Aims

Accumulated evidence indicates that local cell origins may ingrain differences in the phenotypic activity of human osteoblasts. We hypothesized that these differences may also exist in osteoblasts harvested from the same bone type at periarticular sites, including those adjacent to the fixation sites for total joint implant components.

Lateral epicondylitis, or ’tennis elbow’, is a common condition that usually affects patients between 35 and 55 years of age. It is generally self-limiting, but in some patients it may continue to cause persistent symptoms, which can be refractory to treatment. This review discusses the mechanism of disease, symptoms and signs, investigations, current management protocols and potential new treatments.

Cite this article: Bone Joint J 2013;95-B:1158–64.

Objectives

There is increasing application of bone morphogenetic proteins (BMPs) owing to their role in promoting fracture healing and bone fusion. However, an optimal delivery system has yet to be identified. The aims of this study were to synthesise bioactive BMP-2, combine it with a novel α-tricalcium phosphate/poly(D,L-lactide-co-glycolide) (α-TCP/PLGA) nanocomposite and study its release from the composite.

Articular cartilage repair remains a challenge to surgeons and basic scientists. The field of tissue engineering allows the simultaneous use of material scaffolds, cells and signalling molecules to attempt to modulate the regenerative tissue. This review summarises the research that has been undertaken to date using this approach, with a particular emphasis on those techniques that have been introduced into clinical practice, via in vitro and preclinical studies.

Carbonate-substituted hydroxyapatite (CHA) is more osteoconductive and more resorbable than hydroxyapatite (HA), but the underlying mode of its action is unclear. We hypothesised that increased resorption of the ceramic by osteoclasts might subsequently upregulate osteoblasts by a coupling mechanism, and sought to test this in a large animal model.

Defects were created in both the lateral femoral condyles of 12 adult sheep. Six were implanted with CHA granules bilaterally, and six with HA. Six of the animals in each group received the bisphosphonate zoledronate (0.05 mg/kg), which inhibits the function of osteoclasts, intra-operatively.

After six weeks bony ingrowth was greater in the CHA implants than in HA, but not in the animals given zoledronate. Functional osteoclasts are necessary for the enhanced osteoconduction seen in CHA compared with HA.

The effects of the method of fixation and interface conditions on the biomechanics of the femoral component of the Birmingham hip resurfacing arthroplasty were examined using a highly detailed three-dimensional computer model of the hip. Stresses and strains in the proximal femur were compared for the natural femur and for the femur resurfaced with the Birmingham hip resurfacing. A comparison of cemented versus uncemented fixation showed no advantage of either with regard to bone loading. When the Birmingham hip resurfacing femoral component was fixed to bone, proximal femoral stresses and strains were non-physiological. Bone resorption was predicted in the inferomedial and superolateral bone within the Birmingham hip resurfacing shell. Resorption was limited to the superolateral region when the stem was not fixed. The increased bone strain observed adjacent to the distal stem should stimulate an increase in bone density at that location. The remodelling of bone seen during revision of failed Birmingham hip resurfacing implants appears to be consistent with the predictions of our finite element analysis.

The Cambridge Cup has been designed to replace the horseshoe-shaped articular cartilage of the acetabulum and the underlying subchondral bone. It is intended to provide physiological loading with minimal resection of healthy bone.

The cup has been used in 50 women with displaced, subcapital fractures of the neck of the femur. In 24 cases, the cup was coated with hydroxyapatite. In 26, the coating was removed before implantation in order to simulate the effect of long-term resorption.

The mean Barthel index and the Charnley-modified Merle d’Aubigné scores recovered to their levels before fracture. We reviewed 30 women at two years, 21 were asymptomatic and nine reported minimal pain. The mean scores deteriorated slightly after five years reflecting the comorbidity of advancing age. Patients with the hydroxyapatite-coated components remained asymptomatic, with no wear or loosening. The uncoated components migrated after four years and three required revision. This trial shows good early results using a novel, hydroxyapatite-coated, physiological acetabular component.

There is evidence that fractures heal more rapidly in patients with head injury. We measured the circulating level of interleukin-6 (IL-6) and its soluble receptor (sIL-6R) and soluble glycoprotein 130 (sgp130) in serum from patients who had sustained a head injury with and without fracture and compared these with levels found in control subjects.

