Brett Nemke

Effect of analgesic therapy on clinical outcome measures in a randomized controlled trial using client-owned dogs with hip osteoarthritis

BackgroundPain and impaired mobility because of osteoarthritis (OA) is common in dogs and humans. Efficacy studies of analgesic drug treatment of dogs with naturally occurring OA may be challenging, as a caregiver placebo effect is typically evident. However, little is known about effect sizes of common outcome-measures in canine clinical trials evaluating treatment of OA pain. Forty-nine client-owned dogs with hip OA were enrolled in a randomized, double-blinded placebo-controlled prospective trial. After a 1 week baseline period, dogs were randomly assigned to a treatment (ABT-116 – transient receptor potential vanilloid 1 (TRPV1) antagonist, Carprofen – non-steroidal anti-inflammatory drug (NSAID), Tramadol - synthetic opiate, or Placebo) for 2 weeks. Outcome-measures included physical examination parameters, owner questionnaire, activity monitoring, gait analysis, and use of rescue medication.ResultsAcute hyperthermia developed after ABT-116 treatment (P < 0.001). Treatment with carprofen (P ≤ 0.01) and tramadol (P ≤ 0.001) led to improved mobility assessed by owner questionnaire. Nighttime activity was increased after ABT-116 treatment (P = 0.01). Kinetic gait analysis did not reveal significant treatment effects. Use of rescue treatment decreased with treatment in the ABT-116 and Carprofen groups (P < 0.001). Questionnaire score and activity count at the end of treatment were correlated with age, clinical severity at trial entry, and outcome measure baseline status (SR ≥ ±0.40, P ≤ 0.005). Placebo treatment effects were evident with all variables studied.ConclusionTreatment of hip OA in client-owned dogs is associated with a placebo effect for all variables that are commonly used for efficacy studies of analgesic drugs. This likely reflects caregiver bias or the phenomenon of regression to the mean. In the present study, outcome measures with significant effects also varied between groups, highlighting the value of using multiple outcome measures, as well as an a priori analysis of effect size associated with each measure. Effect size data from the present study could be used to inform design of future trials studying analgesic treatment of canine OA. Our results suggest that analgesic treatment with ABT-116 is not as effective as carprofen or tramadol for treatment of hip arthritis pain in client-owned dogs.

Coating with a Modular Bone Morphogenetic Peptide Promotes Healing of a Bone-Implant Gap in an Ovine Model

Despite the potential for growth factor delivery strategies to promote orthopedic implant healing, there is a need for growth factor delivery methods that are controllable and amenable to clinical translation. We have developed a modular bone growth factor, herein termed “modular bone morphogenetic peptide (mBMP)”, which was designed to efficiently bind to the surface of orthopedic implants and also stimulate new bone formation. The purpose of this study was to coat a hydroxyapatite-titanium implant with mBMP and evaluate bone healing across a bone-implant gap in the sheep femoral condyle. The mBMP molecules efficiently bound to a hydroxyapatite-titanium implant and 64% of the initially bound mBMP molecules were released in a sustained manner over 28 days. The results demonstrated that the mBMP-coated implant group had significantly more mineralized bone filling in the implant-bone gap than the control group in C-arm computed tomography (DynaCT) scanning (25% more), histological (35% more) and microradiographic images (50% more). Push-out stiffness of the mBMP group was nearly 40% greater than that of control group whereas peak force did not show a significant difference. The results of this study demonstrated that mBMP coated on a hydroxyapatite-titanium implant stimulates new bone formation and may be useful to improve implant fixation in total joint arthroplasty applications.

Acceleration of second and fourth metatarsal fracture healing with recombinant human bone morphogenetic protein-2/calcium phosphate cement in horses.

