With age, both men and women experience a decline of sex-hormones and impaired bone repair. This study examined whether bone healing could be improved by combined treatment with the selective androgen and estrogen receptor modulators ostarine (Ost) and raloxifene (Ral), and compared its efficacy with monotherapy in female and male rat models. Three‑month‑old female (Experiment 1, n = 15/group) and 8‑month‑old male (Experiment 2, n = 15/group) Sprague–Dawley rats were either intact (healthy control) or ovariectomized/orchiectomized (Ovx/Orx). Ovx/Orx rats received daily either no treatment, Ost, Ral, or combined Ost + Ral at the respective monotherapy doses. Eight weeks after Ovx or 12 weeks after Orx, rats underwent bilateral metaphyseal osteotomy of the tibia with plate fixation. Healing was assessed five in females or 6 weeks in males later by micro‑CT, biomechanics, and histology. Increased total, callus, and cortical densities as well as bone volume fraction were observed in the Ost + Ral group, accompanied by reduced callus volume and surface area, indicating advanced healing. The effect of Ost + Ral was stronger than that of Ral, whereas Ost alone did not alter bone parameters. Biomechanical properties were improved in the Ral and Ost + Ral groups relative to Ovx/Orx controls. Uterus weight was lowest in Ovx and Ovx + Ral groups and enhanced by Ost and Ost + Ral. Prostate weight was lowest in Orx and Orx + Ral rats and increased by Ost. The combination with Ral reduced the androgenic effect of Ost on prostate. Combined treatment may represent a promising approach for osteoporotic bone repair in both sexes, though potential side effects of Ost require consideration.

Study DesignCadaveric biomechanical analysis.ObjectivesThe specific vertebral region that contributes most critically to pedicle screw fixation remains controversial. This study evaluates screw anchorage under cyclic fatigue loading to determine how bone quality affects the relative contributions of the pedicle and vertebral body to stability.MethodsTwelve human lumbar vertebrae (L1-L4) from donors aged 71.3 ± 14.2 years were selected, including six with normal bone density (>120 mg/cm3) and six osteoporotic (<80 mg/cm3). Each vertebra was bilaterally instrumented with the largest self-tapping polyaxial screws fitting the inner cortical diameter. One pedicle received a 35 mm screw, and the contralateral pedicle received the longest screw without cortical breach. Screw side and specimen order were randomized. Sinusoidal cranial-caudal loading at 0.5 Hz was applied, starting at 100 N and increasing by 1 N per cycle, until 5.4 mm screw head displacement (∼20°) was reached.ResultsIn healthy vertebrae, mean fatigue loads were similar for short (315.6 ± 148.7 N) and long screws (309.0 ± 138.3 N). In osteoporotic bone, long screws (230.9 ± 55.0 N) showed significantly greater fatigue resistance than short screws (175.1 ± 45.5 N; P = .045). Short screws in osteoporotic vertebrae also failed after fewer cycles than long screws in osteoporotic vertebrae (P = .047) and short screws in healthy bone vertebrae (P = .049).ConclusionsIn healthy vertebrae, screw anchorage is mainly pedicular, and extending screw length into the vertebral body adds no benefit. In osteoporotic bone, overall fixation strength declines, but vertebral body contribution increases, so longer screws provide significantly greater stability, whereas shorter screws remain adequate in healthy bone.

Background Pelvic insufficiency fractures are increasingly common in older adults and frequently involve the posterior pelvic ring. However, their population-based three-dimensional distribution has not yet been systematically characterized across the complete Fragility Fractures of the Pelvis (FFP) classification. This study aimed to generate a standardized CT-based three-dimensional fracture map, identify reproducible anatomical hotspots, and visualize fracture distribution across FFP types I–IV. Methods CT datasets from 67 geriatric patients with pelvic insufficiency fractures (mean age 82.78 ± 6.84 years; 77.6% women) were retrospectively analyzed. Fractures were classified according to the FFP classification of Rommens and Hofmann, segmented in 3D Slicer, registered to a standardized pelvic template, and visualized as frequency-based three-dimensional heatmaps in Blender. Results A total of 184 fracture lines were mapped. Fracture clustering was most pronounced in the sacral alae, accounting for 54% of all mapped fracture locations, followed by the parasymphyseal region (22%) and the remaining anterior pelvic ring (15%). Iliac wing and acetabular involvement was less frequent, accounting for 6% and 3%, respectively. FFP-specific heatmaps demonstrated a transition from isolated anterior fractures in FFP type I to progressively broader posterior and bilateral involvement in FFP types II–IV. Conclusion Standardized CT-based three-dimensional fracture mapping identified the sacral alae as the principal hotspot of pelvic insufficiency fractures and visualized characteristic spatial patterns across the FFP classification. This approach provides an anatomical framework for improved CT interpretation and future biomechanical, diagnostic, and surgical-planning studies. MINI ABSTRACT Pelvic insufficiency fractures are an increasing consequence of osteoporosis, but their three-dimensional distribution remains poorly understood. CT-based heatmapping identified the sacral alae as the principal fracture hotspot and visualized progressive posterior extension across the FFP classification. These findings improve the anatomical understanding of osteoporotic pelvic fragility fractures.