Within 12 hours of injury the serum level of IL-6 was significantly higher in patients with head injury and fracture compared with the control group. Levels of IL-6 were also significantly higher in patients with head injury and fracture compared with fracture only. While there was no significant difference in circulating levels of sIL-6R in the initial samples they were increased one week after surgery in patients with head injury and fracture and with head injury only. In addition, reduced levels of sgp130 in patients with head injury with and without fracture indicated a possible reduction of the inhibitory effect of this protein on the activity of IL-6.

Our study suggests that IL-6 may be involved in altered healing of a fracture after head injury.

Synthetic bone substitutes provide an alternative to autograft but do not give equivalent clinical results. Their performance may be enhanced by adding osteogenic growth factors. In this study, TGFβ1 was absorbed on to a carrier of β tricalcium phosphate and Gelfoam® and used to fill a defect around a tibial implant in a rat model of revision arthoplasty.

We added 0.0, 0.02 μg, 0.1 μg or 1.0 μg of TGFβ1 to the carrier and then implanted it around an hydroxyapatite-coated stainless-steel pin in the proximal tibia of rats. The tibiae were harvested at three, six or 26 weeks and the amount of bone formation and ceramic resorption were assessed.

TGFβ1 had no effect on the amount of bone in the defect, the amount of fluorescent label incorporated or the rate of mineral apposition. The growth factor did not significantly affect the amount of β TCP remaining in the tissue at any of the time points.

There is evidence to suggest that fractures heal more rapidly in patients with a head injury as a result of systemic factors released from the site of this injury. We have measured the circulating level of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) in serum because of their known involvement in the stimulation of the activity of osteoblasts and the healing of fractures.

The serum level of IGF-1 was significantly lower in patients with both head injury and fracture and fracture only compared with that in healthy volunteers (p < 0.01 and p < 0.02, respectively). The level of IGFBP-3 was also significantly lower in patients with both head injury and fracture (p < 0.01).

Our findings showed, however, that the level of IGF-1 and IGFBP-3 varied from week to week in both the patients and healthy control subjects. These results indicate that the levels of circulating IGF-1 and IGFBP-3 are unlikely to be responsible for the altered healing of fractures seen in conjunction with head injury.

Particulate prosthetic materials are often studied by adding them to monocytic cells in vitro and measuring the release of cytokines as an indicator of their inflammatory potential. Endotoxin is known to be a contaminant of particle preparations and also stimulates the release of cytokines. It is usual to use a proprietary endotoxin test to avoid erroneous results.

Four different formulations of cement were found to be free from endotoxin using standard, gelclot tests but stimulated different levels of release of cytokines from macrophages. These differences were explained when a more sensitive, kinetic endotoxin assay showed that release correlated with minor contamination with endotoxin. In a repeat experiment using cement particles with low or undetectable levels of endotoxin by kinetic assay, differences in the ability of the formulations to stimulate the release of cytokines were not seen.

Endotoxin is adsorbed on to the surface of particles and it is this combination which stimulates increased release of cytokines. In both the above methods for determination of endotoxin, the water in which the particles had been soaked was examined rather than the particles directly. Further investigations showed that a kinetic assay directly on a particle suspension is the most sensitive method to measure contamination with endotoxin.

We used a rat model in vivo to study the effects of particulate bone cements at the bone-implant interface. A ceramic pin was implanted into the tibiae of 48 rats. Three types of particle of clinically relevant size were produced from one bone-cement base without radio-opacifier, with zirconium dioxide (ZrO₂) and with barium sulphate (BaSO₄). The rats were randomly assigned to four groups to receive one of the three bone cements or normal saline with 2% v/v Sprague-Dawley serum as the control. A total of 10⁹ particles was injected into the knee at 8, 10 and 12 weeks after the original surgery. The animals were killed at 14 weeks and the tibiae processed for histomorphometry. The area of fibrous tissue and the gap between the implant and bone were measured using image analysis.

All three types of particle were associated with a larger area of bone resorption than the control. Only in the case of the BaSO₄-containing cement did this reach statistical significance (p = 0.01). Particles of bone cement appear to promote osteolysis at the bone-implant interface and this effect is most marked when BaSO₄ is used as the radiopaque agent.

We have investigated whether the particle-stimulated release of inflammatory cytokines from human primary macrophages in vitro was dependent upon the type of bone cement used. Particles of clinically relevant size were produced from Palacos R without radio-opacifier, Palacos R with BaSO₄, Palacos R with ZrO₂ and from CMW3 which contains BaSO₄. All four preparations produced significantly greater release of tumour necrosis factor alpha, interleukin-6 and interleukin-1 beta than a negative control but there were no significant differences between them. The differences in the ability to stimulate bone resorption and in clinical performance between proprietary bone cements previously recorded are not explained by the release of the cytokines most commonly implicated in osteolysis.

