Local treatment of a bone graft by soaking in zoledronic acid inhibits bone resorption and bone formation. A bone chamber study in rats.

ABSTRACT: BACKGROUND: Bone grafts are frequently used in orthopaedic surgery. Graft remodelling is advantageous but can occur too quickly, and premature bone resorption might lead to decreased mechanical integrity of the graft. Bisphosphonates delay osteoclastic bone resorption but may also impair formation of new bone. We hypothesize that these effects are dose dependent. In the present study we evaluate different ways of applying bisphosphonates locally to the graft in a bone chamber model, and compare that with systemic treatment. METHODS: Cancellous bone grafts were placed in titanium chambers and implanted in the tibia of 50 male rats, randomly divided into five groups. The first group served as negative control and the grafts were rinsed in saline before implantation. In the second and third groups, the grafts were soaked in a zoledronic acid solution (0.5 mg/ml) for 5 seconds and 10 minutes respectively before being rinsed in saline. In the fourth group, 8 μL of zoledronic acid solution (0.5 mg/ml) was pipetted onto the freeze-dried grafts without rinsing. The fifth group served as positive control and the rats were given zoledronic acid (0.1 mg/kg) systemically as a single injection two weeks after surgery. The grafts were harvested at 6 weeks and analysed with histomorphometry, evaluating the ingrowth distance of new bone into the graft as an equivalent to the anabolic osteoblast effect and the amount (bone volume/total volume; BV/TV) of remaining bone in the remodelled graft as equivalent to the catabolic osteoclast effect. RESULTS: In all chambers, almost the entire graft had been revascularized but only partly remodelled at harvest. The ingrowth distance of new bone into the graft was lower in grafts soaked in zoledronic acid for 10 minutes compared to control (p = 0.007). In all groups receiving zoledronic acid, the BV/TV was higher compared to control. CONCLUSIONS: This study found a strong inhibitory effect on bone resorption by bisphosphonates but also a limited inhibition of the ingrowth of new bone. Local treatment at surgery resulted in stronger inhibition of both resorption and bone formation compared to systemic treatment

Local treatment of cancellous bone grafts with BMP-7 and zoledronate increases both the bone formation rate and bone density: A bone chamber study in rats

Background and purpose The remodeling of morselized bone grafts in revision surgery can be enhanced by an anabolic substance such as a bone morphogenetic protein (BMP). On the other hand, BMPs boost catabolism and might cause a premature resorption, both of the graft and of the new-formed bone. Bisphosphonates inactivate osteoclasts and can be used to control the resorption. We studied a combination of both drugs as a local admix to a cancellous allograft. Methods Cancellous bone allografts were harvested and freeze-dried. Either saline, BMP-7, the bisphosphonate zoledronate, or a combination of BMP-7 and zoledronate were added in solution. The grafts were placed in bone conduction chambers and implanted in the proximal tibia of 34 rats. The grafts were harvested after 6 weeks and evaluated by histomorphometry. Results Bone volume/total volume (BV/TV) was 50% in the grafts treated with the combination of BMP-7 and zoledronate and 16% in the saline controls (p < 0.001). In the zoledronate group BV/TV was 56%, and in the BMP group it was 14%. The ingrowth distance of new bone into the graft was 3.5 mm for the combination of BMP-7 and zoledronate and 2.6 mm in the saline control (p = 0.002). The net amount of retained remodeled bone was more than 4 times higher when BMP-7 and zoledronate were combined than in the controls. Interpretation An anabolic drug like BMP-7 can be combined with an anti-catabolic bisphosphonate as local bone graft adjunct, and the combination increases the amount of remaining bone after remodeling is complete

Allograft bone in hip revision: the effect of locally applied pharmacological treatment.

