Cortical bone loss at the tibia in postmenopausal women with osteoporosis is associated with incident non-vertebral fractures: Results of a randomized controlled ancillary study of HORIZON

BACKGROUND In postmenopausal women, yearly intravenous zoledronate (ZOL) compared to placebo (PLB) significantly increased bone mineral density (BMD) at lumbar spine (LS), femoral neck (FN), and total hip (TH) and decreased fracture risk. The effects of ZOL on BMD at the tibial epiphysis (T-EPI) and diaphysis (T-DIA) are unknown. METHODS A randomized controlled ancillary study of the HORIZON trial was conducted at the Department of Osteoporosis of the University Hospital of Berne, Switzerland. Women with ≥1 follow-up DXA measurement who had received ≥1 dose of either ZOL (n=55) or PLB (n=55) were included. BMD was measured at LS, FN, TH, T-EPI, and T-DIA at baseline, 6, 12, 24, and 36 months. Morphometric vertebral fractures were assessed. Incident clinical fractures were recorded as adverse events. RESULTS Baseline characteristics were comparable with those in HORIZON and between groups. After 36 months, BMD was significantly higher in women treated with ZOL vs. PLB at LS, FN, TH, and T-EPI (+7.6%, +3.7%, +5.6%, and +5.5%, respectively, p<0.01 for all) but not T-DIA (+1.1%). The number of patients with ≥1 incident non-vertebral or morphometric fracture did not differ between groups (9 ZOL/11 PLB). Mean changes in BMD did not differ between groups with and without incident fracture, except that women with an incident non-vertebral fracture had significantly higher bone loss at predominantly cortical T-DIA (p=0.005). CONCLUSION ZOL was significantly superior to PLB at T-EPI but not at T-DIA. Women with an incident non-vertebral fracture experienced bone loss at T-DIA.

Neuromuscular disuse and atrophy: {\it In vivo\/} magnetic resonance studies of intramuscular lipid metabolism and fluid shift changes

We postulated that neuromuscular disuse results in deleteriously affected tissue-vascular fluid exchange processes and subsequently damages the important oxidative bioenergetic process of intramuscular lipid metabolism. The in-depth research reported in the literature is somewhat limited by the ex vivo nature and sporadic time-course characterization of disuse atrophy and recovery. Thus, an in vivo controlled, localized animal model of disuse atrophy was developed in one of the hindlimbs of laboratory rabbits (employing surgically implanted tetrodotoxin (TTX)-filled mini-osmotic pump-sciatic nerve superfusion system) and tested repeatedly with magnetic resonance (MR) throughout the 2-week period of temporarily induced disuse and during the recovery period (following explantation of the TTX-filled pump) for a period of 3 weeks. Controls consisted of saline/"sham"-implanted rabbit hindlimbs. The validity of this model was established with repeated electrophysiologic nerve conduction testing using a clinically appropriate protocol and percutaneously inserted small needle stimulating and recording electrodes. Evoked responses recorded from proximal (P) and distal (D) sites to the sciatic nerve cuff in the TTX-implanted group revealed significantly decreased (p $<$ 0.001) proximal-to-distal (P/D) amplitude ratios (as much as 50-70% below Baseline/pre-implanted and sham-implanted group values) and significantly increased (p $<$ 0.01) differential latency (PL-DL) values (as much as 1.5 times the pre- and sham-implanted groups). By Day 21 of recovery, observed P/D and PL-DL levels matched Baseline/sham-implemented levels. MRI-determined cross-sectional area (CSA) values of Baseline/pre-implanted, sham- or TTX-implanted, and recovering/explanted and the corresponding contralateral hindlimb tibialis anterior (TA) muscles normalized to tibial bone (TB) CSA (in TA/TB ratios) revealed that there was a significant decline (indicative of atrophic response) from pre- and sham-implanted controls by as much as 20% (p $<$ 0.01) at Day 7 and 50-55% (p $<$ 0.001) at Day 13 of TTX-implantation. In the non-implanted contralaterals, a significant increase (indicative of hypertrophic response) by as much as 10% (p $<$ 0.025) at Day 7 and 27% (p $<$ 0.001) at Day 13 + TTX was found. The induced atrophic/hypertrophic TA muscles were observed to be fully recovered by Day 21 post-explantation as evidenced by image TA/TB ratios. End-point biopsy results from a small group of rabbits revealed comprehensive atrophy of both Type I and Type II fibers, although the heterogeneity of the response supports the use of image-guided, volume-localized proton magnetic resonance spectroscopy (MRS) to noninvasively assess tissue-level metabolic changes. MRS-determined results of a 0.25cc volume of tissue within implanted limb TA muscles under resting/pre-ischemic, ischemic-stressed, and post-ischemic conditions at timepoints during and following disuse atrophy/recovery revealed significantly increased intramuscular spectral lipid levels, as much as 2-3 times (p $<$ 0.01) the Baseline/pre-implanted values at Day 7 and 6-7 times (p $<$ 0.001) at Day 13 + TTX, which approached normal levels (compared to pre- and sham-implanted groups) by Day 21 of post-explanation recovery. (Abstract shortened by UMI.) ^

