Denosumab significantly increases bone mineral density and reduces bone turnover compared with monthly oral ibandronate and risedronate in postmenopausal women who remained at higher risk for fracture despite previous suboptimal treatment with an oral bisphosphonate.

UNLABELLED: Managing osteoporotic patients suboptimally adherent to bisphosphonates (BPs) is difficult. Such patients who remained at higher risk for fracture (≥1 risk factor) were transitioned to denosumab or a monthly oral BP. Denosumab-treated subjects had significantly greater increases in bone mineral density and decreases in bone turnover in this 12-month study. INTRODUCTION: A clinical need exists to manage patients who are suboptimally adherent to oral BPs and remain at higher risk for fracture. Here, we compare the effects on bone mineral density (BMD) and bone turnover of transitioning such patients to denosumab or monthly oral BP (ibandronate or risedronate). METHODS: In two previous multicenter, open-label studies, postmenopausal women ≥55 years previously treated with, though suboptimally adherent to, a daily or weekly BP were randomized to denosumab 60 mg subcutaneously every 6 months (N = 852) or oral BP 150 mg monthly (N = 851) for 12 months. In this combined post-hoc analysis, a subset of higher risk subjects was identified, and the percentage changes from baseline in BMD and serum C-telopeptide of type I collagen (sCTX-1) were assessed. RESULTS: In the overall population, denosumab was associated with greater gains in BMD at 12 months than monthly oral BP at the total hip, femoral neck, and lumbar spine (p < 0.0001 for all). In higher risk subjects, denosumab led to greater gains in BMD than oral BPs at the total hip (2.2 vs 0.8 %), femoral neck (1.8 vs 0.3 %), and lumbar spine (3.7 vs 1.4 %) (p < 0.0001 for all). Denosumab also led to greater decreases in sCTX-1 in the overall population and higher risk subjects at months 1 and 6 (p < 0.0001 for both). Adverse events and serious adverse events were generally similar between treatment groups. CONCLUSIONS: Transitioning to denosumab was well tolerated and more effective in increasing BMD and reducing bone turnover than cycling to a monthly oral BP treatment in subjects who remained at higher fracture risk despite suboptimal BP treatment.

Repair with collagen tubules linked with brain-derived neurotrophic factor and ciliary neurotrophic factor in a rat sciatic nerve injury model.

OBJECTIVE: To determine if brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) can be successfully delivered to transected and repaired peripheral nerves by cross-linking the factors to collagen tubules (CTs). METHODS: Forty-eight Sprague-Dawley rats underwent left sciatic nerve transection and repair. In the control group, CTs were implanted with no neurotrophic ligand (n=13). There were 3 experimental groups: CT with BDNF covalently linked to the collagen matrix (CT/BDNF; n=12), CT with CNTF covalently linked (CT/CNTF; n=12), and CT with both BDNF and CNTF covalently linked (CT/BDNF/CNTF; n=11). Functional outcome of neural regeneration was assessed every 10 days using walking track analysis, which was submitted to a sciatic functional index. Nerve morphometry, electrophysiologic studies, and molecular analysis for neural proteins were performed at the completion of the study at postoperative day 90. RESULTS: Animals in all 3 experimental groups achieved significantly superior maximal functional recovery, larger nerve cross-sectional areas, and a greater number of axons when compared with the control CT group (P<.001, P<.05, and P<.05, respectively). The animals in the CT/BDNF/CNTF group displayed the best functional recovery and had the largest axon diameters, greatest amplitude, and the fastest nerve conduction velocities. Molecular analysis revealed significant differences in the expression of neurofilament, neural cell adhesion molecule, myelin-associated glycoprotein, and myelin basic protein. CONCLUSIONS: We present the first evidence that CNTF covalently linked to CTs can improve functional recovery compared with CTs alone. We also support the previous finding that BDNF covalently linked to CTs significantly increases the functional recovery of transected and repaired nerves. Finally, we found that cotreatment produced the best functional recovery in our model.

Functional recovery following nerve injury and repair by silicon tubulization: comparison of laminin-fibronectin, dialyzed plasma, collagen gel, and phosphate buffered solution.

