Cellular pharmacodynamic effects of Pycnogenol® in patients with severe osteoarthritis: a randomized controlled pilot study

Background: The standardized maritime pine bark extract (Pycnogenol$^{®}$) has previously shown symptom alleviating effects in patients suffering from moderate forms of knee osteoarthritis (OA). The cellular mechanisms for this positive impact are so far unknown. The purpose of the present randomized pilot controlled study was to span the knowledge gap between the reported clinical effects of Pycnogenol$^{®}$ and its in vivo mechanism of action in OA patients. Methods: Thirty three patients with severe OA scheduled for a knee arthroplasty either received 100 mg of Pycnogenol$^{®}$ twice daily or no treatment (control group) three weeks before surgery. Cartilage, synovial fluid and serum samples were collected during surgical intervention. Relative gene expression of cartilage homeostasis markers were analyzed in the patients' chondrocytes. Inflammatory and cartilage metabolism mediators were investigated in serum and synovial fluid samples. Results: The oral intake of Pycnogenol$^{®}$ downregulated the gene expression of various cartilage degradation markers in the patients' chondrocytes, the decrease of MMP3, MMP13 and the pro-inflammatory cytokine IL1B were statistically significant (p ≤ 0.05). Additionally, protein concentrations of ADAMTS-5 in serum were reduced significantly (p ≤ 0.05) after three weeks intake of the pine bark extract. Conclusions: This is the first report about positive cellular effects of a dietary supplement on key catabolic and inflammatory markers in patients with severe OA. The results provide a rational basis for understanding previously reported clinical effects of Pycnogenol$^{®}$ on symptom scores of patients suffering from OA

Distribution of constituents and metabolites of maritime pine bark extract (Pycnogenol®^{®}) into serum, blood cells, and synovial fluid of patients with severe osteoarthritis: a randomized controlled trial

The present randomized controlled study aimed to investigate the in vivo distribution of constituents or metabolites of the standardized maritime pine bark extract Pycnogenol$^{®}$. Thirty-three patients with severe osteoarthritis scheduled for a knee arthroplasty were randomized to receive either 200 mg per day Pycnogenol$^{®}$ (P+) or no treatment (Co) over three weeks before surgery. Serum, blood cells, and synovial fluid samples were analyzed using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization (LC-ESI/MS/MS). Considerable interindividual differences were observed indicating pronounced variability of the polyphenol pharmacokinetics. Notably, the highest polyphenol concentrations were not detected in serum. Catechin and taxifolin primarily resided within the blood cells while the microbial catechin metabolite δ-(3,4-dihydroxy-phenyl)-γ-valerolactone, ferulic, and caffeic acid were mainly present in synovial fluid samples. Taxifolin was detected in serum and synovial fluid exclusively in the P+ group. Likewise, no ferulic acid was found in serum samples of the Co group. Calculating ratios of analyte distribution in individual patients revealed a simultaneous presence of some polyphenols in serum, blood cells, and/or synovial fluid only in the P+ group. This is the first evidence that polyphenols distribute into the synovial fluid of patients with osteoarthritis which supports rationalizing the results of clinical efficacy studies