Restenosis after infrapopliteal angioplasty - clinical importance, study update and further directions.

Patients with critical limb ischemia (CLI) represent the most severe form of peripheral arterial disease (PAD) and exhibit high mortality rates. Frequently, PAD in CLI patients involves the infrapopliteal arterial segment challenging endovascular revascularization strategies. Restenosis remains the major drawback of tibial angioplasty encountered in more than two thirds of CLI patients undergoing tibial revascularization. In contrast to earlier observations, tibial patency was recently shown to be essential to attain an optimal clinical outcome in CLI patients subsequent to tibial angioplasty. The exact pathopyhsiological mechanisms of tibial restenosis remains unclear. To date, most of our knowledge on tibial restenosis and its pathophysiology is derived from coronary arteries, based on the similarity of coronary arteries to tibial artery morphology. Nervertheless, multiple antirestenosis concepts are investigated within clinical trials to reduce tibial restenosis.Purpose of the present manuscript is to provide a current update on the pathophysiology of tibial restenosis and potential antirestenosis strategies.

Radiometrical, hormonal and biological correlates of skeletal growth in the female rat from birth to senescence

OBJECTIVE We investigated the skeletal growth profile of female rats from birth to senescence (100weeks) on the basis of sequential radiometrical, hormonal and biochemical parameters. DESIGN Weaning rats entered the study which was divided into two sections: a) sequential measurements of vertebral and tibial growths and bone mineral density (BMD), estimation of mineral content of the entire skeleton (BMC) and chemical analysis of vertebral Ca; and b) determination of basal and pulsatile growth hormone (rGH), insulin-like growth hormone (IGF-I), estradiol (E2), parathyroid hormone (PTH), osteocalcin (OC) and urinary d-pyridinoline (dp) throughout the experimental period. RESULTS Vertebral and tibial growths ceased at week 25 whereas BMD and BMC as well as total vertebral Ca exhibited a peak bone mass at week 40. rGH pulsatile profiles were significantly higher in younger animals coinciding with the period of active growth and IGF-I peaked at 7weeks, slowly declining thereafter and stabilizing after week 60. OC and dp closely paralleled IGF-I coinciding with the period of enhanced skeletal growth, remaining thereafter in the low range indicative of reduced bone turnover. E2 increased during reproductive life but the lower values subsequently recorded were still in the physiological range, strongly suggesting a protective role of this steroid on bone remodeling. PTH followed a similar profile to E2, but the significance of this after completion of growth remains unclear. CONCLUSIONS Mechanisms governing skeletal growth in the female rat appear similar to those in humans. Bone progression and attainment of peak bone mass are under simultaneous control of rGH, IGF-I and calciotropic hormones and are modulated by E2. This steroid seems to protect the skeleton from resorption before senescence whereas the role of PTH in this context remains uncertain.

