EC Orthopaedics

Review Article Volume 16 Issue 2 - 2025

Potential Application of Clodronate in Fibromyalgia

Rosini S1, Rosini S2, Molfetta F3 and Molfetta L3*

1Biomaterial Research Center, Livorno, Italy

2Smile-Restyle, Livorno, Italy

3DISC Department, School of Medical and Pharmaceutical Sciences, University of Genoa, Research Center of Osteoporosis and Osteoarticular Pathologies, Italy

*Corresponding Author: Molfetta L, DISC Department, School of Medical and Pharmaceutical Sciences, University of Genoa, Research Center of Osteoporosis and Osteoarticular Pathologies, Italy.
Received: December 04, 2024; Published: January 21, 2025



Fibromyalgia (FM) is a condition with an uncertain etiology, primarily characterized by chronic widespread pain, particularly in the axial muscles and skeleton, alongside fatigue, sleep disturbances, and mood disorders. This pathology is thought to result from heightened central nervous system (CNS) sensitivity, which amplifies peripheral signals and reflects an altered function of antinociceptive pathways. Although the pathogenesis of FM remains incompletely understood, emerging research highlights the role of potential trigger events that may initiate CNS hypersensitivity.

 Keywords: Fibromyalgia; Clodronate; Microglia; Nociplastic Pain

  1. Fillingim RB. “Individual differences in pain: Understanding the mosaic that makes pain personal”. Pain1 (2017): S11-S18.
  2. Fitzcharles MA., et al. “Nociplastic pain: towards an understanding of prevalent pain conditions”. Lancet10289 (2021): 2098-2110.
  3. Ahd A Atta., et al. “Microglia polarization in nociplastic pain: mechanisms and perspectives”. Inflammopharmacology3 (2023): 1053-1067.
  4. Sarzi-Puttini P., et al. “Fibromyalgia position paper”. Clinical and Experimental Rheumatology 3 (2021): 186-193.
  5. Rekatsina M., et al. “Pathophysiologic approach to pain therapy for complex pain entities: a narrative review”. Pain Therapy1 (2020): 7-21.
  6. Feraco P., et al. “Metabolic abnormalities in pain-processing regions of patients with fibromyalgia: A 3T MR spectroscopy study”. American Journal of Neuroradiology 9 (2011): 1585-1590.
  7. Sturgill J., et al. “Unique cytokine signature in the plasma of patients with fibromyalgia”. Journal of Immunology Research (2014): 938576.
  8. Li WW., et al. “Substance P spinal signaling induces glial activation and nociceptive sensitization after fracture”. Neuroscience 310 (2015): 73-90.
  9. Trang T., et al. “ATP receptors gate microglia signaling in neuropathic pain”. Experimental Neurology 2 (2012): 354-361.
  10. Beggs S., et al. “P2X4R+ microglia drive neuropathic pain”. Nature Neuroscience 8 (2012): 1068-1073.
  11. Andrés-Rodríguez L., et al. “Peripheral immune aberrations in fibromyalgia: A systematic review, meta-analysis and meta-regression”. Brain, Behavior, and Immunity 87 (2020): 881-889.
  12. Theoharides TC., et al. “Mast cells, neuroinflammation and pain in fibromyalgia syndrome”. Frontiers in Cellular Neuroscience 13 (2019): 353.
  13. Cuicui Wang., et al. “The effects of microglia-associated neuroinflammation on Alzheimer’s disease”. Frontiers in Immunology 14 (2023): 1117172.
  14. Sevim Isik., et al. “Microglia mediated neuroinflammation in Parkinson's disease”. Cells7 (2023): 1012.
  15. Colonna M and Butovsky O. “Microglia function in the central nervous system during health and neurodegeneration”. Annual Review of Immunology 35 (2017): 441-468.
  16. Carson MJ. “Microglia as liaisons between the immune and central nervous systems: functional implications for multiple sclerosis”. Glia2 (2002): 218-231.