Background and Objectives: Ventral stabilization of thoracolumbar spine fractures can be achieved using different interbody reconstruction techniques, including titanium cages, vertebral body replacements (VBR), and autologous pelvic bone grafts (APBG). Although all approaches aim to restore anterior column stability and alignment, comparative data on long-term patient-reported outcomes remain limited. The objective of this study was to compare long-term patient-reported wellbeing following ventral stabilization using these three techniques. Materials and Methods: A retrospective, non-randomized single-center cohort study with prospective follow-up was analyzed. Treatment allocation was indication-based. Ninety-one patients treated between 2008 and 2018 underwent ventral stabilization using cage implantation (n = 12), vertebral body replacement (n = 45), or autologous pelvic bone grafting (n = 34). Clinical outcome was assessed at least 12 months postoperatively using a modified Visual Analog Scale Spine Score (VAS-Spine). Statistical analysis included linear and ordinal regression adjusted for age and sex. Potential baseline differences between groups were considered in the interpretation of the results. Results: Sixty-three patients (mean age 52 ± 15 years; 41% female) completed follow-up. The mean VAS-Spine score was lowest after cage implantation (2.7 ± 3.6), followed by VBR (3.9 ± 2.8) and APBG (4.9 ± 1.8; p* = 0.021). The observed difference between cage and APBG approached the minimal clinically important difference reported for VAS-based measures. Patients treated with cage implantation reported less pain during rest and activity and fewer limitations in daily life. No significant differences were observed regarding age or sex. Conclusions: In this observational cohort, cage implantation was associated with more favorable patient-reported outcomes compared with VBR and APBG. Autologous pelvic bone grafting was associated with worse patient-reported outcomes, potentially related to donor-site morbidity. Given the non-randomized design and potential confounding, these findings should be interpreted as associative and hypothesis-generating.

Background The preferred operative treatment of pertrochanteric femoral fracture (PFF) is internal fixation with a proximal femoral nail (PFN). Changes in femoral offset (CFO) greater than 15% after hip arthroplasty appear to be critical and can cause gait instability or clinical pain syndromes. It is currently unclear whether and to what extent this fracture treatment leads to a postoperative CFO. Methods Pre- and postoperative x-rays of 382 patients with PFF who underwent PFN osteosynthesis were analysed to assess CFO and CCD on operated (OS) and non-operated side (NOS). Results In 99.2% (379/382) a postoperative CFO could be found. In 43% (164/382) the FO decreased (FOD) and in 56% (215/382) the FO increased (FOI). A critical FOD was found in 40.9% and a critical FOI in 45.1%. In hip joints with FOD the mean FO between the NOS (54.30 mm [±7.60]) and OS (47.01 mm [±7.54]) likewise as in hip joints with postoperative FOI the mean FO between NOS (49.36 [±7.35]) and OS (57.43 [±7.69]) differed significantly (p<0.001). Preoperative FO (p<0.001) and CCD (p=0.02) correlated with postoperative CFO. Hips with a FO >55 mm and CCD <128° showed postoperative a FOD, while hips with a FO <55 mm and CCD >128° showed a FOI. Conclusion PFF treatment with PFN results in a clustered significant postoperative CFO. In order to avoid a critical CFO postoperatively, the individual morphological parameters of the contralateral hip side, respecting CCD and femoral offset, should be taken into account when treating PFF.

