Six-Month Treatment With Alendronate in Acute Charcot Neuroarthropathy: A randomized controlled trial

doi:10.2337/diacare.28.5.1214

HOME

HELP

FEEDBACK

SUBSCRIPTIONS

Emerging Treatments and Technologies
Brief Report

Six-Month Treatment With Alendronate in Acute Charcot Neuroarthropathy

A randomized controlled trial

Dario Pitocco, MD, Valeria Ruotolo, MD, Salvatore Caputo, MD, Lorena Mancini, MD, Chiara M. Collina, MD, Andrea Manto, MD, Paolo Caradonna, MD and Giovanni Ghirlanda, MD

From the Internal Medicine Institute, Catholic University, Rome, Italy

Address correspondence and reprint requests to Dr. Dario Pitocco, Internal Medicine Institute, Catholic University, L.go A.Gemelli 8, 00168, Rome, Italy. E-mail:dariopitocco{at}virgilio.it

Abbreviations: BMD, bone mineral density • ICTP, COOH-terminal telopeptide of type 1 collagen • VAS, visual analog scale

INTRODUCTION

TOP
INTRODUCTION
RESEARCH DESIGN AND METHODS
RESULTS
CONCLUSIONS
References

Charcot neuroarthropathy is defined by painful or relativelypainless bone and joint deformity in limbs that have lost sensoryinnervation (1). The incidence is $~$ 0.1–5% in diabetic patientswith peripheral neuropathy (2,3). The pathogenesis of Charcotneuroarthropathy is unknown (1,4). In acute Charcot neuroarthropathy,osteoclast activity increases (5). Alendronate is a bisphosphonatethat induces the apoptosis of the osteoclasts (6). The utilizationof the alendronate could improve the clinical signs of acuteCharcot neuroarthropathy and stop bone reabsorption.

RESEARCH DESIGN AND METHODS

TOP
INTRODUCTION
RESEARCH DESIGN AND METHODS
RESULTS
CONCLUSIONS
References

A total of 20 consecutive patients with a new diagnosis of acutepainful Charcot neuroarthropathy were enrolled after the approvalof the ethics committee. The patients gave informed consent.Acute Charcot neuroarthropathy was defined on the basis of atleast three of the following clinical signs: edema, erythema,and skin temperature increase of 2°C compared with contralateralfoot (temperature was measured using an infrared thermometer[Riester] at the site of the maximum deformity of the affectedfoot and on a similar site on the contralateral foot), deformity,tenderness, abnormal motility, and palpatory crunches.

According to a blinded randomization, 11 patients, who weretreated with 70 mg alendronate by mouth once a week (test group),and 9 control subjects were followed for 6 months. All patientsreceived a total contact cast boot for the first 2 months andpneumatic walker for the other 4 months and were examined twicea week (7). Afterward they were transferred to special shoes.Baseline levels of pain were recorded by using 10-cm visualanalog scales (VASs), where 0 was minimal and 10 was maximalpain. Repeat VASs of pain were performed after 6 months. X-raysof the affected feet were taken in two different projections,according to the protocol described by Cavanagh et al. (8).A labeled white cell (In-WBC) bone scan combined with a three-phasetechnetium bone scan (Tc-MDP) and with magnetic resonance ofthe foot (9) were done to obtain a differential diagnosis withosteomyelitis.

Serum collagen COOH-terminal telopeptide of type 1 collagen(ICTP), osteocalcin, testosterone, estradiol, thyroid hormones,parathyroid hormone, follicle-stimulating hormone, and leutinizinghormone were measured in serum by immunoassay in eletrochemiluminescence(Roche, Montclair, NJ).

IGF-1 and calcitriol were measured by chemiluminescence (Nichols),estron by immunoradiometric assay (Immunotech Beckman, Fullerton,CA), and urinary hydroxyprolin through high-performance liquidchromatography (Biorad, Richmond, CA) from 24-h urine collection.

