Skeletal pathologies are often accompanied by bone pain, which has negative effects on the quality of life and functional status of patients. Bone pain can be caused by a wide variety of injuries and diseases including (poorly healed) fractures, bone cancer, osteoarthritis and also iatrogenic by skeletal interventions. Orthopedic interventions are considered to be the most painful surgical procedures overall. Two major groups of medication currently used to attenuate bone pain are NSAIDs and opioids. However, these systemic drugs frequently introduce adverse events, emphasizing the need for alternative therapies that are directed at the pathophysiological mechanisms underlying bone pain. The periosteum, cortical bone and bone marrow are mainly innervated by sensory A-delta fibers and C-fibers. These fibers are mostly present in the periosteum rendering this structure most sensitive to nociceptive stimuli. A-delta fibers and C-fibers can be activated upon mechanical distortion, acidic environment and increased intramedullary pressure. After activation, these fibers can be sensitized by inflammatory mediators, phosphorylation of acid-sensing ion channels and cytokine receptors, or by upregulation of transcription factors. This can result in a change of pain perception such that normally non-noxious stimuli are now perceived as noxious. Pathological conditions in the bone can produce neurotrophic factors that bind to receptors on A-delta fibers and C-fibers. These fibers then start to sprout and increase the innervation density of the bone, making it more sensitive to nociceptive stimuli. In addition, repetitive painful stimuli cause neurochemical and electrophysiological alterations in afferent sensory neurons in the spinal cord, which leads to central sensitization, and can contribute to chronic bone pain. Understanding the pathophysiological mechanisms underlying bone pain in different skeletal injuries and diseases is important for the development of alternative, targeted pain treatments. These pain mechanism-based alternatives have the potential to improve the quality of life of patients suffering from bone pain without introducing undesirable systemic effects.

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对骨痛的理解：叙述性评论

骨骼病变常伴有骨痛，对患者的生活质量和功能状态产生负面影响。骨痛可由多种损伤和疾病引起，包括（未愈合的）骨折、骨癌、骨关节炎以及骨骼干预引起的医源性。整形外科手术被认为是总体上最痛苦的外科手术。目前用于减轻骨痛的两大类药物是非甾体抗炎药和阿片类药物。然而，这些全身性药物经常引起不良事件，强调需要针对骨痛潜在病理生理机制的替代疗法。骨膜、皮质骨和骨髓主要由感觉A-δ纤维和C-纤维支配。这些纤维主要存在于骨膜中，使该结构对伤害性刺激最敏感。A-delta 纤维和 C-纤维可以在机械变形、酸性环境和增加的髓内压下被激活。激活后，这些纤维可被炎症介质、酸敏感离子通道和细胞因子受体的磷酸化或转录因子的上调致敏。这可能导致疼痛感知的改变，使得通常无害的刺激现在被认为是有害的。骨骼中的病理状况可产生与 A-delta 纤维和 C-纤维上的受体结合的神经营养因子。然后这些纤维开始发芽并增加骨骼的神经支配密度，使其对伤害性刺激更加敏感。此外，重复的疼痛刺激会导致脊髓传入感觉神经元的神经化学和电生理改变，从而导致中枢敏感，并可能导致慢性骨痛。了解不同骨骼损伤和疾病中骨痛的病理生理机制对于开发替代的、有针对性的疼痛治疗很重要。这些基于疼痛机制的替代方案有可能改善骨痛患者的生活质量，而不会产生不良的全身效应。了解不同骨骼损伤和疾病中骨痛的病理生理机制对于开发替代的、有针对性的疼痛治疗很重要。这些基于疼痛机制的替代方案有可能改善骨痛患者的生活质量，而不会产生不良的全身效应。了解不同骨骼损伤和疾病中骨痛的病理生理机制对于开发替代的、有针对性的疼痛治疗很重要。这些基于疼痛机制的替代方案有可能改善骨痛患者的生活质量，而不会产生不良的全身效应。