurs in orthopedic patients over 45 years of age and is characterized by localized tendon pain and decreased function, with physiological features such as tendon thickening, neovascularization, and ultrasound hypoechoicity, whereas tendon stiffness may remain unchanged or decrease [26]. At the macroscopic level, the main pathological features of chronic tendinopathy include inflammation, altered collagen ratios, and loss of tissue structure [27]. This condition can affect various anatomical regions, such as the Achilles tendon, patellar tendon, peroneal tendon, gluteus tendon, and shoulder tendons. Clinical diagnostic criteria for chronic tendinopathy vary among different anatomical sites, although there is considerable overlap[28]. Diagnosis of chronic tendinopathy is primarily based on the presence of localized pain and tendon stiffness during loading, as well as a pain response during stretching or resistance testing. Although imaging is not essential for diagnosis, radiography, ultrasound, and MRI can be utilized to further characterize tendinopathies[29], Emerging imaging techniques, including ultrasound tissue characterization, transverse wave elastography, and 7T MRI, offer additional insights into tendon mechanical properties, particularly for research applications[30].Chronic tendinopathy is associated with high morbidity and recurrence, leading to permanent functional impairment, which poses significant risks for patients. Osteoporosis, on the other hand, is a metabolic bone disease characterized by an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Key mechanisms in both diseases include immune-mediated inflammatory responses, oxidative stress, abnormal bone metabolism, and biomechanical abnormalities.
Oxidative stress activation may be a key mechanism underlying the co-pathogenesis of chronic tendinopathy and osteoporosis. An imbalance between the production and removal of reactive oxygen species (ROS) in the body induces oxidative stress, leading to elevated ROS levels and activation of mitogen-activated protein kinase (MAPK), JNK, P38, and ERK pathways, which can promote apoptosis in tendon cells[31]. The research conducted by Wang and colleagues[32] has elucidated that hydrogen peroxide (H2O2)-mediated oxidative stress significantly enhances the activity and mRNA expression of c-Jun N-terminal kinase (JNK) as well as matrix metallopeptidase 1 (MMP1) in human tendon cells. This upregulation has the potential to degrade collagen within the tissue, implying a pivotal role for oxidative stress in the degradation of the tendon extracellular matrix. In a preceding investigation by the same research group33], it was observed that the antioxidant enzyme peroxidoredoxin 5 was upregulated in tendons exhibiting degradation. Subsequent studies have demonstrated that augmenting the expression of peroxiredoxin 5 can mitigate apoptosis and functional impairment of human tendon cells under oxidative stress conditions34]. Yuan et al[35] employed a proteomic approach to investigate the pathogenesis of tendinopathy and identified significant differences in the levels of S100A11, PLIN4, and HYOU1 between the patient and control groups. Their proteomic analysis revealed that these proteins are associated with oxidative stress and chronic inflammation. Oxidative stress damages tendon-derived stem cells (TDSCs), induces tendon cell apoptosis, leads to tendon matrix degradation, and impairs tendon stem cell function, thereby contributing to the development of tendinopathy.. On the other hand, oxidative stress severely disrupts the homeostasis of the bone remodeling process[36]. Compared with young mice, aged mice exhibit upregulation of oxidative stress genes and downregulation of osteoblast-related genes, which may contribute to age-related osteoporosis[37]. In addition, excess reactive oxygen species (ROS) generated by oxidative stress promotes osteoclast differentiation. Antioxidant drugs have proven effective in the treatment of osteoporosis by enhancing osteoblast activity and bone formation, while simultaneously inhibiting osteoclast activity and bone resorption[38].