OBJECTIVE To compare the efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2)/calcium phosphate (CP) to autogenous cancellous bone graft (CBG) and to no treatment on bone healing, in surgically induced osteotomies and ostectomies of the accessory metatarsal bones in an equine model. STUDY DESIGN Experimental. ANIMALS Adult horses (n=9). METHODS Segmental ostectomies of the second metatarsal bone (MT2) and osteotomies of the fourth metatarsal bone (MT4) were performed bilaterally in 9 horses. There were a total of 35 defects (1 MT4 was previously fractured) created and supplemented randomly either with no treatment (untreated control), rhBMP-2/CP cement, or matrix (CPC or CPM), or CBG. Radiography was performed every 2 weeks until study endpoint at 12 weeks. After euthanasia, bone healing was evaluated using radiography, mechanical testing, and histology. Data were analyzed with ANOVA followed by the Duncans Multiple Range Test or nonparametric analyses. RESULTS At 12 weeks, radiographic scores for union were significantly greater for the rhBMP-2 (P<.0001) and CBG (P=.004) groups compared with the untreated control group, for both MT2 ostectomies and MT4 osteotomies. The rhBMP-2 treated MT2 had greater maximum torque to failure in torsion than CBG and control limbs at 12 weeks (P=.011). Histologic analysis demonstrated increased bone formation and more mature bone at the ostectomy site for MT2 in the rhBMP-2 and CBG groups compared with the untreated control group. CONCLUSION Injection of rhBMP-2/CP into surgically induced ostectomies and osteotomies of the accessory metatarsal bones might accelerate early bone healing in the horse. CLINICAL RELEVANCE RhBMP-2/CP may be as effective if not superior to CBG as an adjuvant treatment to accelerate healing of bone defects.

The Effect of Early Hyaluronic Acid Delivery on the Development of an Acute Articular Cartilage Lesion in a Sheep Model

Background Partial-thickness articular cartilage lesions occur with knee trauma and may progress to osteoarthritis. This study evaluates the effectiveness of hyaluronic acid on cartilage healing after acute knee injury in sheep. Hypothesis Early administration of hyaluronic acid to an acute cartilage injury will prevent chondrocyte death and improve cartilage metabolism. Study Design Controlled laboratory study. Methods A 10 × 10 mm partial-thickness articular cartilage lesion was created on the medial condyle of 16 adult sheep stifles (hindlimbs). Eight sheep received intra-articular hyaluronic acid injections at days 0, 8, and 15, and 8 controls received saline. Contralateral stifles were nonoperated controls. All sheep were sacrificed at 12 weeks after surgery. Synovial fluid was drawn before surgery and after euthanasia for collagen II, nitric oxide, and interleukin-1 beta analysis. The medial condyle was analyzed by gross appearance, confocal laser microscopy for cell viability, histologic analysis for cartilage morphology, and dimethylmethylene blue assay for proteoglycan. Results At 12 weeks, histologic analysis revealed that the hyaluronic acid group had significantly better scores than the saline group (P = .001). The hyaluronic acid group had significantly greater glycosaminoglycan content than the saline group (P = .011), and showed a trend of reduced chondrocyte death compared with the saline group (P = .07). Synovial fluid showed no significant differences between the groups in collagen II, nitric oxide, and interleukin-1 beta levels. Conclusion The results demonstrated that early administration of hyaluronic acid shows a significant improvement in cartilage histologic analysis and increased glycosaminoglycan content after acute traumatic cartilage injury. Clinical Relevance Early hyaluronic acid treatment for acute partial-thickness articular cartilage lesions may decrease or delay articular degeneration.

Micropore-induced capillarity enhances bone distribution in vivo in biphasic calcium phosphate scaffolds

UNLABELLED The increasing demand for bone repair solutions calls for the development of efficacious bone scaffolds. Biphasic calcium phosphate (BCP) scaffolds with both macropores and micropores (MP) have improved healing compared to those with macropores and no micropores (NMP), but the role of micropores is unclear. Here, we evaluate capillarity induced by micropores as a mechanism that can affect bone growth in vivo. Three groups of cylindrical scaffolds were implanted in pig mandibles for three weeks: MP were implanted either dry (MP-Dry), or after submersion in phosphate buffered saline, which fills pores with fluid and therefore suppresses micropore-induced capillarity (MP-Wet); NMP were implanted dry. The amount and distribution of bone in the scaffolds were quantified using micro-computed tomography. MP-Dry had a more homogeneous bone distribution than MP-Wet, although the average bone volume fraction, BVF‾, was not significantly different for these two groups (0.45±0.03 and 0.37±0.03, respectively). There was no significant difference in the radial bone distribution of NMP and MP-Wet, but the BVF‾, of NMP was significantly lower among the three groups (0.25±0.02). These results suggest that micropore-induced capillarity enhances bone regeneration by improving the homogeneity of bone distribution in BCP scaffolds. The explicit design and use of capillarity in bone scaffolds may lead to more effective treatments of large and complex bone defects. STATEMENT OF SIGNIFICANCE The increasing demand for bone repair calls for more efficacious bone scaffolds and calcium phosphate-based materials are considered suitable for this application. Macropores (>100μm) are necessary for bone ingrowth and vascularization. However, studies have shown that microporosity (<20μm) also enhances growth, but there is no consensus on the controlling mechanisms. In previous in vitro work, we suggested that micropore-induced capillarity had the potential to enhance bone growth in vivo. This work illustrates the positive effects of capillarity on bone regeneration in vivo; it demonstrates that micropore-induced capillarity significantly enhances the bone distribution in the scaffold. The results will impact the design of scaffolds to better exploit capillarity and improve treatments for large and load-bearing bone defects.

