Bisphosphonates and implants

Bisphosphonates are powerful drugs. Their ability to reduce the risk of osteoporotic fractures has saved thousands of people from becoming a fracture patient. Osteoporosis is due to an imbalance in the maintenance remodeling of the skeleton. This remodeling is different from the repair processes following fracture or bone surgery. Because research on the use of bisphosphonates has mostly focused on osteoporosis, their effects on repair processes have long been overlooked. In bone remodeling, osteoclasts and osteoblasts work closely together—also in a spatial sense—at defined remodeling sites. Their activities are coupled: a decrease in bone resorption due to bisphosphonates leads to a reduction in bone formation to a similar degree. Thus, it was long thought that bisphosphonates would only slow down bone repair. However, in bone repair, osteoblasts can work independently. This is clear if you just look at it in the microscope, where you can see large areas of undisturbed bone formation, separate from areas undergoing resorption and remodeling (Figure 1). A reduction in osteoclast activity can therefore be expected to shift the balance between formation and resorption towards increased net bone formation. During bone repair, bisphosphonates have an anticatabolic, or net anabolic, effect (Figure 2) (Little et al. 2005, Wermelin et al. 2007). Bisphosphonates bind to bone mineral and are taken up by osteoclasts when the latter resorb bone, which inactivates the cell. This mechanism makes bisphosphonates highly osteoclast-specific; free bisphosphonate is quickly excreted via the kidneys. However, some macrophages may be affected, and there is in vitro evidence (Garcia-Moreno et al. 1998, Giuliani et al. 1998) that osteoblasts are stimulated by concentrations of bisphosphonates that are unlikely to occur in vivo (Schindeler and Little 2005). It has been suggested that bisphosphonates may impair fracture healing. Osteoporotic fractures indicate an increased risk of new fractures, and should be an incentive to start prophylactic bisphosphonate treatment. Now, if bisphosphonates impair fracture healing, it would be wise to delay the start of secondary prevention until the fracture is healed. In animal experiments, bisphosphonates increase fracture callus size and delay the regression in size after the fracture has healed (Madsen et al. 1998, Cao et al. 2002). No mechanical impairment had been demonstrated. In large clinical series, no increase in healing complications has been reported (Lyles et al. 2007). It would therefore seem free of risk to start bisphosphonates directly after the first osteoporotic fracture. However, if intravenous bisphosphonates are used, there is a risk that the affinity of the fracture site for bisphosphonates would be so large that the rest of the skeleton would not be reached by a sufficient amount, and remain untreated (Lyles et al. 2007).