Efficacy of medical treatment for Charcot neuroarthropathy: a systematic review and meta-analysis of randomized controlled trials


No pharmacotherapeutic agents are yet recommended for active CN though many anti-resorptive agents have been studied. We conducted a systematic review and meta-analysis of the randomized placebo-controlled trials (RCTs) evaluating the time to remission of active CN with anti-resorptive or antiinflammatory drugs. RCTs published in PubMed, EMBASE, SCOPUS and Cochrane Library from January 1994 to December 2019 were accessed. We reviewed studies and extracted information on study design, participants’ characteristics, time to remission, bone turnover markers, bone mineral content (BMC) and temperature difference between feet. Five RCTs out of 588 total identified records were included. Standardized mean differences (SMD) between groups with 95% CI are summarized. Pharmacotherapy nonsignificantly increased time to remission [SMD 0.52 weeks (− 0.71, 1.75), p = 0.402; I2 = 88.6%] as compared to TCC alone. The pooled median time to remission with the intervention was 18.5 weeks (11.2, 28.1) compared to 16.8 weeks (8.7, 27.7) with TCC. A nonsignificant increase in BMC [SMD 3.39% (− 0.78, 7.56), p = 0.109; I2 = 96.7%], a decrease in foot temperature [SMD − 0.42 °C (− 0.78, − 0.07), p = 0.020; I2 = 0%] and alkaline phosphatase [SMD = −2.51% (− 3.24, − 1.77), p < 0.001; I2 = 0%] was observed with intervention. Limited evidence from available studies does not support the role of anti-resorptive or anti-inflammatory drugs for earlier remission when added to offloading with total contact cast for active CN of the foot.

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Data availability

The data supporting the finding of the present study are available from the corresponding author upon reasonable request.


  1. 1.

    Wukich DK, Sung W, Wipf SA, Armstrong DG (2011) The consequences of complacency: managing the effects of unrecognized Charcot feet. Diabetes Med 28(2):195–198

    CAS  Article  Google Scholar 

  2. 2.

    Sohn MW, Stuck RM, Pinzur M, Lee TA, Budiman-Mak E (2010) Lower-extremity amputation risk after Charcot arthropathy and diabetic foot ulcer. Diabetes Care 33(1):98–100. https://doi.org/10.2337/dc09-1497

    PubMed  Article  Google Scholar 

  3. 3.

    Rastogi A, Goyal G, Kesavan R et al (2020) Long term outcomes after incident diabetic foot ulcer: multicenter large cohort prospective study (EDI-FOCUS investigators) epidemiology of diabetic foot complications study. Diabetes Res Clin Pract 162:108113. https://doi.org/10.1016/j.diabres.2020.108113

    PubMed  Article  Google Scholar 

  4. 4.

    Baal JV, Hubbard R, Game F, Jeffcoate W (2010) Mortality associated with acute Charcot foot and neuropathic foot ulceration. Diabetes Care 33:1086–1089

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Chaudhary S, Bhansali A, Rastogi A (2019) Mortality in Asian Indians with Charcot’s neuroarthropathy: a nested cohort prospective study. Acta Diabetol 56(12):1259–1264

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Jeffcoate WJ (2015) Charcot foot syndrome. Diabet Med 32(6):760–770

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Moura-Neto A, Fernandes TD, Zantut-Witmann DE et al (2012) Charcot foot: skin temperature as a good clinical parameter for predicting disease outcome. Diabetes Res Clin Pract 96:e11–e14

    PubMed  Article  Google Scholar 

  8. 8.

    Game FL, Catlow R, Jones GR et al (2012) Audit of acute Charcot’s disease in the UK: the CDUK study. Diabetologia 55:32–35

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Christensen TM, Gade-Rasmussen B, Pedersen LW, Hommel E, Holstein PE, Svendsen OL (2012) Duration of off-loading and recurrence rate in Charcot osteoarthropathy treated with less restrictive regimen with removable walker. J Diabetes Complic 26:430–434

    Article  Google Scholar 

  10. 10.

