Skip to main content

Advertisement

SpringerLink
Log in

Bisphosphonates, Bone and Joint Pain

  • Bone and Joint Pain (P Mantyh and T Schnitzer, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Bisphosphonates (BPs) have an established role in a number of diseases including osteoporosis, but the role of BPs for treating symptomatic conditions other than bone metastases is less clear. We review recent data on the efficacy of BPs in the treatment of symptomatic bone and joint pain with osteoarthritis (OA) as an example.

Recent Findings

Although controversial, BPs have been reported to improve pain ratings, imaging features, and inflammatory markers in patients with arthritis, more specifically OA. It is possible that their effects in periarticular bone strongly influence the complex inflammatory process within the joints. Recent data also suggests that they can potentially impact synovial and synoviocytes and macrophages. Although more studies are needed to define their contribution in clinical practice, increasing evidence suggests they hold an important function, especially in conditions with periarticular bone involvement such as OA.

Summary

Although BPs are indicated primarily for prevention and treatment of osteoporosis, they can also have potential effects on the inflammatory process of other conditions, including OA. Improvements in pain scale ratings, periarticular findings through imaging, and inflammatory response suggest their potential extra-osteoporotic properties.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Maraka S, Kennel KA. Bisphosphonates for the prevention and treatment of osteoporosis. BMJ. 2015;351:h3783.

    Article  PubMed  CAS  Google Scholar 

  2. Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc. 2008;83(9):1032–45.

    Article  CAS  PubMed  Google Scholar 

  3. Corrado A, Santoro N, Cantatore FP. Extra-skeletal effects of bisphosphonates. Joint Bone Spine. 2007;74(1):32–8.

    Article  CAS  PubMed  Google Scholar 

  4. Chen LR, Ko NY, Chen KH. Medical treatment for osteoporosis: From Molecular to Clinical Opinions. Int J Mol Sci. 2019;20(9).

  5. Cremers S, Papapoulos S. Pharmacology of bisphosphonates. Bone. 2011;49(1):42–9.

    Article  CAS  PubMed  Google Scholar 

  6. Stapleton M, Sawamoto K, Almeciga-Diaz CJ, Mackenzie WG, Mason RW, Orii T, et al. Development of bone targeting drugs. Int J Mol Sci. 2017;18(7).

  7. •• Shima K, Tsuchiya M, Oizumi T, Takano-Yamamoto T, Sugawara S, Endo Y. Inflammatory effects of nitrogen-containing bisphosphonates (N-BPs): modulation by non-N-BPs. Biol Pharm Bull. 2017;40(1):25–33 Provides information that mindronate, zoledronic acid, Ibandronate, pamidronate, alendronate, and risedronate have an inflammatory effect (in mice models) and the non-nitrogen-bisphosphonates etidronate, clodronate and the SLC20/34 can reduce or prevent the inflammatory effect of the other nitrogen-bisphosphonates. They also theorize that Etidronate could potentially reduce the risk of BP-related osteonecrosis of the jaw and Clo could be useful as a combination drug with an N-BP for preventing the inflammatory/necrotic side effects without affecting potent anti-bone-resorptive effects.

    Article  CAS  PubMed  Google Scholar 

  8. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. FDA Approved Drug Products. [Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

  9. European Medicines Agency (EMA). Bisphosphonates. Available from: https://www.ema.europa.eu/en.

  10. •• Xing RL, Zhao LR, Wang PM. Bisphosphonates therapy for osteoarthritis: a meta-analysis of randomized controlled trials. Springerplus. 2016;5(1):1704 Reviews the effect of bisphosphonates for patients with OA and suggest that they are effective in relieving pain and accelerating funtional recovery.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tzschentke TM. Pharmacology of bisphosphonates in pain. Br J Pharmacol. 2019.