Changes in gait patterns often occur with hip osteoarthritis (OA). Clinically, these changes can sometimes be challenging to detect. Traditional gait analysis is often only feasible under laboratory conditions and not part of the routine clinical practice. In this study, changes in the biomechanics of squatting and walking associated of patients with hip OA were analyzed in a clinical setting using the novel method called Computed MyoGraphy (CMG). Movement patterns of individuals with primary hip OA (n = 11; age: 58.82 ± 5.95) and healthy individuals (n = 10; age: 60.40 ± 19.22) were compared. Using the Xsens Awinda system in combination with the novel method of CMG, kinematic, data of two movements, namely “walking” and “squatting,” were recorded and analyzed to obtain the joint contact forces (JCFs) of hip and knee joints. The total and shear JCFs of both hip and knee joints were reduced for OA patients as compared to healthy subjects. For the hip joint, differences were more pronounced on the affected side as compared to the unaffected side. The reduced JCFs observed with primary hip OA patients, particularly on the affected side, are likely responses to pain and other limitations when performing squatting exercises and walks. The newly developed CMG methodology presented in this study provides a standardized and objective approach for gait analysis of patients which could be safely conducted under clinical conditions.

Abstract Background Due to the difference in size between the humeral head and the glenoid, the shoulder joint is prone to instability. Therefore, the reconstruction of the physiological joint morphology is of great importance in shoulder joint preservation and replacement surgery. The aim of this study was to describe physiological reference parameters for the morphology of the glenoid for the first time. Material and methods MRI images of the shoulder joints of 418 patients (mean age: 50.6 years [± 16.3]) were retrospectively analysed in a low-grade osteoarthritic population. The glenoid distance in coronal (GDc) and axial view (GDa), glenoid inclination (GI) and version (GV) as well as scapula neck length (SNL) were measured. Parameters were studied in association for age, gender, side and degeneration grade. Results Mean GDc was 33.4 mm (± 3.6), mean GDa 26.8 mm (± 3.2), mean GI 10.5° (± 6.4), mean GV -0.4 mm (± 5.4) and mean SNL was 33.4 mm (± 4.7). GDa was significant higher in right shoulders (p < 0.001). GDc and GDa showed significant higher mean values in older patients (p < 0.001) and in shoulders with more severe degenerative changes (p < 0.05). While GDc, GDa and SNL were significant larger in male patients (p < 0.001), GI had a higher mean value in female shoulders (p = 0.021). Conclusion Age, gender and shoulder joint degeneration influence changes in the morphological parameters of the glenoid. These findings have to be considered in shoulder diagnostics and surgery. Clinical trial number Not applicable.

OBJECTIVE:This study aimed to investigate the relationship between spinopelvic parameters and radiographic foot axes and to examine whether these associations differ across age groups. METHODS:This retrospective radiographic study analyzed imaging from patients treated at a university medical center for degenerative or traumatic conditions. Cases with weight-bearing, 2-view foot radiographs and standing lumbar spine radiographs, including the femoral heads, were included. Spinopelvic parameters (lumbar lordosis, pelvic tilt, sacral slope, and pelvic incidence) and radiographic foot axes (including hallux valgus angle, tibiotalar angle, and metatarsal declination angle) were measured, and correlation analyses were per formed with age-based subgroup comparisons. RESULTS:A total of 46 Caucasian patients (33 females, 13 males) were included (mean age 55.6 ± 18.5 years). Lumbar lordosis showed a significant negative correlation with hallux valgus angle (r = -0.29, P = .015). Sacral slope was negatively correlated with the hallux valgus angle (r = -0.42, P < .001). Pelvic tilt correlated positively with tibiotalar angle (r = 0.34, P = .004) and metatarsal declination angle (r = 0.25, P = .042). Age-stratified analyses demonstrated age-related differences in correlation patterns. CONCLUSION:Spinopelvic alignment demonstrates measurable associations with radiographic foot alignment, supporting the concept of the spine-pelvis-lower-limb unit as a biomechanically integrated system. Clinically, these findings suggest that integrated, chain oriented assessment and management strategies (considering both spinal and foot alignment, particularly with aging) may be relevant when evalu ating patients with coexisting spine and foot disorders.   Cite this article as: Roch FE, Kletschka F, Jäckle K, et al. Age-dependent associations between spinopelvic alignment and foot axes: A retrospective radiographic study. Acta Orthop Traumatol Turc., 2025;59(6):379-386.