We have investigated whether the thigh tourniquet used during total knee replacement (TKR) influenced the development of postoperative wound hypoxia and was a cause of delayed wound healing.

We allocated randomly 31 patients (31 TKRs) to one of three groups: 1) no tourniquet; 2) tourniquet inflated at low pressure (about 225 mmHg); and 3) tourniquet inflated to high pressure of about 350 mmHg. Wound oxygenation was measured using transcutaneous oxygen electrodes.

In the first week after surgery, patients with a tourniquet inflated to a high pressure had greater wound hypoxia than those with a low pressure. Those without a tourniquet also had wound hypoxia, but the degree and duration were less pronounced than in either of the groups with a tourniquet.

Use of a tourniquet during TKR can increase postoperative wound hypoxia, especially when inflated to high pressures. Our findings may be relevant to wound healing and the development of wound infection.

We used a rat model in vivo to study the effects of the concentration of polyethylene particles on the bone-implant interface around stable implants in the proximal tibia. Intra-articular injections of 10⁴, 10⁶ or 10⁸ high-density polyethylene (HDPE) particles per joint were given 8, 10 and 12 weeks after surgery. The animals were killed after 14 and 26 weeks and the response at the interface determined.

Fibrous tissue was seen at the bone-implant interface when the head of the implant was flush with the top of the tibia but not when it was sunk below the tibial plateau. In the latter case the implant was completely surrounded by a shell of bone. The area of fibrous tissue and that of the gap between the implant and bone was related to the concentration of particles in the 14-week group (p < 0.05).

Foreign-body granulomas containing HDPE particles were seen at the bone-implant interface in animals given 10⁸ particles. The pathology resembles that seen around prostheses with aseptic loosening and we suggest that this is a useful model by which to study this process.

Particulate wear debris can induce the release of bone-resorbing cytokines from cultured macrophages and fibroblasts in vitro, and these mediators are believed to be the cause of the periprosthetic bone resorption which leads to aseptic loosening in vivo. Much less is known about the effects of particulate debris on the growth and metabolism of osteoblastic cells.

We exposed two human osteoblast-like cell lines (SaOS-2 and MG-63) to particulate cobalt, chromium and cobalt-chromium alloy at concentrations of 0, 0.01, 0.1 and 1.0 mg/ml. Cobalt was toxic to both cell lines and inhibited the production of type-I collagen, osteocalcin and alkaline phosphatase. Chromium and cobalt-chromium were well tolerated by both cell lines, producing no cytotoxicity and no inhibition of type-I collagen synthesis. At the highest concentration tested (1.0 mg/ml), however, chromium inhibited alkaline phosphatase activity, and both chromium and cobalt-chromium alloy inhibited osteocalcin expression.

Our results clearly show that particulate metal debris can modulate the growth and metabolism of osteoblastic cells in vitro. Reduced osteoblastic activity at the bone-implant interface may be an important mechanism by which particulate wear debris influences the pathogenesis of aseptic loosening in vivo.

In ten male rats we inserted ceramic ‘drawing-pin’ implants in weight-bearing positions within the right proximal tibia. Two animals were killed 6 weeks after surgery and two more 14 weeks after surgery. The remaining six received intra-articular injections of either high-density polyethylene (4 rats) or saline (2 rats) at 8, 10 and 12 weeks after surgery. These animals were killed two weeks after the last injection.

Histological examination of the bone-implant interface in the control animals showed appositional bone growth around the implant at both 6 and 14 weeks. Polyethylene, but not saline, caused a chronic inflammatory response with numerous foreign-body giant cells in periprosthetic tissues.

Our model of a stable, weight-bearing bone-implant interface provides a simple and reliable system in which to study in vivo the effects of particulate materials used in orthopaedic surgery.

We measured bone mineral density (BMD) in the proximal femur by dual-energy X-ray absorptiometry (DEXA) in 20 patients after cemented total hip arthroplasty over a period of one year. We found a statistically significant reduction in periprosthetic BMD after six months on the medial side and on the lateral side adjacent to the mid and distal thirds of the prosthesis. At one year after operation there was a mean 6.7% reduction in BMD in the region of the calcar and a mean 5.3% increase in BMD in the femoral shaft distal to the tip of the implant. These changes reflect a pattern of reduced stress in the proximal femur and increased stress around the tip of the prosthesis. They support current concepts of bone remodelling in the proximal femur in response to prosthetic implantation.