analysing of their overlapping and their impact on partnership

Die Erektionsstörung (EDi), definiert als die anhaltende Unfähigkeit, eine adäquate Erektion zu erlangen, oder für eine befriedigende sexuelle Aktivität aufrecht zu erhalten, ist die zweithäufigste Sexualfunktions-Störung des Mannes (3, 4). Seit es immer mehr wissenschaftliche Arbeiten zur Prävalenz der Erektionsstörung gibt, steigen parallel dazu auch die Betrachtungsansätze, was deren Ursache betrifft. Unterschied man zu Beginn hierbei noch zwischen organischen und psychischen Ursachen, beginnt man langsam zu hinterfragen, ob hierbei nicht ein unmittelbares Ineinandergreifen vorliegen könnte (5). Parallel hierzu erregte ein weiteres gesellschaftliches Tabuthema wissenschaftliches Interesse, die sexuelle Präferenzstörung. In der Vergangenheit durchgeführte epidemiologische Studien legten nun den Verdacht nahe, ob nicht zwischen genau diesen beiden Tabuthemata Zusammenhänge bestehen könnten (8, 39). Jedoch wurde bis dato keine Analyse der Zusammenhänge zwischen Sexualität und der partnerschaftlichen Situation durchgeführt. Mittels des angepassten Fragebogens zum sexuellen Erleben und Verhalten (FSEV) wurden in einer standardisierten Interviewarbeit 46 Patienten, die zwischen Februar und September 2010 die andrologische Sprechstunde der Charité in Berlin Mitte besuchten und gleichzeitig an einer EDi litten, zu ihrer sexuellen Funktion, ihrer sexuellen Präferenz und ihrer partnerschaftlichen Zufriedenheit befragt (46). Ziel der Befragung war es, mögliche Korrelationen zwischen sexuellen Funktionsstörungen und sexuellen Präferenzstörungen herauszuarbeiten und deren Auswirkungen auf die partnerschaftliche Situation zu thematisieren. Die so gesammelten Daten wurden in eine digitale Rohdatenbank eingegeben und mit Hilfe deskriptiver statistischer Methoden ausgewertet. Zur Überprüfung der aufgestellten Hypothese, dass ein hoher Ausprägungsgrad an EDi mit einem hohen Ausprägungsgrad sexueller Präferenzstörungen einhergehe und, dass eine stark ausgeprägte paraphile Ansprechbarkeit/Paraphilie mit Leidensdruck sich auf die partnerschaftliche Situation auswirkt, wurde der Rangkorrelationskoeffizient Kendalls τb für ordinal skalierte Merkmale angewendet. Es zeigte sich, dass von den 46 befragten Patienten 36 tatsächlich an einer Erektionsstörung (EDi) im Sinne der Definition litten. Von diesen gaben 10 an keine paraphile Ansprechbarkeit vorzuweisen, 26 bejahten eine paraphile Ansprechbarkeit. Von diesen 26 konnten im Sinne der Definition 8 als Paraphile mit Leidensdruck identifiziert werden. Wie bereits in der Berliner Männerstudie (3) festgestellt wurde, konnten als häufigste Erregungsmuster Voyeurismus, Sadismus/Masochismus und Fetischismus festgestellt werden und im Rahmen dieser ebenfalls sehr häufig eine Vorliebe für „spezielle sexuelle Praktiken“ erfasst werden. Es fanden sich insgesamt 8 pädophil/hebephil orientierte Studienteilnehmer, die an EDi litten. Somit sollte überlegt werden, die Urologie, bzw. Andrologie als solche als neuen Ansatzpunkt zum Herausfiltern pädophil orientierter Männer zu betrachten. Bei der Korrelationsanalyse ergab sich ein tendenziell negativer Zusammenhang zwischen dem Schweregrad einer EDi und dem Ausprägungsgrad paraphiler Ansprechbarkeit/einer Paraphilie mit Leidensdruck. Das bedeutet, dass sich eher schwere Erektionsstörungen bei Patienten mit geringer sexueller Neigungsausprägung detektieren ließen. Es zeigte sich auch eine statistisch nahezu signifikante vermehrte partnerschaftliche Unzufriedenheit bei Patienten mit stärker ausgeprägter Paraphilie mit Leidensdruck. Daher sollten mehr Hypothesen bzgl. partnerschaftlicher Bindungssituation und Vorliegen einer sexuellen Präferenzstörung erhoben und geprüft werden, um multiple Ansätze in der Therapie sexueller Funktionsstörungen gewährleisten zu können, da sich eine belastete partnerschaftliche Beziehung an sich schon negativ auf die sexuelle Funktion auswirken kann. Denn nur innerhalb der Paarstruktur kann eine erfolgreiche Therapie sexueller Präferenzstörungen, die mit sexuellen Funktionsstörungen verbunden sind, stattfinden. Die Ergebnisse dieser Studie sollten mit Hinblick auf die kleine Stichprobe, den gewählten Studientyp und das besondere Patientenkollektiv betrachtet werden.Clinical experience over the last decades shows that sexual preference disorders can lead to sexual dysfunction. They might also affect partnership and sexual life in a negative way. Although this is a common theory in sexual medicine, nearly no data has been analyzed in this context so far. This study explores the association between erectile disorder and sexual paraphilias and their influence on an existing partnership in men who sought help in a urologic outpatient clinic of the Charité Berlin for their erectile disorder. These men took part in face-to-face interviews and completed the „Fragebogen zum sexuellen Erleben und Verhalten“ (FSEV) questionnaire. We found that the majority of these patients (N = 36) presented either with a paraphilia without significant strain (N = 18) or with significant strain ( N= 8). This fact alone is outstanding, because 15 out of 36 patients reported sexual preferences with potential endangerment to others (i.e. Exhibitionism, Frotteurism, Pedophilia, Hebephilia). These outcomes suggest that there are needs for specially addressing these problems within the urological/andrological evaluation. Correlations indicated that there are less relations between severity of an erectile disorder, than between the dimension of an impairment of the partnership and the severity of a sexual preference disorder. The patients even seemed to be more compromised by their impaired relationship status, than by the mere erectile disorder. So within a relationship, there are therapeutically possibilities, to work both on a sexual dysfunction and on the sexual preference disorder