Background and purpose:Total hip arthroplasty, a common surgical procedure in orthopedics, is used in patients with severe hip osteoarthritis to relieve pain and to restore the function. The surgery has been shown to be effective, but patients may experience gait limitations after surgery. We used a novel and innovative tool, Computed MyoGraphy (CMG), to analyse the gait kinematics and forces acting within the musculoskeletal system after total hip arthroplasty. Data obtained at different time points before and after surgery were compared with those of healthy subjects. Methods:The gait patterns of patients with primary hip osteoarthritis patients and healthy subjects were compared using the Xsens Awinda system in combination with the CMG system. Joint contact forces and shear joint contact forces were assessed preoperatively at the 5th postoperative day as well as after the rehabilitation examining two types of movements, "walking" and "squatting". Results:As revealed by CMG during both, normal walking and in particular during squatting, pre- and postoperative patients showed lower values for total and shear hip joint contact forces on both sides of the body when compared to healthy subjects. These initial differences in the total and shear joint contact forces at the hip vanished after the completion of the rehabilitation process. Conclusions:Total hip arthroplasty patients are initially limited to squat and walk normally, as they exert lower total and shear hip joint contact forces, interestingly not only on the affected side but also on the contralateral side. Rehabilitation improves the force development to a degree similar to healthy patients. CMG provides clinical usability that objectifies gait analyses and provide useful additional functional information for clinical practice. Trial registration:Prospective study of gait analysis after primary total hip arthroplasty measured by Computed MyoGraphy (CMG) using Myonardo, DRKS00028175. Registered February 16, 2022 - Prospectively registered. Trial registration number DRKS00028175.

Instabilities of the craniocervical junction and the upper cervical spine may necessitate dorsal spinal stabilization to prevent neurological complications, deformities and pain. Among the options available, the implantation of mass or pedicle screws is considered. This study aims to assess the feasibility of pedicle screw placement based on anatomical considerations and its clinical significance. A retrospective analysis was conducted on 210 patients who underwent cervical spine CT scans at a University Medical Center. Pedicle dimensions of the first cervical vertebra and the third to fifth cervical vertebrae were measured bilaterally. The primary endpoint was a pedicle height and width greater than 4 mm, with secondary endpoints including sex-specific and age-specific differences. Results indicate that approximately 50

The aim of the present study was to determine physiological reference values for the morphology of the patella and to analyse these parameters according to patella position in healthy knee joints. Healthy knee joints of 409 patients (mean age, 52.3 years [± 16.8]) were analysed retrospectively on MRI images for Insall-Salvati index (ISI), sagittal patella thickness (PTS) and patella length (PLS) as well as axial patella thickness (PTA) and patella width (PWA). Differences between patellar diameters were analysed depending on ISI, side, age and gender. Mean PTS was 20.1 mm (± 2.4), PLS 44.0 mm (± 4.4), PTA 21.8 mm (± 2.4) and PWA 44.5 mm (± 4.7). Depending on the vertical patellar position (ISI), all patellar parameters (p < 0.01) showed significant differences between patients with a patella alta, norma and baja. In general, a smaller ISI showed higher measured values for the patellar parameters. There were no significant differences for the laterality. Only PTS showed a significant age difference (p = 0.031). All parameters were significantly larger in male compared to female knees (p < 0.001). Reference parameters for the patella morphology are reported. Concluding from the results, a relationship between vertical patellar position and patellar morphology seems to exist. This finding should be taken into account in diagnostics and therapy of patella disorders.

