Can Bisphosphonates Lead To Better Charcot Treatment?

When managing patients in the acute phase of Charcot neuroarthropathy, the hallmark of treatment is immobilization and non-weightbearing of the affected foot until the destructive nature of this stage disappears and the coalescence stage begins. In the past decade, researchers have hypothesized that using bisphosphonates in acute Charcot patients can decrease pathological fractures and permanent deformity, which commonly occur in these patients.If this is true, then using bisphosphonates may also lead to less deformity, shorter treatment time, a decreased need for revisional surgery, decreased ulceration and far less expense than treatment currently entails.
Bisphosphonates are used to treat various diseases of bone and calcium metabolism characterized by increased bone resorption, including osteoporosis, Paget’s disease, primary hyperparathyroidism, hypercalcemia of malignancy and metastatic bone disease. They effectively act by inhibiting osteoclast activity. Bisphosphonates are specifically targeted to the skeleton but may even localize preferentially at sites of active bone resorption.

Understanding The Two
Mechanisms For Bony Resorption
There are two mechanisms described for the development of bony resorption that occurs during the acute stage of Charcot neuroarthropathy. One mechanism notes the increased blood flow to bone while the other theory attributes the bony resorption to unbalanced osteoclastic activity. Evidence exists that autonomic neuropathy with sympathetic denervation resulting in high peripheral blood flow is common in patients with diabetes mellitus. Gough et. al., determined patients with acute Charcot feet had significantly higher levels of osteoclastic activity than patients with chronic Charcot, those with diabetic controls, and normal subjects. Young et. al., concluded minor trauma in diabetic patients with peripheral neuropathy might cause a fracture in those with reduced bone density and cause the development of Charcot neuroarthropathy. After showing increased radionuclide uptake in the feet of neuropathic diabetic patients, Edmonds et. al., suggested increased bone blood flow and arteriovenous shunting led to increased osteoclastic activity and reduced bone density. With either mechanism, the net effect is bony resorption, which, theoretically, you could minimize by using bisphosphonates.
Osteoclasts adhere normally to the bone surface but lack the ruffled border which indicates active resorption. Bisphosphonates do not interfere with osteoclast recruitment or attachment. With one bisphosphonate, alendronate, studies have shown localization in bone about 10 times higher on osteoclast surfaces than on osteoblast surfaces. Bisphosphonates adsorb to the hydroxyapatite crystals in bone and directly block dissolution of this mineral component of bone.
In normal bone, remodeling osteoclasts migrate to the site and initiate bone resorption by developing a ruffled border and releasing acid and proteolytic enzymes, effectively carving out a cavity or “howship’s lacuna.” Once they have finished resorbing bone, osteoblasts migrate to the bone and form a matrix, which later calcifies into bone. At the end of this process, bone formation has matched bone resorption and the bone remains healthy.
In bone remodeling with bisphosphonates, the bisphosphonate molecule attaches to exposed calcium hydroxyapatite crystals at a site to be remodeled. Osteoclasts migrate to these remodeling sites which are now coated with adherent bisphosphonates. As the osteoclasts ingest the bisphosphonate and bone, the bisphosphonate causes the cell to lose its ruffled border, reduce acid and proteolytic enzyme release and become inactive. Osteoblasts move into the area and new bone is formed which over time leads to increased bone mineral density.
How Promising Is The Research
On Bisphosphonates?
When it comes to using bisphosphonates during the acute phase of Charcot, the research is limited, but promising. Research into the use of bisphosphonates during the acute phase of Charcot is limited but promising. In 1994, Selby et. al., performed pamidronate infusion therapy on six diabetic patients who had acute Charcot neuroarthropathy. Researchers gave six IV infusions every two weeks and recorded temperature changes between the affected and non-affected feet to assess Charcot activity.
Two weeks after doing the first infusion, they noticed a rapid and significant fall in the temperature differential between the feet that remained within a normal 2ºC for the remainder of the study. They also saw a significant 25 percent decrease in alkaline phosphatase activity, a marker for bone turnover, by the end of the 12-week study. As noted by Frykberg, et. al., the study made no mention of other concurrent treatments (such as offloading or casting) which also might have modified the acute stage of this disorder.