Physical Function and Health‐Related Quality of Life in Adults Treated With Asfotase Alfa for Pediatric‐Onset Hypophosphatasia

Hypophosphatasia (HPP) is a rare, inherited, metabolic disease characterized by tissue‐nonspecific alkaline phosphatase deficiency resulting in musculoskeletal and systemic clinical manifestations. This observational study evaluated the effectiveness of enzyme replacement therapy with asfotase alfa on physical function and health‐related quality of life (HRQoL) among adults with pediatric‐onset HPP who received asfotase alfa for 12 months at a single center (ClinicalTrial.gov no.: NCT03418389). Primary outcomes evaluated physical function with the 6‐minute walk test (6MWT), timed up‐and‐go (TUG) test, Short Physical Performance Battery (SPPB), and handheld dynamometry (HHD). Secondary outcome measures included the Lower Extremity Functional Scale (LEFS), pain prevalence/intensity, and pain medication use; HRQoL was evaluated using the 36‐Item Short‐Form Health Survey version 2 (SF‐36v2). Safety data were collected throughout the study. All 14 patients (11 women) had compound heterozygous ALPL gene mutations and ≥1 HPP bone manifestation, including history of ≥1 fracture. Mean (min, max) age was 51 (19 to 78) years. From baseline to 12 months of treatment, median 6MWT distance increased from 267 m to 320 m (n = 13; p = 0.023); median TUG test time improved from 14.4 s to 11.3 s (n = 9; p = 0.008). Specific components of the SPPB also improved significantly: median 4‐m gait speed increased from 0.8 m/s to 1.1 m/s (n = 10; p = 0.007) and median repeated chair‐rise time improved from 22 s to 13 s (n = 9; p = 0.008). LEFS score improved from 24 points to 53 points (n = 10; p = 0.002). Improvements in HHD were not clinically significant. SF‐36v2 Physical Component Score (PCS) improved after 12 months of treatment (n = 9; p = 0.010). Pain level did not change significantly from baseline to 12 months of treatment. There were significant improvements on chair‐rise time and SF‐36v2 PCS by 3 months, and on TUG test time after 6 months. No new safety signals were identified. These results show the real‐world effectiveness of asfotase alfa in improving physical functioning and HRQoL in adults with pediatric‐onset HPP. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research

Sarcopenia and Malnutrition Screening in Female Osteoporosis Patients — A Cross-Sectional Study

