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Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of healthy hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease who were undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variant allele frequencies [VAFs] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF, 1% to 2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%), and ASXL1 (3.5%). CHIP is significantly associated with lower hemoglobin, higher mean corpuscular volume, previous or present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AIDs; multivariable adjusted odds ratio, 6.6; 95% confidence interval, 1.7-30; P = .0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for managing patients with OA and AIDs or mild anemia and question the use of hip bone–derived cells as healthy experimental controls.

The bone marrow microenvironment (BMME) plays a key role in the pathophysiology of myelodysplastic syndromes (MDS), clonal blood disorders affecting the differentiation, and maturation of hematopoietic stem and progenitor cells (HSPCs). In lower-risk MDS patients, ineffective late-stage erythropoiesis can be restored by luspatercept, an activin receptor type IIB ligand trap. Here, we investigated whether luspatercept can modulate the functional properties of mesenchymal stromal cells (MSCs) as key components of the BMME. Luspatercept treatment inhibited Smad2/3 phosphorylation in both healthy and MDS MSCs and reversed disease-associated alterations in SDF-1 secretion. Pre-treatment of MDS MSCs with luspatercept restored the subsequent clonogenic potential of co-cultured HSPCs and increased both their stromal-adherence and their expression of both CXCR4 and ß3 integrin. Luspatercept pre-treatment of MSCs also increased the subsequent homing of co-cultured HSPCs in zebrafish embryos. MSCs derived from patients who had received luspatercept treatment had an increased capacity to maintain the colony forming potential of normal but not MDS HSPCs. These data provide the first evidence that luspatercept impacts the BMME directly, leading to a selective restoration of the ineffective hematopoiesis that is a hallmark of MDS.

Context Serum expression of microRNAs (miRs) related to bone metabolism is affected by antiosteoporotic treatment. Objective To investigate the effect of sequential treatments on miR expression in postmenopausal women with osteoporosis. Design Observational, open label, nonrandomized clinical trial. Setting A single-center outpatient clinic. Patients and Interventions Denosumab (Dmab) was administered for 12 months in 37 women who were treatment-naïve (naïve group) (n = 11) or previously treated with teriparatide (TPTD group) (n = 20) or zoledronate (ZOL group) (n = 6). Main Outcome Measures Relative serum expression of miRs linked to bone metabolism at 3 and 6 months of Dmab treatment. Results Baseline relative expression of miR-21a-5p, miR-23a-3p, miR-29a-3p, and miR-338-3p was higher in the TPTD group, while the relative expression of miR-21a-5p was lower in the ZOL group compared to the naïve group. Dmab decreased the relative expression of miR-21a-5p at 3 months (fold change [FC] 0.43, P Conclusions TPTD treatment potentially affects the expression of the pro-osteoclastogenic miR-21a-5p and miRs related to the expression of osteoblastic genes RUNX2 (miR23a-3p), COL1 (miR-29a-3p), and HDAC5 (miR-2861), while sequential treatment with Dmab acts in the opposite direction.

Periostin is a secreted extracellular matrix protein, which was originally described in osteoblasts. It supports osteoblastic differentiation and bone formation and has been implicated in the pathogenesis of several human malignancies, including breast cancer. However, little is known about the prognostic value of serum periostin levels in breast cancer. In this study, we analyzed serum levels of periostin in a cohort of 509 primary, non-metastatic breast cancer patients. Disseminated tumor cell (DTC) status was determined using bone marrow aspirates obtained from the anterior iliac crests. Periostin levels were stratified according to several clinical parameters and Pearson correlation analyses were performed. Kaplan–Meier survival curves were assessed by using the log-rank (Mantel–Cox) test. To identify prognostic factors, multivariate Cox regression analyses were used. Mean serum levels of periostin were 505 ± 179 pmol/l. In older patients (> 60 years), periostin serum levels were significantly increased compared to younger patients (540 ± 184 pmol/l vs. 469 ± 167 pmol/l; p

Context Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of hypoparathyroidism. Objective This work aimed to investigate the safety, tolerability, and efficacy of daily TransCon PTH in adults with hypoparathyroidism. Methods This phase 2, randomized, double-blind, placebo-controlled 4-week trial with open-label extension enrolled 59 individuals with hypoparathyroidism. Interventions included TransCon PTH 15, 18, or 21 µg PTH(1-34)/day or placebo for 4 weeks, followed by a 22-week extension during which TransCon PTH dose was titrated (6-60 µg PTH[1-34]/day). Results By Week 26, 91% of participants treated with TransCon PTH achieved independence from standard of care (SoC, defined as active vitamin D = 0 μg/day and calcium [Ca] ≤ 500 mg/day). Mean 24-hour urine Ca (uCa) decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while normal serum Ca (sCa) was maintained and serum phosphate and serum calcium-phosphate product fell within the normal range. By Week 26, mean scores on the generic 36-Item Short Form Health Survey domains increased from below normal at baseline to within the normal range. The Hypoparathyroidism Patient Experience Scale symptom and impact scores improved through 26 weeks. TransCon PTH was well tolerated with no treatment-related serious or severe adverse events. Conclusion TransCon PTH enabled independence from oral active vitamin D and reduced Ca supplements (≤ 500 mg/day) for most participants, achieving normal sCa, serum phosphate, uCa, serum calcium-phosphate product, and demonstrating improved health-related quality of life. These results support TransCon PTH as a potential hormone replacement therapy for adults with hypoparathyroidism.

Background Ten–eleven translocation methylcytosine dioxygenase 1 (TET1) is involved in DNA demethylation and transcriptional regulation, plays a key role in the maintenance of stem cell pluripotency, and is dysregulated in malignant cells. The identification of cancer stem cells (CSCs) driving tumor growth and metastasis is the primary objective of biomarker discovery in aggressive prostate cancer (PCa). In this context, we analyzed TET1 expression in PCa. Methods A large-scale immunohistochemical analysis of TET1 was performed in normal prostate (NOR) and PCa using conventional slides (50 PCa specimens) and tissue microarrays (669 NOR and 1371 PCa tissue cores from 371 PCa specimens). Western blotting, RT-qPCR, and 450 K methylation array analyses were performed on PCa cell lines. Genome-wide correlation, gene regulatory network, and functional genomics studies were performed using publicly available data sources and bioinformatics tools. Results In NOR, TET1 was exclusively expressed in normal cytokeratin 903 (CK903)–positive basal cells. In PCa, TET1 was frequently detected in alpha-methylacyl-CoA racemase (AMACR)–positive tumor cell clusters and was detectable at all tumor stages and Gleason scores. Pearson’s correlation analyses of PCa revealed 626 TET1-coactivated genes (r > 0.5) primarily encoding chromatin remodeling and mitotic factors. Moreover, signaling pathways regulating antiviral processes (62 zinc finger, ZNF, antiviral proteins) and the pluripotency of stem cells were activated. A significant proportion of detected genes exhibited TET1-correlated promoter hypomethylation. There were 161 genes encoding transcription factors (TFs), of which 133 were ZNF-TFs with promoter binding sites in TET1 and in the vast majority of TET1-coactivated genes. Conclusions TET1-expressing cells are an integral part of PCa and may represent CSCs with oncogenic potential.

