Charcot’s arthropathy is a devastating complication of diabetes mellitus that frequently leads to permanent disability, ulceration and amputation. It is a rapidly progressive and severe form of arthritis. Researchers have equated the acute Charcot foot to a medical emergency since therapies are available that may alter its natural history.1 Unfortunately, the pathophysiology and development are poorly understood. This is frequently complicated by a delay in diagnosis until bony destruction is visible on plain radiographs. This delay often leads to worse outcomes.2 One study found the diagnostic delay averaged 29 weeks.3 Other inflammatory arthridities have treatments that are targeted at the pathophysiologic pathway. For example, there are disease modifying anti-rheumatic drugs (DMARDS) for rheumatoid arthritis (RA). In fact, the standard of care has changed for RA to the point that one should attempt using a DMARD for all patients with RA and not continue endless palliation with only anti-inflammatory medications.4 Perhaps we should approach the treatment of Charcot’s arthropathy, which behaves like an accelerated inflammatory arthritis, in a similar manner to that of RA. Though the exact pathophysiologic mechanisms of this disease process are yet undiscovered, it is generally accepted that trauma (macrotrauma or repetitive moderate trauma) leads to an inflammatory process, which increases blood flow in the extremity. Surprisingly, patients with Charcot have preserved vascular responsiveness in comparison to ulcerated neuropathic patients without Charcot.5 This intact reactivity helps to explain the intense warmth of the affected extremity, which is often 9 to 11ºF higher than the same point on the contralateral limb.6 The hyperemia and inflammation lead to focal osteopenia, allowing joint fragmentation and subluxation. In studies utilizing bone densiometry, researchers have shown the osteopenia.7,8 Researchers showed focalization of the bone loss to the foot in one study which compared the bone mineral density (BMD) of the foot with that of the lumbar spine in those with acute Charcot versus a set of age- and sex-matched controls. The Charcot foot had a T-score three standard deviations below normal (which denotes osteoporosis) in comparison to controls. Yet there was no difference in the stiffness of the lumbar spine between the two groups.7 Other authors have recently discovered the role that the receptor activator of nuclear factor kappa B ligand (RANK-L) plays with osteoporosis and the calcification of vascular smooth muscle cells. They theorize that there is a common thread between the decrease in bone mineral density and the concomitant Mönkeburg’s arteriosclerosis that occurs in patients with Charcot’s arthropathy.9 From what little information that already exists about the disease process, we know that when it comes to treating acute Charcot, we can target our current and future therapies to: • reduce or eliminate trauma; • reduce joint inflammation; and • increase the bone mineral density.
Keys To Addressing Trauma And Joint Inflammation
The mainstay of current medical treatment for Charcot’s arthropathy is offloading of the involved extremity. Long-term immobilization with total contact casts or a Charcot restraint orthotic walker (CROW) are the two methods clinicians employ the majority of the time.10-12 When it comes to an acute event, one should emphasize offloading for at least six months.13 Future approaches may involve early surgical stabilization/immobilization with external fixation.14 Although offloading may prevent further trauma, which reduces inflammation over time, a more urgent antiinflammatory is needed. New and exciting research in Charcot treatments are focusing on interrupting the inflammatory cycle. After trauma initiates the Charcot process, there is an ensuing inflammatory cascade that involves tumor necrosis factor alpha (TNF-a) and interleukin-1 (IL-1).15 These pro-inflammatory cytokines induce RANK-L to mature more osteoclasts, resulting in bone loss.9 Several inflammatory conditions, including rheumatoid arthritis, psoriatic arthritis, Crohn’s disease and ulcerative colitis, respond to tumor necrosis factor-alpha (TNF-a) inhibitors. Researchers have shown that people with diabetes have persistent synthesis of TNF-a during cutaneous inflammation (blister formation) and they theorize that TNF-a inhibitors may play a role in treating diabetic foot conditions.16 However, it is yet unknown whether TNF-a plays a role in the pathogenesis of Charcot’s arthropathy or if its inhibition will prevent joint breakdown. Early stages of a randomized controlled trial utilizing one of these agents is in the planning stages at the Center for Lower Extremity Ambulatory Research (CLEAR) at Rosalind Franklin University of Medicine and Science in Chicago. Some authors have shown that cryotherapy reduces inflammation after acute injury and others have proposed that cooling the diabetic foot may prevent foot wounds.17,18 However, further study is needed before cryotherapy can become an accepted tool in helping to remit a Charcot foot.
How To Address Osteopenia In Those With Acute Charcot
Medical and physical methods to increase bone mineral density are currently accepted methods of treatment for acute Charcot’s arthropathy. The bisphosphonates pamidronate (IV) and alendronate (PO) have both undergone randomized trials to determine their effectiveness.19,20 Their mechanism of action is induced apoptosis of osteoclasts.21 Studies have shown that both bisphosphonates reduce foot temperature and decrease the levels of bone turnover markers. The IV therapy has a much more rapid onset of action (within two weeks) whereas the oral therapy can require up to six months before one sees the benefit. A recent study investigating the use of intranasal calcitonin in acute Charcot foot found a reduction in bone turnover markers in the first three months of follow-up.22 These authors concluded that the use of calcitonin may be superior to that of bisphosphonates since calcitonin acts directly on the RANK-L signaling pathway to reduce bone turnover whereas bisphosphonates indiscriminately induce death of osteoclasts and may have some effect on osteoblasts.22 One can achieve physical stimulation of bone growth through the use of bone stimulators. Various authors have utilized ultrasonic, combined and pulsed electromagnetic field, and implanted DC in patients with Charcot foot.23-25 Physicians would use the implantable stimulators at the time of surgical reconstruction whereas one can apply the external stimulators as an adjunct in treating acute Charcot foot.
Future directions for treating Charcot’s arthropathy are clear. There is still a need for more treatments that are designed to interrupt the natural history of the disease process. We must gain a more complete understanding of the pathophysiology of Charcot’s arthropathy at the biochemical level. As the governments of the world are recognizing diabetic foot disorders as a large financial burden, the funding of research will likely increase. Subsequently, more high quality trials will be initiated and physicians will be able to offer more effective treatments to those who suffer from Charcot foot. Dr. Armstrong is a Professor of Surgery, Chair of Research and Assistant Dean at the William M. Scholl College of Podiatric Medicine at Rosalind Franklin University of Medicine in Chicago. He is the Director of the Center for Lower Extremity Ambulatory Research (CLEAR) at the aforementioned university and is the Co-Chair of the Diabetic Foot Global Conference (DFcon.com). Dr. Rogers is a Research Fellow at the Center for Lower Extremity Research (CLEAR) at the William M. Scholl College of Podiatric Medicine at Rosalind Franklin University of Medicine and Science. Dr. Bevilacqua is a Fellow at CLEAR. He is also a Fellow at the National Center for Limb Preservation. Dr. Steinberg (shown) is an Assistant Professor in the Department of Plastic Surgery at the Georgetown University School of Medicine in Washington, D.C. He is a Fellow of the American College of Foot and Ankle Surgeons.
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