Sarcopenia and malnutrition are important determinants of increased fracture risk in osteoporosis. SARC-F and MNA-SF are well-established questionnaires for identifying patients at risk for these conditions. We sought to evaluate the feasibility and potential added benefit of such assessments as well as the actual prevalence of these conditions in osteoporosis patients. We conducted a cross-sectional, single-center study in female osteoporosis patients ≥ 65 years (SaNSiBaR-study). Results of the sarcopenia (SARC-F) and malnutrition (MNA-SF) screening questionnaires were matched with a functional assessment for sarcopenia and data from patients’ medical records. Out of 107 patients included in the analysis, a risk for sarcopenia (SARC-F ≥ 4 points) and a risk for malnutrition (MNA-SF ≤ 11 points) was found in 33 (30.8%) and 38 (35.5%) patients, respectively. Diagnostic overlap with coincident indicative findings in both questionnaires was observed in 17 patients (16%). As compared to the respective not-at-risk groups, the mean short physical performance battery (SPPB) score was significantly reduced in both patients at risk for sarcopenia (7.0 vs. 10.9 points, p < 0.001) and patients at risk for malnutrition (8.7 vs. 10.5 points, p = 0.005). Still, confirmed sarcopenia according to EWGSOP2 criteria was present in only 6 (6%) of all 107 patients, with only 3 of them having an indicative SARC-F score. Bone mineral density was not significantly different in any of the at-risk groups at any site. In summary, applying SARC-F and MNA-SF in osteoporosis patients appears to be a complementary approach to identify individuals with functional deficits

Feasibility of simple exercise interventions for men with osteoporosis – A prospective randomized controlled pilot study

Background Aging is associated with progressive loss of musculoskeletal performance. Exercise interventions can improve physical function in the elderly but there is a paucity of comparative assessments in order to understand what specific goals can be achieved particularly with less demanding exercise interventions readily accessible for untrained men. Methods Prospective randomized, controlled, single center exploratory trial to compare four distinct exercise interventions, i.e. Resistance Training (RT), Whole Body Vibration Exercise (WBV), Qi Gong (QG) and wearing a Spinal orthosis (SO) for 6 months in men at risk for osteoporosis aged 65–90 years. Primary endpoint was change in isometric one repetition maximum force trunk strength for extension (TSE) and flexion (TSF) compared to baseline, secondary endpoints covered key parameters of geriatric functional assessment, including Handgrip Strength (HS), Chair-Rise-Test (CRT), Usual Gait Speed (UGS) and Timed-Up-and-Go (TUG). Results Altogether 47 men (mean age 77 ±6.1 years) were randomized to RT, (n = 11) WBV (n = 13), QG (n = 10) and SO(n = 13). RT, defined as reference exercise intervention, lead to significant improvements for TSE (p = 0.009) and TSF (p = 0.013) and was significantly superior in the between-group analysis for TSE (p = 0.038). Vibration exercise caused sign. Improvements in TSE (p = 0.014) and CRT (p = 0.005), the Spinal orthosis improved CRT (p = 0.003) and Gait Speed (p = 0.027), while the QG intervention did not attain any sig. Developments. Subgroup analyses revealed most pronounced musculoskeletal progress in vulnerable patients (age ≥ 80 years, pre-sarcopenia, multimorbidity ≥3chronic diseases). Irrespective of the type of exercise, participants ≥80 years experienced significant gains in TSE (p = 0.029) and CRT (p = 0.017). Presarcopenic subjects (Skeletal muscle Index (SMI) ≤10.75 kg/m2) improved in TSE (p = 0.003), CRT (p = 0.001) and UGS (p = 0.016). Multimorbid participants achieved sig. Gains in TSE (p < 0.001), TSF (p = 0.002), UGS (p = 0.036) and HS (p = 0.046). Conclusions In this exploratory trial we found that simple exercise interventions are feasible in elderly men eliciting specific benefits, i.e. improvements are attained in those tasks addressed with the respective exercise modality. While targeted resistance training is superior in increasing TSE, alternative simple exercise interventions also appear to elicit beneficial effects, even in vulnerable patients, i.e. those with low muscle mass, above 80 years of age or multimorbidity