PURPOSE: This study was designed to investigate the potential for enhancement of peripheral nerve regeneration by the manipulation of the neural microenvironment with laminin-fibronectin solution (LF), dialyzed plasma (DP), collagen gel (CG), or phosphate buffered saline (PBS) in a silicon tubulization repair model. METHOD: A rat sciatic nerve model of injury and repair was used to study the effects of exogenous matrix precursors (contained in LF or DP), CG or PBS on nerve regeneration. A total of 50 Sprague-Dawley rats underwent left sciatic nerve transection and repair by silicon tubulization. The silicon tubules were either left empty (E), or filled with solutions of LF, DP, CG, or PBS. Nerve function was assessed preoperatively and then postoperatively, every 10 days for 90 days using sciatic functional indexes (SFI). On postoperative day 90, the sciatic nerves were harvested for histologic analysis and the posterior compartment muscles of each animal were harvested and weighed. Molecular analysis for two proteins associated with neural regeneration was performed on the nerve segments. RESULTS: All five animal groups demonstrated equivalent functional recovery. Comparison of the rate of recovery and mean maximal recovery between each group revealed no statistically significant differences, with P-values ranging from 0.30 to 0.95. Posterior compartment muscle masses were similar in all groups except for LF, whose animals had muscle masses 8-9% lower than CG, PBS, or E (P < 0.05). CONCLUSION: Alteration of the regenerating neural microenvironment with exogenous matrix precursors (LF, DP), CG or PBS failed to improve sciatic functional recovery after nerve transection and silicon tubulization in this model. From this study, we conclude that LF, DP, CG, and PBS do not enhance the rate or degree of recovery of peripheral nerve function across a narrow gap when nerves are repaired by silicon tubulization.

Denosumab compared with risedronate in postmenopausal women suboptimally adherent to alendronate therapy: efficacy and safety results from a randomized open-label study.

Denosumab has been shown to reduce new vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis. In subjects who were treatment-naïve or previously treated with alendronate, denosumab was associated with greater gains in bone mineral density (BMD) and decreases in bone turnover markers when compared with alendronate-treated subjects. This trial was designed to compare the efficacy and safety of denosumab with risedronate over 12 months in postmenopausal women who transitioned from daily or weekly alendronate treatment and were considered to be suboptimally adherent to therapy. In this randomized, open-label study, postmenopausal women aged ≥55 years received denosumab 60 mg subcutaneously every 6 months or risedronate 150 mg orally every month for 12 months. Endpoints included percentage change from baseline in total hip BMD (primary endpoint), femoral neck, and lumbar spine BMD at month 12, and percentage change from baseline in sCTX-1 at months 1 and 6. Safety was also assessed. A total of 870 subjects were randomized (435, risedronate; 435, denosumab) who had a mean (SD) age of 67.7 (6.9) years, mean (SD) BMD T-scores of -1.6 (0.9), -1.9 (0.7), and -2.2 (1.2) at the total hip, femoral neck, and lumbar spine, respectively, and median sCTX-1 of 0.3 ng/mL at baseline. At month 12, denosumab significantly increased BMD compared with risedronate at the total hip (2.0% vs 0.5%), femoral neck (1.4% vs 0%), and lumbar spine (3.4% vs 1.1%; p<0.0001 at all sites). Denosumab significantly decreased sCTX-1 compared with risedronate at month 1 (median change from baseline of -78% vs -17%; p<0.0001) and month 6 (-61% vs -23%; p<0.0001). Overall and serious adverse events were similar between groups. In postmenopausal women who were suboptimally adherent to alendronate therapy, transitioning to denosumab was well tolerated and more effective than risedronate in increasing BMD and reducing bone turnover.

Rat intercostal nerves as experimental nerve grafts.

In this study, we dissected and measured both sets of intercostal nerves including lengths, diameters, and axon counts in 12 adult rats to provide data applicable to experimental nerve graft research. Dissections showed that total lengths of intercostal nerves from the spinal bifurcation to their last arborizations near the midline ranged from 10 to 89 mm, and diameters ranged from less than 0.1 to 0.5 mm from the thinnest to the thickest part. The segment of easiest dissection was the part between the spinal bifurcation and the lateral cutaneous branch. This part was 4-27 mm (mean, 13.3 mm) long and had an almost constant diameter of 0.18-0.5 mm (mean, 0.32 mm). Counts ranged from 201 to 566 axons/ nerve. The segment proximal to the lateral cutaneous branch was the most convenient part to be harvested as a nerve graft, especially in the 8th to 12th intercostal nerves. These nerves could serve as sources for experimental grafts.

Gluteal infarction as a complication of aortofemoral bypass grafting.

Early complications following aortofemoral bypass grafting include acute limb ischemia, renal failure, bowel and spinal cord ischemia, and myocardial infarction. Although the literature recognizes these more common complications, we have found very few reports that raised the possibility of an anatomically determined, soft-tissue infarction as a complication of aortofemoral bypass grafting. Our plastic surgery service was consulted in August and October 1992 to examine 2 patients with soft-tissue complications following aortofemoral bypass grafting. Both patients were found to have complete gluteal infarction. Recognition of muscle infarction following aortofemoral grafting must be distinguished from postoperative pressure sores, since the muscle infarction requires prompt and thorough anatomic debridement to prevent in situ muscle liquefaction and sepsis.

