Children with acute Perthes' disease have asymmetrical lower leg growth and abnormal collagen turnover

Background?Abnormalities in distal growth and low levels of insulin–like growth factor (IGF)–I have been reported in children with Perthes' disease. Our aim was to establish whether the acute phase of Perthes' disease is associated with abnormalities of growth, of bone or of collagen turnover.

Methods?We performed a cross–sectional study of 15 children (3–11 years of age, 13 boys) at acute presentation and a longitudinal cohort study of 9 children. We measured (1) the lengths of both lower legs (by knemometry) at weeks 1, 2, 6 and 12, (2) height and weight at presentation and at the second–year follow–up, and (3) levels of IGF–I, IGFBP–3, collagen markers and bone alkaline phosphatase at weeks 1 and 12, and in year 2.

Results?Height SD scores were normal at presentation but declined thereafter. Lower leg growth was not impaired at presentation but was asymmetrical, ceased during weeks 2–6, and then resumed symmetrically. Patients had persistently low IGF–I, low soft tissue collagen synthesis and enhanced collagen breakdown compared with age– and sex–related reference data. Markers of bone formation increased during follow–up.

Interpretation?Acute changes in lower leg growth reflected differential weight bearing, then immobilization and remobilization. Persistently low IGF–I may have contributed to low soft tissue collagen synthesis and growth. Changes in bone formation markers most likely reflected bone healing.

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Serum somatomedin a in Perthes' disease

Serum somatomedin A, determined by radioreceptor assay in 47 children with Perthes' disease, was significantly reduced as compared to normal children of the same age. Nine children underwent the 1-Dopa tolerance tests to evoke growth hormone release; a normal response was found in eight.

Patients with Perthes' disease tend to be short in stature with “disproportionate skeletal growth” of the limbs; growth is less in the distal than in the proximal extremities. The low serum levels of somatomedin A suggest some growth disturbance during the development of Perthes' disease.     

Lipopolysaccharide impairs fracture healing: an experimental study in rats

Background It has been shown that trauma causes translocation of lipopolysaccharide (LPS) endotoxins from the gut. LPS has been identified as a major bacterial bone resorbing factor. The effects of LPS on bone healing are therefore of clinical interest, as trauma involving fractures followed by sepsis is a clinical scenario. We investigated the effects of systemic and local administration of LPS on the healing of femoral fractures in rats.

Animals and methods In 3 groups, each consisting of 9 rats, a mid-diaphyseal osteotomy/fracture of the femoral bone was performed and then nailed. In one group of animals, LPS was applied intraperitoneally (systemically), and in another group, LPS was applied locally at the fracture site. The third group served as a control. The animals were killed after 6 weeks, and the mechanical characteristics of the healing osteotomies were evaluated.

Results We found that LPS induced a hypertrophic and immature callus, as evaluated by bone mineral content and density. In the rats given LPS intraperitoneally, the mechanical strength characteristics were reduced, as evaluated by bending moment, rigidity, and energy absorption.

Interpretation The rats given LPS intraperitoneally reflect a clinical situation with fracture trauma and endotoxinemia. Our findings indicate that endotoxinemia may impair the fracture healing processes.

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Long-standing increased bone turnover at the fixation points after anterior cruciate ligament reconstruction: a positron emission tomography (PET) study of 8 patients

Background A secure incorporation of the graft in a bone tunnel is a prerequisite for successful anterior cruciate ligament reconstruction. In this cross-sectional pilot study, we studied the healing process with positron emission tomography (PET) scanning.

Patients and methods 8 young patients underwent an anterior cruciate ligament reconstruction with a bonepatellar tendon-bone graft (BTB, n = 4) or a quadruple semitendinosus and gracilis graft (ST/G, n = 4). Regional bone turnover was quantified with an 18F-fluoride PET scan in each patient 1 day, 3 weeks, 7 months, or 22 months after surgery.