Comparison of a New Braid Fixation System to an Interlocking Intramedullary Nail for Tibial Osteotomy Repair in an Ovine Model

OBJECTIVES To compare bone healing of tibial osteotomy repaired with Nitinol wire braid and hardened steel rods (Braid system) and polymethylmethacrylate bone cement with an interlocking intramedullary (IM) nail fixation in an ovine model. STUDY DESIGN In vitro and in vivo experimental study. ANIMALS Adult female sheep (n=22). METHODS Using sheep tibia, a middiaphyseal transverse osteotomy was performed in the right tibia, which were then randomly assigned to the Braid system group or IM nail group (n=5). The left tibia were used as controls. The torsional properties of tibial constructs were compared. The study was repeated in vivo in 12 sheep and mechanical properties and bone healing were evaluated at 12 weeks. RESULTS In vitro, there was no significant difference in torsional stiffness between the groups. In vivo, operative time for the Braid system group was significantly shorter than the IM nail group. At 12 weeks, there were no significant differences in maximum torque and torsional stiffness between IM nail and Braid system groups nor were there significant radiographic or histologic differences between the groups. CONCLUSIONS The Braid system might decrease operative time for repair of transverse middiaphyseal tibial fractures and result in similar bone healing at 12 weeks after surgery compared with an interlocking IM nail repair. CLINICAL RELEVANCE A Nitinol Braid system may be a treatment option for transverse midshaft tibial fractures.

Guided growth of the proximal femur: a pilot study in the lamb model.

Background The concept of guided growth has been used for decades in the lower extremities of children, but has not been applied to correct varus or valgus deformity in the hip, such as those that occur in children with cerebral palsy or developmental dysplasia of the hip. The purpose of this study is to determine whether guided growth techniques are effective at altering the morphology of the proximal femur in a lamb model. Methods Ten, 2-month-old mixed-breed male lambs underwent hemiepiphyseal drilling and screw placement. Drilling occurred eccentrically (inferiorly) in an attempt to close only a portion of the growth plate. In 5 lambs, a sham surgery was performed in which the screw did not cross the proximal femoral physis. Growth was compared between groups and with the opposite hip in which no procedure was performed in both groups. Standardized radiographs were obtained preoperatively and monthly. A 3-dimensional computed tomography scan and standard histology were obtained postnecropsy. Version and neck shaft angle (NSA) was determined and recorded at the time of the index procedure with the aid of fluoroscopy. Radiographs were assessed by measurement of the NSA and the articular trochanteric distance (ATD). Results were compared by using the t test: paired 2 sample for means. Results The NSA and ATD were compared preoperatively and at a mean of 3.3 months after surgery. They were no significant differences preoperatively between the screw or sham group. Postoperatively, the NSA was 132 versus 143 (P=0.006) and the ATD −0.6 mm versus 10 mm (P=0.033) for the screw and sham hips, respectively. The sham group showed no statistical differences between the operative and nonoperative sides postoperatively, although the ATD trended toward a larger number on the “sham” side, possibly because of a growth stimulation effect. Conclusions Screw hemiepiphysiodesis seems to alter the growth of the proximal femur in the lamb model. Significance Further studies are ongoing and with more research this technique could be used to correct or prevent proximal femoral deformity in the growing child. Level of Evidence Level II.

Variance associated with subject velocity and trial repetition during force platform gait analysis in a heterogeneous population of clinically normal dogs.