  12. Burr DB, Gallant MA. Bone remodelling in osteoarthritis. Nat Rev Rheumatol. 2012;8(11):665–73.

    Article  CAS  PubMed  Google Scholar 

  13. Goldring MB, Goldring SR. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann N Y Acad Sci. 2010;1192:230–7.

    Article  CAS  PubMed  Google Scholar 

  14. Goldring SR. Role of bone in osteoarthritis pathogenesis. Med Clin North Am. 2009;93(1):25–35 xv.

    Article  PubMed  Google Scholar 

  15. Walsh DA, Chapman V. Bisphosphonates for osteoarthritis. Arthritis Research & Therapy. 2011;13(5):128.

    Article  CAS  Google Scholar 

  16. •• Vaysbrot EE, Osani MC, Musetti MC, McAlindon TE, Bannuru RR. Are bisphosphonates efficacious in knee osteoarthritis? A meta-analysis of randomized controlled trials. Osteoarthr Cartil. 2018;26(2):154–64 Provides information that bisphosphonates don’t seem to provide symptomatic relief or defer radiographic progression in patients with knee OA.

    Article  CAS  Google Scholar 

  17. Pinto LM, Alghamdi M, Benedetti A, Zaihra T, Landry T, Bourbeau J. Derivation and validation of clinical phenotypes for COPD: a systematic review. Respir Res. 2015;16:50.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lane NE, Shidara K, Wise BL. Osteoarthritis year in review 2016: clinical. Osteoarthr Cartil. 2017;25(2):209–15.

    Article  CAS  Google Scholar 

  19. Bierma-Zeinstra SM, Verhagen AP. Osteoarthritis subpopulations and implications for clinical trial design. Arthritis research & therapy. 2011;13(2):213.

    Article  Google Scholar 

  20. Dell’Isola A, Allan R, Smith SL, Marreiros SS, Steultjens M. Identification of clinical phenotypes in knee osteoarthritis: a systematic review of the literature. BMC Musculoskelet Disord. 2016;17(1):425.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. •• Deveza LA, Melo L, Yamato TP, Mills K, Ravi V, Hunter DJ. Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review. Osteoarthritis and cartilage / OARS. Osteoarthritis Research Society. 2017;25(12):1926–41 Provides information that particular subgroups of patients with knee osteoarthritis maybe more likely to benefit from bisphosphonate therapy than others.

    Article  CAS  Google Scholar 

  22. Lane NE, Brandt K, Hawker G, Peeva E, Schreyer E, Tsuji W, et al. OARSI-FDA initiative: defining the disease state of osteoarthritis. Osteoarthr Cartil. 2011;19(5):478–82.

    Article  CAS  Google Scholar 

  23. Hawker GA, Davis AM, French MR, Cibere J, Jordan JM, March L, et al. Development and preliminary psychometric testing of a new OA pain measure--an OARSI/OMERACT initiative. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2008;16(4):409–14.

    Article  CAS  Google Scholar 

  24. Marchand S. The physiology of pain mechanisms: from the periphery to the brain. Rheum Dis Clin N Am. 2008;34(2):285–309.

    Article  Google Scholar 

  25. Hunter DJ, Guermazi A, Roemer F, Zhang Y, Neogi T. Structural correlates of pain in joints with osteoarthritis. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2013;21(9):1170–8.

    Article  CAS  Google Scholar 

  26. Javaid MK, Kiran A, Guermazi A, Kwoh CK, Zaim S, Carbone L, et al. Individual magnetic resonance imaging and radiographic features of knee osteoarthritis in subjects with unilateral knee pain: the health, aging, and body composition study. Arthritis Rheum. 2012;64(10):3246–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sayre EC, Guermazi A, Esdaile JM, Kopec JA, Singer J, Thorne A, et al. Associations between MRI features versus knee pain severity and progression: data from the Vancouver Longitudinal Study of Early Knee Osteoarthritis. PLoS One. 2017;12(5):e0176833.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Driban JB, Price LL, Lo GH, Pang J, Hunter DJ, Miller E, et al. Evaluation of bone marrow lesion volume as a knee osteoarthritis biomarker - longitudinal relationships with pain and structural changes: data from the Osteoarthritis Initiative. Arthritis Research & Therapy. 2013;15(5):R112.