Dual-energy X-ray absorptiometry (DEXA) is increasingly used to measure changes in bone mineral density (BMD) around femoral prostheses after total hip arthroplasty. We have studied the factors which affect the accuracy of these measurements. The coefficient of variation was < 2% using a hydroxyapatite phantom, 2.7% in an anthropomorphic phantom specimen, and < 1% in repeated measurements on implanted cadaver femora. The precision did not vary with different implant materials or designs. In patients we found a mean precision error of 2.7% to 3.4%. The most significant factor affecting reproducibility was rotation of the femur. We conclude that DEXA is a precise method of measurement for small changes in BMD around femoral implants, but that correct and careful positioning of patients is essential to obtain reliable results.

We investigated in vitro a mechanism by which particulate debris may induce bone resorption and cause implant loosening. We first studied two standard particles: latex, which is considered to be inert, and zymosan, which is inflammatory. Macrophages that phagocytosed either particle became activated, and stimulated 15 times as much bone resorption as did control macrophages. For activation to occur, 100 times more latex than zymosan had to be phagocytosed. We also found that bone cement and polyethylene particles activated macrophages in a similar manner, and that the necessary amounts of these were intermediate between those of latex and zymosan. None of the particles were toxic. It was concluded that implant loosening may result from bone resorption stimulated by mediators released by macrophages that have phagocytosed particles of bone cement or polyethylene.

We compared the mechanical properties of carbon fibre composite bone plates with those of stainless steel and titanium. The composite plates have less stiffness with good fatigue properties. Tissue culture and small animal implantation confirmed the biocompatibility of the material. We also present a preliminary report on the use of the carbon fibre composite plates in 40 forearm fractures. All fractures united, 67% of them showing radiological remodelling within six months. There were no refractures or mechanical failures, but five fractures showed an unexpected reaction; this is discussed.

We investigated the possibility that the macrophages which are seen around implants may stimulate bone resorption and cause loosening. We found that macrophages release mediators that stimulate bone resorption, and that the amount of resorption increased by between 2.5 and 10 times when the macrophages adhered to a foreign surface. This bone resorption depended on the surface energy and roughness of the foreign surface, varying with these physical properties rather than with the chemical nature of the material. It is concluded that loosening of orthopaedic implants is likely to be influenced by the surface energy and roughness of the implant.

Osteonecrosis of the femoral head is a severely disabling complication of steroid immunosuppression in renal transplant patients. We report 31 total hip arthroplasties in 21 renal transplant recipients with an average follow-up of six years. There were no problems with wound healing or infection despite full immunosuppression. Four hips developed symptomatic loosening but the other results were excellent, comparing well with other methods of treatment for osteonecrosis. Ten patients died during the follow-up period. Total hip replacement is a safe and effective treatment for transplant recipients and, in view of their limited life expectancy, should be considered at an early stage in their treatment.

A prospective study was made over a three-year period of 900 consecutive unilateral Colles' fractures. The radiographic features at the time of fracture, after reduction and one week later were measured and correlated with grip strength and range of movement at three years. The most significant radiographic feature to influence the outcome was the presence of shortening of the radius one week after reduction of the fracture. Persistent dorsal tilt, radiocarpal joint involvement and ulnar styloid fracture were each associated with reduced range of movement, but had no effect on grip strength. Extension of the fracture into the distal radio-ulnar joint was associated with reduced grip strength but had no effect on range of movement. Radial tilt of the radial fragment did not correlate with any aspect of the result after three years.

Thirty-nine patients underwent reconstruction of the anterior cruciate ligament with carbon-fibre and a MacIntosh repair; all had a negative pivot shift test after operation. Some patients had persistent pain, mild effusion and synovial thickening; in 10 of these patients the symptoms warranted arthroscopic examination and biopsy at a mean of 16.9 months after the repair. Arthroscopy revealed that the carbon-fibre had not induced the formation of a "new ligament" and that the repair was merely covered by a thin, fibrous sheath. Histological investigations confirmed this finding, with only a suggestion of a fibroblastic response to carbon-fibre found in two patients. Particles of carbon-fibre were found scattered through the knees. Synovitis and breakdown of the skin over subcutaneous carbon-fibre complicated treatment. Failure of the carbon-fibre to bond to bone was detected radiographically.