Neuropilin-2 (NRP2) is a member of the neuropilin receptor family and known to regulate autophagy and mTORC2 signaling in prostate cancer (PCa). Our study investigated the association of immunohistochemical NRP2 expression with clinicopathological data in PCa patients. For this purpose, we generated a tissue microarray with prostate tissue specimens from 400 PCa patients treated by radical prostatectomy. We focused on patients with high-risk factors such as extraprostatic extension (pT ≥ 3), Gleason score ≥8 and/or the presence of regional lymph node metastases (pN1). Protein levels of NRP2, the vascular endothelial growth factor C (VEGFC) and oncogenic v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) gene as an indicator for TMPRSS2-ERG fusion was assessed in relation to the patients' outcome. NRP2 emerged as an independent prognostic factor for cancer-specific survival (CSS) (hazard ratio 2.360, 95% confidence interval = 1.2-4.8; p = 0.016). Moreover, the association between NRP2 expression and shorter CSS was also especially pronounced in patients at high risk for progression (log-rank test: p = 0.010). We evaluated the association between NRP2 and the TMPRSS2-ERG gene fusion status assessed by immunohistochemical nuclear ERG staining. However, ERG staining alone did not show any prognostic significance. NRP2 immunostaining is significantly associated with shorter CSS in ERG-negative tumors (log-rank test: p = 0.012). No prognostic impact of NRP2 expression on CSS was observed in ERG-positive tumors (log-rank test: p = 0.153). Our study identifies NRP2 as an important prognostic marker for a worse clinical outcome especially in patients with a high-risk PCa and in patients with ERG-negative PCa.

Background Neuropilin-1 (NRP-1) is a transmembrane protein that acts as a multifunctional non-tyrosine kinase receptor with an established role in development and immunity. NRP-1 also regulates tumor biology, and high expression levels of tissue NRP-1 have been associated with a poor prognosis. Recently, ELISA-based quantification of soluble NRP-1 (sNRP-1) has become available, but little is known about the prognostic value of sNRP-1 in malignancies. Materials and methods We measured sNRP-1 in the serum of 509 patients with primary early breast cancer (BC) at the time of diagnosis using ELISA. Results Mean serum values of sNRP-1 were 1.88 ± 0.52 nmol/l (= 130.83 ± 36.24 ng/ml). SNRP-1 levels weakly correlated with age, and were higher in peri- and postmenopausal patients compared to premenopausal patients, respectively (p p = 0.005; HR 1.94; 95%CI 1.23–3.06). These findings remained significant after adjustment for tumor stage including lymph node involvement, grading, hormone receptor, HER2 status, and age (p = 0.022; HR 1.78; 95%CI 1.09–2.91). Conclusion Our findings warrant further investigations into the prognostic and therapeutic potential of sNRP-1 in BC.

Prostate cancer (PCa) is a major cause of cancer‐related death in men. Tumor‐derived protein derived from Wnt5A gene (WNT5A) plays an important role in primary and metastatic PCa. Surrounding stroma cells also produce WNT5A, which may modulate the biology of PCa. Here, we assessed the role of stroma‐derived WNT5A (stWNT5A) in primary PCa. A tissue microarray of samples obtained from 400 patients who underwent radical prostatectomy and control samples from 41 patients with benign prostate hyperplasia (BPH) was immunohistochemically assessed for expression of stWNT5A. The cores were scored for staining intensity: 0 (no staining), 1 (weak), 2 (moderate), or 3 (strong) and the stained stromal surface area: 0 (0%), 1 (1–25%), 2 (26–50%), 3 (51–75%), or 4 (76–100%). Gleason Score (GS) and TNM‐stage were assessed by stratifying the cohort into high‐risk (≥ pT3, pN1, GS ≥ 8) and non‐high‐risk patients. Ki67 and TUNEL assays were performed to assess proliferation and apoptosis. Expression of stWNT5A in BPH and tumor‐free control samples was 1.2‐fold higher compared to tumor samples (P, Protein derived from Wnt5A gene (WNT5A) plays an important role in primary and metastatic prostate cancer (PCa). Tumor cells and surrounding stroma cells produce WNT5A. In a tissue microarray, we assessed the role of stroma‐derived WNT5A (stWNT5A) in primary PCa. Expression of stWNT5A is higher in benign tissue and non‐high‐risk PCa.

Over the past years, a growing demand for testosterone replacement therapy in aging men has been noted in the US as well as in Europe. The current evidence for detrimental consequences of low testosterone in old men is largely based on retrospective studies. On the other hand, prospective placebo-controlled randomized trials investigating clinically relevant endpoints are limited. Clinical benefits of testosterone replacement therapy in ageing men include improved sexual function and libido, increase in muscle mass and -function, as well as bone mass accrual. Whether testosterone supplementation in ageing men confers an altered risk for cardiovascular disease and/or prostate cancer remains unclear. Ongoing clinical trials (e. g. TRAVERSE trial, NCT03 518 034) will help to resolve these questions.Der Testosteronmangel des alternden Mannes ist nach wie vor nicht präzise definiert. Verschiedene Fachgesellschaften fordern zwar unisono das Vorliegen spezifischer klinischer Symptome in Verbindung mit konsistent erniedrigten morgendlichen Testosteronspiegeln. Allerdings existieren für letztere keine einheitlichen Grenzwerte. Erschwerend kommt hinzu, dass einzelne Symptome des Testosteronmangels bei unterschiedlichen Testosteron-Schwellenwerten auftreten können. TESTOSTERONERSATZTHERAPIE – ANTI-AGING ODER FALSCHE HOFFNUNG?: Während zahlreiche retrospektive und kleinere prospektive Studien mit suboptimalem Design den Nutzen einer Testosteronersatztherapie im Alter nahelegen, existieren nur wenige Placebo-kontrollierte, randomisierte, doppelt verblindete Untersuchungen, die klinisch relevante Endpunkte verlässlich untersucht haben. Zu diesen zählen: · Libido und Sexualfunktion: Der Ausgleich eines Testosterondefizits im Alter ist mit einer Steigerung von Libido und sexueller Aktivität verbunden. Die Effekte auf die Erektionsfähigkeit sind inkonsistent.. · Muskelmasse und -funktion: Die transdermale Testosteronsupplementierung führt zu einer Zunahme der fettfreien Masse und erhöht gewisse Aspekte der körperlichen Leistungsfähigkeit (Gehstrecke in 6 Minuten, Treppensteigen etc.). · Knochendichte: Eine Testosteronsubstitution erhöht die Knochendichte. Inwieweit diese Veränderungen das individuelle Frakturrisiko senken, bleibt unklar.. · Offene Fragen: Unzureichend definiert bleiben die Auswirkungen einer Testosteronersatztherapie auf das kardiovaskuläre System und das Risiko für die Entwicklung eines Prostatakarzinoms. Die Ergebnisse einer zuletzt initiierten großen klinischen Studie („TRAVERSE Trial“, NCT03518034) mit 5-jährigem Follow-up werden helfen, den kardiovaskulären Aspekt zu klären..