Validation of stress magnetic resonance imaging of the canine stifle joint with and without an intact cranial cruciate ligament.

OBJECTIVE To validate use of stress MRI for evaluation of stifle joints of dogs with an intact or deficient cranial cruciate ligament (CrCL). SAMPLE 10 cadaveric stifle joints from 10 dogs. PROCEDURES A custom-made limb-holding device and a pulley system linked to a paw plate were used to apply axial compression across the stifle joint and induce cranial tibial translation with the joint in various degrees of flexion. By use of sagittal proton density-weighted MRI, CrCL-intact and deficient stifle joints were evaluated under conditions of loading stress simulating the tibial compression test or the cranial drawer test. Medial and lateral femorotibial subluxation following CrCL transection measured under a simulated tibial compression test and a cranial drawer test were compared. RESULTS By use of tibial compression test MRI, the mean ± SD cranial tibial translations in the medial and lateral compartments were 9.6 ± 3.7 mm and 10 ± 4.1 mm, respectively. By use of cranial drawer test MRI, the mean ± SD cranial tibial translations in the medial and lateral compartments were 8.3 ± 3.3 mm and 9.5 ± 3.5 mm, respectively. No significant difference in femorotibial subluxation was found between stress MRI techniques. Femorotibial subluxation elicited by use of the cranial drawer test was greater in the lateral than in the medial compartment. CONCLUSIONS AND CLINICAL RELEVANCE Both stress techniques induced stifle joint subluxation following CrCL transection that was measurable by use of MRI, suggesting that both methods may be further evaluated for clinical use.

Neurotized lateral gastrocnemius muscle transfer for persistent traumatic peroneal nerve palsy: Surgical technique

INTRODUCTION Persistent traumatic peroneal nerve palsy, following nerve surgery failure, is usually treated by tendon transfer or more recently by tibial nerve transfer. However, when there is destruction of the tibial anterior muscle, an isolated nerve transfer is not possible. In this article, we present the key steps and surgical tips for the Ninkovic procedure including transposition of the neurotized lateral gastrocnemius muscle with the aim of restoring active voluntary dorsiflexion. SURGICAL TECHNIQUE The transposition of the lateral head of the gastrocnemius muscle to the tendons of the anterior tibial muscle group, with simultaneous transposition of the intact proximal end of the deep peroneal nerve to the tibial nerve of the gastrocnemius muscle by microsurgical neurorrhaphy is performed in one stage. It includes 10 key steps which are described in this article. Since 1994, three clinical series have highlighted the advantages of this technique. Functional and subjective results are discussed. We review the indications and limitations of the technique. CONCLUSION Early clinical results after neurotized lateral gastrocnemius muscle transfer appear excellent; however, they still need to be compared with conventional tendon transfer procedures. Clinical studies are likely to be conducted in this area largely due to the frequency of persistant peroneal nerve palsy and the limitations of functional options in cases of longstanding peripheral nerve palsy, anterior tibial muscle atrophy or destruction.

Nerve Transfers for Persistent Traumatic Peroneal Nerve Palsy: The Inselspital Bern Experience

