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1.  The natural course of spontaneous osteonecrosis of the knee (SPONK) 
Acta Orthopaedica  2013;84(4):410-414.
Background and purpose
Spontaneous osteonecrosis of the knee (SPONK) is a painful lesion in the elderly, frequently leading to osteoarthritis and subsequent knee surgery. We evaluated the natural course and long-term consequences of SPONK in terms of need for major knee surgery.
Between 1982 and 1988, 40 consecutive patients were diagnosed with SPONK. The short-term outcome has been reported previously (1991). After 1–7 years, 10 patients had a good radiographic outcome and 30 were considered failures, developing osteoarthritis. In 2012, all 40 of the patients were matched with the Swedish Knee Arthroplasty Register (SKAR) and their medical records were reviewed to evaluate the long-term need for major knee surgery.
At the 2012 review, 33 of the 40 patients had died. The mean follow-up time from diagnosis to surgery, death, or end of study was 9 (1–27) years. 17 of 40 patients had had major knee surgery with either arthroplasty (15) or osteotomy (2). All operated patients but 1 were in the radiographic failure group and had developed osteoarthritis in the study from 1991. 6 of 7 patients with large lesions (> 40% of the AP radiographic view of the condyle) at the time of the diagnosis were operated. None of the 10 patients with a lesion of less than 20% were ever operated.
It appears that the size of the osteonecrotic lesion can be used to predict the outcome. Patients showing early signs of osteoarthritis or with a large osteonecrosis have a high risk of later major knee surgery.
PMCID: PMC3768043  PMID: 23799344
2.  The effect of a biphasic injectable bone substitute on the interface strength in a rabbit knee prosthesis model 
In joint prosthetic surgery, various methods are used to provide implant stability. We used an injectable bone substitute, composed of calcium sulfate/hydroxyapatite, as bone defect filler to stabilize a tibia prosthesis in an experimental rabbit model. The aim of the study was to investigate and compare the stability of prosthetic fixation with and without the use of an injectable bone substitute.
Sixteen rabbits were used and the tibia prostheses were implanted bilaterally, one side with the prosthesis alone and the other side with the prosthesis and calcium sulfate/hydroxyapatite (Cerament™). The rabbits were randomly divided into two groups and euthanized after 6 and 12 weeks, respectively. The prosthesis was extracted measuring the pull-out force in an Instron tester, and the bone surrounding the former prosthesis site was analyzed by histology, histomorphometry, and micro-computed tomography.
At 6 weeks no difference in maximum pull-out force was found between the prostheses fixed with or without Cerament™. At 12 weeks the maximum pull-out force for the prostheses with Cerament™ was significantly higher than that for the prostheses without Cerament™ (p = 0.04). The maximum pull-out force at 12 weeks was significantly higher than that at 6 weeks for the prostheses fixed with Cerament™ (p = 0.03) but not for the prostheses without.
We conclude that early prosthesis-bone interface strength is not influenced by a bone substitute. However, during remodeling, the bone substitute might provide improved mechanical support for the prosthesis. The results support further studies of the use of injectable calcium sulfate/hydroxyapatite in fixation of prosthetic joint implants.
PMCID: PMC3734137  PMID: 23899023
Injectable bone substitute; Hydroxyapatite; Calcium sulfate; Interface strength; Histomorphometry
3.  Augmentation of autologous bone graft by a combination of bone morphogenic protein and bisphosphonate increased both callus volume and strength 
Acta Orthopaedica  2013;84(1):106-111.
Background and purpose
Bone morphogenic proteins (BMPs) can be used in non-unions to replace autograft. BMPs induce osteoblasts and (less well known) also osteoclasts, which can in turn be controlled by a bisphosphonate. In the present study, our aim was to improve the biological effect of autologous bone graft by adding an anabolic BMP, with or without bisphosphonates, in an open-fracture model prone to non-union.