The inflammatory response plays a key role in the pathomechanisms of both tendinopathy and osteoporosis[39][40][41]. Signaling molecules released from necrotic cells or activated immune cells in the extracellular environment trigger a robust recruitment of Th1 T cells, neutrophils, and M1-type macrophages[42].This process promotes the release of pro-inflammatory factors from tendon cells, including TNF-α, IFN-γ, IL-1β, and iNOS. Subsequently,, inflammatory signaling pathways, such as NF-κB and NLRP3, are activated, regulating the expression and transcription of inflammation-associated genes[43][44]. Following tendon injury, inflammatory cells such as neutrophils and macrophages release inflammatory factors including IL-1 and TNF-α during the early stages of healing[45]. Stimulated by these inflammatory factors, IκB undergoes phosphorylation and degradation through various signaling pathways, thereby activating the NF-κB signaling pathway and regulating the inflammatory response. This represents a classic mechanism of NF-κB activation. In addition, NF-κB activation can also occur through CD40-mediated non-classical pathways and the hypoxic environment induced by tendon injury[46][47]. Furthermore, Snouwaert et al. demonstrated that the inflammatory response triggered by NLRP3 mutations in humanized mice is closely linked to the development of osteoporosis[48]. The activation of NLRP3 inflammasomes, which consist of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD), and caspase-1, promotes the maturation and release of proinflammatory cytokines, such as pro-IL-1β and IL-18[49]. Additionally, NLRP3 may be associated with bone loss resulting from bacterial infections[50].Levels of NLRP3 inflammasomes were examined in serum samples from patients with postmenopausal osteoporosis (PMOP) (n = 55) and healthy controls (n = 29) using ELISA. The results revealed that NLRP3 inflammasome levels were significantly higher in PMOP patients compared to controls. These findings suggest that the NLRP3 inflammasome may play a crucial role in the pathomechanisms of PMOP and could serve as a potential new biomarker for its diagnosis[51]. The NLRP3 inflammasome contributes to inflammation by promoting the maturation and release of pro-inflammatory cytokines, such as IL-1β and IL-18, and by activating inflammatory responses[52].IL-1β, a key member of the IL-1 family plays a significant role in estrogen deficiency-induced bone loss[53][54]. High levels of IL-1β can impede osteogenic differentiation by activating the NF-κB signaling pathway and inhibiting the BMP/Smad signaling cascade[55]. Simultaneously, IL-1β diminishes Runx2 activation by initiating the MAPK pathway, which subsequently inhibits osteoblast differentiation[56]. The study results demonstrated that reducing NLRP3 expression led to decreased levels of IL-1β and IL-18, while concurrently increasing the levels of Runx2, OCN, ALP, Sp7, Smad1, and Smad5, thus promoting bone formation [57].
Osteoporosis is a condition marked by reduced bone mineral density and deterioration of bone microstructure, leading to increased bone fragility and heightened susceptibility to fractures under minimal stress[58]. In biomechanical evaluations, the impact of osteoporosis on the mechanical properties of bone, considered as a sublaminar material, is typically assessed through measurements of compressive elastic modulus, strength, and strain in bone microfascicles[59]. Studies have demonstrated that the modulus of elasticity in bone is significantly reduced in patients with osteoporosis. This reduction is associated with relatively minor decreases in bone strength, slight increases in destructive strain, and corresponding changes in material toughness[60]. The stiffness and toughness of bone are partially dependent on its mineral content. Even relatively small changes in mineral content due to osteoporosis can significantly reduce the bone's mechanical properties and increase its fragility. In osteoporosis, both decreases and increases in mineral content can negatively impact the mechanical properties of bone. Low mineral content leads to reduced stiffness and strength, while high mineral content decreases toughness[61]. Based on its linearly arranged type I collagen fiber structure, tendon, as a dynamic connective tissue, has the ability to withstand constant tensile forces, making it particularly sensitive to mechanical loading[62]. Tendon cells are crucial for maintaining the stability of the tendon’s internal environment and serve as a primary source of extracellular matrix proteins and regulatory enzymes[63]. Mechanical strain on tendons can prompt tendon cells to release cytokines and matrix metalloproteinases, potentially leading to inflammation and apoptosis, which may subsequently trigger tendinopathy[64]. In vivo modeling studies have demonstrated that excessive mechanical loading induces the recruitment of immune cells, especially monocytes, which play a significant role in the development of tendinopathy[65]. Monocyte recruitment and chemokine release following mechanical loading promote a local inflammatory response, which may ultimately lead to changes in tendon pathology. The interaction between these biomechanical and inflammatory processes supports a model where monocyte migration to sites of mechanical stress and the response of resident cells, like tissue macrophages, to strain highlights the complex relationship between tendinopathy and osteoporosis[66][67].
Our study has several limitations. Firstly, the research was conducted primarily with a European population, which limits the generalizability of our findings to other populations. Secondly, larger genome-wide association studies (GWAS) are needed to improve the capacity of Mendelian randomization (MR) studies to detect associations.. Thirdly, due to limitations in the GWAS summary statistics, our Mendelian randomization analyses could not be stratified by gender, ethnicity, or underlying disease. We investigated the causal relationship between bone mineral density (BMD) and chronic tendinopathy across different age and anatomical site groups. The results revealed a strong causal association between BMD and calcific tendinitis of the shoulder joint at all examined sites. However, within the different age groups, we observed only suggestive evidence of a causal relationship between BMD and calcific tendinitis of the shoulder in the 45–60 and > 60 age groups. This may be attributable to the limited number of BMD samples in each age group and the heterogeneous nature of the populations studied. Future studies will require larger, homogenous population samples to more thoroughly evaluate the relationship between total BMD and chronic tendinopathy across different age groups. Fourthly, data sources for osteoporosis and chronic tendinopathy used in Mendelian randomization analyses should avoid including overlapping participants across both samples.