Background: In osteonecrosis the vascular supply of the bone is interrupted and the living cells die. The inorganic mineral network remains intact until ingrowing blood vessels invade the graft. Accompanying osteoclasts start to resorb the bone trabeculae and gradually replace the bone. If the osteonecrosis occurs in mechanically loaded parts, like in the subchondral bone of a loaded joint, the remodelling might lead to a weakening of the bone and, in consequence to a joint collapse. Systemic bisphosphonate treatment can reduce the resorption of necrotic bone. In the present study we investigate if zoledronate, the most potent of the commercially available bisphosphonates, can be used to reduce the amount or speed of bone graft remodeling.

BackgroundBisphosphonates increase the callus size and strength in animal fracture studies. In a human non-randomized pilot study of high tibial osteotomies in knee osteoarthritis, using the hemicallotasis (HCO) technique, bisphosphonates shortened the healing time by 12 days. In the present randomized study, we wanted to determine whether a single infusion of zoledronic acid reduces the time to clinical osteotomy healing. Results from the same trial, showing improved pin fixation with zoledronate, have been published separately.Methods46 consecutive patients (aged 35–65 years) were operated. At 4 weeks postoperatively, the patients were randomized to an intravenous infusion of either zoledronic acid or sodium chloride. Dual-energy X-ray absorptiometry (DEXA) was performed 10 weeks postoperatively. Radiographs were taken at 10 weeks and every second week until there was radiographic and clinical healing. Healing was evaluated blind, with extraction of the external fixator as the endpoint. At 1.5 years, an additional radiograph was taken and the hip-knee-ankle (HKA) angle measured to evaluate whether correction had been retained.ResultsAll osteotomies healed with no difference in healing time between the groups (77 (SD 7) days). Bone mineral density and bone mineral content, as assessed with DEXA, were similar between the groups. Radiographically, both groups had retained the acquired correction at the 1.5-year follow-up.InterpretationIn this randomized comparison, a single infusion of zoledronic acid increased the pin fixation of the external frame but did not shorten the healing time. In both groups, the external fixator was extracted almost 2 weeks earlier than in previous studies. The early extraction did not cause a loss of correction in either group.

Remodeling of a bone graft can be influenced both by anabolic substances, such as a bone morphogenic protein (BMP) and by anticatabolic substances, such as the bisphosphonates. BMPs are potent bone anabolic substances, but also boost catabolism and cause resorption. Bisphosphonates inhibit osteoclast function and can be used to postpone resorption. In the present study a combination of both drugs was explored in a rat bone chamber model. Cancellous bone grafts were treated with either BMP-7 or saline and placed in a bone chamber implanted in the proximal tibia. After 2 weeks, an injection of either zoledronate 0.1 mg/kg or saline was given subcutaneously. The rats were killed after 6 weeks, and bone ingrowth distance into the graft and graft resorption were measured by histomorphometry. BMP-7 significantly (p ¼ 0.007) increased new bone ingrowth distance into the graft from 2.0 mm (SD ¼ 0.98 mm) in the controls to 3.1 mm (SD ¼ 0.93 mm). If bisphosphonate was not given, most of the newly formed and old graft bone was resorbed. A single injection of zoledronate significantly (p < 0.001) increased the trabecular volume/total volume to 40% (SD ¼ 9%) compared to 14% (SD ¼ 10%) in the nonbisphosphonate treated. In total, the net amount of bone increased by 400% when BMP-7 and zoledronate combined was compared to saline. A bone graft can be treated with BMP-7 to increase new bone formation and at the same time be protected against premature catabolism by a single dose of a bisphosphonate. This combination might be useful in various conditions in orthopedic reconstruction. Healing and normal physiological skeletal repair 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. These pathways are mediated by a number of effector cells, primarily the catabolic bone-resorbing osteoclasts and the anabolic bone-forming osteoblasts, which produce new bone tissue to restore skeletal integrity. A balance between them is required for normal fracture repair and bone graft remodeling. Delayed healing or non-union can be a failure of the anabolic response, an increased or premature catabolic response, or sometimes both. 1 The anabolic and catabolic responses can be manipulated with pharmaceuticals, and in the bone conduction chamber, 2 we can study how drugs, separately or in combinations, influence bone formation and resorption.Bisphosphonates reduce osteoclastic catabolic activity in experimental studies. Circulating bisphosphonates bind to bone mineral, and, when the bone is resorbed by osteoclasts, bisphosphonates are internalized and interfere with cell metabolism leading to osteoclast apoptosis. 3 Systemic bisphosphonate treatment can postpone resorption of a bone graft. 4 In fractures, postponing the catabolic response and in consequence the resorption of the new-forming callus, leads to a stronger callus. 5 Bone morphogenic proteins (BMPs) bind to specific cell receptors, starting a signaling cascade that l...

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