Determining the pharmacologic window of bisphosphonates that mitigates severe injury-induced osteoporosis and muscle calcification, while preserving fracture repair.

Following severe injury, biomineralization is disrupted and limited therapeutic options exist to correct these pathologic changes. This study utilized a clinically relevant murine model of polytrauma including a severe injury with concomitant musculoskeletal injuries to identify when bisphosphonate administration can prevent the paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues, yet not interfere with musculoskeletal repair. INTRODUCTION: Systemic and intrinsic mechanisms in bone and soft tissues help promote biomineralization to the skeleton, while preventing it in soft tissues. However, severe injury can disrupt this homeostatic biomineralization tropism, leading to adverse patient outcomes due to a paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues. There remains a need for therapeutics that restore the natural tropism of biomineralization in severely injured patients. Bisphosphonates can elicit potent effects on biomineralization, though with variable impact on musculoskeletal repair. Thus, a critical clinical question remains as to the optimal time to initiate bisphosphonate therapy in patients following a polytrauma, in which bone and muscle are injured in combination with a severe injury, such as a burn. METHODS: To test the hypothesis that the dichotomous effects of bisphosphonates are dependent upon the time of administration relative to the ongoing biomineralization in reparative bone and soft tissues, this study utilized murine models of isolated injury or polytrauma with a severe injury, in conjunction with sensitive, longitudinal measure of musculoskeletal repair. RESULTS: This study demonstrated that if administered at the time of injury, bisphosphonates prevented severe injury-induced bone loss and soft tissue calcification, but did not interfere with bone repair or remodeling. However, if administered between 7 and 21 days post-injury, bisphosphonates temporally and spatially localized to sites of active biomineralization, leading to impaired fracture callus remodeling and permanence of soft tissue calcification. CONCLUSION: There is a specific pharmacologic window following polytrauma that bisphosphonates can prevent the consequences of dysregulated biomineralization, yet not impair musculoskeletal regeneration.

Inhibition of vascular endothelial growth factor in young adult mice causes low bone blood flow and bone strength with no effect on bone mass in trabecular regions.

OBJECTIVE: To determine the effect of an antibody to vascular endothelial growth factor (VEGF) on bone blood flow, bone strength, and bone mass in the young adult mouse. METHODS: Ten-week-old male BALB/cJ mice were body weight-randomized into either a rodent anti-VEGF monoclonal antibody (anti-VEGF, B20-4.1.1; 5 mg/kg 2×/wk.; n = 12) group or a vehicle (VEH; n = 12) group. After 42 days, mice were evaluated for bone blood flow at the distal femur by 18F-NaF-PET/CT and then necropsied. Samples from trabecular and cortical bone regions were evaluated for bone strength by mechanical testing, bone mass by peripheral quantitative computed tomography (pQCT), and micoarchitecture (MicroCT). Hydration of the whole femur was studied by proton nuclear magnetic resonance relaxometry (1H NMR). RESULTS: Distal femur blood flow was 43% lower in anti-VEGF mice than in VEH mice (p = 0.009). Ultimate load in the lumbar vertebral body was 25% lower in anti-VEGF than in VEH mice (p = 0.013). Bone mineral density (BMD) in the trabecular region of the proximal humeral metaphysis by pQCT, and bone volume fraction and volumetric BMD by MicroCT were the same in the two groups. Volume fraction of bound water (BW) of the whole femur was 14% lower in anti-VEGF than in VEH mice (p = 0.003). Finally, BW, but not cortical tissue mineral density, helped section modulus explain the variance in the ultimate moment experienced by the femur in three-point bending. CONCLUSION: Anti-VEGF caused low bone blood flow and bone strength in trabecular bone regions without influencing BMD and microarchitecture. Low bone strength was also associated with low bone hydration. These data suggest that bone blood flow is a novel bone property that affects bone quality.

Technical note: Recommendations for a standard procedure to assess cortical bone at the tissue-level in vivo using impact microindentation.

