Parvis Farahmand

Comparative effects of teriparatide and risedronate in glucocorticoid-induced osteoporosis in men: 18-month results of the EuroGIOPs trial.

Data on treatment of glucocorticoid‐induced osteoporosis (GIO) in men are scarce. We performed a randomized, open‐label trial in men who have taken glucocorticoids (GC) for ≥3 months, and had an areal bone mineral density (aBMD) T‐score ≤ –1.5 standard deviations. Subjects received 20 μg/d teriparatide (n = 45) or 35 mg/week risedronate (n = 47) for 18 months. Primary objective was to compare lumbar spine (L1–L3) BMD measured by quantitative computed tomography (QCT). Secondary outcomes included BMD and microstructure measured by high‐resolution QCT (HRQCT) at the 12th thoracic vertebra, biomechanical effects for axial compression, anterior bending, and axial torsion evaluated by finite element (FE) analysis from HRQCT data, aBMD by dual X‐ray absorptiometry, biochemical markers, and safety. Computed tomography scans were performed at 0, 6, and 18 months. A mixed model repeated measures analysis was performed to compare changes from baseline between groups. Mean age was 56.3 years. Median GC dose and duration were 8.8 mg/d and 6.4 years, respectively; 39.1% of subjects had a prevalent fracture, and 32.6% received prior bisphosphonate treatment. At 18 months, trabecular BMD had significantly increased for both treatments, with significantly greater increases with teriparatide (16.3% versus 3.8%; p = 0.004). HRQCT trabecular and cortical variables significantly increased for both treatments with significantly larger improvements for teriparatide for integral and trabecular BMD and bone surface to volume ratio (BS/BV) as a microstructural measure. Vertebral strength increases at 18 months were significant in both groups (teriparatide: 26.0% to 34.0%; risedronate: 4.2% to 6.7%), with significantly higher increases in the teriparatide group for all loading modes (0.005 < p < 0.015). Adverse events were similar between groups. None of the patients on teriparatide but five (10.6%) on risedronate developed new clinical fractures (p = 0.056). In conclusion, in this 18‐month trial in men with GIO, teriparatide showed larger improvements in spinal BMD, microstructure, and FE‐derived strength than risedronate.

Evidence for integrin receptor involvement in megakaryocyte‐fibroblast interaction: A possible pathomechanism for the evolution of myelofibrosis

Megakaryocytes are assumed to be functionally linked with the evolution of myelofibrosis, complicating chronic myeloproliferative disorders. It has already been shown that megakaryocytes will promote fibroblast growth in vitro when in spatial proximity. Here, we demonstrate that the integrin receptors α3β1 and α5β1 are involved in this megakaryocyte‐fibroblast interaction. Upon addition of anti‐α3 and ‐α5 antibodies to megakaryocyte‐fibroblast cocultures, fibroblast growth was significantly impaired, and megakaryocyte attachment to the fibroblast feederlayer was significantly reduced. Unilateral blocking of megakaryocytes with anti‐α3 or ‐α5 antibodies resulted in a suppression of adhesion, probably reflecting the prominent function of fibronectin receptors on the megakaryocyte surface. Moreover, the oligopeptide RGDS (Asp‐Gly‐Asp‐Ser) caused a significant reduction of fibroblast growth as well as megakaryocyte adhesion. This feature reinforces that fibronectin receptors are involved. In addition, fibroblast proliferation was impaired by the application of fibronectin antibodies recognizing the cell‐binding domain. However, no effect was observable with respect to megakaryocyte adhesion. In conclusion, our in vitro studies demonstrate the involvement of β1‐integrins, in particular the fibronectin receptor in the megakaryocyte‐dependent fibroblast proliferation and therefore suggest a pivotal role of megakaryocytes in the complex pathomechanism causing myelofibrosis. J. Cell. Physiol. 176:445–455, 1998.

Selectins (CD62L, CD62P) and megakaryocytic glycoproteins (CD41a, CD42b) mediate megakaryocyte-fibroblast interactions in human bone marrow.