Serum alkaline phosphatase was measured by colorimetric assay(Roche-Hitachi) and serum bone alkaline phosphatase by electrophoreticmethod (Isopal Sebia ITA). Bone mineral density (BMD) measurementsof the lumbar spine (L2-L4), proximal femur, and feet were performedby dual-energy X-ray absorptiometry using a Hologic QDR 2000densitometer. The affected foot was manually positioned on thescan table and the scan started at the toes and moved towardcalcaneus. The software used for the lumbar spine was automaticallyapplied to the foot scan. Determination of size and locationof the region of interest (phalanx, tarsus, or metatarsus) wasmade manually, and the measure of the BMD of the single regionof interest was defined automatically by the spinal software.Reproducibility was assessed by taking 10 repeated measurements;the foot was moved and repositioned between measurements. ANOVAwas used to compare the test group and the control group. Significancewas set at P < 0.05.

RESULTS

TOP
INTRODUCTION
RESEARCH DESIGN AND METHODS
RESULTS
CONCLUSIONS
References

All patients had a Neuropathy Disability Score >5 (10), apathological conduction velocity, a vibration perception threshold>25 volts (11), and an autonomic neuropathy according toEwing and Clarke with a score >4 (12). No subjects had osteomyelitisor peripheral vascular disease (defined as an ankle-brachialindex of <0.9) throughout the study (Table 1). The midfootwas the most affected. Five patients had uninfected foot ulcers(cultures of debrided tissue were always negative) that healedduring the study.

View this table:
[in this window]
[in a new window]

Table 1— Test group results

ICTP did not show significant difference between the two groups(0.54 ± 0.05 vs. 0.56 ± 0.06 ng/ml, P < 0.6)at the outset, but after 6 months, the test group showed a significantdecrease (0.54 ± 0.05 vs. 0.30 ± 0.03 ng/ml, P< 0.05). In the test group, hydroxyprolin followed the sametrend (18 ± 3.2 vs. 13 ± 3.6 mg/l, P < 0.05).Bone alkaline phosphatase reduction was almost significant (36± 4.8 vs. 23 ± 3.9%, P = 0.06). Dual-energy X-rayabsorptiometry demonstrated an improvement in total foot mineralization(0.18 ± 0.06 vs. 0.24 ± 0.08 g/cm², P < 0.05)and in the distal phalanxes (0.194 ± 0.03 vs. 0.242 ±0.05 g/cm², P < 0.01) in the test group that had an improvementof the mineralization of the femur. VAS score for pain was significantlyimproved in the test group (6.5 ± 0.9 vs. 4.2 ±0.8, P < 0.05). No significant changes were evident in thecontrol group (6.7 ± 1 vs. 6.1 ± 1.1).

At the outset, the affected foot was 3.6 ± 1.1°Chotter in the test group and 3.4 ± 1.2°C hotter inthe control group. After 6 months, both groups had a significantimprovement (–1.7°C in the test group and –1.5°Cin the control group). Reduction of IGF-1 was observed onlyin the test group (142.8 ± 24 vs. 123.5 ± 41 ng/ml,P < 0.05). No side effects were reported.

CONCLUSIONS

TOP
INTRODUCTION
RESEARCH DESIGN AND METHODS
RESULTS
CONCLUSIONS
References

This study is based on the utilization of alendronate takenby mouth to stop the progression of Charcot neuroarthropathy(13). After 6 months, we showed that there is a significantreduction of ICTP and hydroxyprolin, markers indicative of bonereabsorption. The test group showed an increase of the footbone density compared with the control group that was more evidentin the distal phalanxes, which were the foot bones with thelowest BMD, than in the midfoot. We suppose that bisphosphonatesare more effective where bone reabsorbtion is more marked. Thesignificant reduction of IGF-1 levels in the test group couldimprove bone density, lowering the blood supply to bones (14).

Off-loading, which reduces inflammation, together with alendronate,which decreases the cytokine production within the bones ofthe foot, could explain the reduction of pain (15,16). Furthermore,bisphosphonates have a central antinociceptive effect connectedwith the Ca²⁺ mechanism. Ca influx releases substances involvedin nociception and inflammation, such as substance P, vasoactiveintestinal peptide, neuropeptide Y, prostaglandin, serotonin,and kinines (17–19). We did not detect the initial fallof the temperature linked to the bisphosphonates because wechecked it at the beginning and end of the study (20). In conclusion,we observed a clinical improvement of acute Charcot neuroarthropathyby using alendronate.

Footnotes

D.P. and V.R. contributed equally to this work.

A table elsewhere in this issue shows conventional and SystèmeInternational (SI) units and conversion factors for many substances.