Results The highest activity level was found 3 weeks after surgery, but the activity at the femoral fixation points was markedly increased even after 7 months. The bone turnover was almost normalized 22 months after the operation.

Interpretation It would take at least 7 months until an anterior cruciate ligament graft, fixed with an interference screw, is completely incorporated. This finding is important for postoperative rehabilitation. Furthermore, PET is a feasible tool when studying new ways of fixing soft tissue to bone.     

Do non-steroidal anti-inflammatory drugs cause endoprosthetic loosening? A 10-year follow-up of a randomized trial on ibuprofen for prevention of heterotopic ossification after hip arthroplasty

Background Non-steroidal anti-inflammatory drugs (NSAIDs) are known to be potent inhibitors of new bone formation. We investigated whether NSAIDs given at surgery influence the long-term results after total hip arthroplasty (THA).

Patients and methods We performed a 10-year follow-up on 142 of 144 patients who had taken part in a randomized trial on the preventive effects of the NSAID ibuprofen on heterotopic ossification after THA. 96 patients were treated with ibuprofen: 48 for 1 week postoperatively, 48 for 2 weeks postoperatively, and 48 patients were not treated.

Results 13 patients had been revised. All revisions except 1 belonged to groups treated with ibuprofen. The 10-year risk for revision was significantly higher in the ibuprofen-treated patients (p = 0.05). Eleven of the revisions occurred due to fractures of the femur (2) or aseptic loosening (9), reasons that may be attributed to negative effects of ibuprofen. For these patients, the 10-year risk for revision was not statistically significantly different between treated and untreated patients (p = 0.08). In addition to the revised patients, 94 other patients were alive at the 10-year follow-up and 84 underwent radiographic examination. 9 loose prostheses were found radiographically, but these were equally distributed between ibuprofen-treated and untreated hips.

Interpretation The high proportion of revisions in the ibuprofen groups, in combination with clinical and experimental evidence of inhibitory effects on new bone formation of NSAIDs, warrants further investigation of the effects of these drugs on prosthetic fixation.

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Tissue concentrations of vancomycin and Moxifloxacin in periprosthetic infection in rats

Background A one-step exchange of an endoprosthesis with periprosthetic infection requires effective antibiotics at high concentrations around the endoprosthesis. We evaluated the tissue distribution of vancomycin and Moxifloxacin in a standardized in vivo model of periprosthetic infection.

Methods 36 male rats with periprosthetic infection of the left hind leg, induced by a standardized procedure, received either antibiotic treatment with vancomycin or Moxifloxacin twice daily for 2 weeks, or a sham treatment. After the last administration, different tissues from each animal were evaluated for concentrations of antibiotic.

Results Compared to plasma, the tissue concentrations of Moxifloxacin were higher in all tissues investigated (lung, muscle, fat, bone) and the tissue-plasma ratio of Moxifloxacin was considerably higher than that of vancomycin. The concentrations of Moxifloxacin were equally high in the infected and the uninfected hind leg, whereas the vancomycin concentrations were significantly higher in the infected leg.

Interpretation The standardized model of periprosthetic infection described here can be extrapolated to different bacterial and mycotic pathogens, and also to different antibiotics or therapeutic regimes. It provides a way of correlating tissue concentrations with clinical outcome in future studies.     

One fracture is enough! Experience with a prospective and consecutive osteoporosis screening program with 239 fracture patients

Background Fracture and low bone mineral density both have strong predictive value for future fractures. The risk of future fractures can be reduced by medi-cal treatment if patients with osteoporosis are identified, for example by screening fracture patients for low bone mineral density. We suggest that these screening rou-tines be organized at orthopedics departments and we report our experience with such a screening system.

Patients and methods We screened all patients between 50-75 years of age with a wrist, vertebral, prox-imal humerus, or hip fracture visiting our orthopedics department by measuring bone mineral density (BMD) using DEXA scans. After diagnosis, the patients were referred to their primary care physician for treatment.