Impact microindentation is a novel method for measuring the resistance of cortical bone to indentation in patients. Clinical use of a handheld impact microindentation technique is expanding, highlighting the need to standardize the measurement technique. Here, we describe a detailed standard operation procedure to improve the consistency and comparability of the measurements across centers.

Changes in skeletal collagen cross-links and matrix hydration in high- and low-turnover chronic kidney disease.

UNLABELLED: Chronic kidney disease (CKD) increases fracture risk. The results of this work point to changes in bone collagen and bone hydration as playing a role in bone fragility associated with CKD. INTRODUCTION: Clinical data have documented a clear increase in fracture risk associated with chronic kidney disease (CKD). Preclinical studies have shown reductions in bone mechanical properties although the tissue-level mechanisms for these differences remain unclear. The goal of this study was to assess collagen cross-links and matrix hydration, two variables known to affect mechanical properties, in animals with either high- or low-turnover CKD. METHODS: At 35 weeks of age (>75% reduction in kidney function), the femoral diaphysis of male Cy/+ rats with high or low bone turnover rates, along with normal littermate (NL) controls, were assessed for collagen cross-links (pyridinoline (Pyd), deoxypyridinoline (Dpd), and pentosidine (PE)) using a high-performance liquid chromatography (HPLC) assay as well as pore and bound water per volume (pw and bw) using a (1)H nuclear magnetic resonance (NMR) technique. Material-level biomechanical properties were calculated based on previously published whole bone mechanical tests. RESULTS: Cortical bone from animals with high-turnover disease had lower Pyd and Dpd cross-link levels (-21% each), lower bw (-10%), higher PE (+71%), and higher pw (+46%) compared to NL. Animals with low turnover had higher Dpd, PE (+71%), and bw (+7%) along with lower pw (-60%) compared to NL. Both high- and low-turnover animals had reduced material-level bone toughness compared to NL animals as determined by three-point bending. CONCLUSIONS: These data document an increase in skeletal PE with advanced CKD that is independent of bone turnover rate and inversely related to decline in kidney function. Although hydration changes occur in both high- and low-turnover disease, the data suggest that nonenzymatic collagen cross-links may be a key factor in compromised mechanical properties of CKD.

Total knee replacement with interlocking stems: a preliminary report.

Revision total knee replacements or primary total knee replacements with large amounts of bone loss frequently require long-stemmed prostheses to stabilize the components. The hypothesis of the current study was that long-stemmed prostheses can be fixed with interlocking screws, provide a successful outcome, avoid extensive stress-shielding, and allow easy revision in the future. Ten patients with a minimum 2-year followup were studied. Outcomes were studied preoperatively and postoperatively using the Short Form-12 questionnaires, physical examinations, and radiographs. Complications were recorded. Ability to do activities of daily living, strenuous work, and sedentary work were recorded on a 10-point analog scale. Results indicated that 80% of stems well-fixed as shown on serial radiographs, functional outcome scores postoperatively improved significantly from preoperatively, pain was improved significantly, and positive bone remodeling without stress-shielding was seen in 80% of patients, but 20% had significant stress-shielding in the metaphysis. Complications included two periprosthetic fractures for which the patients did not require revision surgery, and one infection. Long-stemmed total knee components with interlocking fixation seem to be a reasonable alternative when large bone defects exist in the femur or tibia.

Toward standardization of methods of determination of fracture properties of acrylic bone cement and statistical analysis of test results.

A succinct critical review of the literature on the fatigue, fatigue crack propagation, and fracture toughness (herein collectively termed "fracture properties") of acrylic bone cement is presented, whereby it is pointed out that a plethora of test conditions have been used. This situation precludes meaningful interstudy comparisons and mitigates against a definitive delineation of the effect of a named variable on a specified fracture property. A case for standardization of test conditions is thus made, culminating in the presentation of a recommended set of such conditions. In addition, it is shown that many literature parametric studies employed inappropriate statistical methods for performing pairwise comparisons, and all these studies have not addressed the issue of possible interactions between the parameters being investigated. A methodology for addressing these deficiencies is presented in the present report, and its use is illustrated with a set of notional fatigue test results.