    Wennberg L, Lundgren P, Axelsson R, Aspelin P, Gerok-Andersson K, Åkerlund B (2017) Diabetic osteoarthropathy care in Sweden—need for improvement: a national inventory. J Clin Transl Endocrinol 9:32–37

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Jeffcoate WJ, Game F, Cavanagh PR (2005) The role of proinflammatory cytokines in the cause of neuropathic osteoarthropathy (acute Charcot foot) in diabetes. Lancet 366:2058–2061

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Mabilleau G, Petrova NL, Edmonds ME, Sabokbar A (2008) Increased osteoclastic activity in acute Charcot’s osteoarthropathy: the role of receptor activator of nuclear factor-kappaB ligand. Diabetologia 51:1035–1040

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Folestad A, Alund M, Asteberg S (2015) Role of Wnt/β-catenin and RANKL/OPG in bone healing of diabetic Charcot arthropathy patients. Acta Orthop 86(4):415–425

    PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Bruhn-Olszewska B, Korzon-Burakowska A, Węgrzyn G, Jakóbkiewicz-Banecka J (2017) Prevalence of polymorphisms in OPG, RANKL and RANK as potential markers for Charcot arthropathy development. Sci Rep 29(1):1–9

    Google Scholar 

  15. 15.

    Petrova NL, Edmonds ME (2013) Medical management of Charcot arthropathy. Diabetes Obes Metab 15(3):193–197

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Jude EB, Selby PL, Burgess J et al (2001) Bisphosphonates in the treatment of Charcot neuroarthropathy: a double-blind randomised controlled trial. Diabetologia 44:2032–2037

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Pitocco D, Ruotolo V, Caputo S, Mancini L, Collina CM, Manto A et al (2005) Six-month treatment with alendronate in acute Charcot neuroarthropathy: a randomized controlled trial. Diabetes Care 28:1214–1215

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Bem R, Jirkovská A, Fejfarová V, Skibová J, Jude EB (2006) Intranasal calcitonin in the treatment of acute Charcot neuroosteoarthropathy: a randomized controlled trial. Diabetes Care 29:1392–1394

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Pakarinen TK, Laine HJ, Mäenpää H, Mattila P, Lahtela J (2011) The effect of zoledronic acid on the clinical resolution of Charcot neuroarthropathy: a pilot randomized controlled trial. Diabetes Care 34:1514–1516

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Rogers LC, Frykberg RG, Armstrong DG et al (2011) The Charcot foot in diabetes. Diabetes Care 34(9):2123–2129

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Richard JL, Almasri M, Schuldiner S (2012) Treatment of acute Charcot foot with bisphosphonates: a systematic review of the literature. Diabetologia 55:1258–1264

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Busch-Westbroek TE, Delpeut K, Balm R et al (2018) Effect of single dose of RANKL antibody treatment on acute Charcot neuro-osteoarthropathy of the foot. Diabetes Care 41:e21–e22

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Das L, Bhansali A, Prakash M, Jude E, Rastogi A (2019) Effect of methylprednisolone or zoledronic acid for the resolution of active Charcot neuroarthropathy in diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Care 42:e1–e2. https://doi.org/10.2337/dc19-1659

    CAS  Article  Google Scholar 

  24. 24.

    Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62:1006–1012

    PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Rastogi A, Bhansali A, Jude EB. Efficacy of medical treatment for active Charcot neuroarthropathy of foot: Systematic Review And Meta-Analysis. PROSPERO 2020 CRD42020164615. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020164615. Accessed 25 Apr 2020

  26. 26.

    Selby PL, Young MJ, Adams JE, Boulton AJM (1994) Bisphosphonate: a new treatment for diabetic Charcot neuroarthropathy. Diabet Med 11:14–20

    Article  Google Scholar 

  27. 27.

    Bharat R, Bal A, Sundaram S et al (2013) A comparative study of zoledronic acid and alendronate in the management of acute Charcot arthropathy of foot in patients with diabetes mellitus. Ind J Endocrinol Metab 17:110–116

    Article  Google Scholar 

  28. 28.

    Anderson JJ, Woelffer KE, Holtzman JJ, Jacobs AM (2004) Bisphosphonates for the treatment of Charcot neuroarthropathy. J Foot Ankle Surg 43:285–289

    PubMed  Article  Google Scholar 

  29. 29.