The clinical success of primary hip replacement is paramount but the need for revisions will continue to increase due to the increasing number of operated individuals. In Sweden, the number of hip revisions in 2012 exceeded 2,300. During implant loosening, some of the bone in the femur is lost, which can make the revision more difficult. One way of handling bone loss has been the impaction technique. Allograft bone is morsellised and impacted into the defect before a prosthesis is inserted. Mechanically, the allograft bone immediately contributes to prosthetic stability. Biologically, the graft triggers an inflammatory response with ingrowth of fibrous tissue and blood vessels, accompanied by osteoclasts from the host. Parts of the graft bone are resorbed and degraded, and are eventually at least partially replaced with new living bone. In our first hypothesis, we suggested that resorption of the allograft that is too fast could reduce stability and result in implant loosening. We believed that this could be inhibited by local treatment of the graft with a bisphosphonate. Our second hypothesis was that by adding bone-inductive BMP-7 to the bisphosphonate, new bone formation would also be stimulated, leading to an increase in stability. In papers I and II, the effect of the bisphosphonate zoledronate and BMP-7 on allografts was investigated in a bone conduction chamber in rats. We found a strong synergism of the combined treatment compared to the saline control. Local treatment with the bisphosphonate was efficient but it also tended to inhibit bone formation. In paper III, the same drugs were evaluated in a more clinically relevant prosthetic model in rabbits. A knee prosthesis was inserted into the tibia, which had been filled with impacted, morsellised allograft soaked in BMP-7 and/or zoledronate. Micro-CT showed increased bone density after zoledronate treatment relative to the saline control, but by histology the bone surrounding the prosthesis had a more unstable structure when BMP-7 was used combined with zoledronate. In paper IV, 30 patients had their femoral hip implant revised with the impaction bone grafting technique, and were randomised to have the bone graft soaked in either clodronate—a bisphosphonate— or saline. DXA scans were performed postoperatively and at 3 and 12 months to evaluate the effect of the study drug. Radiostereometry (RSA) was performed postoperatively, after 6 weeks, and after 3 and 12 months, to measure implant micromotion. Bone density and implant motion were similar in both groups and no significant differences were found. In conclusion, we found that local administration of bisphosphonate is effective in inhibiting bone graft resorption in animal models and that the mode of application may matter. The addition of BMP-7 may lead to reduced stability and cannot be recommended. Finally, we were unable to show any effect of the bisphosphonate clodronate on bone density or implant motion in our clinical study on hip revision with impaction bone grafting

Local treatment of a bone graft by soaking in zoledronic acid inhibits bone resorption and bone formation. A bone chamber study in rats

Abstract Background Bone grafts are frequently used in orthopaedic surgery. Graft remodelling is advantageous but can occur too quickly, and premature bone resorption might lead to decreased mechanical integrity of the graft. Bisphosphonates delay osteoclastic bone resorption but may also impair formation of new bone. We hypothesize that these effects are dose dependent. In the present study we evaluate different ways of applying bisphosphonates locally to the graft in a bone chamber model, and compare that with systemic treatment. Methods Cancellous bone grafts were placed in titanium chambers and implanted in the tibia of 50 male rats, randomly divided into five groups. The first group served as negative control and the grafts were rinsed in saline before implantation. In the second and third groups, the grafts were soaked in a zoledronic acid solution (0.5 mg/ml) for 5 seconds and 10 minutes respectively before being rinsed in saline. In the fourth group, 8 μL of zoledronic acid solution (0.5 mg/ml) was pipetted onto the freeze-dried grafts without rinsing. The fifth group served as positive control and the rats were given zoledronic acid (0.1 mg/kg) systemically as a single injection two weeks after surgery. The grafts were harvested at 6 weeks and analysed with histomorphometry, evaluating the ingrowth distance of new bone into the graft as an equivalent to the anabolic osteoblast effect and the amount (bone volume/total volume; BV/TV) of remaining bone in the remodelled graft as equivalent to the catabolic osteoclast effect. Results In all chambers, almost the entire graft had been revascularized but only partly remodelled at harvest. The ingrowth distance of new bone into the graft was lower in grafts soaked in zoledronic acid for 10 minutes compared to control (p = 0.007). In all groups receiving zoledronic acid, the BV/TV was higher compared to control. Conclusions This study found a strong inhibitory effect on bone resorption by bisphosphonates but also a limited inhibition of the ingrowth of new bone. Local treatment at surgery resulted in stronger inhibition of both resorption and bone formation compared to systemic treatment.</p

