Pharmacological manipulation of fracture healing and bone remodeling

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

Systemic zoledronate treatment both prevents resorption of allograft bone and increases the retention of new formed bone during revascularization and remodelling

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. METHODS: Bone grafts were harvested and placed in a bone chamber inserted into the tibia of a rat. Host tissue could grow into the graft through openings in the chamber. Weekly injections with 1.05 μg zoledronate or saline were given subcutaneously until the rats were harvested after 6 weeks. The specimens were fixed, cut and stained with haematoxylin/eosin and used for histologic and histomorphometric analyses. RESULTS: By histology, the control specimens were almost totally resorbed in the remodeled area and the graft replaced by bone marrow. In the zoledronate treated specimens, both the old graft and new-formed bone remained and the graft trabeculas were lined with new bone. By histomorphometry, the total amount of bone (graft+ new bone) within the remodelled area was 35 % (SD 13) in the zoledronate treated grafts and 19 % (SD 12) in the controls (p = 0.001). Also the amount of new bone was increased in the treated specimens (22 %, SD 7) compared to the controls (14 %, SD 9, p = 0.032). CONCLUSION: We show that zoledronate can be used to decrease the resorption of both old graft and new-formed bone during bone graft remodelling. This might be useful in bone grafting procedure but also in other orthopedic conditions, both where necrotic bone has to be remodelled i.e. after osteonecrosis of the knee and hip and in Perthes disease, or in high load, high turnover conditions like delayed union, periprosthetic osteolysis or bone lengthening operations. In our model an increased net formation of new bone was found which probably reflects that new bone formed was retained by the action of the bisphosphonates rather than a true anabolic effect

A single dose zoledronic acid enhances pin fixation in high tibial osteotomy using the hemicallotasis technique. A double-blind placebo controlled randomized study in 46 patients.

INTRODUCTION: Bisphosphonates have been shown to reduce osteoclastic activity and enhance pin fixation in both experimental and clinical studies. In this prospective, randomized study of high tibial osteotomy using the hemicallotasis (HCO) technique, we evaluate whether treatment by one single infusion of zoledronic acid can enhance the pin fixation. MATERIALS AND METHODS: 46 consecutive patients (35-65 years) were operated on for knee osteoarthritis by the HCO technique. After the osteotomy, two hydroxyapatite-coated pins were inserted in the metaphyseal bone and two non-coated pins in the diaphyseal bone. The insertion torque was measured by a torque force screw driver. Four weeks postoperatively, the patients were randomized to either one infusion of zoledronic acid or sodium chloride intravenously. At time for removal of the pins, the extraction torque forces of the pins were measured. RESULTS: All osteotomies healed and no difference was found in time to healing. The mean extraction torque force in the non-coated pins in the diaphyseal bone was doubled in the zoledronic treated group (4.5 Nm, SD 2.1) compared to the placebo group (2.4 (SD 1.0, p<0.0001). The mean extraction torque forces of the hydroxyapatite-coated pins in the metaphyseal bone were similar in the zoledronic acid group (4.7 Nm, SD 1.3) and in the placebo group (4.0 Nm, SD 1.3). DISCUSSION: A single infusion of zoledronic acid improved twofold the fixation of non-coated pins in diaphyseal bone. Bisphosphonates might be an alternative to hydroxyapatite-coated pins in nonosteoporotic bone

Manipulating the anabolic and catabolic response in bone graft remodeling: Synergism by a combination of local BMP-7 and a single systemic dosis of zoledronate.

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 = 0.007) increased new bone ingrowth distance into the graft from 2.0 mm (SD = 0.98 mm) in the controls to 3.1 mm (SD = 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 = 9%) compared to 14% (SD = 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. (c) 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

A single bisphosphonate infusion does not accelerate fracture healing in high tibial osteotomies.

Background Bisphosphonates 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. Methods 46 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. Results All 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. Interpretation In 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

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (&gt;59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P &lt;.001). Overall motor and cognitive performance (P &lt;.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P &lt;.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P &lt;.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P &lt;.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients