Changes in cross-sectional geometry of the distal femoral metaphysis associated with inflammatory arthritis are reduced by a bisphosphonate (zoledronate).

An increased risk of fracture is a feature of rheumatoid arthritis and of animal models of inflammatory arthritis. We examined geometrical changes in the metaphyseal cortex of the distal femur in an animal model of inflammatory arthritis. Additionally, we examined the effect of a bisphosphonate in preventing these changes. Five groups of rabbits were studied: normal controls, those with inflammatory arthritis, and three groups with arthritis treated with bisphosphonate. To determine geometrical properties, image analysis was performed on digitized cross sections of the femoral metaphyseal cortices. The results demonstrated that the posterior cortical wall was significantly less thick in rabbits with arthritis than in normal rabbits and in the rabbits in the three bisphosphonate treatment groups (p < 0.05). Moment of inertia about the lateral-medial axis was reduced in rabbits with arthritis compared with normal rabbits (p < 0.05). Cross-sectional area was not significantly different between groups. The changes suggest a mechanism of weakening of bone in arthritis; when the results are coupled with results of previous porosity studies, severe directional weakness is apparent. Bisphosphonate was effective in preserving bone integrity in inflammatory arthritis.

Carrageenan-induced arthritis in the rat.

This study documents a model of carrageenan-induced chronic inflammatory arthritis in the rat, using quantitative histomorphometric assessment. Ten Sprague-Dawley female rats were randomly assigned to one of two groups. Arthritis was induced in the right tibiofemoral joint by 7 intra-articular injections of 0.02 mL of 1% carrageenan in the arthritic group over 24 days. The control (normal) group was injected with 0.02 mL of saline in the right tibiofemoral joint. Sagittal sections of the right knee joint (distal femur and proximal tibia) were assessed by histomorphometry using the LECO 2001 image analysis system. Articular cartilage thickness, epiphyseal plate thickness, subchondral bone plate thickness, trabecular bone volume and thickness of the synovial lining cell layer were measured. Differences between normal and arthritic groups were statistically significant for articular cartilage thickness of the femur, epiphyseal plate thickness of both the femur and tibia, subchondral bone plate thickness of the tibia and the thickness of the synovial lining cell layer. These findings demonstrate that carrageenan-induced arthritic changes are similar to other, established models of arthritis in the rat.

Pamidronate prevents bone loss associated with carrageenan arthritis by reducing resorptive activity but not recruitment of osteoclasts.

Carrageenan arthritis is associated with high-turnover bone loss. We sought to determine whether the bisphosphonate pamidronate can modify this effect of inflammatory arthritis. Sixty mature, New Zealand White rabbits were randomly assigned to five groups: normal; normal with a therapeutic dose of pamidronate (300 microg/kg/day, administered subcutaneously); arthritis (induced in the right tibiofemoral joint with 10 intraarticular carrageenan injections); arthritis with a therapeutic dose of pamidronate (300 microg/kg/day, subcutaneous); and arthritis with a low dose of pamidronate (7.5 microg/kg/day, subcutaneous). All animals received the fluorochrome calcein green (0.5 g/l/day) in drinking water ad libitum from days 21 to 49. Undecalcified, transverse sections of the distal femur were photographed or imaged to determine bone volume; new bone volume; resting, eroded, osteoid, and osteoblast perimeters; and osteoclast number. Results were evaluated with analysis of variance and pairwise Bonferroni's tests. In trabecular bone adjacent to the joint affected by carrageenan arthritis, resting perimeter was substantially reduced compared with normal joints, and primary indices of osteoblast and osteoclast activity were abnormally high (p < 0.001). Daily treatment with a therapeutic dose of pamidronate (300 microg/kg/day, subcutaneous) during the induction of arthritis significantly decreased new bone volume, osteoid perimeter, and osteoblast perimeter compared with the untreated arthritis group (p < 0.001). Osteoclast number and eroded perimeter remained abnormally high despite treatment with pamidronate. The concomitant increase of bone volume and these osteoclast indices show that pamidronate prevents bone loss in this model of experimental inflammatory arthritis by inhibiting the resorptive activity, but not the formation or recruitment, of osteoclasts. These findings are relevant to the use of bisphosphonates in the treatment of rheumatoid arthritis.

