Rheumatology: Current Research
Open Access

Pathological Mechanisms of Pain in Paget's Disease

Kosaku Murakami^{* *}Correspondence: Kosaku Murakami, Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan, Email:

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About the Study

Paget's Disease of Bone (PDB), also known as osteitis deformans, is a chronic and localized bone disorder characterized by abnormal bone remodeling. This condition primarily affects older adults and can lead to a range of skeletal abnormalities, including bone pain, deformities, and an increased risk of fractures. Among the various manifestations of PDB, pain is one of the most common and debilitating symptoms, significantly affecting the quality of life of affected individuals. Despite its prevalence, the exact pathological mechanisms responsible for pain in PDB remain a subject of ongoing research.

Bone remodeling

The hallmark of Paget's Disease is the abnormal and excessive remodeling of affected bones. This process is driven by increased bone resorption and formation, leading to chaotic bone structure and compromised mechanical integrity. While the exact cause of this dysregulated bone remodeling remains unclear, genetic factors, including mutations in SQSTM1 (Sequestosome 1) and VCP (Valosin-Containing Protein) genes, have been implicated. Abnormalities in signaling pathways, such as the RANK/RANKL/OPG axis, are also thought to contribute to the pathogenesis of PDB.

The increased bone turnover in Paget's disease can directly induce pain. As old bone is rapidly resorbed and replaced with new bone, microfractures and microcracks may occur, activating pain-sensing nerve fibers within the bone matrix. Additionally, the altered bone architecture in PDB can put mechanical stress on surrounding tissues, leading to further pain perception. Inflammation at the bone site can exacerbate these processes by promoting the release of pain-inducing molecules.

Neuroinflammation and pain

Emerging evidence suggests that neuroinflammation plays a pivotal role in the pathogenesis of pain in Paget's disease. The bone microenvironment in PDB is characterized by increased production of pro-inflammatory cytokines and chemokines, such as Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), and Interleukin-1β (IL-1β). These molecules act as mediators of neuroinflammation by sensitizing peripheral nerve endings and promoting the recruitment of immune cells to the affected area.

The inflammatory milieu within Paget's Disease-afflicted bone can lead to the activation of nociceptors, specialized sensory nerve fibers that respond to noxious stimuli. Nociceptor activation triggers pain signals that are transmitted to the central nervous system, leading to the perception of pain. Additionally, immune cells infiltrating the bone tissue release various neuroactive substances, including prostaglandins and substance P, which further sensitize nerve endings and intensify the pain experience.

Nerve sensitization and chronic pain

In Paget's disease, the chronic inflammation and aberrant bone remodeling can result in a state of nerve sensitization, where pain signaling pathways become hypersensitive and persistent. This process can lead to chronic pain, a hallmark feature of PDB. Nerve sensitization involves both peripheral and central mechanisms.

Peripheral sensitization: Peripheral nerve endings in the bone become hyperexcitable due to the continuous release of inflammatory mediators. This heightened sensitivity results in lower pain thresholds and increased responsiveness to mechanical and chemical stimuli. Consequently, even minor changes in bone structure or inflammation can trigger intense pain sensations.

Central sensitization: Chronic pain in PDB is not solely driven by peripheral sensitization. Changes in the central nervous system, particularly the spinal cord and brain, also contribute to the persistence of pain. Central sensitization involves an amplification of pain signals within the central nervous system, making the perception of pain more intense and long-lasting. This phenomenon can lead to a heightened state of pain even in the absence of ongoing peripheral stimuli.

Pain is a prevalent and distressing symptom in Paget's Disease of Bone, impacting the lives of affected individuals. While the precise mechanisms underlying pain in PDB are multifaceted and not fully elucidated, research has highlighted the significantroles of abnormal bone remodeling, neuroinflammation, and nerve sensitization.