Maximizing bone formation in posterior spine fusion using rhBMP-2 and zoledronic acid in wild type and NF1 deficient mice.

Spinal pseudarthrosis is a well described complication of spine fusion surgery in NF1 patients. Reduced bone formation and excessive resorption have been described in NF1 and anti-resorptive agents may be advantageous in these individuals. In this study, 16 wild type and 16 Nf1(+/-) mice were subjected to posterolateral fusion using collagen sponges containing 5 µg rhBMP-2 introduced bilaterally. Mice were dosed twice weekly with 0.02 mg/kg zoledronic acid (ZA) or sterile saline. The fusion mass was assessed for bone volume (BV) and bone mineral density (BMD) by microCT. Co-treatment using rhBMP-2 and ZA produced a significant increase (p < 0.01) in BV of the fusion mass compared to rhBMP-2 alone in both wild type mice (+229%) and Nf1(+/-) mice (+174%). Co-treatment also produced a significantly higher total BMD of the fusion mass compared to rhBMP-2 alone in both groups (p < 0.01). Despite these gains with anti-resorptive treatment, Nf1(+/-) deficient mice still generated less bone than wild type controls. TRAP staining on histological sections indicated an increased osteoclast surface/bone surface (Oc.S/BS) in Nf1(+/-) mice relative to wild type mice, and this was reduced with ZA treatment.

Posterolateral inter-transverse lumbar fusion in a mouse model.

BACKGROUND: Spinal fusion is a common orthopaedic procedure that has been previously modeled using canine, lapine, and rodent subjects. Despite the increasing availability of genetically modified mouse strains, murine models have only been infrequently described. PURPOSE: To present an efficient and minimally traumatic procedure for achieving spinal fusion in a mouse model and determine the optimal rhBMP-2 dose to achieve sufficient fusion mass. METHOD: MicroCT reconstructions of the unfused mouse spine and human spine were compared to design a surgical approach. In phase 1, posterolateral lumbar spine fusion in the mouse was evaluated using 18 animals allocated to three experimental groups. Group 1 received decortication only (n=3), Group 2 received 10 µg rhBMP-2 in a collagen sponge bilaterally (n=6), and Group 3 received 10 µg rhBMP-2 + decortication (n=9). The surgical technique was assessed for intra-operative safety, efficacy, access and reproducibility. Spines were harvested for analysis at 3 weeks (Groups 1, 2) and 1, 2, and 3 weeks (Group 3). In phase 2, a dose response study was carried out in an additional 18 animals with C57BL6 mice receiving sponges containing 0, 0.5, 1, 2.5, 5 µg of rhBMP-2 per sponge bilaterally. RESULTS: The operative procedure via midline access was rapid and reproducible, and fusion of the murine articular processes was found to be analogous to the human procedure. Unlike reports from other species, decortication alone (Group 1) yielded no new bone formation. Addition of rhBMP-2 (Groups 2 and 3) yielded a significant bone mass that bridged the L4-L6 vertebrae. The subsequent dose response experiment revealed that 0.5 µg rhBMP-2 per sponge was sufficient to create a fusion mass. CONCLUSION: We describe a new approach for mouse lumbar spine fusion that is safe, efficient, and highly reproducible. The technique we employed is analogous to the human midline procedure and may be highly suitable for genetically modified mouse models.

Muscle strength, gait, and balance in 20 patients with hip osteoarthritis followed for 2 years after THA.

BACKGROUND: Patients with hip osteoarthritis (OA) have muscular weakness, impaired balance, and limp. Deficits in the different limb muscles and their recovery courses are largely unknown, however. We hypothesized that there is persisting muscular weakness in lower limb muscles and an impaired balance and gait 2 years after THA. PATIENTS AND METHODS: 20 elderly patients with unilateral OA were assessed before, and 6 and 24 months after surgery for maximal voluntary isometric strength of hip and knee muscles and by gait analysis, postural stability, and clinical scores (HHS, SF-36, EuroQoL). RESULTS: Hip muscles showed a remaining 6% weakness compared to the contralateral healthy limb 2 years after THA. Preoperatively and 6 months postoperatively, that deficit was 18% and 12%, respectively. Knee extensors fully recovered a preoperative 27% deficit after 2 years. Gait analysis demonstrated a shorter single stance phase for the OA limb compared to healthy limb preoperatively, that had already recovered at the 6-month follow-up. Balance of two-foot standing showed improvement in both sagittal and lateral sway after operation. All clinical scores improved. INTERPRETATION: Muscle strength data demonstrated a slow but full recovery of muscles acting about the knee, but there was still a deficit in hip muscle strength 2 years after THA. Gait and balance recovered after the operation. To accelerate improvement in muscular strength after THA, postoperative training should probably be more intense and target hip abductors.

Reduced muscle radiological density, cross-sectional area, and strength of major hip and knee muscles in 22 patients with hip osteoarthritis.

BACKGROUND: Patients with hip osteoarthritis (OA) typically suffer joint pain, and often experience muscular weakness. We hypothesized that substantial atrophy would manifest in multiple muscle groups along the affected limb, resulting in severe muscle dysfunction. PATIENTS AND METHODS: We assessed 22 elderly patients with unilateral OA for maximal voluntary isometric strength of hip and knee muscles using a dynamometer that was developed for the purpose. Cross-sectional area (CSA) and radiological density (RD; in Hounsfield units: HU) of hip and knee muscles were assessed using CT. We determined SF-36, HHS, and EQ-5D. RESULTS: Hip extension, flexion, adduction, abduction, and knee extension strength were reduced (11- 29%; p < 0.01) in the OA limb relative to the healthy limb. Muscle CSA of hip extensors, flexors, adductors, knee extensors and flexors, but not hip abductors, was reduced (11-19%; p < 0.01) in the OA limb, where RD of all muscle groups except hip flexors was reduced (5-15 HU; p < 0.01). The clinical scores confirmed impairment. INTERPRETATION: Major muscles functioning around the hip and knee showed substantial loss of strength and mass, which contributes to the reduced ambulatory capacity of OA patients. Reduced muscle CSA could not fully explain the loss in strength. Infiltration with fat or other non-contractile components, as indicated by a reduced RD, in OA limb muscles was substantial.

Test methods to detect hip and knee muscle weakness and gait disturbance in patients with hip osteoarthritis.

OBJECTIVE: To evaluate test methods for hip and knee muscle weakness and gait disturbance. DESIGN: Test-retest. SETTING: Orthopedic university clinic. PARTICIPANTS: Ten young (age, 36+/-6 y) and 13 elderly (age, 69+/-8 y) healthy volunteers and 11 patients (age, 69+/-8 y) with unilateral hip osteoarthritis (OA) were tested for muscular strength. Twenty-five volunteers (age, 42+/-14 y) underwent gait analysis. INTERVENTIONS: A dynamometer assessing maximal voluntary isometric force of hip and knee muscles and an optosensor walkway detecting limp were developed. Tests evaluated reproducibility and tolerance in patients with OA and elderly subjects. MAIN OUTCOME MEASURES: Relative coefficient of variation (CV%) and force (in newtons). RESULTS: CV% for unilateral strength measurements ranged from 7% to 12% for specific muscle groups. CV% for gait parameters ranged from 4% to 8%, except for the double-support phase. Tests were well tolerated, and no patient had to discontinue because of fatigue. Differences related to sex, age, and disease were detected. CONCLUSIONS: Our dynamometer system provides reliable measurements of hip and knee muscle strength in young and old people, and variation is comparable to previous data. Our photocell technique for gait analysis is reliable in people with normal gait. Both methods are attractive because they are affordable, nonstationary, and easy to use.