Summary: Background: Older adult patients (ie, those aged ≥60 years) undergoing surgery for hip fracture repair frequently experience loss of muscle mass and strength due to poor mobility and delayed functional recovery. No proven treatment is currently available to enhance recovery of physical function in this growing patient population. This study aimed to investigate whether bimagrumab, a human monoclonal antibody targeting activin type 2 receptors, can improve post-surgical recovery. Methods: This multicentre, double-blind, randomised, parallel-group, placebo-controlled, phase 2a/b trial was done at 50 clinical research centres in 18 countries. Participants aged 60 years or older with a body-mass index of 15–35 kg/m2 who had undergone internal fixation or hemiarthroplasty for a proximal femoral fracture (confirmed by radiography) in the previous 6 weeks were eligible. Patients with a history of a high-energy subtrochanteric fracture or any other lower limb fracture in the past 6 months, or any major surgery of the lower limbs in the past 3 months were excluded. Participants were randomly assigned (2:1:2:2) via interactive response technology to receive intravenous treatment with placebo, bimagrumab 70 mg, bimagrumab 210 mg, or bimagrumab 700 mg every 4 weeks for 24 weeks. Participants, investigators, site personnel, and study sponsor personnel in participating countries were masked to treatment assignment. The primary endpoint was the change from baseline in total lean body mass, measured by dual-energy x-ray absorptiometry, at week 24 in the full analysis set, which included all randomised participants who had received at least one dose of the assigned treatment. Key secondary endpoints included changes in habitual gait speed (measured in m/s) and short physical performance battery score between baseline and 24 weeks. Safety and tolerability were assessed by recording adverse events and vital signs on weeks 4, 8, 12, 24, and 48, and by laboratory assessments and electrocardiography at the screening visit and on days 1, 84, and 168. Safety was assessed in all randomised participants who had received at least one dose of study drug, analysed according to treatment received. This study was registered with ClinicalTrials.gov, NCT02152761. Findings: Between Sept 16, 2014, and Dec 15, 2017, 384 patients were screened, of whom 250 patients were enrolled and randomly assigned to the placebo group (n=72), the bimagrumab 70 mg group (n=34), the bimagrumab 210 mg group (n=69), or the bimagrumab 700 mg group (n=75). A total of 207 (83%) participants completed the 24-week treatment period. There was a significant absolute increase in lean body mass from baseline compared with placebo (0·2 kg [SD 2·0]) in the bimagrumab 210 mg group (1·9 kg [1·7]; p

IMPORTANCE: The benefits of vitamin D, omega-3 fatty acids, and exercise in disease prevention remain unclear. OBJECTIVE: To test whether vitamin D, omega-3s, and a strength-training exercise program, alone or in combination, improved 6 health outcomes among older adults. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled, 2 × 2 × 2 factorial randomized clinical trial among 2157 adults aged 70 years or older who had no major health events in the 5 years prior to enrollment and had sufficient mobility and good cognitive status. Patients were recruited between December 2012 and November 2014, and final follow-up was in November 2017. INTERVENTIONS: Participants were randomized to 3 years of intervention in 1 of the following 8 groups: 2000 IU/d of vitamin D(3), 1 g/d of omega-3s, and a strength-training exercise program (n = 264); vitamin D(3) and omega-3s (n = 265); vitamin D(3) and exercise (n = 275); vitamin D(3) alone (n = 272); omega-3s and exercise (n = 275); omega-3s alone (n = 269); exercise alone (n = 267); or placebo (n = 270). MAIN OUTCOMES AND MEASURES: The 6 primary outcomes were change in systolic and diastolic blood pressure (BP), Short Physical Performance Battery (SPPB), Montreal Cognitive Assessment (MoCA), and incidence rates (IRs) of nonvertebral fractures and infections over 3 years. Based on multiple comparisons of 6 primary end points, 99% confidence intervals are presented and P

Context Osteoporosis and anemia are among the most common diseases in the aging population with an increasing prevalence worldwide. Objective As the bone-derived hormone fibroblast growth factor 23 (FGF-23) was recently reported to regulate erythropoiesis, we examined age-related associations between hemoglobin levels and bone quality, bone turnover, and FGF-23 concentrations. Design We used data from more than 5000 adult subjects who participated in the population-based cohorts of the Study of Health in Pomerania (SHIP and SHIP-Trend). Bone quality was assessed by quantitative ultrasound at the heel, bone turnover by measurement of carboxy-terminal telopeptide of type I collagen (CTX), and intact amino-terminal propeptide of type I procollagen (P1NP) serum concentrations, respectively. Anemia was defined as hemoglobin Results Anemic subjects had poorer bone quality, higher fracture risk, and lower serum levels of P1NP than nonanemic individuals. Linear regression models revealed positive associations between hemoglobin and bone quality in subjects aged 40 or above and inverse associations with CTX in subjects aged 60 or above. Hemoglobin and FGF-23 concentrations were inversely associated, while FGF-23 was not related to bone quality or turnover. Conclusion Our data corroborate a close link between FGF-23 and anemia, which is related to poor bone quality in elderly people. We observed no direct association of FGF-23 with bone parameters. Further studies are needed clarifying the role of FGF-23 on bone and red blood cell production.