Effect of vein grafting on the survival of microvascularly transplanted muscle flaps.

Since vein grafting is often required during transplantation of free muscle flaps but is associated with a higher failure rate than those flaps transplanted with primary anastomoses, we sought to compare primary repair with the use of vein grafting in an experimental setting. We transplanted the gracilis muscle to the contralateral side in 98 rats using four different methods of vessel repair. In the Control group (n = 28), both femoral vessels were anastomosed primarily. In Experimental Group 1 (n = 25), the femoral artery was anastomosed with an epigastric vein graft and the femoral vein was anastomosed primarily. In Experimental Group 2 (n = 25), the femoral vein was anastomosed with a femoral vein graft and the femoral artery was anastomosed primarily. In Experimental Group 3 (n = 20), both femoral vessels were anastomosed with vein grafts. The Control and Experimental Groups 1-3 survival rates were 89.3, 76.0, 84.0, and 70.0%, respectively; none of the experimental group survival rates was significantly different from that of the control (P < 0.5). This study demonstrates that the use of size-matched, interpositional vein grafts in the arterial or venous pedicle of the rat gracilis muscle flap during transplantation did not significantly decrease flap survival as compared to primary arterial or venous anastomoses. If the observed failure rate persisted with expansion of the study groups to 60-100 animals each, the failure rate of flaps with vein grafts would be significantly lower and comparable to failure rates reported in some clinical series. The large numbers necessary to significantly show this decrease make this model impractical for further studies.

Rat tail replantation as a training model for microvascular procedures of digit replantation.

In this study we sought to evaluate the potential of rat tail replantation as a tool for very-small-vessel microvascular anastomoses. We used 10 adult Sprague-Dawley rats. The tail was completely amputated 2.0-cm distal to the base of the tail. Then the tail was replanted with anastomoses of two superficial dorsal veins from both sides and one artery. All 10 replanted tails were pink, viable, and normal-appearing at all daily inspections performed from the first to the fourteenth postoperative days. This model can provide a training tool for the acquisition of superior microvascular surgical technique for the repair of very small vessels that stimulate digital replantation.

Results of termino-lateral neurorrhaphy to original and adjacent nerves.

In this comprehensive investigation, we studied three different neurorrhaphy models in an attempt to elucidate the potential of termino-lateral nerve repair to original and adjacent nerves. In experimental group 1, the peroneal nerve was sectioned and then attached to the posterior tibial nerve in a termino-lateral fashion. In experiment group 2, the motor nerves to the gastrocnemius muscle were sectioned and then attached to the posterior tibial nerve in a termino-lateral fashion. In experimental group 3, the obturator nerve (L2-4) was sectioned and attached to the sciatic nerve (L4-6) in a termino-lateral fashion. For the control in each group, the same type of nerve used in each respective group was transected without repair. Experimental groups 1 and 2 showed viable axons in the peroneal nerve distal to the neurorrhaphy site. Experimental group 3 showed no viable axons at these sites. No regeneration was observed in the transected nerve without repair in all three control groups. This study suggests that termino-lateral neurorrhaphy is a viable means of repairing damaged nerves if the distal segment of the sectioned nerve is reattached to its original trunk distal to its original branch point. However, the results from experimental group 3 demonstrate that termino-lateral neurorrhaphy cannot be used to repair nerves when the donor and recipient nerves originate from different spinal cord levels.

Functional recovery of transected nerves treated with systemic BDNF and CNTF.

The purpose of this study was to investigate the effect of systemic co-injections of ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) on the functional recovery of transected sciatic nerves repaired by epineurial coaptation (EC) or collagen tubulization (CT). Forty Sprague-Dawley rats underwent transection of their sciatic nerves and repair by either EC or CT. With each repair technique, systemic injections of neurotrophic factors or control injections of lactated Ringer's solution were given. This resulted in four treatment groups: EC, EC + BDNF/CNTF, CT, and CT + BDNF/CNTF. Nerve function was assessed using sciatic functional indices (SFI). Animals whose nerves were repaired by CT (P = 0.01), CT + BDNF/CNTF (P = 0.04), and EC + BDNF/CNTF (P = 0.04) all had better functional recovery than those whose nerves were repaired by EC. There were no significant differences among these three groups, however. Animals in the CT group manifested the most rapid rate of recovery (P = 0.02 compared with EC). Collagen tubulization and systemic co-injections of BDNF/CNTF improve the rate and extent of sciatic functional recovery after nerve repair. The improvement in recovery conferred is not additive.