Results Between November 1, 2002, and October 31, 2003, 239 patients were investigated and only 13% had normal BMD values. 45% of the patients were diagnosed with osteopenia and 42% with osteoporosis.

Interpretation Screening of fracture patients who visit an orthopedics department appears to be an effec-tive way of identifying individuals with low bone min-eral density. The screening routines can be organized as an osteoporosis team consisting of a doctor, a nurse and a secretary at each department. Today, these patients are largely undetected and untreated—at least in our region. In our series, only 13 patients had been DEXA-scanned and were treated by antiresorptive drugs at the time of fracture. ▪     

Excellent results with femoral revision surgery using an extensively hydroxyapatite-coated stem: 59 patients followed for 10-16 years

Background The outcome of femoral component revision with either cemented or proximally coated stems has been disappointing, but revision with extensively coated stems has been promising. We report long-term outcome of a grit-blasted titanium stem entirely plasma sprayed with hydroxyapatite (HA), in femoral revision surgery.

Patients and methods During 1988 to 1993, we performed 66 femoral revisions in 65 patients (49 women) aged mean 58 (28-86) years. 3 patients died before the 10-year follow-up and 4 did not come for the follow-up examination because they had no hip problems, as confirmed by telephone and by a written reply. 1 of these, however, was previously controlled at 10 years. Thus, 59 patients (60 hips) were followed by clinical and radiographic analysis for 10-16 years after femoral stem revision.

Results 1 stem was re-revised due to mechanical failure, and none were revised because of infection. We noticed a low degree of proximal bone loss and a low incidence of distal bone hypertrophy. These observations indicate no significant net transfer of stress proximally to distally, and a somewhat physiological weight distribution from the stem to the femoral bone. The bone changes confirmed a well-fixed femoral component in asymptomatic patients.

Interpretation Our findings indicate good long-term results with a fully HA-coated stem in femoral revision surgery. ▪     

Exogenous collagen-enhanced recruitment of mesenchymal stem cells during rabbit articular cartilage repair

Background Despite the well-known effect of type-I collagen in promoting cartilage repair, the mechanism still remains unknown. In this study we investigated this mechanism using a rabbit model of cartilage defects.

Animals and methods 5-mm-diameter full-thickness defects were created on both patellar grooves of 53 Japanese white rabbits (approximately 13 weeks old). The left defect was filled with collagen gel and the right defect was left empty. The rabbits were killed and examined morphometrically until the twenty-fourth postoperative week, by (1) evaluation of matrix production, (2) enumeration of the total number of cells engaged in cartilage repair, (3) enumeration of the proliferating cells, (4) localization of mesenchymal stem cells, and (v) localization of apoptotic cells.

Results We found that type-I collagen enhances cell recruitment, and thereby increases the number of proliferating cells. A considerable proportion of the proliferating cells were identified as bone marrow-derived mesenchymal stem cells. However, type-I collagen does not prevent the chondrocyte precursors from undergoing apoptotic disengagement from the chondrogenic lineage.

Interpretation Type-I collagen promotes cartilage repair by enhancing recruitment of bone marrowderived mesenchymal stem cells. Additional use of agent(s) that sustain mesenchymal stem cells along the chondrogenic path of differentiation may constitute an appropriate environment for cartilage repair.     

Low metacarpal index predicts hip fracture: a prospective population study of 3,561 subjects with 15 years of follow-up

Background Metacarpal index (MCI), measured from hand radiographs as the ratio between combined cortical thickness and bone diameter, has been suggested for assessment of bone mass and risk of osteoporotic fracture. We studied MCI for its ability to predict hip fractures.

Methods Hand radiographs were taken and MCI determined in 3,561 subjects from a representative population sample of 8,000 Finns who were 30 years of age or over in 1978-80. Record linkage to the National Hospital Discharge Register identified 117 subjects who had been hospitalized for primary treatment of hip fracture by the end of 1994.

