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Context
Primary aldosteronism (PA) is the most frequent form of endocrine hypertension. Besides its deleterious impact on cardiovascular target organ damage, PA is considered to cause osteoporosis.
Patients and methods
We assessed bone turnover in a subset of 36 postmenopausal women with PA. 18 patients had unilateral PA and were treated by adrenalectomy, whereas 18 patients had bilateral PA and received mineralocorticoid receptor antagonist (MRA) therapy respectively. 18 age- and BMI-matched females served as controls. To estimate bone remodeling, we measured the bone turnover markers intact procollagen 1 N-terminal propeptide, bone alkaline phosphatase, osteocalcin and tartrate resistant acid phosphatase 5b in plasma by chemiluminescent immunoassays at time of diagnosis and one year after initiation of treatment.
Study design
Observational longitudinal cohort study.
Setting
Tertiary care hospital.
Results
Compared with controls, patients with PA had mildly elevated osteocalcin at baseline (p = 0.013), while the other bone markers were comparable between both groups. There were no differences between the unilateral and the bilateral PA subgroup. One year after initiation of MRA treatment with spironolactone bone resorption and bone formation markers had significantly decreased in patients with bilateral PA. In contrast, patients adrenalectomized because of unilateral PA showed no significant change of bone turnover markers.
Conclusion
This study shows that aldosterone excess in postmenopausal women with PA is not associated with a relevant increase of bone turnover markers at baseline. However, we observed a significant decrease of bone markers in patients treated with spironolactone, but not in patients treated by adrenalectomy.
Patients affected by gastroenteropancreatic–neuroendocrine tumors (GEP–NETs) have an increased risk of developing osteopenia and osteoporosis, as several factors impact on bone metabolism in these patients. In fact, besides the direct effect of bone metastasis, bone health can be affected by hormone hypersecretion (including serotonin, cortisol, and parathyroid hormone-related protein), specific microRNAs, nutritional status (which in turn could be affected by medical and surgical treatments), and vitamin D deficiency. In patients with multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome associated with NET occurrence, bone damage may carry other consequences. Osteoporosis may negatively impact on the quality of life of these patients and can increment the cost of medical care since these patients usually live with their disease for a long time. However, recommendations suggesting screening to assess bone health in GEP–NET patients are missing. The aim of this review is to critically analyze evidence on the mechanisms that could have a potential impact on bone health in patients affected by GEP–NET, focusing on vitamin D and its role in GEP–NET, as well as on factors associated with MEN1 that could have an impact on bone homeostasis.
The glycoprotein sclerostin has been identified as a negative regulator of bone growth. It exerts its function by interacting with the Wnt co-receptor LRP5/6, blocks the binding of Wnt factors and thereby inhibits Wnt signalling. Neutralizing anti-sclerostin antibodies are able to restore Wnt activity and enhance bone growth thereby presenting a new osteoanabolic therapy approach for diseases such as osteoporosis. We have generated various Fab antibodies against human and murine sclerostin using a phage display set-up. Biochemical analyses have identified one Fab developed against murine sclerostin, AbD09097 that efficiently neutralizes sclerostin's Wnt inhibitory activity. In vitro interaction analysis using sclerostin variants revealed that this neutralizing Fab binds to sclerostin's flexible second loop, which has been shown to harbour the LRP5/6 binding motif. Affinity maturation was then applied to AbD09097, providing a set of improved neutralizing Fab antibodies which particularly bind human sclerostin with enhanced affinity. Determining the crystal structure of AbD09097 provides first insights into how this antibody might recognize and neutralize sclerostin. Together with the structure–function relationship derived from affinity maturation these new data will foster the rational design of new and highly efficient anti-sclerostin antibodies for the therapy of bone loss diseases such as osteoporosis.