The global prevalence of osteoporotic fractures and the socioeconomic burden is increasing with aging of the population. Frailty, sarcopenia, malnutrition and a propensity to falls are contributing to osteoporotic fractures in old age with an estimated 750 000 fragility fractures per year in Germany. Despite this increasing number of fractures, osteoporosis remains underdiagnosed and undertreated in the geriatric population. In order to estimate fracture risk in elderly patients, it is important to combine bone mineral density measurement by dual-energy X-ray absorptiometry (DXA) with a problem-oriented geriatric assessment. This includes evaluation of muscle strength, walking speed, nutritional status, risk of falls, as well as cognitive function. Since age per se is the dominant fracture risk factor in women over 70 and men over 80, it is possible to omit DXA measurement in this age group, especially after an incident fragility fracture. The cornerstones of an effective fall and fracture prevention include a targeted training of strength, endurance, coordination and balance in addition to a healthy and active lifestyle. Because of the high prevalence of calcium and/or vitamin D deficiency in old age, close monitoring and appropriate substitution are essential in the management of osteoporosis in the elderly. Anti-osteoporotic drugs are effective and well tolerated in the geriatric population and should be initiated to prevent fractures in high risk cohorts and for secondary prevention. Recently, coordinator-based fracture liaison services have been shown to effectively reduce fracture risk in the high risk geriatric population.Aufgrund der demografischen Entwicklung wird eine steigende Prävalenz osteoporotischer Frakturen und demzufolge ein höherer Versorgungsbedarf erwartet. Trotz der Häufigkeit osteoporotischer Frakturen (ca. 765 000 Fragilitätsfrakturen pro Jahr in Deutschland) und zahlreicher Therapieoptionen erhalten in den meisten Ländern, einschließlich Deutschland, nur etwa 10 % aller Patienten eine leitliniengerechte Behandlung.Zur Einschätzung des Frakturrisikos ist neben der Messung der Knochendichte die Beurteilung des Sturzrisikos von entscheidender Bedeutung. Ein problemorientiertes geriatrisches Assessment zur Abschätzung des Sturzrisikos sollte neben Muskelkraft, Gehgeschwindigkeit und Ernährungszustand auch die psychische und kognitive Situation umfassen. Bei Frauen über 70 Jahren und Männern über 80 Jahren ist das AlterBewegung kombiniert mit gezieltem Training von Kraft, Ausdauer, Koordination und Balance sind neben einem allgemein gesunden und aktiven Lebensstil Grundpfeiler einer effektiven Sturz- und Frakturprävention. Eine ausreichende Versorgung mit Kalzium und Vitamin D sollte vor dem Einsatz spezifischer Osteoporose-Medikamente garantiert sein. Die zugelassenen Osteoporose-Medikamente sind gut verträglich und reduzieren auch bei geriatrischen Patienten das Frakturrisiko. Die Therapie der Osteoporose beim geriatrischen Patienten ist immer eine individualisierte Therapie. KONSEQUENZ FüR DEN KLINISCHEN ALLTAG: Eine effektive Osteoporose-Therapie in der Geriatrie erfordert einen ganzheitlichen, interdisziplinären Ansatz.

Myelodysplastic syndromes (MDS) are clonal malignant hematopoietic disorders in the elderly characterized by ineffective hematopoiesis. This is accompanied by an altered bone microenvironment, which contributes to MDS progression and higher bone fragility. The underlying mechanisms remain largely unexplored. Here, we show that myelodysplastic NUP98‑HOXD13 (NHD13) transgenic mice display an abnormally high number of osteoblasts, yet a higher fraction of nonmineralized bone, indicating delayed bone mineralization. This was accompanied by high fibroblast growth factor-23 (FGF-23) serum levels, a phosphaturic hormone that inhibits bone mineralization and erythropoiesis. While Fgf23 mRNA expression was low in bone, brain, and kidney of NHD13 mice, its expression was increased in erythroid precursors. Coculturing these precursors with WT osteoblasts induced osteoblast marker gene expression, which was inhibited by blocking FGF-23. Finally, antibody-based neutralization of FGF-23 in myelodysplastic NHD13 mice improved bone mineralization and bone microarchitecture, and it ameliorated anemia. Importantly, higher serum levels of FGF‑23 and an elevated amount of nonmineralized bone in patients with MDS validated the findings. C‑terminal FGF‑23 correlated negatively with hemoglobin levels and positively with the amount of nonmineralized bone. Thus, our study identifies FGF-23 as a link between altered bone structure and ineffective erythropoiesis in MDS with the prospects of a targeted therapeutic intervention.

The effects of erythropoietin on osteoblasts and bone formation are controversial. Since patients with myelodysplastic syndromes often display excessively high erythropoietin levels, we aimed to analyze the effect of erythropoietin on osteoblast function in myelodysplastic syndromes and define the role of Wnt signaling in this process. Expression of osteoblast-specific genes and subsequent osteoblast mineralization was increased in mesenchymal stromal cells from healthy young donors by in vitro erythropoietin treatment. However, erythropoietin failed to increase osteoblast mineralization in old healthy donors and in patients with myelodysplasia, whereas the basal differentiation potential of the latter was already significantly reduced compared to that of age-matched controls (P

Endocrine therapies, including tamoxifen or aromatase inhibitors, are indispensable for the treatment of patients with estrogen receptor (ER)- and/or progesterone-positive breast cancer. Whereas tamoxifen displays partial ER agonistic effects in bone, aromatase inhibitors increase bone resorption and fracture risk. The Wnt inhibitors dickkopf-1 (DKK-1) and sclerostin negatively impact bone formation and are considered targets for the treatment of bone disorders. However, the effect of endocrine therapies on serum DKK-1 and sclerostin levels in patients with primary breast cancer remains elusive. Serum DKK-1 and sclerostin levels were measured at primary diagnosis as well as 3–5 days and 12 months after surgery in a cohort of 45 pre- and postmenopausal women with primary estrogen receptor-positive breast cancer treated with adjuvant tamoxifen or aromatase inhibitors. Mean baseline levels ±SD for DKK-1 and sclerostin were 29.7 ± 14.6 and 27.1 ± 16.2 pmol/l, respectively. A significant negative correlation of DKK-1 levels and age was observed (r = −0.32; p