BACKGROUND Patients in whom conventional peroneal nerve repair surgery failed to reconstitute useful foot lift need to be evaluated for their suitability to undergo a concomitant tendon transfer procedure or nerve transfers. OBJECTIVE To report our first clinical experience with nerve transfers for persistent traumatic peroneal nerve palsy. METHODS Between 2007 and 2013, 8 patients were operated on for foot drop after unsuccessful nerve surgery. Six patients without fatty degeneration of the anterior tibial muscle and proximal lesion of the peroneal nerve were oriented for tibial to peroneal nerve transfer. In the other 2 cases where the anterior and lateral compartments were destructed, the anterior tibial muscle function was reconstructed with a neurotized lateral gastrocnemius transfer. For each patient, we graded postoperative results using the Bureau of Meteorology Research Centre scheme and the Ninkovic assessment scale. RESULTS Of the 6 patients who underwent nerve transfer of the anterior tibial muscle, 2 patients had excellent results, 1 patient had good results, 1 patient had fair results, and 2 patients had poor results. Of the 2 patients that underwent neurotized lateral gastrocnemius transfer, 1 patient achieved excellent results after tenolysis, whereas 1 patient achieved poor results. After the nerve transfer, 5 patients did not wear an ankle-foot orthosis. Four patients did not limp. Four patients were able to walk barefoot, navigate stairs, and participate in activities. CONCLUSION Early clinical results after tibial to peroneal nerve transfer and neurotized lateral gastrocnemius transfer appear mixed. The results of nerve transfer seem, on the whole, less reliable than the literature reports on tendon transfer. ABBREVIATIONS EMG, electromyographyNAP, nerve action potential.

The Importance of Patency in Patients with Critical Limb Ischemia Undergoing Endovascular Revascularization for Infrapopliteal Arterial Disease.

Critical limb ischemia (CLI) represents the most severe form of peripheral arterial disease (PAD) and frequently occurs in medically frail patients. CLI patients frequently exhibit multi-segmental PAD commonly including the tibial arterial segment. Endovascular therapy has been established as first-line revascularization strategy for most CLI patients. Restenosis was reported to occur in up to more than two-thirds of CLI patients undergoing angioplasty of complex tibial arterial obstructions. Nevertheless, favorable clinical outcomes were observed for infrapopliteal angioplasty when compared with bypass surgery, despite higher patency rates for the latter. Based on these observations, infrapopliteal patency was considered to be only of secondary importance upon clinical outcomes in CLI patients. In contrast to these earlier observations, however, recent findings from two randomized clinical trials indicate that infrapopliteal patency does impact on clinical outcomes in CLI patients. The purpose of the present manuscript is to provide a critical reappraisal of the present literature on the clinical importance of tibial arterial patency in CLI patients undergoing endovascular revascularization and to discuss utility and limitations of currently available anti-restenosis technologies.

Mapping tibiofemoral gonarthrosis: an MRI analysis of non-traumatic knee cartilage defects

OBJECTIVE Arthroscopy is "the gold standard" for the diagnosis of knee cartilage lesions. However, it is invasive and expensive, and displays all the potential complications of an open surgical procedure. Ultra-high-field MRI now offers good opportunities for the indirect assessment of the integrity and structural changes of joint cartilage of the knee. The goal of the present study is to determine the site of early cartilaginous lesions in adults with non-traumatic knee pain. METHODS 3-T MRI examinations of 200 asymptomatic knees with standard and three-dimensional double-echo steady-state (3D-DESS) cartilage-specific sequences were prospectively studied for early degenerative lesions of the tibiofemoral joint. Lesions were classified and mapped using the modified Outerbridge and modified International Cartilage Repair Society classifications. RESULTS A total of 1437 lesions were detected: 56.1% grade I, 33.5% grade II, 7.2% grade III and 3.3% grade IV. Cartographically, grade I lesions were most common in the anteromedial tibial areas; grade II lesions in the anteromedial L5 femoral areas; and grade III in the centromedial M2 femoral areas. CONCLUSION 3-T MRI with standard and 3D-DESS cartilage-specific sequences demonstrated that areas predisposed to early osteoarthritis are the central, lateral and ventromedial tibial plateau, as well as the central and medial femoral condyle. ADVANCES IN KNOWLEDGE In contrast with previous studies reporting early cartilaginous lesions in the medial tibial compartment and/or in the medial femoral condyle, this study demonstrates that, regardless of grade, lesions preferentially occur at the L5 and M4 tibial and L5 and L2 femoral areas of the knee joint.