    Vopat ML, Nentwig MJ, Chong ACM, Agan JL, Shields NN, Yang SY (2018) Initial diagnosis and management for acute Charcot neuroarthropathy. Kans J Med 11(4):114–119

    PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Rastogi A, Prakash M, Bhansali A (2019) Varied presentations and outcomes of Charcot neuroarthropathy in patients with diabetes. Int J Diabetes Dev Ctries 39(3):513–522

    Article  Google Scholar 

  31. 31.

    Armstrong DG, Lavery LA (1997) Monitoring healing of acute Charcot’s arthropathy with infrared dermal thermometry. J Rehabil Res Dev 34:317–321

    CAS  PubMed  Google Scholar 

  32. 32.

    Hastings MK, Sinacore DR, Fielder FA, Johnson JE (2005) Bone mineral density during total contact cast immobilization for a patient with neuropathic (Charcot) arthropathy. PhyTher 85(3):249–256

    Google Scholar 

  33. 33.

    Minaire P (1989) Immobilization osteoporosis: a review. Clin Rheumatol 8:95–103

    PubMed  Article  Google Scholar 

  34. 34.

    Pitocco D, Zelano G, Gioffre G et al (2009) Association between osteoproterin G1181C and T245G polymorphisms and diabetic Charcot neuroarthropathy: a case control study. Diabetes Care 32:1694–1697

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Korzon-Burakowska A, Jakobkiewicz-Banecka J, Fiedosiuk A et al (2012) Osteoprotegerin gene polymorphism in diabetic Charcot neuroarthropathy. Diabetes Med 29:771–775

    CAS  Article  Google Scholar 

  36. 36.

    Petrova NL, Edmonds ME (2015) Acute Charcot neuro-osteoarthropathy. Diabetes Metab Res Rev 32(suppl 1):281–286

    Google Scholar 

  37. 37.

    Stansberry KB et al (1999) Intravenous biphosphonate rapidly reverses the paradoxical increase in blood flow to the foot in Charcot neuropathy (abstr). Diabetes 48(suppl 1):A92

    Google Scholar 

  38. 38.

    Guis S, Pellissier JF, Amiaud D et al (1999) Healing of Charcot’s joint by pamidronate infusion. J Rheum 26:1843–1845

    CAS  PubMed  Google Scholar 

  39. 39.

    Rastogi A, Hajela A, Prakash M et al (2019) Teriparatide (recombinant human parathyroid hormone [1-34]) increases foot bone remodeling in diabetic chronic Charcot neuroarthropathy: a randomized double-blind placebo-controlled study. J Diabetes 11(9):703–710

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Anastasilakis AD, Polyzos SA, Makras P (2018) THERAPY OF ENDOCRINE DISEASE: denosumab vs bisphosphonates for the treatment of postmenopausal osteoporosis. Eur J Endocrinol 179(1):R31–R45

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Kendler DL, Roux C, Benhamou CL et al (2010) Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy. J Bone Miner Res 25(1):72–81

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Anastasilakis AD, Polyzos SA, Gkiomisi A et al (2015) Denosumab versus zoledronic acid in patients previously treated with zoledronic acid. Osteoporos Int 26(10):2521–2527

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Miller PD, Pannacciulli N, Brown JP et al (2016) Denosumab or zoledronic acid in postmenopausal women with osteoporosis previously treated with oral bisphosphonates. J Clin Endocrinol Metab 101(8):3163–3170

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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A.R. conceived the design, research question, search strategy, acquisition of the data, data analysis, interpretation of results and wrote the initial draft of the manuscript. A.B. conducted the initial search for articles, revised and critically edited the manuscript. E.B.J. contributed to the design, interpretation of results and edited the manuscript. All authors agree on the final version of the manuscript and A.R. will act as the guarantor of the manuscript.

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Correspondence to Ashu Rastogi.

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Rastogi, A., Bhansali, A. & Jude, E.B. Efficacy of medical treatment for Charcot neuroarthropathy: a systematic review and meta-analysis of randomized controlled trials. Acta Diabetol (2021). https://doi.org/10.1007/s00592-020-01664-9

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  • Charcot neuroarthropathy
  • Bisphosphonate
  • Anti-resorptive
  • Denosumab
  • Clinical remission
  • Methylprednisolone
  • Standardized mean difference