Effects of asfotase alfa in adults with pediatric-onset hypophosphatasia over 24 months of treatment.

BACKGROUND: Hypophosphatasia (HPP) is a rare, heritable metabolic disorder caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Asfotase alfa (AA) is a human recombinant TNSALP that promotes bone mineralization and is approved to treat eligible patients with HPP. METHODS: This prospective single-center observational study evaluated AA in adults with pediatric-onset HPP over 2 years of treatment (ClinicalTrials.govNCT03418389). Primary outcomes evaluated physical function; secondary outcomes assessed quality of life (QoL) and pain. RESULTS: The study included 17 females and 5 males (mean age: 48.7 years). Median distance walked in the 6-Minute Walk Test increased significantly from baseline to 12 months (P = 0.034) and results were sustained. Median Timed Up and Go test time significantly decreased from baseline at 12 (P = 0.003) and 24 months (P = 0.005), as did the median chair rise time test at 12 (P = 0.003) and 24 months (P < 0.002). The change from baseline in usual gait speed was significant at 12 (P = 0.003) and 24 months (P = 0.015). Mean dominant and nondominant hand grip strength improved at 24 months (P = 0.029 and P = 0.019, respectively). Median Short Form 36 Physical Component Summary scores significantly improved from baseline at 12 (P = 0.012) and 24 (P = 0.005) months, and median Lower Extremity Functional Scale scores improved from baseline at 12 (P = 0.001) and 24 (P = 0.002) months. No significant change was noted in pain level at these timepoints. While injection site reactions occurred in 86.4 % of the participants, there were no severe side effects or safety findings. CONCLUSIONS: Adults with pediatric-onset HPP treated with AA experienced marked improvement in functional and QoL outcomes that were observed as early as within 3 months of initial treatment and were sustained over 24 months.

Metal artifact reduction in ultra-high-resolution cone-beam CT imaging with a twin robotic X-ray system.

Cone-beam computed tomography (CBCT) has been shown to be a powerful tool for 3D imaging of the appendicular skeleton, allowing for detailed visualization of bone microarchitecture. This study was designed to compare artifacts in the presence of osteosynthetic implants between CBCT and multidetector computed tomography (MDCT) in cadaveric wrist scans. A total of 32 scan protocols with varying tube potential and current were employed: both conventional CBCT and MDCT studies were included with tube voltage ranging from 60 to 140 kVp as well as additional MDCT protocols with dedicated spectral shaping via tin prefiltration. Irrespective of scanner type, all examinations were conducted in ultra-high-resolution (UHR) scan mode. For reconstruction of UHR-CBCT scans an additional iterative metal artifact reduction algorithm was employed, an image correction tool which cannot be used in combination with UHR-MDCT. To compare applied radiation doses between both scanners, the volume computed tomography dose index for a 16 cm phantom (CTDIvol) was evaluated. Images were assessed regarding subjective and objective image quality. Without automatic tube current modulation or tube potential control, radiation doses ranged between 1.3 mGy (with 70 kVp and 50.0 effective mAs) and 75.2 mGy (with 140 kVp and 383.0 effective mAs) in UHR-MDCT. Using the pulsed image acquisition method of the CBCT scanner, CTDIvol ranged between 2.3 mGy (with 60 kVp and 0.6 mean mAs per pulse) and 61.0 mGy (with 133 kVp and 2.5 mean mAs per pulse). In essence, all UHR-CBCT protocols employing a tube potential of 80 kVp or more were found to provide superior overall image quality and artifact reduction compared to UHR-MDCT (all p < .050). Interrater reliability of seven radiologists regarding image quality was substantial for tissue assessment and moderate for artifact assessment with Fleiss kappa of 0.652 (95% confidence interval 0.618-0.686; p < 0.001) and 0.570 (95% confidence interval 0.535-0.606; p < 0.001), respectively. Our results demonstrate that the UHR-CBCT scan mode of a twin robotic X-ray system facilitates excellent visualization of the appendicular skeleton in the presence of metal implants. Achievable image quality and artifact reduction are superior to dose-comparable UHR-MDCT and even MDCT protocols employing spectral shaping with tin prefiltration do not achieve the same level of artifact reduction in adjacent soft tissue.

Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders.

CONTEXT: Many different inherited and acquired conditions can result in premature bone fragility/low bone mass disorders (LBMDs). OBJECTIVE: We aimed to elucidate the impact of genetic testing on differential diagnosis of adult LBMDs and at defining clinical criteria for predicting monogenic forms. METHODS: Four clinical centers broadly recruited a cohort of 394 unrelated adult women before menopause and men younger than 55 years with a bone mineral density (BMD) Z-score < -2.0 and/or pathological fractures. After exclusion of secondary causes or unequivocal clinical/biochemical hallmarks of monogenic LBMDs, all participants were genotyped by targeted next-generation sequencing. RESULTS: In total, 20.8% of the participants carried rare disease-causing variants (DCVs) in genes known to cause osteogenesis imperfecta (COL1A1, COL1A2), hypophosphatasia (ALPL), and early-onset osteoporosis (LRP5, PLS3, and WNT1). In addition, we identified rare DCVs in ENPP1, LMNA, NOTCH2, and ZNF469. Three individuals had autosomal recessive, 75 autosomal dominant, and 4 X-linked disorders. A total of 9.7% of the participants harbored variants of unknown significance. A regression analysis revealed that the likelihood of detecting a DCV correlated with a positive family history of osteoporosis, peripheral fractures (> 2), and a high normal body mass index (BMI). In contrast, mutation frequencies did not correlate with age, prevalent vertebral fractures, BMD, or biochemical parameters. In individuals without monogenic disease-causing rare variants, common variants predisposing for low BMD (eg, in LRP5) were overrepresented. CONCLUSION: The overlapping spectra of monogenic adult LBMD can be easily disentangled by genetic testing and the proposed clinical criteria can help to maximize the diagnostic yield.