Background The PARADIGHM registry of adult and pediatric patients with chronic hypoparathyroidism evaluates the long-term safety and effectiveness of treatment with recombinant human parathyroid hormone, rhPTH(1-84), and describes the clinical disease course under conditions of routine clinical practice. In this first report, we detail the registry protocol and describe the baseline characteristics of two adult patient cohorts from an interim database analysis. One cohort after study entry were prescribed rhPTH(1-84), and the other cohort received conventional therapy of calcium and active vitamin D. Methods An observational study of patients with chronic hypoparathyroidism in North America and Europe, collecting data for ≥10 years per patient. Main outcome measures were baseline patient demographics, clinical characteristics, medications, and disease outcome variables of symptoms, biochemical parameters, and health assessments. Baseline is the enrollment assessment for all variables except biochemical measurements in patients treated with rhPTH(1-84); those measurements were the most recent value before the first rhPTH(1-84) dose. Exclusion criteria applied to the analysis of specified outcomes included pediatric patients, patients who initiated rhPTH(1-84) prior to enrollment, and those who received rhPTH(1-34). Clinically implausible biochemical outlier data were excluded. Results As of 30 June 2019, data of 737 patients were analyzed from 64 centers; 587 (80%) were women, mean ± SD age 49.1±16.45 years. At enrollment, symptoms reported for patients later prescribed rhPTH(1-84) (n=60) and those who received conventional therapy (n=571), respectively, included fatigue (51.7%, 40.1%), paresthesia (51.7%, 29.6%), muscle twitching (48.3%, 21.9%), and muscle cramping (41.7%, 33.8%). Mean serum total calcium, serum phosphate, creatinine, and estimated glomerular filtration rate were similar between cohorts. Health-related quality of life (HRQoL) 36-item Short Form Health Survey questionnaire scores for those later prescribed rhPTH(1-84) were generally lower than those for patients in the conventional therapy cohort. Conclusions At enrollment, based on symptoms and HRQoL, a greater percentage of patients subsequently prescribed rhPTH(1-84) appeared to have an increased burden of disease than those who received conventional therapy despite having normal biochemistry measurements. PARADIGHM will provide valuable real-world insights on the clinical course of hypoparathyroidism in patients treated with rhPTH(1-84) or conventional therapy in routine clinical practice. Trial registration EUPAS16927, NCT01922440

Purpose Diabetes and osteoporosis occur frequently in older adults and are both associated with increased fracture risk. Denosumab treatment reduced new vertebral, nonvertebral, and hip fractures over 3 years, with continued low fracture incidence for up to 10 years in postmenopausal women with osteoporosis. However, its effects in diabetic subjects with osteoporosis have not yet been investigated. Methods Post hoc analysis of the 3-year, placebo-controlled FREEDOM study and 7-year Extension included postmenopausal women with osteoporosis and diabetes. Effects on BMD, vertebral, and nonvertebral fracture incidence were evaluated. Results Of 7808 subjects in FREEDOM, 508 with diabetes received denosumab (n = 266) or placebo (n = 242). Among those, BMD increased significantly with denosumab versus placebo in FREEDOM, and continued to increase during the Extension in long-term (continuing denosumab) and crossover (placebo to denosumab) denosumab subjects. In FREEDOM, denosumab-treated subjects with diabetes had significantly lower new vertebral fracture rates (1.6%) versus placebo (8.0%) (RR: 0.20 [95% CI 0.07–0.61]; p = .001). Nonvertebral fracture incidence was higher with denosumab (11.7%) versus placebo (5.9%) (HR: 1.94 [95% CI 1.00–3.77]; p = .046), although there were fewer hip fractures with denosumab (World Health Organization, 2017 [ 1 ]) than placebo (4; nonsignificant). During the first 3 years in FREEDOM Extension, new vertebral and nonvertebral fracture incidences were low in long-term and crossover denosumab diabetic groups (≤6%), consistent with the overall Extension population; yearly nonvertebral fracture incidence was comparable to the FREEDOM placebo group. Conclusion Denosumab significantly increased BMD and decreased vertebral fracture risk in subjects with osteoporosis and diabetes. No reduction in nonvertebral fractures was observed.

Purpose: We assessed serum concentrations of the receptor activator of NFκB ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG), two proteins implicated in the development and progression of breast cancer, in 509 patients with primary, nonmetastatic breast cancer. Then the results were evaluated with regards to the occurrence of bone metastases, the presence of disseminated tumor cells (DTC) in the bone marrow, survival, and risk of developing metastatic disease. Experimental Design: Before surgery, two bone marrow aspirates were analyzed for DTC using density centrifugation followed by immunocytochemistry (pan-cytokeratin antibody A45-B/B3). RANKL and OPG levels in the serum were measured by ELISA. Results: RANKL levels were significantly lower in women >60 years (P < 0.0001) and RANKL/OPG ratios higher in lymph node–positive patients (P < 0.05). High OPG serum levels were associated with a higher risk of death from breast cancer [HR 1.94; 95% confidence interval (CI) 1.23–3.07; P = 0.005] and OPG was an independent prognostic marker for breast cancer–specific survival (BCSS; multivariate analyses, P = 0.035). RANKL levels were 33% higher (P < 0.0001) in DTCpos patients (41%), whereas high levels were associated with a significantly better BCSS in DTCneg patients as compared with low levels (HR 0.524; 95% CI 0.30–0.95; P = 0.04). RANKL serum levels were significantly increased in patients who developed bone metastases (P = 0.01) and patients within the highest quartile of RANKL had a significantly increased risk of developing bone metastases compared with those in the lowest (HR 4.62; 95% CI 1.49–14.34; P = 0.03). Conclusions: These findings warrant further investigation as they provide a rationale for novel diagnostic or therapeutic approaches.

Prior osteoporosis therapies may affect the skeletal response to denosumab. We compared the effect of denosumab (60 mg every 6 months for 12 months) on bone mineral density and bone metabolism parameters in postmenopausal women with low bone mass who were either treatment-naïve (n = 30), or previously treated either with zoledronic acid (n = 30), or teriparatide (n = 22).We assessed lumbar spine bone mineral density (BMD) and measured serum concentrations of the bone turnover markers pro-collagen type 1 N-terminal propeptide (PINP) and C-terminal-cross-linking telopeptide of type 1 collagen (CTX), as well as sclerostin, dickkopf-1 (Dkk-1), and myostatin.Lumbar spine BMD increased equivalently in all three groups after 12 months of denosumab compared to baseline (p 0.001). Serum PINP and CTX decreased significantly with denosumab in pre-treated women reaching the same nadir levels as in treatment-naïve patients (p 0.001). Women pre-treated with teriparatide displayed lower baseline myostatin concentrations as compared to the other two groups (p 0.001). Changes in lumbar spine BMD in teriparatide pre-treated women correlated with changes in bone turnover markers and myostatin.Denosumab induced similar increases in lumbar spine BMD in treatment-naïve and pre-treated patients and suppressed serum PINP and CTX to the same levels regardless of prior treatments. In teriparatide pre-treated patients the magnitude of change in bone turnover markers is associated with BMD response.