A new method of determining the J-integral fracture toughness of very tough polymers: application to ultra high molecular weight polyethylene.

The thrust of the present work was the development of a new modification to the ASTM E813-89 method for determining the J-integral fracture toughness, JIc, of ductile polymers. The advantages and limitations of the modification, vis a vis the ASTM E813-89 and the hysteresis methods, are presented. The modification was then applied to investigate the effect of sterilization method on the JIc of ultra-high-molecular-weight polyethylene (UHMWPE) specimens that were subsequently aged (heated, in a cylindrical pressure vessel, in oxygen gas at 507 kPa and 70 degrees C for 14 d). Relative to the unsterilized material, it was found that gamma-irradiating the polymer leads to a significant drop in its JIc, while sterilization using either ethylene oxide or gas plasma produced no effect on its JIc. The clinical implications of the present results for the in vivo performance of UHMWPE counterfaces, and, hence, hip and knee arthroplasties, are fully discussed.

A methodology for examining the plausibility of accelerated aging protocols for UHMWPE components.

In light of the time-intensive nature of using real-time shelf-aged specimens in research into property changes of ultra-high-molecular-weight polyethylene (UHMWPE), accelerated thermal diffusion oxidative aging (usually referred to as accelerated aging) is frequently resorted to. A number of such aging protocols have been reported in the literature, with various claims for their producing changes in the properties of the polymer being the same as or similar to those seen in real-time shelf-aged samples. The thrust of the present work is the presentation of a methodology for examining such claims. The methodology is applied to six properties (% crystallinity, melting temperature, oxidation index, ultimate tensile strength, ultimate tensile elongation, and tensile toughness) of 4150HP UHMWPE grade, sterilized using six different methods, prior to and following the use of a specific accelerated aging protocol (oxygen gas at 70 degrees C and 507 kPa pressure; 14 d.). These six properties have been identified in the literature as being strongly correlated with the clinical wear of UHMWPE articular components. It is shown that the claim for the protocol used in the present work (in terms of the simulated equivalent shelf aging time) is plausible. It needs to be emphasized, however, that this conclusion is tentative given the paucity of the relevant literature results that are currently available and which are vital to the application of the methodology.

Effect of mixing method on selected properties of acrylic bone cement.

The present study was an investigation of the effect of the method of mixing the constituents of CMW3 bone cement on selected physical and mechanical properties of the fully polymerized cement. Five such methods were used: hand mixing; "active" vacuum mixing; mixing in a machine that allowed simultaneous mechanical mixing and centrifugation; mixing using this machine followed by application of a "passive" vacuum; and application of a passive vacuum followed by mixing in the machine. It was found that the best overall results were obtained from cement that had been mixed using the second and fifth methods and the values of the properties were: density, 1220 to 1246 kg/m3; areal porosity, 0.02 to 7.04%; ultimate compressive strength, 84 to 112 MPa; ultimate compressive strain, 5.1 to 6.4%; and compressive modulus of elasticity, 2249 to 2877 MPa.

Electric cataract: a rare clinical entity.

Bilateral crystalline lens opacities developed in a 39-year-old black male who had been involved in an electrical accident approximately 1 yr before our examination. The anterior subcapsular opacities had feathered edges and a slightly raised center. The typical appearance and progressive course of the opacities, as well as the history, led to the diagnosis of electric cataract.

Pupillary examination.

Examination of the pupils is an essential part of the evaluation of patients in optometric practice. In this article, the normal pupil and pupillary reflexes are reviewed, along with a discussion of anisocoria and specific anomalies of the pupils. Explanation of step by step office examination techniques is presented, as well as a discussion of the pathophysiology of abnormal pupils.