Can Bisphosphonates Lead To Better Charcot Treatment?
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
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.