Charcot neuro-osteoarthropathy is a rare condition that affects subjects with diabetes with neuropathy (1). Although the underlying pathophysiology is largely unknown, increased receptor activator of nuclear factor κ-B ligand (RANKL) activation in Charcot neuro-osteoarthropathy has been observed (2). As monoclonal RANKL antibody treatment (denosumab, Prolia) reduces osteoporosis-related fractures (3), we studied its effect on fracture resolution time and clinical outcomes in acute Charcot neuro-osteoarthropathy. All patients with diabetes seen at our foot clinic between 2012 and 2016 were categorized by modified Brodsky classification (4) and treated according to a standardized total contact cast (TCC) protocol. This comprises weekly TCC changes and subsequent conventional X-ray imaging every 4 weeks, as well as supplementation daily with calcium 500 mg/cholecalciferol 800 IE to achieve adequate plasma calcium (between 2.2 and 2.5 mmol/L) and vitamin D levels (>30 nmol/L). All subjects with an acute Charcot foot seen between 2012 and 2014 were included as historic control subjects. From 2014 to 2016, subjects were treated with TCC and a single injection of denosumab 60 mg subcutaneously, followed by plasma calcium check 1 week later.

Upon blinding of radiological case data, fracture resolution (improved consolidation of subchondral bone marrow, decreased subchondral lysis, improved lining of the subchondral bone, and a decrease in soft tissue edema) was scored on conventional X-rays of the affected foot (three-way view) by two independent musculoskeletal radiologists (M.M. and F.F.S.). Time to cessation of TCC was based on edema resolution and less than 2°C temperature difference between both feet measured thrice with TempTouch (Xilas Medical). Complication rates (Table 1) were scored by an independent clinician (K.D.) until 1-year follow-up. The study was reviewed and approved by the institutional review board of the Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Table 1

Baseline characteristics

Denosumab (n = 11)Usual care (n = 11)
Age (years) 59 ± 7 56 ± 16 
Sex (men/women) 7/4 3/8 
Type 1/type 2 diabetes 1/10 5/6* 
Duration of diabetes (years) 16 ± 12 21 ± 8 
BMI (kg/m233 ± 5 26 ± 6* 
Alendronate use 
Neuropathy 11 11 
Retinopathy 
Albuminuria 
Peripheral arterial occlusive disease 
Systolic blood pressure (mmHg) 132 ± 10 131 ± 10 
Diastolic blood pressure (mmHg) 77 ± 10 76 ± 11 
Heart rate (bpm) 74 ± 4 76 ± 6 
HbA1c (%) 8.1 ± 1.4 8.2 ± 1.2 
HbA1c (mmol/mol) 65 ± 15 67 ± 13 
Creatinine clearance (mL/min) 117 ± 60 91 ± 27 
Calcium (mmol/L) 2.5 ± 0.1 2.4 ± 0.1 
Albumin (g/L) 45 ± 3 44 ± 3 
25-OH vitamin D (nmol/L) 51 ± 13 38 ± 17 
Charcot foot location (left/right) 6/5 7/4 
Modified Brodsky   
 Type-1 
 Type-2 
 Type-3A 
 Type-3B 
 Type-4 
 Type-5 
Fracture resolution on imaging (days) 109 ± 45 174 ± 69# 
TCC duration (days) 123 ± 43 182 ± 49# 
Progressive malalignment of Charcot foot (end of TCC) 
Charcot foot recurrence <12 months 
Ulcer development <12 months 
Amputation <12 months 
 Transmetatarsal amputation 
 Transtibial amputation 
Denosumab (n = 11)Usual care (n = 11)
Age (years) 59 ± 7 56 ± 16 
Sex (men/women) 7/4 3/8 
Type 1/type 2 diabetes 1/10 5/6* 
Duration of diabetes (years) 16 ± 12 21 ± 8 
BMI (kg/m233 ± 5 26 ± 6* 
Alendronate use 
Neuropathy 11 11 
Retinopathy 
Albuminuria 
Peripheral arterial occlusive disease 
Systolic blood pressure (mmHg) 132 ± 10 131 ± 10 
Diastolic blood pressure (mmHg) 77 ± 10 76 ± 11 
Heart rate (bpm) 74 ± 4 76 ± 6 
HbA1c (%) 8.1 ± 1.4 8.2 ± 1.2 
HbA1c (mmol/mol) 65 ± 15 67 ± 13 
Creatinine clearance (mL/min) 117 ± 60 91 ± 27 
Calcium (mmol/L) 2.5 ± 0.1 2.4 ± 0.1 
Albumin (g/L) 45 ± 3 44 ± 3 
25-OH vitamin D (nmol/L) 51 ± 13 38 ± 17 
Charcot foot location (left/right) 6/5 7/4 
Modified Brodsky   
 Type-1 
 Type-2 
 Type-3A 
 Type-3B 
 Type-4 
 Type-5 
Fracture resolution on imaging (days) 109 ± 45 174 ± 69# 
TCC duration (days) 123 ± 43 182 ± 49# 
Progressive malalignment of Charcot foot (end of TCC) 
Charcot foot recurrence <12 months 
Ulcer development <12 months 
Amputation <12 months 
 Transmetatarsal amputation 
 Transtibial amputation 

Data are mean ± SD or n. bpm, beats per minute. Peripheral arterial occlusive disease was excluded when both dorsal pedal and posterior tibial artery pulsations were felt or confirmed by a duplex ultrasonography. Differences in clinical variables between the denosumab- and usual-care–treated subjects were tested with unpaired t test or Mann-Whitney test based on Gaussian distribution.

*

P < 0.05,

#

P < 0.01.

Although no adverse events or hypocalcemia were observed, fracture resolution was significantly shorter after denosumab (average 109 ± 45 days) compared with the usual-care group (average 174 ± 69 days), with a good correlation (Pearson r = 0.79, P < 0.01) between the two radiologists (M.M., 119 ± 42 vs. 172 ± 53 days, and F.F.S., 98 ± 48 vs. 176 ± 86 days) (Table 1). Moreover, time to clinical cessation and malalignment in Chopart-Lisfranc joint at end of TCC was also significantly lower with denosumab (123 ± 43 vs. 181 ± 49 days, P < 0.01). None of the subjects developed a contralateral Charcot foot during 1-year follow-up. Whereas ulcer recurrence was similar in both groups, there was an (nonsignificant) increased Charcot recurrence and amputation rate in the conventional treatment group during 1-year follow-up.

This single-center observational study has certain limitations including use of historic control subjects and blinding of only the involved radiologists, which limits generalization of the results to other diabetic foot centers. Also, BMI was increased in the denosumab group due to a higher number of subjects with type 2 diabetes, and more subjects in the usual-care group were treated with bisphosphonates until publication of the review by Richard et al. in 2012 (5). Nevertheless, both confounders tend toward underestimation of denosumab treatment, but efficacy needs to be formally assessed in a larger, randomized, and appropriately blinded trial.

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

Author Contributions. T.E.B.-W., R.B., T.S., E.J.P., and M.N. conceived the study. K.D., S.A.B., F.F.S., and M.M. performed the blinded analyses. All authors had full insight in the study data and critically reviewed the manuscript. T.E.B.-W. 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.

Prior Presentation. This study was presented as an abstract at the Dutch Diabetes Research Meeting (ADDRM/NVDO), Oosterbeek, the Netherlands, 1–2 December 2016.

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