Surgical stabilization of the spine by vertebral body replacement (VBR) is used for spinal disorders such as traumatic fractures to provide an anatomical re-adjustment of the spine to prevent late detrimental effects and pain [1–4]. This study addresses the clinical outcome after a ventral intervention with VBR and bisegmental fusion. The study includes 76 patients (mean age: 59.34 ± 15.97; 34 females and 42 males) with fractures in the lower thoracic and lumbar spine. They were selected from patients of our hospital who received an anterolateral VBR surgery on the corresponding lower spine region over a nine-year period. Only patients were examined with X-rays and complete follow-up records. Exclusion criteria were changes due to degeneration and pathological fractures. Patients were divided into two groups, the thoracotomy group (Th10-L1) and the lumbotomy group (L2-5), respectively. Minimum one year after surgery, patients were asked about their well-being using a precasted questionnaire. No significant differences with respect to the subjective impression of the patients concerning their back pain, spinal functional impairment, their general functional status and their quality of life impairment. Unfortunately, however, only a rather modest but significant increase of the post-surgical life quality was reported. Patients who underwent VBR in the lower thoracic or lumbar spine show modest long-term well-being. The results suggest that injuries to the lower thoracic or lumbar spine requiring vertebral body replacement should be classified as severe injuries since they adversely affect the patients’ long-term well-being. Study of clinical outcome of patients after vertebral body replacement of the ventral thoracal and lumbal spine, DRKS00031452. Registered 10th March 2023 - Prospectively registered. Trial registration number DRKS00031452.

ObjectiveClosed reduction and dynamic hip screw (DHS) osteosynthesis are preferred as joint‐preserving therapy in case of medial femoral neck fractures (MFNFs). A change in the femoral offset (CFO) can cause gait abnormality, impingement, or greater trochanteric pain syndrome. It is unknown whether the femoral offset (FO) can be postoperatively fully restored. The aim of the study was to investigate the extent of a possible CFO in hip joints after DHS osteosynthesis in the case of an MFNF.MethodsIn this retrospective study, 104 patients (mean age: 71.02 years, men: n = 50, women: n = 54) with MFNF who underwent closed reduction and DHS osteosynthesis were analyzed by postoperative x‐rays to assess CFO between the operated (OS) and nonoperated joint side (NOS). The studies covered the time period 2010–2020. A statistical comparison was performed between the mean values of FO between OS and NOS, taking into account patient age, gender, and fracture severity.ResultsAll operated hip joints showed a CFO. In 76.0% (79 of 104), the FO decreased (FOD), and in 24.0% (25 of 104), the FO increased (FOI). A critical CFO (>15% CFO) was detected in 52.9% (55 of 104). In hip joints with postoperative FOD, the mean FO between NOS (49.15 mm [±6.56]) and OS (39.32 mm [±7.87]) and in hip joints with postoperative FOI the mean FO between NOS (41.59 [±8.21]) and OS (47.27 [±6.68]) differed significantly (p < 0.001). Preoperative FO (r S: −0.41; p > 0.001) and caput–collum–diaphyseal angle (CCD; r S: 0.34; p > 0.001) correlated with postoperative CFO. FOD was found in hip joints with a preoperative FO >44 mm and CCD <134° vice versa FOI in hip joints with a preoperative FO <44 mm and CCD >134°.ConclusionClosed reduction and DHS osteosynthesis in patients with MFNF result in a clustered significant CFO. The individual FO should be taken into account pre‐ and intraoperatively to avoid a postoperative extensive CFO.

Transossäre Zerreißungen stellen eine besondere Form der diskoligamentären Verletzung der Halswirbelsäule (HWS) dar und treten bei ankylosierenden Erkrankungen der Wirbelsäule auf, wobei die ankylosierende Spondylitis und die diffuse idiopathische skeletale Hyperostose (DISH) die wesentlichen Entitäten sind. Die infolge der Grunderkrankung veränderte Biomechanik der Wirbelsäule stellt besondere Herausforderungen an die Diagnostik und Therapie. Bereits Niedrigrasanztraumen können schwerwiegende Verletzungen der HWS verursachen. Ihre Diagnose kann aufgrund der oftmals erschwerten Beurteilbarkeit der projektionsradiographischen Primärdiagnostik wiederum zusätzlich erschwert sein. Neben einer korrekten Diagnosestellung ist ein differenziertes therapeutisches Konzept von hoher Bedeutung, da Behandlungsverläufe auch aufgrund der in der Mehrzahl der Fälle bestehenden Komorbiditäten komplikationsbehaftet sein können. Nicht zuletzt im Hinblick auf die hohe Rate sekundär auftretender neurologischer Defizite ohne adäquate Stabilisierung ist die anzustrebende Therapie eine operative Stabilisierung. Abweichend von der Versorgung bei „klassischen“ diskoligamentären Verletzungen der mobilen HWS stellt die langstreckige dorsal instrumentierte Spondylodese den gängigen Versorgungsstandard dar, wobei auch ventrale Stabilisierungen (als alleiniges oder ggf. additives Verfahren) ihren Stellenwert haben. Der ebenfalls vom regulären Patienten abweichende intraoperative Situs bedeutet eine zusätzliche Herausforderung.

