Charcot osteoarthropathy (CO) is an unusual and frequently misdiagnosed complication of diabetes mellitus. The delayed diagnosis can have severe consequences for patients’ limb and life. Its diagnosis is based firstly in its clinical suspicion, is mainly clinical and is confirmed by imaging tests, like magnetic resorance imaging. Specific biomarkers for its early detection and therapy have not been found yet. The understanding of CO pathogenesis and measurement of molecules involved in this can head to this direction. The purpose of this review is to summarize/describe the most current studies measuring biomarkers in people with CO. Confocal corneal microscopy (CCM), inflammatory markers including IL-1, IL-6 and TNF-a, bone metabolism markers like RANK, RANKL, OPG, advanced glycation end products (AGEs) and bone mineral density (BMD) were among the most popular ones included in a large number of studies of the last 20 years and people with CO have significant different levels of the above comparing to non-Charcot groups. Future and larger studies can lead to the discovery of novel biomarkers of the prompt detection of this special entity at an early stage.
novel biomarkers for early detection of the Charcot osteoarthropathy. Created with www.BioRender.com. https://BioRender.com/e94r964
HarrisAViolandM. 2024. Charcot Neuropathic Osteoarthropathy. In StatPearls Treasure Island (FL) ineligible companies. Disclosure: Melanie Violand declares no relevant financial relationships with ineligible companies. StatPearls Publishing LLC.
2.
SommerTCLeeTH. Charcot foot: The diagnostic dilemma. Am Fam Physician. 2001;64(9):1591–1598.
3.
SchmidtBM. Clinical insights into charcot foot. Best Pract Res Clin Rheumatol. 2020;34(3):101563.
4.
DardariD. An overview of charcot's neuroarthropathy. J Clin Transl Endocrinol. 2020;22:100239.
5.
KorstGSRatliffHTTorianJJimohROJupiterDC. Delayed diagnosis of charcot foot: A systematic review. J Foot Ankle Surg. 2022;61(5):1109–1113.
6.
BobircăAMusetescuAEBordianuA, et al.Novel biomarkers predictive of diabetic charcot foot-an overview of the literature. Life (Basel). 2022;12(11):1944.
7.
JansenRBChristensenTMBülowJRørdamLJørgensenNRSvendsenOL. Markers of local inflammation and bone resorption in the acute diabetic charcot foot. J Diabetes Res. 2018;2018:5647981.
8.
TriebK. The charcot foot: Pathophysiology, diagnosis and classification. Bone Joint J. 2016;98-b(9):1155–1159.
9.
GrecoTMascioAComisiC, et al.RANKL-RANK-OPG pathway in charcot diabetic foot: Pathophysiology and clinical-therapeutic implications. Int J Mol Sci. 2023;24(3):3014.
10.
PetrovaNLShanahanCM. Neuropathy and the vascular-bone axis in diabetes: Lessons from charcot osteoarthropathy. Osteoporos Int. 2014;25(4):1197–1207.
11.
JeffcoateW. Vascular calcification and osteolysis in diabetic neuropathy-is RANK-L the missing link?Diabetologia. 2004;47(9):1488–1492.
12.
CallegariACoonsMLRicksJLRosenfeldMEScatenaM. Increased calcification in osteoprotegerin-deficient smooth muscle cells: Dependence on receptor activator of NF-κB ligand and interleukin 6. J Vasc Res. 2014;51(2):118–131.
13.
MengstieMAChekol AbebeEBehaile TeklemariamA, et al.Endogenous advanced glycation end products in the pathogenesis of chronic diabetic complications. Front Mol Biosci. 2022;9:1002710.
14.
Bruhn-OlszewskaBKorzon-BurakowskaAWęgrzynGJakóbkiewicz-BaneckaJ. Prevalence of polymorphisms in OPG, RANKL and RANK as potential markers for charcot arthropathy development. Sci Rep. 2017;7(1):501.
15.
Simó-ServatOPlanasACiudinASimóRHernándezC. Assessment of advanced glycation end-products as a biomarker of diabetic outcomes. Endocrinol Diabetes Nutr (Engl Ed). 2018;65(9):540–545.
16.
WitzkeKAVinikAIGrantLM,et al.Loss of RAGE defense: A cause of charcot neuroarthropathy?Diabetes Care. 2011;34(7):1617–1621.
17.
DuanPBonewaldLF. The role of the wnt/β-catenin signaling pathway in formation and maintenance of bone and teeth. Int J Biochem Cell Biol. 2016;77(Pt A):23–29.
18.
WangLJiangYZhaoC. The effects of advanced glycation end-products on skin and potential anti-glycation strategies. Exp Dermatol.2024;33(4):e15065.
19.