Results High age, low body mass index, tall stature and smoking at baseline showed, independently of each other, significant associations with low MCI. Low MCI was a strong predictor of hip fracture. When adjusted for all potential confounding factors, the relative risk of hip fracture per decrement of MCI by one standard deviation (0.1) was 1.5 (95% CI 1.2-1.8).

Interpretation Low MCI is associated with known risk factors of osteoporosis and predicts hip fracture. Since hand radiographs are easily available at low cost, measurements of MCI can be used as an alternative approach to find osteoporotic individuals with a high risk of hip fracture. ▪     

Platelet-rich plasma accelerated surgical angio-genesis in vascular-implanted necrotic bone: an experimental study in rabbits

Background Platelets contain many kinds of growth factors with the ability to accelerate angiogenesis. We analyzed whether a single injection of platelet-rich plasma (PRP) would accelerate surgical angiogenesis in necrotic bone implanted with vascular tissue.

Methods We used 24 Japanese White rabbits. PRP was refined from autologous blood by separation twice with centrifugation. A removed iliac bone was frozen in liquid nitrogen to ensure complete cellular necrosis. A narrow hole was made in the bone and the saphenous vascular bundle was passed through the hole. The bone was wrapped after injection of either 1 mL (1) PRP, or (2) saline solution into the hole, and was placed subcu-taneously in the thigh. In both groups, angiogenesis was compared 1 week and 2 weeks after surgery.

Result Angiogenesis was observed along the implanted vascular bundle in both groups. At 1 and 2 weeks after surgery, both the vessel density and the average length of newly formed vessels of the experimental group were significantly greater than in the control group. Both the vessel density and the length were greater after 2 weeks than after 1 week.

Interpretation A single injection of PRP accelerates surgical angiogenesis in vascular-implanted necrotic bone.     

Indomethacin inhibits bone formation in inductive allografts but not in autografts: studies in rat

Background Non-steroidal anti-inflammatory drugs (NSAIDs) are known to have inhibitory effects on new bone formation. We wanted to analyze some effects of the NSAID indomethacin on different inductive stimuli for bone formation.

Methods We experimentally induced heterotopic new bone with demineralized allogeneic bone matrix (DABM) and with bone autografts in rats, in order to study the effects of indomethacin on new bone formation at 3 and 6 weeks.

Results Indomethacin inhibited net bone formation in DABMs by 30% at 6 weeks. At 6 weeks, the mineral accretion rate was unaffected, indicating that it is at the early phase of the inductive process that mineral accretion is sensitive to inhibition by indomethacin, but not at the later stages.

In traumatized skeletal bone, the ⁴⁵Ca-specific activity was higher than in non-traumatized bone, while indomethacin significantly reduced the ⁴⁵Ca uptake at 3 weeks, but not at 6 weeks.

In the autografts, a net mineral loss occurred, but neither mineral content nor ⁴⁵Ca incorporation was affected by Indomethacin treatment.

Interpretation Indomethacin inhibited the early phase of new bone formation in heterotopic DABMs and the early bone healing process in traumatized skeletal bone, but did not affect resorption or bone formation in heterotopic autografts. ▪     

Alendronate treatment in the revision setting, with and without controlled implant motion: an experimental study in dogs

Introduction Bisphosphonates have been proposed to delay or prevent loosening of joint replacement implants by reducing bone resorption. It is known, however, that implant motion prevents the bone anchorage necessary to maintain secure implant fixation.

Methods We used our experimental implant model with controlled motion to evaluate the relative effects of implant motion and bisphosphonate. We implemented our established 8-week experimental revision protocol to obtain a bony and soft tissue setting of revision joint replacement in 16 dogs. At 8 weeks, we had stabilized half of the implants. The other half of the implants continued pistoning. Half of the dogs were exposed to alendronate (oral).

