Skip to main content
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes Care

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes Care
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
e-Letters: Observations

Effect of Methylprednisolone or Zoledronic Acid on Resolution of Active Charcot Neuroarthropathy in Diabetes: A Randomized, Double-Blind, Placebo-Controlled Study

  1. Liza Das1,
  2. Anil Bhansali1,
  3. Mahesh Prakash2,
  4. Edward B. Jude3 and
  5. Ashu Rastogi1⇑
  1. 1Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
  2. 2Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research, Chandigarh, India
  3. 3Tameside Hospital NHS Foundation Trust and University of Manchester, Ashton under Lyne, U.K.
  1. Corresponding author: Ashu Rastogi, ashuendo{at}gmail.com
Diabetes Care 2019 Dec; 42(12): e185-e186. https://doi.org/10.2337/dc19-1659
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

Charcot neuroarthropathy (CN) is a complex syndrome affecting people with diabetes and peripheral neuropathy but preserved vascularity. Without early intervention, active CN may have long-term consequences (1). Recent studies suggest the role of proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), in mediating inflammatory osteolysis by activating the receptor activator of nuclear factor-κB (RANKL-NF-κB) pathway, thus perpetuating bone loss in an insensate foot with active CN (2,3). The goal of treatment in active CN is therefore to curtail the ongoing inflammation and/or osteolysis. Antiresorptive agents to inhibit osteolysis have been used with modest success (4,5), but anti-inflammatory agents have not been evaluated for CN. We studied the efficacy of methylprednisolone (MP) or zoledronic acid (ZA) in comparison with placebo in active CN along with total contact cast (TCC) as the primary modality.

Included participants had a clinical diagnosis of active CN (erythematous and swollen) with a foot temperature difference exceeding 2°C by infrared dermal thermometry (FLIR Systems, Inc., Orlando, FL) compared with a similar site on the opposite foot, substantiated by X-ray and/or MRI. Bone turnover markers (BTMs) P1NP and CTX (Elecsys; Roche Diagnostics, Mannheim, Germany) were estimated by electrochemiluminescence immunoassay (ECLIA) (Roche Cobas 600 Analyzer; Roche Diagnostics) with coefficient of variation (CV) 1.5% to 4.7%. Inflammatory cytokines (TNF-α, IL-1β) were estimated by ELISA (human high sensitivity kits BMS223HS and BMS224HS; Thermo Fisher Scientific) with CV of 6% to 8%. Participants were immobilized with standardized fiberglass TCC and subsequently randomized to receive MP 1 g in 100 mL normal saline (group A), ZA 5 mg in 100 mL infusion (group B), or placebo 100 mL normal saline (group C) once a month for three consecutive months. All participants were followed fortnightly, with change of cast as required. An average of three temperature recordings 30 min after removal of cast was recorded. Remission was defined as a temperature difference <2°C on two successive follow-up visits. Bone mineral content, BTMs, and inflammatory cytokines were evaluated at baseline and 6 months. The study was approved by the institutional ethics committee, and informed consent was obtained from all participants (NCT03289338). A modified intention-to-treat analysis was performed.

Thirty-six participants were included in the study. Baseline characteristics of the cohort are summarized in Table 1. The mean ± SD time for clinical resolution in the whole cohort was 15.5 ± 4.2 weeks. Time to resolution was significantly higher in the MP group (19.4 ± 2.8 weeks) as compared with either the ZA (14.6 ± 4.4 weeks, P = 0.01) or placebo (13.5 ± 2.9, P = 0.01) group; however, there was no difference between ZA and placebo (P = 0.98). MP reduced TNF-α by 27% (P = 0.03) and IL-1β by 30% (P = 0.02) from baseline as compared with placebo. The reduction of cytokines was comparable between ZA and placebo. BTM analysis revealed an 18% increase in CTX and 5% reduction in P1NP with MP. CTX was reduced by 35% and 11% and P1NP was reduced by 24% and 19% with ZA and placebo, respectively. Adverse events included worsened glycemia with MP and flu-like reaction (n = 5) and acute kidney injury (n = 2) with ZA.

View this table:
  • View inline
  • View popup
Table 1

Clinical and biochemical parameters of the participants at baseline and follow-up

This is the first randomized, placebo-controlled study comparing the effects of MP and ZA with standard of care in patients with active CN of the foot. Pulse MP prolonged time to remission as compared with either ZA or placebo. Inflammatory markers declined in all groups, but bone resorption increased and bone formation decreased with the use of MP, translating into an overall loss of bone mass.