[Clavicle stress fracture following reverse shoulder arthroplasty]. / Insuffizienzfraktur der Klavikula nach Implantation einer inversen Schulterendoprothese.

We present a rare case of clavicle fracture following reverse shoulder arthroplasty (RSA). This complication may be caused by the higher tension of the deltoid muscle after RSA, similarly to stress fractures of the acromion. Associated bone disease, i.e. osteoporosis, may contribute. In the few case reports available, the affected patients showed significant functional impairments. In the current case, the fracture was addressed with plate fixation. Despite good intraoperative results, osteosynthesis failure with secondary dislocation of the fracture occurred.

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. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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.

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.

Differential impact of osteoporosis, sarcopenia and obesity on physical performance in aging men.

PURPOSE: Aging and concurrent constitutional changes as sarcopenia, osteoporosis and obesity are associated with progressive functional decline. Coincidence and mutual interference of this risk factors require further evaluation. METHODS: Cross-sectional evaluation of musculoskeletal health in a community-dwelling cohort of men aged 65-90 years. Objectives included descriptive analysis of age-related decline in physical performance, prevalence of osteoporosis (FRAX-Score), sarcopenia (EWGSOP criteria) and obesity (BMI > 30 kg/m2) and their coincidence/interference. RESULTS: Based on 507 participants assessed, aging was associated with progressive functional deterioration, regarding power (chair rise test -1.54% per year), performance (usual gait speed -1.38% per year) and muscle force (grip strength -1.52% per year) while muscle mass declined only marginally (skeletal muscle index -0.29% per year). Prevalence of osteoporosis was 41.8% (n = 212) while only 22.9% (n = 116) of the participants met the criteria for sarcopenia and 23.7% (n = 120) were obese. Osteosarcopenia was found in n = 79 (15.6%), sarcopenic obesity was present in 14 men (2.8%). A combination of all three conditions could be confirmed in n = 8 (1.6%). There was an inverse correlation of BMI with physical performance whereas osteoporosis and sarcopenia did not interfere with functional outcomes. CONCLUSION: Based on current definitions, there is considerable overlap in the prevalence of osteoporosis and sarcopenia, while obesity appears to be a distinct problem. Functional decline appears to be associated with obesity rather than osteoporosis or sarcopenia. It remains to be determined to what extend obesity itself causes performance deficits or if obesity is merely an indicator of insufficient activity eventually predisposing to functional decline.

Impact of whole-body vibration exercise on physical performance and bone turnover in patients with monoclonal gammopathy of undetermined significance.

OBJECTIVE: Monoclonal Gammopathy of Undetermined Significance (MGUS) is a risk factor for reduced physical performance, osteoporosis, and fractures due to compromised musculoskeletal metabolism. In this condition it is unknown whether whole-body vibration (WBV) exercise favorably alters physical performance and bone metabolism. METHODS: To evaluate the effect of three-months WBV exercise (30 min; 2x/week) including an optional three-month extension on physical performance, bone metabolism and bone mineral density. Endpoints included functional assessments, bone turnover markers and bone mineral density assessed by peripheral quantitative computed tomography of the tibia. RESULTS: Fifteen MGUS patients (median age 62.0, nine female) completed the first three months of which ten completed the three-month extension. Measures of physical functioning including chair rise test, timed up and go and 6-minute walk test improved (p = 0.007; p = 0.009; p = 0.005) after three and six months of WBV exercise. Total tibial bone mineral density remained unaltered (p > 0.05). WBV exercise tended to increase levels of sclerostin (p = 0.093) with a transient increase in osteoclast resorption markers (N-terminal telopeptide of collagen type 1, tartrate resistant acid phosphatase 5b) after three months while Dickkopf-1 (p = 0.093), procollagen I N-terminal propeptide (p = 0.074) and total alkaline phosphatase (p = 0.016) appeared to decline. No exercise-related adverse events were reported. CONCLUSION: WBV exercise in MGUS patients improves indicators of physical performance. Observed trends in bone turnover markers and changes in distal tibial bone mineral density may indicate a regulatory effect of WBV exercise on bone metabolism and warrants further evaluation by large scale studies.

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.

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. TRIAL REGISTRATION: ISRCTN10754119 . Retrospectively registered 08/10/2015.

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.