    Article  Google Scholar 

  29. Zhang Y, Nevitt M, Niu J, Lewis C, Torner J, Guermazi A, et al. Fluctuation of knee pain and changes in bone marrow lesions, effusions, and synovitis on magnetic resonance imaging. Arthritis Rheum. 2011;63(3):691–9.

    Article  PubMed  Google Scholar 

  30. Lo GH, Hunter DJ, Zhang Y, McLennan CE, Lavalley MP, Kiel DP, et al. Bone marrow lesions in the knee are associated with increased local bone density. Arthritis Rheum. 2005;52(9):2814–21.

    Article  PubMed  Google Scholar 

  31. Lowitz T, Museyko O, Bousson V, Laouisset L, Kalender WA, Laredo JD, et al. Bone marrow lesions identified by MRI in knee osteoarthritis are associated with locally increased bone mineral density measured by QCT. Osteoarthr Cartil. 2013;21(7):957–64.

    Article  CAS  Google Scholar 

  32. Messent EA, Buckland-Wright JC, Blake GM. Fractal analysis of trabecular bone in knee osteoarthritis (OA) is a more sensitive marker of disease status than bone mineral density (BMD). Calcif Tissue Int. 2005;76(6):419–25.

    Article  CAS  PubMed  Google Scholar 

  33. •• Lo GH, Schneider E, Driban JB, Price LL, Hunter DJ, Eaton CB, et al. Periarticular bone predicts knee osteoarthritis progression: data from the Osteoarthritis Initiative. Semin Arthritis Rheum. 2018;48(2):155–61 Provides information that periarticular health in knees in people with OA associate with loss of radiographic joint space over a relatively short time frame, therefore the periarticular bone could be a therapeutic target in OA.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Taljanovic MS, Graham AR, Benjamin JB, Gmitro AF, Krupinski EA, Schwartz SA, et al. Bone marrow edema pattern in advanced hip osteoarthritis: quantitative assessment with magnetic resonance imaging and correlation with clinical examination, radiographic findings, and histopathology. Skelet Radiol. 2008;37(5):423–31.

    Article  Google Scholar 

  35. Flora L. Comparative antiinflammatory and bone protective effects of two diphosphonates in adjuvant arthritis. Arthritis Rheum. 1979;22(4):340–6.

    Article  CAS  PubMed  Google Scholar 

  36. Dunn CJ, Galinet LA, Wu H, Nugent RA, Schlachter ST, Staite ND, et al. Demonstration of novel anti-arthritic and anti-inflammatory effects of diphosphonates. J Pharmacol Exp Ther. 1993;266(3):1691–8.

    CAS  PubMed  Google Scholar 

  37. Makkonen N, Salminen A, Rogers MJ, Frith JC, Urtti A, Azhayeva E, et al. Contrasting effects of alendronate and clodronate on RAW 264 macrophages: the role of a bisphosphonate metabolite. Eur J Pharm Sci. 1999;8(2):109–18.

    Article  CAS  PubMed  Google Scholar 

  38. van Lent PL, Holthuysen AE, van den Bersselaar L, van Rooijen N, van de Putte LB, van den Berg WB. Role of macrophage-like synovial lining cells in localization and expression of experimental arthritis. Scand J Rheumatol Suppl. 1995;101:83–9.

    Article  PubMed  Google Scholar 

  39. Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L, Foidart JM, et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther. 2002;302(3):1055–61.

    Article  CAS  PubMed  Google Scholar 

  40. Ceponis A, Waris E, Monkkonen J, Laasonen L, Hyttinen M, Solovieva SA, et al. Effects of low-dose, noncytotoxic, intraarticular liposomal clodronate on development of erosions and proteoglycan loss in established antigen-induced arthritis in rabbits. Arthritis Rheum. 2001;44(8):1908–16.

    Article  CAS  PubMed  Google Scholar 

  41. Itoh F, Aoyagi S, Kusama H, Kojima M, Kogo H. Effects of clodronate and alendronate on local and systemic changes in bone metabolism in rats with adjuvant arthritis. Inflammation. 2004;28(1):15–21.