The role of inflammation in the etiopathogenesis of active Charcot foot is unequivocal (2). We observed that MP, a potent anti-inflammatory agent, delays time to remission compared with TCC alone for active CN, despite an effective reduction of the proinflammatory milieu, suggesting that ongoing osteolysis is mediated through activation of the cytokine-independent RANKL pathway. Moreover, MP aggravates hyperglycemia and negatively regulates both CGRP (a neuropeptide that antagonizes RANKL) and osteoprotegerin (a decoy receptor for RANKL), and these may contribute to increased RANKL-NF-κB activity independent of cytokines. Therefore, it is conceivable that although inflammation is pivotal to the pathogenesis of active CN, reducing inflammatory cytokines alone may not suffice for an earlier resolution of active CN.

We observed no added benefit of ZA for earlier remission of CN as compared with TCC alone, as previously documented (5). The strengths of this study include an intensive follow-up, a comparison of a potent anti-inflammatory agent (MP) with ZA and TCC, and a prospective analysis of BTMs and inflammatory markers. In conclusion, MP does not reduce time to remission in active CN of the foot despite reduction in inflammatory cytokines.

Article Information

Acknowledgments

The investigators are grateful to all patients and their families for their commitment to this study.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. L.D. wrote the initial draft of the manuscript. L.D., A.B., and A.R. conceived the study. L.D. and A.R. were involved in clinical care of the participants and their follow-up. L.D., A.B., E.B.J., and A.R. were involved in editing and revision of the manuscript. M.P. provided relevant radiological expertise. A.B., E.B.J., and A.R. did a critical analysis of the manuscript and its editing. A.R. randomized the participants and administered the study drug. All authors approved the final manuscript. A.R. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Footnotes

  • Clinical trial reg. no. NCT03289338, clinicaltrials.gov

  • Received August 17, 2019.
  • Accepted September 8, 2019.
  • © 2019 by the American Diabetes Association.
http://www.diabetesjournals.org/content/license

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

References

  1. ↵
    1. Chaudhary S,
    2. Bhansali A,
    3. Rastogi A
    . Mortality in Asian Indians with Charcot’s neuroarthropathy: a nested cohort prospective study. Acta Diabetol 2019;56:1259–1264
    OpenUrl
  2. ↵
    1. Jeffcoate WJ,
    2. Game F,
    3. Cavanagh PR
    . The role of proinflammatory cytokines in the cause of neuropathic osteoarthropathy (acute Charcot foot) in diabetes. Lancet 2005;366:2058–2061
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    1. Petrova NL,
    2. Dew TK,
    3. Musto RL, et al
    . Inflammatory and bone turnover markers in a cross-sectional and prospective study of acute Charcot osteoarthropathy. Diabet Med 2015;32:267–273
    OpenUrlCrossRefPubMed
  4. ↵
    1. Busch-Westbroek TE,
    2. Delpeut K,
    3. Balm R, et al
    . Effect of single dose of RANKL antibody treatment on acute Charcot neuro-osteoarthropathy of the foot. Diabetes Care 2018;41:e21–e22
    OpenUrlFREE Full Text
  5. ↵
    1. Pakarinen TK,
    2. Laine HJ,
    3. Mäenpää H,
    4. Mattila P,
    5. Lahtela J
    . The effect of zoledronic acid on the clinical resolution of Charcot neuroarthropathy: a pilot randomized controlled trial. Diabetes Care 2011;34:1514–1516
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top
Diabetes Care: 42 (12)

In this Issue

December 2019, 42(12)
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by Author
  • Masthead (PDF)
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes Care.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Effect of Methylprednisolone or Zoledronic Acid on Resolution of Active Charcot Neuroarthropathy in Diabetes: A Randomized, Double-Blind, Placebo-Controlled Study
(Your Name) has forwarded a page to you from Diabetes Care
(Your Name) thought you would like to see this page from the Diabetes Care web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Effect of Methylprednisolone or Zoledronic Acid on Resolution of Active Charcot Neuroarthropathy in Diabetes: A Randomized, Double-Blind, Placebo-Controlled Study
Liza Das, Anil Bhansali, Mahesh Prakash, Edward B. Jude, Ashu Rastogi
Diabetes Care Dec 2019, 42 (12) e185-e186; DOI: 10.2337/dc19-1659

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Effect of Methylprednisolone or Zoledronic Acid on Resolution of Active Charcot Neuroarthropathy in Diabetes: A Randomized, Double-Blind, Placebo-Controlled Study
Liza Das, Anil Bhansali, Mahesh Prakash, Edward B. Jude, Ashu Rastogi
Diabetes Care Dec 2019, 42 (12) e185-e186; DOI: 10.2337/dc19-1659
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Article Information
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Interferent Effect of Hydroxyurea on Continuous Glucose Monitoring
  • Creating Composite Indices From Continuous Variables for Research: The Geometric Mean
  • Early Worsening of Diabetic Nephropathy in Type 2 Diabetes After Rapid Improvement in Chronic Severe Hyperglycemia
Show more e-Letters: Observations

Similar Articles

Navigate

  • Current Issue
  • Standards of Care Guidelines
  • Online Ahead of Print
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Care Print ISSN: 0149-5992, Online ISSN: 1935-5548.