Background Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) are hematological stem cell diseases mainly of the elderly. Studies indicate a close relationship between bone metabolism and hematopoietic stem cells within the osteo-hematopoietic niche. However, it remains unclear how the disturbed interaction within the osteo-hematopoietic niche affects bone homeostasis in MDS and AML patients. Methods We utilized data of a large German statutory health insurance of approximately 2 million persons living in the German federal state of Saxony. Applying case definitions based on diagnosis, procedures and prescriptions we identified prevalent and incident cases with MDS, AML and osteoporosis (OSP) in persons aged ≥60 years. We applied time-to-event analyses to determine the relationship of MDS and AML with OSP with a specific focus on temporality. Results Among all individuals aged ≥60 years (n = 891,095), 2.62% (n = 23,326), 0.14% (n = 1219) and 0.10% (n = 893) were identified with incident OSP, MDS and AML, respectively. The risk of incident OSP was significantly increased in patients with prevalent MDS (sex and age-adjusted model: HR = 1.87, 95%CI: 1.51–2.23). Conversely, patients with prevalent OSP had an increased risk to be diagnosed with incident MDS in the adjusted model (HR = 1.42, 1.19–1.65). For AML no significant associations were observed (adjusted models: inc. OSP with pre. AML; HR = 1.06, 0.65–1.47; inc. AML with pre. OSP; HR = 0.82, 0.41–1.23). Discussion Our results could indicate a clinically relevant relationship between MDS and OSP in elderly patients, most likely resulting from a disturbed microenvironment within the osteo-hematopoietic niche. An alternative, non-causal explanation that MDS is caused by the medication prescribed for OSP can be partially ruled out, as the association between the two diseases remains if incident OSP cases are considered in patients with pre-existing MDS. These results need to be confirmed within other prospective studies and may allow then for comprehensive strategies for the prevention, early detection and clinical care of patients with MDS and OSP.

Fragility fractures and cardiovascular diseases often coincide. However, data on shared risk factors and markers are scarce. Our aim was to assess the independent associations of serum osteoprotegerin (OPG) levels with the risk of fracture and cardiovascular outcomes (acute coronary syndrome, cardiac death) in older men. A cohort of 819 home-dwelling men aged 60 to 87 years was followed prospectively for 8 years. Serum OPG was measured at baseline by ELISA. Bone mineral density (BMD) at femoral neck and Trabecular Bone Score (TBS) were assessed by DXA. Clinical risk factors and Fracture Risk Assessment Tool (FRAX) were assessed. The incident events (self-reported peripheral fractures and acute coronary syndrome, cardiac death reported by a proxy) confirmed by a health professional were retained for the statistical analysis. Incident vertebral fractures were assessed on lateral DXA scans after 4 and 8 years. Hazard risk (HR) was assessed using the Cox model. After adjustment for FRAX corrected for femoral neck BMD and TBS, diabetes mellitus, ischemic heart disease, and prior falls, the risk of fracture was twofold higher in the highest versus the lowest OPG quartile (HR 2.35; 95% CI, 1.35 to 4.10). The risk of vertebral and nonvertebral fracture was higher in the highest versus the lowest OPG quartile (OR 2.76 [95% CI, 1.08 to 7.05] and HR 2.46 [95% CI, 1.23 to 4.92]). The risk of major osteoporotic fracture was higher in the fourth versus the first OPG quartile (HR 2.43; 95% CI, 1.16 to 5.10). The risk of cardiovascular outcome (adjusted for confounders) was higher in the highest versus the lowest OPG quartile (HR 3.93; 95% CI, 1.54 to 10.04). The risk of fracture and cardiovascular outcome was higher in the highest OPG quartile versus the lower quartiles combined (HR 2.06 [95% CI, 1.35 to 3.14] and HR 2.98 [95% CI, 1.60 to 5.54], respectively). In conclusion, in older men, higher serum OPG levels represent an independent risk factor for cardiovascular and fracture risk. © 2017 American Society for Bone and Mineral Research.

Denosumab has been shown to reduce new vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis. In subjects who were treatment-naive or previously treated with alendronate, denosumab was associated with greater gains in bone mineral density (BMD) and decreases in bone turnover markers when compared with alendronate-treated subjects. This trial was designed to compare the efficacy and safety of denosumab with risedronate over 12 months in postmenopausal women who transitioned from daily or weekly alendronate treatment and were considered to be suboptimally adherent to therapy. In this randomized, open-label study, postmenopausal women aged ≥55 years received denosumab 60 mg subcutaneously every 6 months or risedronate 150 mg orally every month for 12 months. Endpoints included percentage change from baseline in total hip BMD (primary endpoint), femoral neck, and lumbar spine BMD at month 12, and percentage change from baseline in sCTX-1 at months 1 and 6. Safety was also assessed. A total of 870 subjects were randomized (435, risedronate; 435, denosumab) who had a mean (SD) age of 67.7 (6.9) years, mean (SD) BMD T-scores of -1.6 (0.9), -1.9 (0.7), and -2.2 (1.2) at the total hip, femoral neck, and lumbar spine, respectively, and median sCTX-1 of 0.3 ng/mL at baseline. At month 12, denosumab significantly increased BMD compared with risedronate at the total hip (2.0% vs 0.5%), femoral neck (1.4% vs 0%), and lumbar spine (3.4% vs 1.1%; p