Received for publication January 20, 2005. Accepted for publication January 26, 2005.

References

TOP
INTRODUCTION
RESEARCH DESIGN AND METHODS
RESULTS
CONCLUSIONS
References

Edmonds ME: Progress in care of the diabetic foot. Lancet 354:270–272, 1999[Medline]
Sanders LJ, Frykberg RG: Diabetic neuropathic osteoarthropathy: Charcot foot. In The High Risk Foot in Diabetes Mellitus. Levin ME, O’Neal LW, Bowker JH, Eds. New York, Churchill Livingstone, 1991, p. 297–338
Rajbhandari SM, Jenkins RC, Davies C, Tesfaye S: Charcot neuroarthropathy in diabetes mellitus. Diabetologia 45:1085–1096, 2002[Medline]
Frykberg RG, Kozak GP: The diabetic charcot foot. In Management of Diabetic Foot Problems. 2nd ed. Kozak GP, Campbell DR, Fryberg RG, Haberwshaw GM, Eds. Philadelphia, WB Saunders, 1995, 88–97
Piaggesi A, Marcocci C, Golia F, Gregorio S, Baccetti F, Navalesi R: Markers for Charcot’s neurogenic osteoarthropathy in diabetic patients (Abstract). Diabetes 49 (Suppl. 1):A32, 2000
Rogers MJ: New insights into the molecular mechanism of action of bisphosphonate. Curr Pharm Des 9:2643–2658, 2003[Medline]
Armstrong DG, Tood WF, Lavery LA, Harkless LB, Bushmann TR: The natural history of acute Charcot’s arthropathy in a diabetic foot speciality clinic. Diabet Med 14:357–363, 1997[Medline]
Cavanagh PR, Young MJ, Adams JE, Vickers KL, Boulton AJM: Radiographic abnormalities in the feet of patients with diabetic neuropathy. Diabetes Care 17:201–209, 1994[Abstract]
Tomas MB, Patel M, Marvin SE, Palestro CJ: The diabetic foot. Br J Radiol 73:443–450, 2000[Abstract]
Young MJ, Boulton AJM, Macleod AF, Williamd DRR, Sonksen PK: A multicentre study of the prevalence of diabetic peripheral neuropathy in the UK hospital clinic population. Diabetologia 36:150–154, 1993[Medline]
MJ Young, Breddy JL, Veves A, Boulton AJM: The prediction of diabetic neuropathic foot ulceration using vibration perception thresholds: a prospective study. Diabetes Care 17:557–560, 1994[Abstract]
Ewing DJ, Clarke BF: Diagnosis and management of diabetic autonomic neuropathy. BMJ 285:916–918, 1982
Jude EB, Boulton AJ: Medical treatment of Charcot’s arthropathy. J Am Podiatr Med Assoc 92:381–383, 2002[Abstract/Free Full Text]
Kapitola J, Zak J, Lacinova Z, Justova V: Effect of growth hormone and pamidronate on bone blood flow, bone mineral and IGF-I levels in the rat. Physiol Res 49 (Suppl. 1):S101–S106, 2000
Mc Crory JL, Morag E, Norkitis AJ: Healing of Charcot fractures: skin temperature and radiographic correlates. Foot 8:158–165, 1998
Haworth CD, Selby PL, Webb AK, Mawer EB, Adams JE, Freemont AJ: Severe bone pain after intravenous pamidronate in adult patients with cystic fibrosis. Lancet 352:1753–1754, 1998[Medline]
Bonabello A, Galmozzi MR, Bruzzese T, Zara GP: Analgesic effect of bisphosphonates in mice. Pain 91:269–275, 2001[Medline]
Carr DB, Goudas LC: Acute pain. Lancet 353:2051–2058, 1997
Miranda HF, Bustamante D, Kramer V, Pelissier T, Saavedra H, Paeile C, Fernandez E, Pinardi G: Antinociceptive effects of Ca2+ channel blockers. Eur J Pharmacol 217:137–141, 1992[Medline]
Jude EB, Selby PL, Burgess J, Lilleystone P, Mawer EB, Page SR, Donohoe M, Foster AVM, Edmonds ME, Boulton AJM: Bisphosphonates in the treatment of Charcot neuroarthropathy: a double-blind randomised controlled trial. Diabetologia 44:2032–2037, 2001[Medline]