Factors that contribute to variance in ground reaction forces (GRF) include dog morphology, velocity, and trial repetition. Narrow velocity ranges are recommended to minimize variance. In a heterogeneous population of clinically normal dogs, it was hypothesized that the dog subject effect would account for the majority of variance in peak vertical force (PVF) and vertical impulse (VI) at a trotting gait, and that narrow velocity ranges would be associated with less variance. Data from 20 normal dogs were obtained. Each dog was trotted across a force platform at its habitual velocity, with controlled acceleration (±0.5 m/s(2)). Variance effects from 12 trotting velocity ranges were examined using repeated-measures analysis-of-covariance. Significance was set at P <0.05. Mean dog bodyweight was 28.4 ± 7.4 kg. Individual dog and velocity significantly affected PVF and VI for thoracic and pelvic limbs (P <0.001). Trial number significantly affected thoracic limb PVF (P <0.001). Limb (left or right) significantly affected thoracic limb VI (P = 0.02). The magnitude of variance effects from largest to smallest was dog, velocity, trial repetition, and limb. Velocity ranges of 1.5-2.0 m/s, 1.8-2.2 m/s, and 1.9-2.2 m/s were associated with low variance and no significant effects on thoracic or pelvic limb PVF and VI. A combination of these ranges, 1.5-2.2 m/s, captured a large percentage of trials per dog (84.2 ± 21.4%) with no significant effects on thoracic or pelvic limb PVF or VI. It was concluded that wider velocity ranges facilitate capture of valid trials with little to no effect on GRF in normal trotting dogs. This concept is important for clinical trial design.

Comparison of Single-Versus Double-Tunnel Tendon-to-Bone Healing in an Ovine Model A Biomechanical and Histological Analysis

Background The double-bundle technique has recently gained much interest in ligament reconstruction. In addition to potential kinematic advantages, perhaps double tunnels have the potential for faster and more secure tendon-to-bone healing. Hypothesis Placement of tendons in 2 osseous tunnels, as opposed to 1, will enhance tendon fixation as determined biomechanically and histologically. Study Design Controlled laboratory study. Methods Fourteen sheep were used, and an extra-articular tendon graft reconstruction was performed on both knees of each sheep. In 1 randomly selected knee, the long digital extensor tendon was released from the femur and placed into a single tunnel in the proximal tibia. In the contralateral knee, the tendon was split and placed into 2 tibial tunnels. Ten sheep were analyzed by mechanical testing, and the remaining 4 were subjected to histologic evaluation at 6 weeks after surgery. Paired t tests were used for statistical analysis. Results Mechanical testing demonstrated that the peak load (981.8 ± 143.2 N, mean ± SD) and stiffness (570.9 ± 114.6 N/mm) at 6 weeks after surgery in the double-tunnel group were significantly greater than for the single-tunnel group (714.8 ± 94.2 N and 432.2 ± 56.7 N/mm, respectively; load, P =. 007; stiffness, P =. 03). Histologic analysis suggested similar tendon-to-bone healing for both groups. Conclusion This study demonstrated enhanced biomechanical fixation of the tendon to the surrounding bone in the double-tunnel compared with the single-tunnel technique in this ovine model. Clinical Relevance The double-tunnel technique may provide better fixation and healing in human ligament reconstruction.

Variance associated with the use of relative velocity for force platform gait analysis in a heterogeneous population of clinically normal dogs

Factors that contribute to variance in ground reaction forces (GRFs) include dog morphology, velocity, and trial repetition. Narrow velocity ranges are recommended to minimize variance. In a heterogeneous population, it may be preferable to minimize data variance and efficiently perform force platform gait analysis by evaluation of each individual dog at its preferred velocity, such that dogs are studied at a similar relative velocity (V*). Data from 27 normal dogs were obtained including withers and shoulder height. Each dog was trotted across a force platform at its preferred velocity, with controlled acceleration (±0.5 m/s(2)). V* ranges were created for withers and shoulder height. Variance effects from 12 trotting velocity ranges and associated V* ranges were examined using repeated-measures analysis-of-covariance. Mean bodyweight was 24.4 ± 7.4 kg. Individual dog, velocity, and V* significantly influenced GRF (P <0.001). Trial number significantly influenced thoracic limb peak vertical force (PVF) (P <0.001). Limb effects were not significant. The magnitude of variance effects was greatest for the dog effect. Withers height V* was associated with small GRF variance. Narrow velocity ranges typically captured a smaller percentage of trials and were not consistently associated with lower variance. The withers height V* range of 0.6-1.05 captured the largest proportion of trials (95.9 ± 5.9%) with no significant effects on PVF and vertical impulse. The use of individual velocity ranges derived from a withers height V* range of 0.6-1.05 will account for population heterogeneity while minimizing exacerbation of lameness in clinical trials studying lame dogs by efficient capture of valid trials.