Results Stabilization of the revision implant was more effective at improving fixation (higher shear strength) than administering alendronate. As expected, the fibrous membrane remained under unstable conditions, even with alendronate. With alendronate and stabilized implants, increased bone was observed near the sclerotic shell of the revision cavity, but it was reduced with alendronate when the implant was unstable.

Interpretation Our findings suggest that it may be difficult for alendronate administration alone to rescue implants that are already loose. In implants that have not progressed to loosening, alendronate may increase bone density at the border with the sclerotic shell, but the effect of this bone in delaying eventual loosening is not known.     

Safe fixation with two acetabular screws after Ganz periacetabular osteotomy

Background and purpose With Ganz periacetabular osteotomy, the osteotomized acetabular fragment is reoriented in an adducted, extended, and rotated position. The acetabular fragment is fixated with 2 screws and the patients are allowed 30 kg of weight bearing immediately after surgery. We were interested in examining the stability of the reoriented acetabulum after Ganz osteotomy; thus, the migration of the acetabular fragment was assessed by radiostereometry.

Patients and methods 32 dysplastic patients (27 females; 32 hips) were included in the study. Median age was 39 (20-57) years. Radiostereometric examinations were done at 1 week, 4 weeks, 8 weeks and 6 months. Data are presented as mean (SD).

Results 6 months postoperatively, the acetabular fragment had migrated 0.7 (0.8) mm medially, and 0.7 (0.5) mm proximally. Mean rotation in adduction was 0.5° (1.3). In other directions, mean migration was below 0.5 mm/°. There were no statistically significant differences in migration at 8 weeks and 24 weeks postoperatively regarding translation and rotation.

Interpretation Due to the limited amount of migration, we find our postoperative partial weight-bearing regime safe.     

Structural allografts for bone stock reconstruction in two-stage revision for infected total hip arthroplasty: good outcome in 16 of 18 patients followed for 5-14 years

Background The use of massive bone allografts in cases of revision of failed total hip arthroplasties (THAs) due to infection is controversial.

Patients and methods 18 patients presented with infection at the site of a THA and were treated with a two-stage protocol. In the first stage, the prosthesis was removed together with all necrotic tissues and cement material if present. A custom-made mold of Palacos R cement containing 1 g of gentamicin was then inserted in 17 of the 18 patients. Systemic antibiotics were used during the interval period. In the second stage, the patients had either acetabular or femoral reconstruction using bulk allograft bone.

Results Mean follow-up was 9 (5-14) years. 1 patient presented with recurrent infection and underwent a Girdlestone resection arthroplasty as definitive treatment. Another patient had a mechanical failure of the acetabular component, which was revised 10 years after the second stage of the reconstruction. The mean Harris Hip Score improved from 34 points preoperatively to 71 points at the last review. By our definition, 16/18 of the patients had a successful outcome.

Interpretation Our results support the use of massive allografts in staged reconstructions of infected THAs complicated by considerable bone loss. ▪     

6 Weeks with the von Rosen splint is sufficient for treatment of neonatal hip instability

Background There is no concensus on the optimal treatment time for unstable hips in the newborn. We analyzed the efficiency of a treatment program that has been used for 10 years at our hospital, in which all unstable hips (subluxatable, Barlow-positive and Ortolani-positive) are treated with the von Rosen splint for 6 weeks.

Patients and methods Between 1988 and 1997, 32,171 children were born alive at the hospital. During this period 247 children had a clinically unstable hip diagnosed. 223 of the 247 children underwent a radiographic follow-up after 5-15 years.

Results 1 patient with bilateral instability and treated with a splint for 6 weeks showed a dislocated left hip at the radiographic examination at 8 months, which is part of the screening program, and needed operative treatment. 1 patient did not follow the treatment program and showed a dislocated hip at the age of 3. Another 4 patients required more treatment than the 6 weeks with the splint.