Rat femurs were osteotomized and fixed with an intramedullary K-wire. Autograft was placed at the osteotomy, mixed with either saline or BMP-7. After 2 weeks, the rats had a single injection of saline or of a bisphosphonate (zoledronate). The rats were killed after 6 weeks and the femurs were evaluated by radiography, micro-CT, histology, and 3-point bending test.
All fractures healed. The callus volume was doubled in the BMP-treated femurs (p < 0.01) and increased almost 4-fold in the femurs treated with both BMP and systemic zoledronate (p < 0.01) compared to autograft. In mechanical testing, the autograft group reached approximately half the strength of the contralateral, non-osteotomized femur (p < 0.001). By adding BMP to the autograft, the strength was doubled (p < 0.001) and with both BMP and systemic zoledronate, the strength was increased 4-fold (p < 0.001) compared to autograft alone.
The combination of BMP and bisphosphonate as an adjunct to autograft is superior to autograft alone or combined with BMP. The combination may prove valuable in the treatment of non-unions.
PMCID: PMC3584593  PMID: 23409846
4.  Local treatment of a bone graft by soaking in zoledronic acid inhibits bone resorption and bone formation. A bone chamber study in rats 
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.
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.
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.
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.
PMCID: PMC3528664  PMID: 23217097
Zoledronic acid; Bisphosphonates; Allograft; Local treatment; Bone remodelling
5.  Treatment of spontaneous osteonecrosis of the knee (SPONK) by a bisphosphonate 
Acta Orthopaedica  2012;83(5):511-514.
Background and purpose
Primary spontaneous osteonecrosis of the knee is a painful lesion in the elderly without any known cause. The onset of pain is usually acute. The prognosis is poor with high frequency of osteoarthritis, joint surface collapse, and subsequent knee surgery. In the present study, we determined whether bisphosphonates can prevent the joint surface collapse by delaying the post-necrotic remodeling.
Patients and methods
Between 2006 and 2009, 17 consecutive patients (mean age 68 years) with clinical and radiographic signs of knee osteonecrosis were identified and given alendronate, 70 mg perorally, once a week for a minimum of 6 months. The patients were followed clinically, radiographically, and by MRI.
10 of the 17 patients did not develop osteoarthritis (group A), 4 patients developed mild osteoarthritis but no knee joint surface collapse (group B), and 3 patients had a joint surface collapse (group C). 2 of the 3 patients in group C—as compared to none in the other groups—stopped medication prematurely, due to side effects.
Compared to a previous, untreated series of osteonecrosis patients at our hospital, the clinical results in the present series appeared better. 59% of the patients had a complete radiographic recovery, as compared to 25% in the original study. 12% were failures regarding need to undergo surgery when bisphosphonates were given, as compared to 32% in the previous untreated series. An anticatabolic drug delaying the remodeling might be an effective treatment in osteonecrosis of the knee but further (preferably randomized) studies are necessary.
PMCID: PMC3488179  PMID: 22998531
6.  External or internal fixation in the treatment of non-reducible distal radial fractures? 
Acta Orthopaedica  2011;82(5):610-613.
Background and purpose
We have previously shown in a randomized study that in the first year after treatment, open reduction and internal fixation resulted in better grip strength and forearm rotation than closed reduction and bridging external fixation. In the present study, we investigated whether this difference persists over time.
Patients and methods
The 50 patients included in the original study (mean age 53 years, 36 women) were sent a QuickDASH questionnaire and an invitation to a radiographic and clinical examination after a mean of 5 (3–7) years.
All 50 patients returned the QuickDASH questionnaire and 45 participated in the clinical and radiographic examination. In the internal fixation group, the grip strength was 95% (SD 12) of the uninjured side and in the external fixation group it was 90% (SD 21) of the uninjured side (p = 0.3). QuickDASH score, range of motion, and radiographic parameters were similar between the groups.
The difference originally found between internal and external fixation in distal radial fractures at 1 year regarding grip strength and range of motion was found to diminish with time. At 5 years, both groups had approached normal values.
PMCID: PMC3242960  PMID: 21895505
7.  A single bisphosphonate infusion does not accelerate fracture healing in high tibial osteotomies 
Acta Orthopaedica  2011;82(4):465-470.