Treatments for Hypophosphatasia

Hypophosphatasia due to genetically determined deficient activity of the tissue non-specific alkaline phosphatase (TNAP) is characterized by a wide spectrum of potential clinical manifestations, both, regarding the type of symptoms, as well as the severity of associated deficits. Appropriate treatment strategies should be built on a multimodal approach specifically considering individual disease manifestation. For patients with disease onset before adulthood, enzyme replacement therapy with Asfotase alfa (Strensiq) is approved in Europe to treat the bone manifestation of the disease. Both, available data from clinical trials as well as clinical routine experience confirm basically encouraging results of that treatment in severely affected children with substantial improvement regarding radiographic and functional outcome parameters as well as overall survival. Even in adult patients with severe disease manifestation pursuant to the approval, first results confirm substantial amelioration of disease-specific deficits and functional improvements. Meanwhile, there is also data supporting safety and efficacy of long-term treatment Asfotase alfa over several years. While inflammatory pain, which is typically perceived as being burdensome, can commonly be addressed successfully with NSAIDs on-demand, overall musculoskeletal health requires sustained, multimodal, supportive treatment strategies including exercise interventions as well as age and health state adjusted technical orthopedic support. The use and potential clinical impact of Phosphate and Vitamin B6 on the course of the disease requires further investigation. Current data regarding the use of bone-targeted compounds is critical in terms of antiresorptives while osteoanabolic treatment strategies appear feasible. Ideally, the entirety of therapeutic measures should be coordinated and overlooked at an experienced center while individual tasks can preferably be accomplished at local facilities near the patient's home

Efficacy of Zoledronic Acid in the Treatment of Nonmalignant Painful Bone Marrow Lesions: A Triple‐Blind, Randomized, Placebo‐Controlled Phase III Clinical Trial (ZoMARS)

Bone marrow lesions (BML) represent areas of deteriorated bone structure and metabolism characterized by pronounced water‐equivalent signaling within the trabecular bone on magnetic resonance imaging (MRI). BML are associated with repair mechanisms subsequent to various clinical conditions associated with inflammatory and non‐inflammatory injury to the bone. There is no approved treatment for this condition. Bisphosphonates are known to improve bone stability in osteoporosis and other bone disorders and have been used off‐label to treat BML. A randomized, triple‐blind, placebo‐controlled phase III trial was conducted to assess efficacy and safety of single‐dose zoledronic acid (ZOL) 5 mg iv with vitamin D 1000 IU/d as opposed to placebo with vitamin D 1000 IU/d in 48 patients (randomized 2:1) with BML. Primary efficacy endpoint was reduction of edema volume 6 weeks after treatment as assessed by MRI. After treatment, mean BML volume decreased by 64.53% (±41.92%) in patients receiving zoledronic acid and increased by 14.43% (±150.46%) in the placebo group (p = 0.007). A decrease in BML volume was observed in 76.5% of patients receiving ZOL and in 50% of the patients receiving placebo. Pain level (visual analogue scale [VAS]) and all categories of the pain disability index (PDI) improved with ZOL versus placebo after 6 weeks but reconciled after 6 additional weeks of follow‐up. Six serious adverse events occurred in 5 patients, none of which were classified as related to the study drug. No cases of osteonecrosis or fractures occurred. Therefore, single‐dose zoledronic acid 5 mg iv together with vitamin D may enhance resolution of bone marrow lesions over 6 weeks along with reduction of pain compared with vitamin D supplementation only

Insuffizienzfraktur der Klavikula nach Implantation einer inversen Schulterendoprothese

Wir stellen den seltenen Fall einer Insuffizienzfraktur der Klavikula nach Implantation einer inversen Schulterendoprothese (RSA) vor. Als Ursache solcher Frakturen wird eine vermehrte Zugbelastung durch den Musculus deltoideus nach RSA diskutiert. In den wenigen verfügbaren Fallberichten zeigten die betroffenen Patienten deutliche Funktionseinschränkungen. Die Versorgung erfolgte im vorliegenden Fall mit Plattenosteosynthese. Trotz intraoperativ gutem Korrekturergebnis kam es im Verlauf ohne Trauma zum Osteosyntheseversagen mit weiterer Dislokation der Fraktur