Die Knochendichte ist ein Maß für die Bruchfestigkeit eines Knochens. Ihre Erfassung spielt eine wichtige Rolle in Prävention und Diagnostik der Osteoporose. Um die gemessenen Knochendichtewerte eines Patienten beurteilen zu können, sind Referenzwerte notwendig, die das Geschlecht, das Alter und bei den Frauen den Menopausenstatus mitberücksichtigen. Da geographisch bedingte Unterschiede in der Knochendichte bestehen, ist es sinnvoll Referenzdaten aus dem Gebiet zu rekrutieren, für das sie später auch gelten sollen. In der vorliegenden Studie wurde die Knochendichte an 3 Lokalisationen des proximalen Femur gemessen, am Schenkelhals, am Trochanter und am Ward´s Triangle. Das Kollektiv bestand aus 695 gesunden deutschen Männern und Frauen zwischen 18 und 80 Jahren, mit einer Gewichtung im mittleren Altersbereich. Anhand eines Fragebogens wurden das Alter, die Körpermaße und die wichtigsten anamnestischen Daten erfasst und nach Anwendung von Ausschlußkriterien nur gesunde, weder medikamentös, noch familiär belastete Probanden in die Auswertungen miteinbezogen. Die Probanden stammen aus 3 deutschen Städten, aus Halle, Chemnitz und Köln. Die Knochendichtemessungen wurden durch einen DXA Osteodensitometer (QDR 1000, Hologic) vorgenommen, der in einem Meßfahrzeug installiert war. Somit war der Einsatz desselben Osteodensitometers an verschiedenen Orten möglich und das Zusammenfügen der gemessenen Daten unproblematisch. Bei einem Teil des Kollektivs wurden Griffstärkemessungen durchgeführt. Die Probanden wurden getrenntgeschlechtlich in Dekaden unterteilt und für jede Altersgruppe die durchschnittliche Knochendichte mit Standardabweichung dargestellt. Für die Knochendichte am Schenkelhals und am Ward´s triangle wurden zusätzlich die Spannweiten zwischen plus/minus 1 Standardabweichung und plus/minus 2 Standardabweichungen ermittelt und tabellarisch aufgelistet. Untersucht wurde der Einfluß von Alter, Größe, Gewicht, bei einem Teilkollektiv der Griffstärke und bei den Frauen des Menopausenstatus auf die Knochendichte. Die Untersuchung führte zu folgenden Ergebnissen: - Die Analyse über den Altersgang der Knochendichte zeigt eine - mit zunehmendem Alter einhergehende - Abnahme der Konochendichte, insbesondere bei den Frauen. Stark betroffen ist dabei die Knochendichte am Ward´s Triangle, etwas geringer betroffen die Knochendichte am Schenkelhals. - Das Körpergewicht hat eine deutliche und begünstigende Wirkung auf die Knochendichte am proximalen Femur bei Männern und Frauen, insbesondere auf den Schenkelhals. Dieser Einfluß übertrifft in unserem, eher jüngeren Kollektiv auch die altersbedingte Wirkung an der Knochendichte. - Die Griffstärke repräsentiert die Muskelkraft, die bei den Männern und prämenopausalen Frauen eine positive und signifikante Korrelation zur Knochendichte zeigt. - Die Körpergröße hat verglichen mit den anderen anthropometrischen Werten eine geringe Auswirkung auf die Knochendichte am proximalen Femur. - Der Menopausenstatus beeinflußt die altersabhängigen Veränderungen an der Knochendichte, v.a. am Ward´s Triangle. So ist bei den postmenopausalen Frauen der jährliche Knochendichteverlust höher, als bei den Frauen vor der Menopause. - Wir fanden keine relevanten Unterschiede zwischen unseren Knochendichtewerten und den Werten von weißen US-Amerikanern aus einer anderen Studie. Das läßt auf eine Vergleichbarkeit von deutschen und nordamerikanischen Knochendichtewerten schließen.
Background
The role of cement-augmented screw fixation for calcaneal fracture treatment remains unclear. Therefore, this study was performed to biomechanically analyze screw osteosynthesis by reinforcement with either a calcium phosphate (CP)-based or polymethylmethacrylate (PMMA)-based injectable bone cement.
Methods
A calcaneal fracture (Sanders type IIA) including a central cancellous bone defect was generated in 27 synthetic bones, and the specimens were assigned to 3 groups. The first group was fixed with four screws (3.5 mm and 6.5 mm), the second group with screws and CP-based cement (Graftys (R) QuickSet; Graftys, Aix-en-Provence, France), and the third group with screws and PMMA-based cement (Traumacem (TM) V+; DePuy Synthes, Warsaw, IN, USA). Biomechanical testing was conducted to analyze peak-to-peak displacement, total displacement, and stiffness in following a standardized protocol.