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.
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.
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.
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.
PMCID: PMC3237038  PMID: 21689069
8.  Local treatment of cancellous bone grafts with BMP-7 and zoledronate increases both the bone formation rate and bone density 
Acta Orthopaedica  2011;82(2):228-233.
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.
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.
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.
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.
PMCID: PMC3235296  PMID: 21434769
9.  Open reduction and internal fixation compared to closed reduction and external fixation in distal radial fractures 
Acta Orthopaedica  2009;80(4):478-485.
Background and purpose In unstable distal radial fractures that are impossible to reduce or to maintain in reduced position, the treatment of choice is operation. The type of operation and the choice of implant, however, is a matter of discussion. Our aim was to investigate whether open reduction and internal fixation would produce a better result than traditional external fixation.
Methods 50 patients with an unstable or comminute distal radius fracture were randomized to either closed reduction and bridging external fixation, or open reduction and internal fixation using the TriMed system. The primary outcome parameter was grip strength, but the patients were followed for 1 year with objective clinical assessment, subjective outcome using DASH, and radiographic examination.
Results At 1 year postoperatively, grip strength was 90% (SD 16) of the uninjured side in the internal fixation group and 78% (17) in the external fixation group. Pronation/supination was 150° (15) in the internal fixation group and 136° (20) in the external fixation group at 1 year. There were no differences in DASH scores or in radiographic parameters. 5 patients in the external fixation group were reoperated due to malunion, as compared to 1 in the internal fixation group. 7 other cases were classified as radiographic malunion: 5 in the external fixation group and 2 in the internal fixation group.
Interpretation Internal fixation gave better grip strength and a better range of motion at 1 year, and tended to have less malunions than external fixation. No difference could be found regarding subjective outcome.
PMCID: PMC2823185  PMID: 19857180
10.  Measures and time points relevant for post-surgical follow-up in patients with inflammatory arthritis: a pilot study 
Rheumatic diseases commonly affect joints and other structures in the hand. Surgery is a traditional way to treat hand problems in inflammatory rheumatic diseases with the purposes of pain relief, restore function and prevent progression. There are numerous measures to choose from, and a combination of outcome measures is recommended. This study evaluated if instruments commonly used in rheumatologic clinical practice are suitable to measure outcome of hand surgery and to identify time points relevant for follow-up.
Thirty-one patients (median age 56 years, median disease duration 15 years) with inflammatory rheumatic disease and need for post-surgical occupational therapy intervention formed this pilot study group.
Hand function was assessed regarding grip strength (Grippit), pain (VAS), range of motion (ROM) (Signals of Functional Impairment (SOFI)) and grip ability (Grip Ability Test (GAT)). Activities of daily life (ADL) were assessed by means of Disabilities of the Arm, Shoulder and Hand Outcome (DASH) and Canadian Occupational Performance Measure (COPM). The instruments were evaluated by responsiveness and feasibility; follow-up points were 0, 3, 6 and 12 months.
All instruments showed significant change at one or more follow-up points. Satisfaction with activities (COPM) showed the best responsiveness (SMR>0.8), while ROM measured with SOFI had low responsiveness at most follow-up time points. The responsiveness of the instruments was stable between 6 and 12 month follow-up which imply that 6 month is an appropriate time for evaluating short-term effect of hand surgery in rheumatic diseases.
We suggest a core set of instruments measuring pain, grip strength, grip ability, perceived symptoms and self-defined daily activities. This study has shown that VAS pain, the Grippit instrument, GAT, DASH symptom scale and COPM are suitable outcome instruments for hand surgery, while SOFI may be a more insensitive test. However, the feasibility of this protocol in clinical practice awaits prospective studies.
PMCID: PMC2691396  PMID: 19442265
11.  Systemic zoledronate treatment both prevents resorption of allograft bone and increases the retention of new formed bone during revascularization and remodelling. A bone chamber study in rats 
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.
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.
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).
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.
PMCID: PMC1557502  PMID: 16889666

Results 1-11 (11)