SummaryAim Type 1 diabetes mellitus (T1DM) increases fragility fractures due to low bone mass, micro-architectural alterations and decreased bone formation. Sclerostin is expressed by osteocytes and inhibits osteoblastic bone formation. We evaluated serum sclerostin levels in T1DM and their association with bone mineral density (BMD), bone turnover, glycaemic control and physical activity. Patients and Methods In a cross-sectional study, 128 men and premenopausal women with long-standing T1DM (mean age 43·4 ± 8·8 years, diabetes duration 22·4 ± 9·5 years) and 77 age-, BMI (Body Mass Index) and gender-matched healthy individuals were evaluated. Results Serum sclerostin levels were higher in T1DM compared with controls, irrespective of gender (male 0·55 ± 0·17 vs 0·49 ± 0·12 ng/ml, P = 0·046; female 0·52 ± 0·19 ng/ml vs 0·43 ± 0·12 ng/ml, P = 0·012). Partial correlation analysis adjusted for age and gender revealed a positive correlation between serum sclerostin levels and BMD at lumbar spine and femoral neck in T1DM and between BMD at lumbar spine, femoral neck and total hip in controls. Bone turnover markers, parathyroid hormone, calcium and vitamin D did not correlate with serum sclerostin levels in T1DM or controls. Physical activity was not associated with serum sclerostin levels. A multivariate analysis revealed that only the interaction of T1DM and age affects serum sclerostin levels but not T1DM alone. The influence of age on serum sclerostin levels was more pronounced in T1DM compared with controls. Conclusions Sclerostin serum levels were increased in patients with T1DM, and the positive correlation of age with serum sclerostin levels was stronger in T1DM. There was no effect of serum sclerostin levels on markers of bone metabolism and they do not explain the detrimental effects of T1DM on BMD.

ObjectiveTo assess the association between abdominal aortic calcification (AAC) and serum levels of myostatin, a negative regulator of skeletal muscle mass, which has been implicated in the development of atherosclerotic lesions in mice.Design and patientsWe assessed AAC semiquantitatively from the lateral spine scans obtained using dual energy X-ray absorptiometry in 1071 men aged 20–87 years. Serum myostatin levels were measured by an immunoassay that detects all myostatin forms.ResultsTotal myostatin serum levels did not differ between men with or without self-reported ischemic heart disease, hypertension, or diabetes mellitus. Total serum myostatin levels were higher in men with higher serum calcium levels and lower in men with higher serum concentrations of highly sensitive C-reactive protein. Men with AAC had lower myostatin levels compared with men without AAC. Prevalence of AAC (AAC score >0) was lower in the highest myostatin quartile compared with the three lower quartiles (P0) were lower (OR=0.62; 95% confidence interval (95% CI), 0.45–0.85; PPConclusionsIn older men, total myostatin serum levels are inversely correlated with AAC. Further studies are needed to investigate mechanisms underlying this association and to assess utility of myostatin as a cardiovascular marker.

Calcification inhibitor deficiencies, mineral imbalance, and phenotypic transformation of vascular cells to osteogenic cells initiate and sustain vascular calcification. Fibroblast growth factor-23 (FGF23) is a key molecule regulating mineral homeostasis.Our objective was to assess the association of serum FGF23 levels with mineral metabolism parameters and abdominal aortic calcification (AAC) in men.This was a cross-sectional analysis in the STRAMBO cohort.Men holding a private health insurance cover with Mutuelle de Travailleurs de la Région Lyonnaise were included in the study.Participants included male volunteers aged 20-87 (n = 1130).Nonfasting blood collection was done. AAC was semiquantitatively assessed from vertebral fracture assessment scans obtained using dual-energy x-ray absorptiometry.We evaluated the association between FGF23 concentration and AAC severity in men.In 350 men aged 60 yr or younger, FGF23 levels decreased with age (r = -0.21; P0.001) but were not associated with any other parameter. In 780 men aged over 60 yr, serum FGF23 correlated with age (r = 0.37; P0.001) and, after adjustment for confounders, with glomerular filtration rate (r = -0.31; P0.001) and PTH levels (r = 0.25; P0.001). After adjustment for confounders, self-reported ischemic heart disease, diabetes mellitus as well as higher concentrations of C-reactive protein and osteoprotegerin were all associated with higher FGF23 levels. After adjustment for confounders, subjects in the highest FGF23 quartile had higher prevalence of severe AAC compared with the three lower quartiles combined (odds ratio = 1.88; 95% confidence interval = 1.22-2.85; P0.005).In healthy older men, circulating FGF23 is associated with parameters of mineral metabolism, including bone metabolism-regulating cytokines, and with severe AAC independent of traditional risk factors.

Osteoprotegerin (OPG) is an inhibitor of bone resorption, but its relationship to bone microarchitecture remains unclear.Our objective was to study the relationship between OPG concentration and bone microarchitecture in men.We conducted a cross-sectional study of a population-based cohort of 1149 men aged 20-87 yr.We assessed bone microarchitecture at the distal radius and tibia by high-resolution peripheral quantitative computed tomography (XtremeCT Scanco) and measured serum OPG concentration and bone turnover markers: osteocalcin, bone-specific alkaline phosphatase, N-terminal extension type I collagen propeptide, C-terminal type 1 collagen telopeptide, and urinary deoxypyridinoline.Differences were assessed in bone microarchitectural parameters across the OPG quartiles in the models adjusted for age, weight, height, physical activity, ischemic heart disease, diabetes mellitus, calcium intake, serum levels of free testosterone, bioavailable 17β-estradiol, PTH, 25-hydroxycholecalciferol, and creatinine.After adjustment for the confounders, men in the highest (fourth) quartile of OPG levels (4.55 pmol/liter) had higher total cross-sectional area and trabecular area at the distal radius and distal tibia (3.3-6.0%, P0.05). At both skeletal sites, the highest OPG quartile was associated with lower cortical thickness (8.2%, P0.001, and 3.7%, P0.05) and volumetric bone mineral density (vBMD, 2.7%, P0.001, and 1.6%, P0.005) compared with the three lower quartiles combined. Associations of OPG level with trabecular vBMD, number, thickness, and distribution were not significant. Men in the fourth OPG quartile had higher levels of bone resorption markers (11.8-13.1%, P0.01-0.001).Men with higher serum OPG concentration had lower cortical thickness and vBMD, probably due to accelerated endo- and intracortical bone turnover, but higher cross-sectional area possibly due to periosteal apposition.