Previous in vitro studies are in keeping with the finding that isolated and enriched megakaryocytes attach to bone marrow fibroblasts and generate an increased growth of these cells. This process was assumed to depend on a close spatial relationship between both cell types which supports the paracrine effect of platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-beta1. Moreover, adhesion molecules including beta1 integrin receptors and fucosylated structures were determined to play an important role in these complex interactions. However, up to now the influence of megakaryocyte expressed glycoproteins CD41a and CD42b in these processes was not investigated. In addition, the role of megakaryocytic CD62P and also of CD62L, both adhesion molecules of the selectin group, could also be of interest. Following isolation and enrichment of bone marrow megakaryocytes and fibroblasts, both cell populations were characterized regarding their expression of these factors by applying immunocytochemical techniques. Additionally, their influence on adhesion of megakaryocytes to fibroblasts as well as fibroblast growth was evaluated by comparative megakaryocyte-fibroblast co-cultures and inhibition studies using specific monoclonal antibodies (mabs). Fibroblast monocultures served as controls. In these experiments, selectin-specific antibodies significantly reduced megakaryocyte attachment to fibroblast feeder layers and fibroblast growth in the co-cultures. The effect of CD41a and CD42b specific antibodies was limited to megakaryocyte-dependent fibroblast growth. These results elucidate the involvement of the selectins CD62P and CD62L in the basal activation of megakaryocytes inducing their attachment to bone marrow fibroblasts. In contrast, the megakaryocyte glycoproteins CD41a and CD42b exert their effect on the megakaryocyte dependent fibroblast growth. Altogether, it is tempting to speculate that the various interactions of these mediators reflect certain steps in the complex pathomechanisms causing the evolution of (reactive) myelofibrosis in hematopoietic neoplasias accompanied by megakaryocytic proliferation.

Rapid pain relief and remission of sternocostoclavicular hyperostosis after intravenous ibandronate therapy

Sternocostoclavicular hyperostosis (SCCH) is an infrequent but painful, localized disturbance of bone metabolism of unknown etiology. The diagnosis of SCCH is generally one of exclusion, and it is therefore frequently missed or delayed, leaving patients with pain that frequently fails to respond to standard analgesic therapy. Consequently, SCCH leads to significantly impaired quality of life. Characteristic increased localized bone turnover and inflammatory osteitis provide a strong rationale for using intravenous bisphosphonates to treat the condition. We report on three patients with long-standing, treatment-refractory SCCH in whom intravenous ibandronate injections (a single administration of 4 mg followed by 2 mg every 3 months for up to a year) produced prompt, dramatic, persistent pain relief and resolution of the other symptoms of the disease. We also review recent evidence suggesting that SCCH is more common than generally believed and that technetium-99 bone scanning can aid in making an accurate diagnosis.

Aminopyridine Treatment in a Patient With Bilateral Vestibular Failure and Cryptogenic Downbeat Nystagmus