FolestadAÅlundMAstebergS,et al.Role of Wnt/β-catenin and RANKL/OPG in bone healing of diabetic charcot arthropathy patients. Acta Orthop. 2015;86(4):415–425.
20.
GouveriEPapanasN. Charcot osteoarthropathy in diabetes: A brief review with an emphasis on clinical practice. World J Diabetes. 2011;2(5):59–65.
21.
DardariD. Trends in the pathophysiology of charcot neuroarthropathy. Trends Endocrinol Metab. 2023;34(2):61–62.
22.
DehghaniCRussellAWPerkinsBA, et al.A rapid decline in corneal small fibers and occurrence of foot ulceration and charcot foot. J Diabetes Complications. 2016;30(8):1437–1439.
23.
KhanAPetropoulosINPonirakisG, et al.Corneal confocal microscopy detects severe small fiber neuropathy in diabetic patients with charcot neuroarthropathy. J Diabetes Investig. 2018;9(5):1167–1172.
24.
PetropoulosINBitirgenGFerdousiM, et al.Corneal confocal microscopy to image small nerve fiber degeneration: Ophthalmology meets neurology. Front Pain Res (Lausanne). 2021;2:725363.
25.
HerlynAPrakasamRKPeschelS, et al.Corneal subbasal nerve Plexus changes in severe diabetic charcot foot deformity: A pilot study in search for a DNOAP biomarker. J Diabetes Res. 2018;2018:5910639.
26.
PasquierJThomasBHoarau-VéchotJ, et al.Circulating microparticles in acute diabetic charcot foot exhibit a high content of inflammatory cytokines, and support monocyte-to-osteoclast cell induction. Sci Rep.2017;7(1):16450.
27.
PetrovaNLDewTKMustoRL,et al.Inflammatory and bone turnover markers in a cross-sectional and prospective study of acute charcot osteoarthropathy. Diabet Med. 2015;32(2):267–273.
28.
DharmadasSKumarHPillayM,et al.Biomarkers for early detection of charcot arthropathy: A prospective study on type 2 diabetes patients with severe neuropathy. Foot Ankle Int. 2024;45(2):175–178.
29.
BaumhauerJFO'keefeRJSchonLCPinzurMS. Cytokine-induced osteoclastic bone resorption in charcot arthropathy: An immunohistochemical study. Foot Ankle Int. 2006;27(10):797–800.
30.
MabilleauGPetrovaNEdmondsMESabokbarA. Number of circulating CD14-positive cells and the serum levels of TNF-α are raised in acute charcot foot. Diabetes Care. 2011;34(3):e33.
31.
WukichDKSchaperNCGoodayC, et al.Guidelines on the diagnosis and treatment of active charcot neuro-osteoarthropathy in persons with diabetes mellitus (IWGDF 2023). Diabetes Metab Res Rev.2024;40(3):e3646.
32.
HingsammerAMBauerDRennerNBorbasPBoeniTBerliM. Correlation of systemic inflammatory markers with radiographic stages of charcot osteoarthropathy. Foot Ankle Int. 2016;37(9):924–928.
33.
MabilleauGPetrovaNLEdmondsMESabokbarA. Increased osteoclastic activity in acute charcot's osteoarthropathy: The role of receptor activator of nuclear factor-kappaB ligand. Diabetologia. 2008;51(6):1035–1040.
34.
PatelKBernsteinBGrahnBStoltzfusJ. Bone Markers in Charcot Neuroarthropathy. Research Square; 2020.
35.
JansenRBSvendsenOL. A review of bone metabolism and developments in medical treatment of the diabetic charcot foot. J Diabetes Complications. 2018;32(7):708–712.
36.
PetrovaNLFosterAVEdmondsME. Calcaneal bone mineral density in patients with charcot neuropathic osteoarthropathy: Differences between type 1 and type 2 diabetes. Diabet Med. 2005;22(6):756–761.
37.
SinacoreDRHastingsMKBohnertKL,et al.Inflammatory osteolysis in diabetic neuropathic (charcot) arthropathies of the foot. Phys Ther. 2008;88(11):1399–1407.
38.
ChristensenTMBülowJSimonsenLHolsteinPESvendsenOL. Bone mineral density in diabetes mellitus patients with and without a charcot foot. Clin Physiol Funct Imaging. 2010;30(2):130–134.
39.
JansenRBChristensenTMBülowJ,et al.Bone mineral density and markers of bone turnover and inflammation in diabetes patients with or without a charcot foot: An 8.5-year prospective case-control study. J Diabetes Complications. 2018;32(2):164–170.
40.
SvendsenOLRabeOCWinther-JensenMAllinKH. How common is the rare charcot foot in patients with diabetes?Diabetes Care. 2021;44(4):e62–e63.