Bone abnormalities in the surgical treatment of patients with rheumatoid arthritis.

Profound abnormalities of bone are an important component of the morbidity of rheumatoid arthritis and partly determine the orthopaedic treatment of patients. The principal bone abnormality, which is osteoporosis associated with rapid remodeling, degrades the mechanical properties of the skeleton in juxtaarticular bone, in the diaphyses of long bones, in the pelvis, and in the base of skull. Abnormalities of bone affect clinical decision making in the surgical treatment of patients with rheumatoid arthritis and must be considered for the optimal treatment of these patients. Increased fracture risk and compromised bony fixation complicate fracture treatment. Techniques of surgery must be modified to protect bone from intraoperative fracture. Methods of fixation of implants and other devices must be appropriate to the biomechanics of the bone. Bone healing usually is rapid if not compromised by mechanical instability. Specific patterns of bone deformation and failure can be identified in the evolution of rheumatoid arthritis. Bone graft used in reconstruction of the protruded acetabulum is incorporated rapidly. Bone resorption with joint instability is a common feature of rheumatoid arthritis; however, the opposite pattern of bony ankylosis with stiffness is observed in a smaller percentage of patients. Recognition of the tissue type is necessary for the individualization of surgical procedures to achieve optimal joint stability and mobility. Based on growing understanding of the pathophysiology of bone in patients with rheumatoid arthritis, new pharmacologic therapies may become available for the prevention and treatment of bone abnormalities in patients with rheumatoid arthritis.

Fractal dimension as a measure of altered trabecular bone in experimental inflammatory arthritis.

Our previous studies in experimental inflammatory arthritis (EIA) and in human rheumatoid arthritis demonstrated rapid remodeling with a 5-fold increase in bone resorption and bone formation. Normal condylar trabecular bone is typically anisotropic, with its orientation along lines of stress; rapid remodeling in a pathological state could disturb the usual order of trabeculae. This study assessed change in the structure of trabecular bone of the distal femoral epiphysis after induction of EIA, using a measure of "fractal dimension," which may be considered a quantitative description of the degree of irregularity of complex surfaces. Data was obtained from specimens in which EIA had been induced in the rabbit knee by 10 injections of carrageenan over 49 days. Photographic enlargements of embedded undecalcified cross-sections of the distal femur were digitized, and software written on a Sun workstation was used to define repeatable regions of interest (ROIs) in the images. The ROIs were subjected to fractal analysis by a power law method. The fractal dimension of the trabecular bone pattern within the ROI was estimated by fitting an equation of the form A (epsilon) = lambda epsilon (2-D) to the data. In this equation, A (epsilon) is the area of the "surface" formed by modeling the ROI data as a three-dimensional structure with the grey-level magnitude providing the third dimension, lambda is a scaling constant, epsilon is the size of the measuring "tool" used to measure the area, and D is the fractal dimension. A Mann-Whitney U-test applied to the average of the data from all ROIs showed that the two distributions of fractal dimension were significantly different (p < 0.005). There were only two overlaps between data points for arthritis (with these values higher) and normal groups (n = 11 for each group). Since Howship's lacunae were too small to be resolved in the system utilized, we consider the difference in fractal dimension to be primarily related to trabecular surface orientation, rather than to the increased number of asperities (resorptive foci) occurring due to increased turnover in bone affected by inflammatory arthritis. The results suggest that fractal dimension may be a useful tool for assessing the degree of structural damage to trabeculae in conditions similar to EIA.

Pharmaceutical services in the United States Army.

The status of pharmaceutical services in the United States Army is described. The Army Medical Department (AMEDD) has 157 commissioned pharmacy officers and 399 civilian pharmacists working in the United States and overseas. Pharmaceutical services are provided from fixed medical treatment facilities on Army installations and, during war and other field operations, field hospitals. Reductions in personnel and facility closures have helped align the AMEDD with the size of the Army's activeduty force, but there has been only a 15% reduction in the number of eligible beneficiaries. Measures such as the interservice TRICARE program have been implemented to help meet the continued high demand for pharmaceutical services cost-effectively. Army pharmacy is similar to civilian pharmacy, except that Army hospitals often include high-volume outpatient pharmacies not usually found in civilian institutions. Pharmacists are being given direct patient care roles on multidisciplinary teams. Army pharmacists participate in field exercises so that they will be prepared to provide services under combat conditions. The AMEDD trains its own pharmacy technicians in a highly structured 18-week course. A triservice Pharmacoeconomic Center (PEC) has been established with the goal of providing prescribers with the tools for making cost-effective decisions about drug therapy, including a formulary. Army pharmacy officers have broad opportunities to further their education and training. In preparing for the next century, Army pharmacists need to continue to prove their value to the AMEDD, the Army, and the Department of Defense.