An analysis of IN.PACT DEEP randomized trial on the limitations of the societal guidelines-recommended hemodynamic parameters to diagnose critical limb ischemia.

OBJECTIVE Recent small single-center data indicate that the current hemodynamic parameters used to diagnose critical limb ischemia are insensitive. We investigated the validity of the societal guidelines-recommended hemodynamic parameters against core laboratory-adjudicated angiographic data from the multicenter IN.PACT DEEP (RandomIzed AmPhirion DEEP DEB vs StAndard PTA for the treatment of below the knee Critical limb ischemia) Trial. METHODS Of the 358 patients in the IN.PACT DEEP Trial to assess drug-eluting balloon vs standard balloon angioplasty for infrapopliteal disease, 237 had isolated infrapopliteal disease with an available ankle-brachial index (ABI), and only 40 of the latter had available toe pressure measurements. The associations between ABI, ankle pressure, and toe pressure with tibial runoff, Rutherford category, and plantar arch were examined according to the cutoff points recommended by the societal guidelines. Abnormal tibial runoff was defined as severely stenotic (≥70%) or occluded and scored as one-, two-, or three-vessel disease. A stenotic or occluded plantar arch was considered abnormal. RESULTS Only 14 of 237 patients (6%) had an ABI <0.4. Abnormal ankle pressure, defined as <50 mm Hg if Rutherford category 4 and <70 mm Hg if Rutherford category 5 or 6, was found only in 37 patients (16%). Abnormal toe pressure, defined as <30 mm Hg if Rutherford category 4 and <50 mm Hg if Rutherford category 5 or 6, was found in 24 of 40 patients (60%) with available measurements. Importantly, 29% of these 24 patients had an ABI within normal reference ranges. A univariate multinomial logistic regression found no association between the above hemodynamic parameters and the number of diseased infrapopliteal vessels. However, there was a significant paradoxic association where patients with Rutherford category 6 had higher ABI and ankle pressure than those with Rutherford category 5. Similarly, there was no association between ABI and pedal arch patency. CONCLUSIONS The current recommended hemodynamic parameters fail to identify a significant portion of patients with lower extremity ulcers and angiographically proven severe disease. Toe pressure has better sensitivity and should be considered in all patients with critical limb ischemia.

Effects of estrogen on growth plate senescence and epiphyseal fusion

Estrogen is critical for epiphyseal fusion in both young men and women. In this study, we explored the cellular mechanisms by which estrogen causes this phenomenon. Juvenile ovariectomized female rabbits received either 70 μg/kg estradiol cypionate or vehicle i.m. once a week. Growth plates from the proximal tibia, distal tibia, and distal femur were analyzed after 2, 4, 6, or 8 weeks of treatment. In vehicle-treated animals, there was a gradual senescent decline in tibial growth rate, rate of chondrocyte proliferation, growth plate height, number of proliferative chondrocytes, number of hypertrophic chondrocytes, size of terminal hypertrophic chondrocytes, and column density. Estrogen treatment accelerated the senescent decline in all of these parameters. In senescent growth plates, epiphyseal fusion was observed to be an abrupt event in which all remaining chondrocytes were rapidly replaced by bone elements. Fusion occurred when the rate of chondrocyte proliferation approached zero. Estrogen caused this proliferative exhaustion and fusion to occur earlier. Our data suggest that (i) epiphyseal fusion is triggered when the proliferative potential of growth plate chondrocytes is exhausted; and (ii) estrogen does not induce growth plate ossification directly; instead, estrogen accelerates the programmed senescence of the growth plate, thus causing earlier proliferative exhaustion and consequently earlier fusion.

Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides but exhibit only subtle defects in their nervous system.