    Article  CAS  PubMed  Google Scholar 

  42. Harada H, Nakayama T, Nanaka T, Katsumata T. Effects of bisphosphonates on joint damage and bone loss in rat adjuvant-induced arthritis. Inflamm Res. 2004;53(2):45–52.

    Article  CAS  PubMed  Google Scholar 

  43. •• Corrado A, Maruotti N, Cantatore FP. Bisphosphonates and osteoarthritis. Journal of Gerontology and Geriatrics. 2017;65:124–9 Reviews the effects of bisphosphonates in OA and suggests that the they may determine some positive structural and symptomatic effects in the treatment of OA through different mechanisms including osteoclasts/osteoblasts function, and inhibiting the synovial inflammation.

    Google Scholar 

  44. Herman S, Kronke G, Schett G. Molecular mechanisms of inflammatory bone damage: emerging targets for therapy. Trends Mol Med. 2008;14(6):245–53.

    Article  CAS  PubMed  Google Scholar 

  45. Iannitti T, Rosini S, Lodi D, Frediani B, Rottigni V, Palmieri B. Bisphosphonates: focus on inflammation and bone loss. Am J Ther. 2012;19(3):228–46.

    Article  PubMed  Google Scholar 

  46. Sandell LJ, Aigner T. Articular cartilage and changes in arthritis. An introduction: cell biology of osteoarthritis. Arthritis Res. 2001;3(2):107–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Okimura A, Okada Y, Makihira S, Pan H, Yu L, Tanne K, et al. Enhancement of cartilage matrix protein synthesis in arthritic cartilage. Arthritis Rheum. 1997;40(6):1029–36.

    Article  CAS  PubMed  Google Scholar 

  48. Cantatore FP, Acquista CA, Pipitone V. Evaluation of bone turnover and osteoclastic cytokines in early rheumatoid arthritis treated with alendronate. J Rheumatol. 1999;26(11):2318–23.

    CAS  PubMed  Google Scholar 

  49. Cantatore FP, Introsso AM, Carrozzo M. Effects of bisphosphonates on interleukin 1, tumor necrosis factor alpha, and beta 2 microglobulin in rheumatoid arthritis. J Rheumatol. 1996;23(6):1117–8.

    CAS  PubMed  Google Scholar 

  50. van Lent PL, Holthuysen AE, van den Bersselaar LA, van Rooijen N, Joosten LA, van de Loo FA, et al. Phagocytic lining cells determine local expression of inflammation in type II collagen-induced arthritis. Arthritis Rheum. 1996;39(9):1545–55.

    Article  PubMed  Google Scholar 

  51. Mehlhorn AT, Rechl H, Gradinger R, Stemberger A. Alendronate decreases TRACP 5b activity in osteoarthritic bone. Eur J Med Res. 2008;13(1):21–5.

    CAS  PubMed  Google Scholar 

  52. Buckland-Wright JC, Messent EA, Bingham CO 3rd, Ward RJ, Tonkin C. A 2 yr longitudinal radiographic study examining the effect of a bisphosphonate (risedronate) upon subchondral bone loss in osteoarthritic knee patients. Rheumatology (Oxford). 2007;46(2):257–64.

    Article  CAS  Google Scholar 

  53. Bingham CO 3rd, Buckland-Wright JC, Garnero P, Cohen SB, Dougados M, Adami S, et al. Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study. Arthritis Rheum. 2006;54(11):3494–507.

    Article  CAS  PubMed  Google Scholar 

  54. Davis AJ, Smith TO, Hing CB, Sofat N. Are bisphosphonates effective in the treatment of osteoarthritis pain? A meta-analysis and systematic review. PLoS One. 2013;8(9):e72714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Spector TD, Conaghan PG, Buckland-Wright JC, Garnero P, Cline GA, Beary JF, et al. Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173]. Arthritis Research & Therapy. 2005;7(3):R625–33.

