BACKGROUND/OBJECTIVES: Osteoporosis causes a bone mass reduction and often determines acute and chronic pain. Understanding the biochemical and neurophysiological mechanisms behind this pain is crucial for developing new, effective rehabilitative and therapeutic approaches. This systematic review synthesizes recent advances in muscle-bone interactions and molecular pathways related to osteoporosis-associated pain. METHODS: We carried out a systematic review including studies published from 2018 to 2024 using PubMed, Scopus, clinicaltrials.gov and Cochrane Library. The Cochrane Collaboration tool was used to assess bias risk. The review adhered to PRISMA guidelines and is registered with PROSPERO (CRD42024574456); Results: Thirteen studies were included. It emerged that osteoporosis causes progressive bone loss due to disruptions in biochemical processes and muscle-bone interactions. This condition is also closely associated with the development of pain, both acute and chronic. Key findings include the role of the miR-92a-3p/PTEN/AKT pathway and the impact of muscle-bone disconnection on bone health. Mechanotransduction is critical for bone maintenance. Effective pain management and rehabilitation strategies include physical therapy and physical exercise, yoga, Pilates, and cognitive behavioral therapy (CBT); they all improve pain relief and functional outcomes by enhancing muscle strength, flexibility, and balance. Pharmacological options such as NSAIDs, opioids, and new agents like SHR-1222, along with surgical interventions like percutaneous vertebroplasty, offer additional pain reduction, especially when included in individualized rehabilitation projects; Conclusions: This review highlights advancements in understanding osteoporotic pain mechanisms and identifies promising treatments. Integrating targeted therapies and rehabilitation strategies can enhance patients' pain relief.