Gangliosides, sialic acid-containing glycosphingolipids, are abundant in the vertebrate (mammalian) nervous system. Their composition is spatially and developmentally regulated, and gangliosides have been widely believed to lay essential roles in establishment of the nervous system, especially in neuritogenesis and synaptogenesis. However, this has never been tested directly. Here we report the generation of mice with a disrupted beta 1,4-N-acetylgalactosaminyltransferase (GM2/GD2 synthase; EC 2.4.1.92) gene. The mice lacked all complex gangliosides. Nevertheless, they did not show any major histological defects in their nervous systems or in gross behavior. Just a slight reduction in the neural conduction velocity from the tibial nerve to the somatosensory cortex, but not to the lumbar spine, was detected. These findings suggest that complex gangliosides are required in neuronal functions but not in the morphogenesis and organogenesis of the brain. The higher levels of GM3 and GD3 expressed in the brains of these mutant mice may be able to compensate for the lack of complex gangliosides.

Patient Variability in Sciatic Nerve Branch Point Distance Using Ultrasound Guided Localization

Background and Objectives: Improved ultrasound and needle technology make popliteal sciatic nerve blockade a popular anesthetic technique and imaging to localize the branch point of the common peroneal and posterior tibial components is important because successful blockade techniques vary with respect to injection of the common trunk proximally or separate injections distally. Nerve stimulation, ultrasound, cadaveric and magnetic resonance studies demonstrate variability in distance and discordance between imaging and anatomic examination of the branch point. The popliteal crease and imprecise, inaccessible landmarks render measurement of the branch point variable and inaccurate. The purpose of this study was to use the tibial tuberosity, a fixed bony reference, to measure the distance of the branch point. Method: During popliteal sciatic nerve blockade in the supine position the branch point was identified by ultrasound and the block needle was inserted. The vertical distance from the tibial tuberosity prominence and needle insertion point was measured. Results: In 92 patients the branch point is a mean distance of 12.91 cm proximal to the tibial tuberosity and more proximal in male (13.74 cm) than female patients (12.08 cm). Body height is related to the branch point distance and is more proximal in taller patients. Separation into two nerve branches during local anesthetic injection supports notions of more proximal neural anatomic division. Limitations: Imaging of the sciatic nerve division may not equal its true anatomic separation. Conclusion: Refinements in identification and resolution of the anatomic division of the nerve branch point will determine if more accurate localization is of any clinical significance for successful nerve blockade.

MR morphometry of posterior tibialis muscle in adult acquired flat foot

We conducted magnetic resonance imaging of the posterior tibial (PT) and flexor digitorum longus (FDL) muscle bellies in 12 patients undergoing surgical treatment for unilateral posterior tibial tendon (PTT) dysfunction. All patients had atrophy of the PT muscle compared to the normal leg (mean 10.7%, p=0.008). In those patients with a complete rupture of PTT there was replacement of the PT muscle by fatty infiltration. Conversely, the FDL muscle showed a compensatory hypertrophy (mean 17.2%, p

Effect of cyclic pneumatic soft tissue compression on simulated distal radius fractures

We investigated the effect of pneumatic pressure applied to the proximal musculature of the sheep foreleg on load at the site of a transverse osteotomy of the distal radius. The distal radii of 10 fresh sheep foreleg specimens were osteotomized and a pressure sensor was inserted between the two bone fragments. An inflatable cuff, connected to a second pressure sensor, was positioned around the proximal forelimb musculature and the leg then was immobilized in a plaster cast. The inflatable cuff was inflated and deflated repeatedly to various pressures. Measurements of the cuff pressure and corresponding change in pressure at the osteotomy site were recorded. The results indicated that application of pneumatic pressure to the proximal foreleg musculature produced a corresponding increase in load at the osteotomy site. For the cuff pressures tested (109.8-238.4 mm Hg), there was a linear correlation with the load at the osteotomy site with a gradient of 12 mm Hg/N. It is conceivable, based on the results of this study, that a technique could be developed to provide dynamic loading to accelerate fracture healing in the upper limb of humans.