A case report by Guis et. al., in 1998 described how they used pamidronate infusion therapy to treat one patient who was experiencing acute Charcot neuroarthropathy. They employed an MRI, technetium bone scans, nerve conduction studies and performed a biopsy of the sural nerve to determine Charcot. The patient received a pamidronate infusion every four months for two years and wore regular shoes.
Researchers saw clinical improvement within six months (two infusions). During this time, bone and joint destruction had ceased and the physicians saw gradual signs of a reconstructive healing process in the previously affected sites. However, many aspects of this case indicated the patient was in the chronic phase of Charcot. Furthermore, the study never determined markers of bone turnover and skin temperature measurements. Lastly, the initial clinical exam failed to mention erythema or increased temperature of the affected foot.
Young et. al., reported on two cases in which patients were determined had Charcot neuroarthropathy. In addition to noting increased skin temperature of greater than 2o and edema, researchers determined the patients’ condition via bone density scanning, bone scans, measuring temperature differentials and serial radiography. Doctors treated the patients with immobilization and intravenous pamidronate.
The patients with acute Charcot who were treated with immobilization and bisphosphonates had a shorter acute phase, according to Young. The author gave three infusions of pamidronate every two weeks. By the third infusion, Young was able to achieve resolution of the clinical markers of activity as measured by skin temperature differences.
These three reports of bisphosphonate therapy hold promise that inhibiting osteoclastic activity actually can arrest the destructive changes associated with the acute phase of Charcot neuroarthropathy. Immobilizing the affected limb is still the cornerstone of treatment during this phase as it will help you prevent progression of the hyperemia and subsequent fractures. You would best perform future studies to assess the effectiveness by treating an experimental group with immobilization and bisphosphonates and compare the group with a control group treated with immobilization only.
All Bisphosphonates
Are Not Created Equal
When you consider bisphosphonate therapy for acute Charcot neuroarthropathy, it is important also to consider the actual bisphosphonate used, since their mechanisms of action and efficacies appear to be slightly different. The three studies cited previously utilized pamidronate, but it is important to point out that the three reports were European studies and pamidronate is the most popular bisphosphonate in Europe. In the United States, alendronate, a newer drug, is the most commonly used bisphosphonate.
To compare the two drugs, look at their effectiveness at treating Paget’s disease of bone because this is the only indication common to both. Clinical studies indicate that alendronate (administered as 40mg tablets orally once a day for six months) leads to a 65 percent or greater decrease of serum alkaline phosphatase in 85 percent of patients within six months of treatment. Pamidronate (30mg administered intravenously over four hours for three consecutive days) decreased serum alkaline phosphatase by at least 50 percent in 61 percent of patients with a median of one month of treatment.
Pamidronate appears to act more rapidly than alendronate at decreasing bone resorption, but it was less efficacious. Be aware conservative treatment with both pamidronate and alendronate possibly may be more effective than either treatment alone. Certainly this is speculation, but concomitant use of both is not contraindicated.
In Conclusion
The notion that bisphosphonate therapy would benefit patients with acute Charcot seems plausible. Although the literature on this topic is sparse and largely anecdotal, it is an impetus to perform well-planned prospective studies to determine if this type of therapy is beneficial.
Without doubt, emphasizing immobilization during the acute phase is key to preventing progressive and severe structural deformity. However, if bisphosphonates can help minimize the osseous changes, which predispose patients to pathological fractures and subsequent deformity, then it should become part of the standard regimen.

Dr. Steinberg is an Assistant Professor in the Department of Orthopaedics/ Podiatry Service at the University of Texas Health Science Center.
Mr. Rogers is a fourth-year student at Des Moines University College of Podiatric Medicine and Surgery.

References:

References

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3. Gough A, Abraha H, Li F, et al: Measurement of markers of osteoclast and osteoblast activity in patients with acute and chronic diabetic Charcot neuroarthropathy. Diabet Med 14:527-531, 1997.

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5. Edmonds ME, Clarke MB, Newton S, Barrett J, Watkins PJ: Increased uptake of bone radiopharmaceutical in diabetic neuropathy. Q J Med 57:843-855, 1985.

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