The data on the use of a one- or two-screw technique (1S, 2S) for ventral osteosynthesis of type II dens fractures are contradictory. The aim was to design an apparatus to mimic the physiological conditions and test stability with 1S, 2S, and a headless compression screw (HCS) for osteosynthesis of artificially created type II odontoid fractures. The apparatus was mounted on a Zwick materials testing machine. A total of 18 C1–2 specimens were stratified into three groups (1S, 2S, HCS). Odontoid fractures were artificially created, and osteosynthesis was performed. Each specimen was tested at loads increasing from 1 to 40 N. Screw loosening was observed visually, by fatigue data, and by a camera tracking system. Analysis of the Zwick data and the camera data revealed a significant higher stability after 2S compared to 1S and HCS treatment (Zwick data: p = 0.021, camera data: p < 0.001), while visible screw loosening showed a superiority of the 2S only over HCS (p = 0.038). The developed apparatus allowed the dynamic study of the atlantoaxial joint with a high approximation to physiological conditions. The results demonstrated superiority of the 2S over the 1S and HCS in biomechanical stability in the treatment of type II odontoid fractures.

Introduction: Previously, we have shown that hyponatremia (HypoNa) impairs bone tissue to a similar extent as estrogen deficiency and that both factors have a synergistic adverse effect on bone healing.The present study investigated whether HypoNa worsens the effect of estrogen depletion on bone in an ovariectomized rat model for postmenopausal osteoporosis.

BACKGROUND:Free chatbots powered by large language models offer lateral ankle sprains (LAS) treatment recommendations but lack scientific validation. METHODS:The chatbots-Claude, Perplexity, and ChatGPT-were evaluated by comparing their responses to a questionnaire and their treatment algorithms against current clinical guidelines. Responses were graded on accuracy, conclusiveness, supplementary information, and incompleteness, and evaluated individually and collectively, with a 60 % pass threshold. RESULTS:The collective analysis of the questionnaire showed Perplexity scored significantly higher than Claude and ChatGPT (p < 0.001). In the individual analysis, Perplexity provided significantly more supplementary information than the other chatbots (p < 0.001). All chatbots met the pass threshold. In the algorithm evaluation, ChatGPT scored significantly higher than the others (p = 0.023), with Perplexity below the pass threshold. CONCLUSIONS:Chatbots' recommendations generally aligned with current guidelines but sometimes missed crucial details. While they offer useful supplementary information, they cannot yet replace professional medical consultation or established guidelines.

INTRODUCTION:Fragility fractures without significant trauma of the pelvic ring in older patients have an increasing incidence due to demographic change. Influencing factors other than osteoporotic bone quality that lead to an insufficiency fracture are not yet known. However, it is suspected that the pelvic tilt (PT) has an effect on the development of such an insufficiency fracture. This study explores the influence of the PTs in patients with insufficiency fractures of the posterior pelvic ring.MATERIALS AND METHODS:A total of 49 geriatric patients with fragility fractures of the pelvic ring were treated at a university hospital level-1 trauma center during a period between February and December 2023, and their fractures were classified according to the FFP classification of Rommens and Hofmann. Complete sets of computer tomography (CT) and radiological images were available to determine the PT angle of the patients.RESULTS:34 FFP type 2 and 15 FFP type 3 classified patients were included in the study. Significant difference was seen in the pelvic tilt (PT) angle between the patient group with insufficiency fractures (n= 49; mean age: 78.02 ± 11.80) and the control group with lumbago patients (n= 53; mean age: 69.23 ± 11.23). The PT was significantly higher in the patients with insufficiency fractures (25.74° ± 4.76; p⁎⁎⁎⁎ ≤ 0.0001).CONCLUSIONS:The study demonstrates a significant extension of the PT angle of individuals with insufficiency fractures when compared to those with lumbago. The result suggests a potential association between pelvic tilt and fracture susceptibility.TRIAL REGISTRATION:A retrospective study about the influence of sagittal balance of the spine on insufficiency fractures of the posterior pelvic ring measured by the "pelvic tilt angle", DRKS00032120. Registered 20th June 2023 - Prospectively registered. Trial registration number DRKS00032120.