    Article  CAS  Google Scholar 

  56. Deveza LA, Bierma-Zeinstra SMA, van Spil WE, Oo WM, Saragiotto BT, Neogi T, et al. Efficacy of bisphosphonates in specific knee osteoarthritis subpopulations: protocol for an OA Trial Bank systematic review and individual patient data meta-analysis. BMJ Open. 2018;8(12):e023889.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Carbone LD, Nevitt MC, Wildy K, Barrow KD, Harris F, Felson D, et al. The relationship of antiresorptive drug use to structural findings and symptoms of knee osteoarthritis. Arthritis Rheum. 2004;50(11):3516–25.

    Article  PubMed  Google Scholar 

  58. •• Fu SH, Wang CY, Yang RS, Wu FL, Hsiao FY. Bisphosphonate use and the risk of undergoing total knee arthroplasty in osteoporotic patients with osteoarthritis: a nationwide cohort study in Taiwan. J Bone Joint Surg Am. 2017;99(11):938–46 Provides information that among patients with osteoporosis and osteoarthritis, bisphosphonate use was associated with a lower risk of total knee arthroplasty, and lower consumption of pain medications, especially for those with high adherence and longer treatment duration.

    Article  PubMed  Google Scholar 

  59. •• Neogi T, Li S, Peloquin C, Misra D, Zhang Y. Effect of bisphosphonates on knee replacement surgery. Ann Rheum Dis. 2018;77(1):92–7 Provides information that older bisphosphonates users women with incident knee OA had lower risk of knee replacement than nonusers of bisphosphonates, suggesting a potential beneficial effect of bisphosphonates on knee osteoarthritis.

    Article  CAS  PubMed  Google Scholar 

  60. •• Saviola G, Abdi-Ali L, Povino MR, Campostrini L, Sacco S, Dalle Carbonare L, et al. Intramuscular clodronate in erosive osteoarthritis of the hand is effective on pain and reduces serum COMP: a randomized pilot trial-The ER.O.D.E. study (ERosive Osteoarthritis and Disodium-clodronate Evaluation). Clin Rheumatol. 2017;36(10):2343–50 Reviews informations that intramuscular clodronate is effective in the treatment of active painful erosive osteoarthritis of the hand. CLO is able to reduce pain and to decrease the pain-related disability, and could also play a role as a disease-modifying drug.

    Article  PubMed  Google Scholar 

  61. •• Frediani B, Toscano C, Falsetti P, Nicosia A, Pierguidi S, Migliore A, et al. Intramuscular clodronate in long-term treatment of symptomatic knee osteoarthritis: a randomized controlled study. Drugs R D. 2020;20(1):39–45 Provides information that intramuscular administrations of clodronate are effective in the management of symptomatic knee osteoarthritis, improving functional outcomes and reducing pain and bone marrow edema.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. •• Kolasinski SL, Neogi T, Hochberg MC, Oatis C, Guyatt G, Block J, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheum. 2020;72(2):220–33 Guidelines that provides directions for clinicians and patients making treatment decisions for the management of OA. According to them, bisphosphonates are strongly recommended against in patients with knee, hip, and/or hand OA.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Rheumatology, Department of Medicine, The University of Arizona College of Medicine, Tucson, AZ, USA

    Michel Villatoro-Villar & C. Kent Kwoh

  2. University of Arizona Arthritis Center, The University of Arizona College of Medicine, 1501 N. Campbell Avenue, Suite, Tucson, AZ, 8303, USA

    C. Kent Kwoh

Authors
  1. Michel Villatoro-Villar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Kent Kwoh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Kent Kwoh.

Ethics declarations

Conflict of Interest

MVV – no disclosures. CKK – Institutional grants from Abbvie, Lilly, Pfizer, GSK, Cumberland Pharmaceuticals; DSMB – Kolon Tissue Gene; Consulting – Regeneron, LG Chem, Express Scripts.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Bone and Joint Pain

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Villatoro-Villar, M., Kwoh, C.K. Bisphosphonates, Bone and Joint Pain. Curr Osteoporos Rep 19, 417–428 (2021). https://doi.org/10.1007/s11914-021-00687-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-021-00687-7

Keywords

Search

Navigation