Preserved periprosthetic bone stock at 5 years post-operatively with uncemented short hip stem in both collared and collarless version

Introduction: Previous bone density studies have generally shown bone resorption around both cemented and uncemented total hip arthroplasty (THA) stems. This is presumed to be due to stress shielding. Short stems have been introduced partly to preserve bone in the proximal femur by a more physiological loading of the bone. The purpose of this study was to evaluate bone remodeling around a short, fully hydroxyapatite-coated titanium stem that comes in a collared and collarless version. Patients and methods: A prospective cohort of 50 patients included in a study evaluating the Furlong Evolution stem has been followed for 5 years. Examination was done with dual energy X-ray absorptiometry (DXA) postoperatively, at 1, 2 and 5 years. Clinical outcome was followed with radiography and both general and hip specific outcome measures. Results: The two versions of the stem behaved similarly regarding bone remodeling. After an initial decrease up to 1 year, bone mineral density (BMD) increased in all Gruen zones up to 2 years and at 5 years bone stock was still preserved compared with postoperatively (net BMD + 1.2% (95% CI − 0.4 to 2.8)). Increase in BMD occurred mainly in the greater trochanter and distally around the stem with a decrease in the calcar area. Both versions showed excellent clinical outcome up to 5 years. Conclusion: This short stem seems to preserve proximal bone stock up to 5 years, exhibiting similar behaviour both with and without a collar. Trial registration number and date of registration: ClinicalTrials.gov, (identifier: NCT01894854). July 10, 2013

Decreased migration with locally administered bisphosphonate in cemented cup revisions using impaction bone grafting technique : A randomized, controlled study evaluated with RSA and DXA with a 2-year follow-up

Background and purpose — Impaction bone grafting (IBG) in revision hip surgery is an established method in restoring bone stock deficiencies. We hypothesized that local treatment of the morsellized allograft with a bisphosphonate in cemented revision would, in addition to increased bone density, also reduce the early migration of the cup as measured by radiostereometry (RSA). Patients and methods — 20 patients with aseptic cup loosening underwent revision using the IBG technique. The patients were randomized to either clodronate (10 patients) or saline (10 patients, control group) as local adjunct to the morsellized bone. The outcome was evaluated by dual-energy X-ray absorptiometry (DXA) during the first year regarding periacetabular bone density and with radiostereometric analysis (RSA) for the first 2 years regarding cup migration. Results — 2 patients were lost to follow-up: 9 patients remained in the clodronate and 9 in the control group. Less proximal migration was found in the clodronate group compared with the controls, measured both over time (mixed-models analysis, p = 0.02) as well as at the specified time points up to 2 years (0.22 mm and 0.59 mm respectively, p = 0.02). Both groups seemed to have stabilized at 1 year. We found similar bone mineral density measured by DXA, and similar RSA migration in the other directions. No cups were re-revised. Interpretation — Local treatment of the allograft bone with clodronate reduced early proximal migration of the revised cup but without any measurable difference in periacetabular bone density

Locally administered bisphosphonate in hip stem revisions using the bone impaction grafting technique : a randomised, placebo-controlled study with DXA and five-year RSA follow-up

Background: Bisphosphonates have previously been shown to increase the density of impacted graft bone. In the present study we hypothesise that bisphosphonates also reduce early stem subsidence. We examined the effect of locally applied bisphosphonate to allografts on prosthetic micromotion and bone density in femoral stem revision with impaction grafting. Methods: 37 patients were randomised to either clodronate or saline as local adjunct to the morsellised allograft bone. 24 patients were finally analysed per protocol and evaluated by dual-energy x-ray absorptiometry (DXA) during the first year and with radiostereometric analysis (RSA) for 5 years. Results: There were no significant differences neither in bone density, nor in migratory behaviour between the groups. The femoral stems had subsided 3.6 mm in both groups (p = 0.99) at 5 years and there was no difference as measured over time with mixed models analysis. The clinical outcome was good in both groups. Conclusion: Clodronate as a local addendum to allograft bone in hip revision did not increase bone density or reduce micromotion of the implant