Interaction between IGF-1, Inflammation, and Neuropathy in the Pathogenesis of Acute Charcot Neuroarthropathy: Lessons from Alendronate Therapy and Future Perspectives of Medical Therapy

In our previous study on Charcot neuroarthropathy (CN) among 20 consecutive patients, 11 patients were treated with 70 mg of alendronate per os once a week and 9 with placebo according to a blinded randomization. Our study demonstrated that alendronate stops the progression of CN [1]. In the same trial we performed the hormonal pattern [parathyroid hormone, osteocalcin, calcitriol, thyroid functioning, testosterone, estrogens, luteinizing hormone LH, follicle stimulating hormone FSH, and insulin growth factor-1 (IGF-1)] observing only a significant decrease in the plasmatic levels of IGF-1 (measured by a two-site chemiluminescence immunoassay in human serum, with an intra-assay coefficient of variation of 5.3%, an interassay coefficient of variation of 5.7%, and a calculated sensitivity of 6 ng/ml, Nichols Institute Diagnostics, San Juan Capistrano, USA) in the treated group after six months (142.8±24.2 vs. 123.5±29.4 ng/ml p<0.05) while the control group did not show any change in IGF-1 levels (145.2±21 vs. 144.8±18.6 ng/ml). Statistical calculations were performed using StatView software (version 4.01; SAS Institute, Cary, NC). Values are given as means±SD. Comparisons between diabetic and control groups and within individual groups were made using ANOVA and Scheffe's F test for multiple comparisons.

This result should be underlined because IGF-1 could play an important role in Charcot foot pathogenesis and a variation of its levels could mediate the effect of alendronate. IGF-1 has vasodilatory effects [2]. Kapitola et al. showed [3] that bisphosphonate reduced bone flow and bone resorption decreasing IGF-I levels. The reduction of local blood flow seems to be one of the mechanisms through which bisphosphonates might inhibit the action of osteoclasts in other conditions associated with regional hyperemia [4].

IGF-I modulates bone resorption by regulating expression of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappa (RANK) ligand (RANKL) in bone cells. In vitro, IGF-1 increased RANKL and decreased OPG expression in mouse stromal cells, supporting pro-reabsorption activity in vitro [5]. A worsening of this situation might be also linked to autonomic neuropathy with a lack of direct innervation of cells of the macrophage lineage that proliferate into preosteoclasts and osteoclasts with a probable consequent lowering of OPG production [6].

Moreover, the decrease of IGF-1 levels is a confirm that alendronate stops bone reabsorption in acute Charcot foot, because IGF-1 is incorporated into bone matrix through a linkage to IGFBP-5 and hydroxyapatite and is released during osteoclastic bone turnover and reabsorption [7] that are more marked in acute Charcot neuroarthropathy.

Although the effect of alendronate on IGF-1 is still not clear, a decrease of IGF-1 levels linked to the utilization of alendronate could lower the blood supply to bones and simultaneously decrease the activity of the osteoclasts through a change in the regulation of OPG-RANKL system, improving bone density. Another important consequence of this result is the possible involvement of a local action of IGF-1 in the pathogenesis of Charcot foot.

Furthermore OPG-RANKL system is influenced by the inflammation because tumor necrosis factor (TNF) and interleukin 1 trigger increased expression of RANKL, leading to activation of Rank and maturation of osteoclasts [8] [9].

These are the reasons why we have planned a study in vitro ex vivo in which we would like to evaluate the effect of IGF-1 and inflammation simultaneously on RANKL expression of monocytes extracted from peripheral blood samples of 30 subjects with acute Charcot neuroarthropathy without ulcers, 30 patients with uncomplicated type 2 diabetes, and 20 controls without diabetes. We will use 1 ng/ml of lipopolysaccharide (LPS) to approximate the condition existing in vivo during an inflammatory state, which reflects the LPS concentration detected during clinical infections. To demonstrate an overexpression of RANKL could have important consequences from a therapeutical point of view. Denosumab [10], a monoclonal antibody directed against RANKL, with a powerful suppression of resorption and rapid offset of action, could be a new therapeutical agent to treat acute Cahrcot neuroarthropathy.

References

• 1 Pitocco D, Ruotolo V, Caputo S, Mancini L, Collina MC, Manto A, Caradonna P, Ghirlanda G. Six-month treatment with alendronate in acute Charcot neuroarthropathy: a randomized controlled trial.  Diabetes Care. 2005;  28 1214-1215
• 2 Haylor J, Singh I. Nitric oxide synthesis inhibitor prevents vasodilation by insulin-like growth factor I.  Kidney Int. 1991;  39 333-335
• 3 Kapitola J, Zak J, Jutova V. Effect of growth hormone and pamidronate on bone blood flow, bone mineral and IGF-I levels in the rat.  Physiol Res. 2000;  49 ((Suppl 1)) S101-S106
• 4 Cortet B. Treatment of severe, recalcitrant reflex sympathetic dystrophy: assessment of efficacy and safety of the second generation bisphosphonate pamidronate.  Clin Rheumatol. 1997;  16 51-56
• 5 Rubin J. IGF-I regulates osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand in vitro and OPG in vivo.  J Clin Endocrinol Metab. 2002;  87 4273-4279
• 6 Tracey KJ. The inflammatory reflex.  Nature. 2002;  120 853-859
• 7 Ueland T. GH/IGF-I and bone resorption in vivo and in vitro.  Eur J Endocrinol. 2005;  152 327-323
• 8 Saidenberg-Kermanac’h N, Bessis NC. Osteoprotegerin and inflammation.  Eur Cytokine Netw. 2002;  13 144-153
• 9 Lam J, Abu-Amer Y. Tumour necrosis factor superfamily cytokines and the pathogenesis of inflammatory osteolysis.  Ann Rheum Dis. 2002;  61 ((Suppl 2)) ii82-ii83
• 10 Kostenuik PJ. Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength.  Curr Opin Pharmacol. 2005;  5 618-625

Correspondence