I n a recent issue of this journal, Kalla et al (1) reported that 4-aminopyridine (4-AP) alleviates the symptoms of downbeat nystagmus (DBN) significantly more than 3,4diaminopyridine (3,4-DAP). Both drugs are potassiumchannel blockers, but 4-aminopyridine is lipid-soluble and more easily crosses the blood-brain-barrier. 3,4-diaminopyridine is not lipid soluble, with direct effects in the peripheral nervous system and indirect effects in the central nervous system via its metabolites (1,2). In the report by Kalla et al (1), 1 male patient suffered from bilateral vestibular failure (disorder of the peripheral nervous system) as well as DBN (disorder of the central nervous system). We now document this case in detail. At the time of the study, the patient was 58 years old. Ten years earlier, he had traveled to Indonesia, where he suffered from extreme diarrhea with severe weight loss, followed by the development of tinnitus, oscillopsia, postural instability, and bilateral vestibular failure. MRI of the brain was normal. On examination, he was found to have DBN, which was documented with electronystagmography. The patient showed improvement of DBN following the administration of 3,4-DAP but not with 4-AP. The reason for this finding might be that the effects of 3,4-DAP are more balanced between the peripheral and the central nervous systems, while the effects of 4-AP are primarily on the central nervous system. It had been suggested that the combination of bilateral vestibular failure and idiopathic DBN is due to a multisystem channelopathy, decreasing the calcium currents through P/Q channels and thus impacting potassium channels both in the peripheral and the central nervous systems (3–6). This multisystem channelopathy could explain disorders not only in the peripheral nervous system (such as bilateral vestibular failure) but also in the central nervous system (such as DBN). 3,4-DAP may restore the excitability of the cerebellar Purkinje cells at a similar pace as it restores peripheral functioning, hence stabilizing the feedback loop between their central effect on eye movements and their interaction with peripheral structures responsible for balance. Rainer Spiegel, PhD Department of Neurology and IFB Munich University Hospital, Campus Großhadern Munich, Germany Roger Kalla, MD Jens Classen, MD Stanislavs Bardins, MSc Fábio Anciães da Silva, MD Parvis Farahmand, MD Ales Hahn, MD Erich Schneider, PhD Nicole Rettinger, CO Klaus Jahn, MD Thomas Brandt, MD, FRCP Michael Strupp, MD Integrated Center for Research and Treatment of Vertigo Balance and Ocular Motor Disorders University of Munich Hospital Munich, Germany rainer.spiegel@med.uni-muenchen.de

Resting in darkness improves downbeat nystagmus: evidence from an observational study.

Resting in an upright position during daytime decreases downbeat nystagmus (DBN). When measured in brightness only, that is, without intermitting exposure to darkness, it does not make a significant difference whether patients have previously rested in brightness or in darkness. In real‐world scenarios, people are often exposed to brightness and darkness intermittently. The aim of this study was to analyze whether resting in brightness or resting in darkness was associated with a lower post‐resting DBN after intermitting exposures to brightness and darkness. Eight patients were recorded with three‐dimensional video‐oculography in brightness and darkness conditions, each following two 2‐h resting intervals under either brightness or darkness resting conditions. The dependent variable was DBN intensity, measured in mean slow phase velocity. A repeated measures ANOVA with the factors measurement condition (brightness vs. darkness), resting condition (brightness vs. darkness), and time (after first vs. second resting interval) showed a significant effect for the factor resting condition, where previous resting in darkness was associated with a significantly lower DBN relative to previous resting in brightness (P < 0.01). The clinical relevance is to advise patients with DBN to rest in darkness.

Preventing road injuries in children by applying feedback devices

Objective: The objective of this article is to determine how to prevent road injuries in schoolchildren by reducing the prevalence of speeding. Methods: On a busy road in the neighborhood of a preschool and two secondary schools in Oberhaching (greater Munich, Germany), a board was mounted next to the road (visible to the drivers as well as the pedestrians). The board consisted of a picture of a smiling child. Underneath the picture, an LED display read “Thank you!” in green blinking letters when the speed limit was adhered to and “Slowly!” in red blinking letters when speeding was detected. The main outcome assessment was the number of drivers adhering to the speed limit in the experimental condition (i.e., facing the device) compared to the number in the control condition (on the same road within the same time period but traveling in the opposite direction; i.e., drivers not facing the device). Results: In the control condition 27.6 percent (230) of drivers adhered to the speed limit compared to 41.1 percent (427) of drivers in the experimental condition, χ2 = 36.1, P < .0001. Only 12 drivers exceeded the speed limit by more than 20 km per hour in the experimental condition, whereas 34 drivers did so in the control condition, χ2 = 9.6, P < .01. Discussion: The display is associated with a significantly lower percentage of speeding drivers but does not seem to be sufficient, because the majority of drivers still did not observe the speed limit in the presence of the display. Additional factors on how speed reduction can be achieved will be discussed in the light of future applications and possible modifications of the device.