Results
The peak-to-peak displacement under a 200-N load was not significantly different among the groups; however, peak-to-peak displacement under a 600- and 1000-N load as well as total displacement exhibited better stability in PMMA-augmented screw osteosynthesis compared to screw fixation without augmentation. The stiffness of the construct was increased by both CP- and PMMA-based cements.
Conclusion
Addition of an injectable bone cement to screw osteosynthesis is able to increase fixation strength in a biomechanical calcaneal fracture model with synthetic bones. In such cases, PMMA-based cements are more effective than CP-based cements because of their inherently higher compressive strength. However, whether this high strength is required in the clinical setting for early weight-bearing remains controversial, and the non-degradable properties of PMMA might cause difficulties during subsequent interventions in younger patients.
Summary
In adult hypophosphatasia (HPP) patients, elevated lumbar spine dual X-ray absorptiometry (DXA) values are associated with markers of disease severity and disease-specific fracture risk while femoral bone mineral density (BMD), being largely unaffected by the disease severity, may still be useful to monitor other causes of increased fracture risk due to low BMD.
Introduction
Hypophosphatasia (HPP) is a rare inherited metabolic disorder due to deficient activity of the tissue-nonspecific alkaline phosphatase (TNAP). Clinical manifestation in adult HPP patients is manifold including an increased risk for fractures, but data regarding clinical significance of DXA measurement and associations with fracture risk and disease severity is scarce.
Methods
Retrospective single-center analysis of DXA scans in patients with confirmed HPP (documented mutation, clinical symptoms, low alkaline phosphatase activity). Further data evaluation included disease-related fractures, laboratory results (alkaline phosphatase, pyridoxalphosphate, phosphoethanolamine), and medical history.
Results
Analysis included 110 patients (84 female, mean age of 46.2 years) of whom 37.3% (n = 41) were harboring two mutations. Average T-Score level at the lumbar spine was − 0.1 (SD 1.9), and mean total hip T-Score was − 1.07 (SD 0.15). Both lower ALP activity and higher substrate levels (pyridoxalphosphate and phosphoethanolamine) were significantly correlated with increased lumbar spine T-Score levels (p < 0.001) while BMD at the hip was not affected by indicators of disease severity. Increased lumbar spine BMD was significantly associated with an increased risk for HPP-related fractures, prevalent in 22 (20%) patients (p < 0.001) with 21 of them having biallelic mutations.
Conclusion
BMD in adult HPP patients is not systematically reduced. Conversely, increased lumbar spine BMD appears to be associated with severely compromised mineralization and increased risk for HPP-related fractures while BMD at the hip appears unaffected by indicators of disease severity, suggesting suitability of this anatomic location for assessing and discerning disorders with increased fracture risk owing to reduced BMD like osteoporosis.
Trial registration number
German register for clinical studies (DRKS00014022)
Date of registration
02/10/2018 – retrospectively registered
Sarcopenia and Malnutrition Screening in Female Osteoporosis Patients — A Cross-Sectional Study
(2021)
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.
Knowledge of local bone quality is essential for surgeons to determine operation techniques. A device for intraoperative measurement of local bone quality has been developed by the AO-Research Foundation (DensiProbe®). We used this device to experimentally measure peak breakaway torque of trabecular bone in the proximal femur and correlated this with local bone mineral density (BMD) and failure load. Bone mineral density of 160 cadaver femurs was measured by ex situ dual-energy X-ray absorptiometry. The failure load of all femurs was analyzed by side-impact analysis. Femur fractures were fixed and mechanical peak torque was measured with the DensiProbe® device. Correlation was calculated whereas correlation coefficient and significance was calculated by Fisher’s Z-transformation. Moreover, linear regression analysis was carried out. The unpaired Student’s t-test was used to assess the significance of differences. The Ward triangle region had the lowest BMD with 0.511 g/cm2 (±0.17 g/cm2), followed by the upper neck region with 0.546 g/cm2 (±0.16 g/cm2), trochanteric region with 0.685 g/cm2 (±0.19 g/cm2) and the femoral neck with 0.813 g/cm2 (±0.2 g/cm2). Peak torque of DensiProbe® in the femoral head was 3.48 Nm (±2.34 Nm). Load to failure was 4050.2 N (±1586.7 N). The highest correlation of peak torque measured by Densi Probe® and load to failure was found in the femoral neck (r=0.64, P<0.001). The overall correlation of mechanical peak torque with T-score was r=0.60 (P<0.001). A correlation was found between mechanical peak torque, load to failure of bone and BMD in vitro. Trabecular strength of bone and bone mineral density are different aspects of bone strength, but a correlation was found between them. Mechanical peak torque as measured may contribute additional information about bone strength, especially in the perioperative testing.
