Pharmacological manipulation of fracture healing and bone remodeling

Sammanfattning: Drug treatment has been and will continue to be a successful method in modern medicine that can change the course of a disease. However, it is surprisingly seldom used in the more technically oriented orthopedic surgery. Bone healing and physiological skeletal remodeling involve a complex set of regulated signaling pathways that control the formation of new bone matrix and the resorption of damaged bone at the disease or injury site. Pharmaceutical substances, both anabolic drugs increasing bone formation and anti-catabolic drugs decreasing bone resorption, can be used to modulate fracture healing.
In the experimental studies, we used bone grafts placed in bone chambers in rats. In the first study the grafts were untreated and the animals received weekly injections with zoledronate, an anti-resorptive drug, or saline as control. In the second study the grafts were either pretreated with a bone inducing protein, BMP-7 or saline before surgery. As BMP-7 also induces resorption, the rats received either an injection of zoledronate or saline after two weeks. We saw that weekly injections of zoledronate decreased the resorption of both old graft and new-formed bone during bone graft remodeling. The combination of local BMP-7 and a single injection of zoledronate increased the bone formation substantially and at the same time protected the graft against premature catabolism.
In the clinical studies, we used high tibial osteotomies as a clinical model to study the effect of a bisphosphonate in fracture healing and pin fixation. Forty-eight patients were randomized to either an infusion of 4 mg zoledronate or saline after four weeks. Zoledronate almost doubled the fixation of the non-coated pins in the diaphyseal bone. The healing time was not affected.
In conclusion, bisphosphonates in experimental models delay the resorption of remodeling bone without disturbing the formation. BMP can be used to stimulate bone formation and can be combined with a bisphosphonate to control the simultaneously induced bone resorption. In humans single infusion of zoledronate almost doubled the pin-fixation in cortical diaphyseal bone.