We found no dysplastic hips at the radiographic follow-up. There was no late dysplasia and there were no late dislocations in children born in Lund between 1988 and 1997 who were diagnosed at other Swedish centers that treat developmental dysplasia of the hip (DDH).

Interpretation We conclude that the present screening and 6-week treatment in a von Rosen splint prevent almost all cases of late dysplasia and late dislocation of the hip.     

A cost analysis of three methods of treating femoral shaft fractures in children

Introduction There is no consensus as to which is best treatment of femoral fractures in children.

Patients and methods We performed a cost analysis comparing three treatments of femoral shaft fractures in children aged 3-15 years at 3 hospitals during the same period (1993-2000). The analysis included total medical costs and costs for the care provider and were calculated from the time of injury up to 1 year.

Results At hospital 1, treatment consisted of external fixation and early mobilization. At hospital 2, the treatment was skin or skeletal traction in hospital for 1-2 weeks, followed by home traction. At hospital 3, treatment was skin or skeletal traction in hospital until the fracture healed.

Results The average total costs per patient were EUR 10,000 at hospital 1, EUR 23,000 at hospital 2, and EUR 38,000 at hospital 3.

Interpretation The main factor for determining the cost of treatment was the number of days in hospital, which was lower in children treated with external fixation.     

Systemic zoledronate precoating of a bone graft reduces bone resorption during remodeling

Background Cartilage degeneration often occurs after osteosynthesis of a devascularized intermediary fragment in a joint fracture, in mosaicplasty or in whole-joint toe-to-finger transplantation. Hypothetically, the degeneration is secondary to a collapse of the transferred subchondral bone as it remodels during high mechanical load. Bisphosphonates are used to reduce resorption of necrotic bone. We tested a systemic pretreatment before harvesting the graft in order to protect the bone and cartilage against collapse and secondary arthrosis.

Methods Rats were given one zoledronate injection and bone grafts were harvested. The grafts were frozen, thawed and placed into bone chambers, and implanted into another batch of rats. Graft resorption and new bone formation was measured by histomorphometric analysis and compared with untreated grafts.

Results In the remodeled area of the controls, the graft was almost totally resorbed and replaced by bone marrow. In the zoledronate-treated specimens, the graft remained and the graft trabeculas were lined with new bone. By histomorphometry, the total amount of bone (graft plus new bone) within the remodeled area was 16% in the zoledronate-treated grafts and 5% in the controls (p = 0.003).

Interpretation A bone graft can be pretreated with bisphosphonate and remain protected against resorption once implanted again. ▪     

Locally delivered TGF-beta1 and IGF-1 enhance the fixation of titanium implants: a study in dogs

Background Osteogenic growth factors have been suggested to enhance the fixation of implants used in joint replacement. We examined the effect of locally delivered transforming growth factor-β1 and insulin-like growth factor-1 in a biodegradable poly (D, L-lactide) coating.

Material and methods In a paired study using 9 dogs, unloaded titanium implants surrounded by a 1-mm gap were inserted into the proximal humerus. The growth factors were incorporated in a poly (D, L-lactide) coating at a 1% (w/w) ratio of TGF-β1 and a 5% (w/w) ratio of IGF-1. Control implants were uncoated. After 4 weeks, the implants were evaluated by mechanical push-out test and by histomorphometry.

Results A twofold increase was seen in mechanical fixation (strength, stiffness, energy absorption) for the growth factor-treated implants (p = 0.04). Similar results were seen in histomorphometry, as bone ongrowth was 2.5 times higher (p = 0.02), and gap healing was 30-110% higher (p = 0.04) for the growth factor-treated implants than for the control implants. Ongrowth of fibrous tissue was eliminated by the treatment.

Interpretation TGF-beta-1 and IGF-1, locally delivered in a biodegradable poly(D,L-lactide) coating, enhance the mechanical fixation and osseointegration of titanium implants in cancellous bone, and no fibrous tissue is produced in the growth factor treated implants.