Dynamic resistance exercise (DRT) might be the most promising agent for fighting sarcopenia in older people. However, the positive effect of DRT on osteopenia/osteoporosis in men has still to be confirmed. To evaluate the effect of low‐volume/high‐intensity (HIT)‐DRT on bone mineral density (BMD) and skeletal muscle mass index (SMI) in men with osteosarcopenia, we initiated the Franconian Osteopenia and Sarcopenia Trial (FrOST). Forty‐three sedentary community‐dwelling older men (aged 73 to 91 years) with osteopenia/osteoporosis and SMI‐based sarcopenia were randomly assigned to a HIT‐RT exercise group (EG; n = 21) or a control group (CG; n = 22). HIT‐RT provided a progressive, periodized single‐set DRT on machines with high intensity, effort, and velocity twice a week, while CG maintained their lifestyle. Both groups were adequately supplemented with whey protein, vitamin D, and calcium. Primary study endpoint was integral lumbar spine (LS) BMD as determined by quantitative computed tomography. Core secondary study endpoint was SMI as determined by dual‐energy X‐ray absorptiometry. Additional study endpoints were BMD at the total hip and maximum isokinetic hip−/leg‐extensor strength (leg press). After 12 months of exercise, LS‐BMD was maintained in the EG and decreased significantly in the CG, resulting in significant between‐group differences (p < 0.001; standardized mean difference [SMD] = 0.90). In parallel, SMI increased significantly in the EG and decreased significantly in the CG (p < 0.001; SMD = 1.95). Total hip BMD changes did not differ significantly between the groups (p = 0.064; SMD = 0.65), whereas changes in maximum hip−/leg‐extensor strength were much more prominent (p < 0.001; SMD = 1.92) in the EG. Considering dropout (n = 2), attendance rate (95%), and unintended side effects/injuries (n = 0), we believe our HIT‐RT protocol to be feasible, attractive, and safe. In summary, we conclude that our combined low‐threshold HIT‐RT/protein/vitamin D/calcium intervention was feasible, safe, and effective for tackling sarcopenia and osteopenia/osteoporosis in older men with osteosarcopenia.
Osteoporose wird definiert als erworbene, generalisierte Skeletterkrankung, die durch eine verminderte Knochenfestigkeit und einen pathologischen Knochenverlust charakterisiert wird. Durch die Störung der Mikroarchitektur kommt es zu strukturellen und funktionellen Defiziten im Sinne von Fragilitätsfrakturen. Mechanische Stimulation erhält die Gewebemasse und stimuliert deren kontinuierliche Anpassung. Östrogene spielen bei der Entwicklung, dem Wachstum und der Regeneration des Knochens eine bedeutende Rolle und wirken über Bindung an die Östrogenrezeptoren ER und ER in bestimmten Zielgeweben. Östrogenrezeptoren sind unverändert sehr geeignete Targets für die Entwicklung von Medikamenten im Rahmen der Osteoporosetherapie wie z.B. die selektiven Östrogen-Rezeptor-Modulatoren (SERMs). Die molekulare Klärung der Einflüsse von ER und ER ist unverändert von großer klinischer Bedeutung. Die Herstellung stabiler Zelllinien mit Überexpression von Reportergenkonstrukten und Rezeptoren kann dabei hilfreich sein. In dieser Arbeit wurde eine stabile Zelllinie mit Überexpression von ERβ etabliert, die unterschiedliche Wirkung von ER und ER wurden analysiert und die Effekte von zyklischer Dehnung auf Reportergenexpression unter der Kontrolle von mechanosensitiven responsiven Elementen wurden charakterisiert.