  17. Harte SE., et al. “The neurobiology of central sensitization”. Journal of Applied Biobehavioral Research 2 (2018): e12137.
  18. Rekatsina M., et al. “Pathophysiologic approach to pain therapy for complex pain entities: a narrative review”. Pain Therapy1 (2020): 7-21.
  19. Harris RE., et al. “Elevated insular glutamate in fibromyalgia is associated with experimental pain”. Arthritis and Rheumatology 10 (2009): 3146-3152.
  20. Valdés M., et al. “Increased glutamate/glutamine compounds in the brains of patients with fibromyalgia: a magnetic resonance spectroscopy study”. Arthritis and Rheumatology 6 (2010): 1829-1836.
  21. Feraco P., et al. “Metabolic abnormalities in pain-processing regions of patients with fibromyalgia: a 3T MR spectroscopy study”. American Journal of Neuroradiology 9 (2011): 1585-1590.
  22. Cruz-Almeida Y., et al. “Brain gamma-aminobutyric acid, but not glutamine and glutamate levels are lower in older adults with chronic musculoskeletal pain: considerations by sex and brain location”. Pain Reports3 (2021): e952.
  23. Russell IJ., et al. “Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome”. Arthritis and Rheumatology 11 (1994): 1593-1601.
  24. Chu J., et al. “ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain”. Science Advances 13 (2023): eade9931.
  25. Burnstock G. “Purinergic mechanisms and pain”. Advances in Pharmacology 75 (2016): 91-137.
  26. Makoto Tsuda., et al. “P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury”. Nature6950 (2003): 778-783.
  27. Justyna Suwara., et al. “The ATP-dependent pathways and human diseases”. Current Medicinal Chemistry 11 (2023): 1232-1255.
  28. Kazuhiro Shima., et al. “The bisphosphonates clodronate and etidronate exert analgesic effects by acting on glutamate- and/or ATP-related pain transmission pathways”. Biological and Pharmaceutical Bulletin 5 (2016): 770-777.
  29. Hasuzawa N., et al. “Physiopathological roles of vesicular nucleotide transporter (VNUT), an essential component for vesicular ATP release”. Biochimica et Biophysica Acta (BBA) - Biomembranes 12 (2020): 183408.
  30. Yuri Kato., et al. “Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain”. Proceedings of the National Academy of Sciences of the United States of America 31 (2017): E6297-E6305.
  31. Takahiro Masuda., et al. “Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain”. Nature Communications 7 (2016): 12529.
  32. Yoshinori Moriyama and Masatoshi Nomura. “Clodronate: A vesicular ATP release blocker”. Trends in Pharmacological Sciences 1 (2018): 13-23.
  33. Shin-ichiro Hiraga., et al. “Neuroplasticity related to chronic pain and its modulation by microglia”. Inflammation and Regeneration 1 (2022): 15.
  34. Latremoliere A and Woolf CJ. “Central sensitization: A generator of pain hypersensitivity by central neural plasticity”. Journal of Pain 9 (2009): 895-926.
  35. Varenna M., et al. “Intravenous clodronate in the treatment of reflex sympathetic dystrophy syndrome. A randomized, double blind, placebo controlled study”. Journal of Rheumatology 6 (2000): 1477-1483.
  36. Gatti D., et al. “Management of patients with complex regional pain syndrome type I”. Osteoporosis International 8 (2016): 2423-2431.
  37. Frediani B., et al. “Intramuscular clodronate in long-term treatment of symptomatic knee osteoarthritis: A randomized controlled study”. Drugs in R&D 1 (2020): 39-45.
  38. Frediani B., et al. “Clodronate in the management of different musculoskeletal conditions”. Minerva Medica4 (2018): 300-325.

Molfetta L., et al. "Potential Application of Clodronate in Fibromyalgia." EC Orthopaedics 16.2 (2025): 01-06.

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