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.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
The data supporting the finding of the present study are available from the corresponding author upon reasonable request.
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
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
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
Baal JV, Hubbard R, Game F, Jeffcoate W (2010) Mortality associated with acute Charcot foot and neuropathic foot ulceration. Diabetes Care 33:1086–1089
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
Jeffcoate WJ (2015) Charcot foot syndrome. Diabet Med 32(6):760–770
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
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
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
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
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
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
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
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
Petrova NL, Edmonds ME (2013) Medical management of Charcot arthropathy. Diabetes Obes Metab 15(3):193–197
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
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
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
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
Rogers LC, Frykberg RG, Armstrong DG et al (2011) The Charcot foot in diabetes. Diabetes Care 34(9):2123–2129
Richard JL, Almasri M, Schuldiner S (2012) Treatment of acute Charcot foot with bisphosphonates: a systematic review of the literature. Diabetologia 55:1258–1264
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
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
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
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
Selby PL, Young MJ, Adams JE, Boulton AJM (1994) Bisphosphonate: a new treatment for diabetic Charcot neuroarthropathy. Diabet Med 11:14–20
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
Anderson JJ, Woelffer KE, Holtzman JJ, Jacobs AM (2004) Bisphosphonates for the treatment of Charcot neuroarthropathy. J Foot Ankle Surg 43:285–289
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
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
Armstrong DG, Lavery LA (1997) Monitoring healing of acute Charcot’s arthropathy with infrared dermal thermometry. J Rehabil Res Dev 34:317–321
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
Minaire P (1989) Immobilization osteoporosis: a review. Clin Rheumatol 8:95–103
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
Korzon-Burakowska A, Jakobkiewicz-Banecka J, Fiedosiuk A et al (2012) Osteoprotegerin gene polymorphism in diabetic Charcot neuroarthropathy. Diabetes Med 29:771–775
Petrova NL, Edmonds ME (2015) Acute Charcot neuro-osteoarthropathy. Diabetes Metab Res Rev 32(suppl 1):281–286
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
Guis S, Pellissier JF, Amiaud D et al (1999) Healing of Charcot’s joint by pamidronate infusion. J Rheum 26:1843–1845
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
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
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
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
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
Conflict of interest
All authors declare that they have nothing to disclose.
The study does not involve any human subjects or animal and does not require disclosure to the rights.
The study was exempted from the informed consent disclosure as it did not involve any himan subjects.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Managed by Massimo Federici.
About this article
Cite this article
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
- Charcot neuroarthropathy
- Clinical remission
- Standardized mean difference