Zoledronate (CGP 42'446), a bisphosphonate, protects against metaphyseal intracortical defects in experimental inflammatory arthritis.

This study investigated zoledronate (CGP 42'446), a bisphosphonate, as a potential prophylactic and therapeutic agent against intracortical defects in metaphyseal bone in an experimental model of inflammatory arthritis. Inflammatory arthritis was induced in the right tibiofemoral joint of rabbits by the repeated injection of carrageenan. Three groups of animals were treated with the bisphosphonate daily, beginning at different points after the induction of arthritis. Cross sections of the right distal femoral metaphysis were prepared, and intracortical defects were examined by computerized image analysis. The percentage of total bone area with defects (the ratio of void area to total bone area) was greatly increased in the arthritic group compared with that in the normal group (p < 0.001). In all groups treated with the bisphosphonate, there was a significantly lower percentage of total bone area with defects compared with that in the arthritic group (p < 0.001). Treatment was likewise effective in reducing the zonal (anterior and posterior) predilection for the formation of defects observed in arthritis. Although inflammatory arthritis has a substantial effect in producing intracortical defects in metaphyseal bone, a bisphosphonate, zoledronate, was considerably effective in preventing these changes from occurring.

A cost-effectiveness analysis of typhoid fever vaccines in US military personnel.

Typhoid fever has been a problem for military personnel throughout history. A cost-effectiveness analysis of typhoid fever vaccines from the perspective of the US military was performed. Currently 3 vaccine preparations are available in the US: an oral live Type 21A whole cell vaccine; a single-dose parenteral, cell subunit vaccine; and a 2-dose parenteral heat-phenol killed, whole cell vaccine. This analysis assumed all vaccinees were US military personnel. Two pharmacoeconomic models were developed, one for personnel who have not yet been deployed, and the other for personnel who are deployed to an area endemic for typhoid fever. Drug acquisition, administration, adverse effect and lost work costs, as well as the costs associated with typhoid fever, were included in this analysis. Unique military issues, typhoid fever attack rates, vaccine efficacy, and compliance with each vaccine's dosage regimen were included in this analysis. A sensitivity analysis was performed to test the robustness of the models. Typhoid fever immunisation is not cost-effective for US military personnel unless they are considered imminently deployable or are deployed. The most cost-effective vaccine for US military personnel is the single-dose, cell subunit parenteral vaccine.

Bisphosphonate (pamidronate/APD) prevents arthritis-induced loss of fracture toughness in the rabbit femoral diaphysis.

Patients with rheumatoid and other inflammatory arthritis have an increased risk for fracture. This study was designed to determine the effect of experimental inflammatory arthritis on the material properties (fracture toughness and shear modulus) and structural properties (torque, angular deflection, and absorbed energy) of femoral diaphyseal bone tested in torsion to fracture, as well as the effect on these properties of APD (3-amino-1-hydroxypropylidene-1,1-bisphosphonate), a drug known to block osteoclast activity. Two dose levels were investigated. Experimental inflammatory arthritis was induced by intra-articular injection of carrageenan into the right tibiofemoral joint, given over 7 weeks, in three groups of animals. Simultaneously, daily subcutaneous injections of APD were given to three groups of rabbits. Five groups (12 animals each) were established: normal, arthritis, normal/high dose APD, arthritis/high dose APD, and arthritis/low dose APD. The diaphyses of each excised right femur were loaded to fracture in torsion at an angular deflection rate of 8 degrees/sec. In the arthritis group, the fracture toughness was 39% lower than in the normal group, and the structural properties all were reduced significantly. By contrast, the shear modulus was unaffected by arthritis. In this study, the higher dose level (0.3 mg/kg of body weight) of APD prevented loss of fracture toughness and maintained the structural properties in experimental inflammatory arthritis; the low dose was not effective.