Skeletal metastases represent a frequent complication in patients with advanced prostate cancer (PCa) and often require bisphosphonate treatment to limit skeletal-related events. Metastasized PCa cells disturb bone remodeling. Since the WNT signaling pathway regulates bone remodeling and has been implicated in tumor progression and osteomimicry, we analyzed the WNT profile of primary PCa tissues and PCa cell lines and assessed its regulation by bisphosphonates. Prostate tissue (n = 18) was obtained from patients with benign prostate hyperplasia (BPH) and PCa patients with different disease stages. Serum samples were collected from 62 patients. Skeletal metastases were present in 17 patients of whom 6 had been treated with zoledronic acid. The WNT profile and its regulation by bisphoshonates were analyzed in tissue RNA extracts and serum samples as well as in osteotropic (PC3) and non-osteotropic (DU145, LNCaP) PCa cell lines. Several members of the WNT pathway, including WNT5A, FZD5, and DKK1 were highly up-regulated in PCa tissue from patients with advanced PCa. Interestingly, osteotropic cells showed a distinct WNT profile compared to non-osteotropic cells. While WNT5A, FZD5, and DKK1 were highly expressed in PC3 cells, WNT1 and SFRP1 mRNA levels were higher in DU145 cells. Moreover, zoledronic acid down-regulated mRNA levels of WNT5A (−34%), FZD5 (−60%), and DKK1 (−46%) in PC3 cells. Interestingly, patients with skeletal metastases who received zoledronic acid had twofold higher DKK1 serum levels compared to bisphosphonate-naive patients. The WNT signaling pathway is up-regulated in advanced PCa, differentially expressed in osteotropic versus non-osteotropic cells, and is regulated by zoledronic acid. J. Cell. Biochem. 112: 1593–1600, 2011. © 2011 Wiley-Liss, Inc.

Milk fat globule-epidermal growth factor 8 (MFG-E8) is an anti-inflammatory glycoprotein that mediates the clearance of apoptotic cells and is implicated in the pathogenesis of autoimmune and inflammatory diseases. Because MFG-E8 also controls bone metabolism, we investigated its role in rheumatoid arthritis (RA), focusing on inflammation and joint destruction. The regulation of MFG-E8 by inflammation was assessed in vitro using osteoblasts, in arthritic mice and in patients with RA. K/BxN serum transfer arthritis (STA) was applied to MFG-E8 knock-out mice to assess its role in the pathogenesis of arthritis. Stimulation of osteoblasts with lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α downregulated the expression of MFG-E8 by 30% to 35%. MFG-E8-deficient osteoblasts responded to LPS with a stronger production of pro-inflammatory cytokines. In vivo, MFG-E8 mRNA levels were 52% lower in the paws of collagen-induced arthritic (CIA) mice and 24% to 42% lower in the serum of arthritic mice using two different arthritis models (CIA and STA). Similarly, patients with RA (n = 93) had lower serum concentrations of MFG-E8 (–17%) compared with healthy controls (n = 140). In a subgroup of patients who had a moderate to high disease activity (n = 21), serum concentrations of MFG-E8 rose after complete or partial remission had been achieved (+67%). Finally, MFG-E8-deficient mice subjected to STA exhibited a stronger disease burden, an increased number of neutrophils in the joints, and a more extensive local and systemic bone loss. This was accompanied by an increased activation of osteoclasts and a suppression of osteoblast function in MFG-E8-deficient mice. Thus, MFG-E8 is a protective factor in the pathogenesis of RA and subsequent bone loss. Whether MFG-E8 qualifies as a novel biomarker or therapeutic target for the treatment of RA is worth addressing in further studies.

Since the soluble receptor activator of the NF-κB ligand (sRANKL) as well as the endogenous anti-resorptive cytokine osteoprotegerin (OPG) are produced by osteoblasts and given that these cells undergo significant changes during antiresorptive treatment, we hypothesized that treatment with bisphosphonates (BP) would be accompanied by changes in serum OPG and sRANKL levels. In a prospective, randomized controlled trial of previously untreated postmenopausal women with osteoporosis, oral BP therapy (daily doses of either 10 mg alendronate or 5 mg risedronate) in combination with calcium/vitamin D was compared to calcium/vitamin D treatment alone (control group). Follow-up at 2, 6 and 12 months was completed for 56 patients. Standardized spinal X-rays were performed at baseline, and DEXA measurements at the femoral neck and trochanter were made at baseline and after 1 year. Serum OPG and sRANKL levels were measured with a polyclonal antibody-based ELISA system. After 1 year, there was a non-significant loss in neck and trochanteric bone mineral density (BMD) in the CTR group and a mean increase of 3.3% and 4.6% in the combined BP group (both p

Vascular calcification may occur at different areas of the vessel wall, including the intima in atherosclerosis and the media in Mönckeberg’s sclerosis. Medial calcification of arteries is common in patients with diabetes mellitus or chronic renal failure. Osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand are essential modulators of bone homeostasis and may be involved in the process of vascular calcification. In this study we investigated arteries from patients with Mönckeberg’s sclerosis and atherosclerosis. Apoptosis, which precedes vascular calcification in vitro, was assessed by an in situ ligation assay and was localized to the medial layer of arteries (Mönckeberg’s sclerosis) and the neointima (atherosclerosis). Immunohistochemistry and in situ hybridization revealed OPG immunoreactivity and mRNA expression surrounding calcified areas in the medial layer (Mönckeberg’s sclerosis), whereas OPG was mainly expressed adjacent to calcified neointimal lesions (atherosclerosis). Receptor activator of nuclear factor-κB ligand protein and mRNA were barely or not detectable. Of note, TNF-related apoptosis-inducing ligand, an inducer of apoptosis that is also blocked by OPG, displayed a similar spatial distribution as OPG. In summary, we demonstrate enhanced apoptosis adjacent to vascular calcification, and the concurrent expression of regulators of apoptosis and osteoclastic differentiation, TNF-related apoptosis-inducing ligand and OPG, suggesting their involvement in the pathogenesis of vascular calcification.

Vascular calcification results from an imbalance between increased extracellular levels of calcium and phosphate, reduced solubility, and low levels of calcification inhibitors in blood or the vascular wall. Fetuin-A is a major circulating calcification inhibitor. Rodent models of fetuin-A deficit indicate its calcification inhibiting potential. Clinical studies suggest its role as a biomarker in vascular disease. This cross-sectional study was performed in a cohort of 974 men aged ≥ 40 years (average 68 years) consisting of men holding health insurance cover with Mutuelle des Travailleurs de la Région Lyonnaise. Abdominal aortic calcification (AAC) was assessed semi-quantitatively on lateral dual energy X-ray absorptiometry (DXA) spine scans. Serum fetuin-A was measured by an immunoassay. After adjustment for confounders (age, lifestyle, body composition, health status, treatment, glomerular filtration rate [GFR], hormones, and cytokines), prevalence of severe AAC (AAC score4) decreased with increasing fetuin-A levels (OR=0.68 per SD increase, 95% CI: 0.54-0.84, p0.001). After adjustment for confounders, low fetuin-A and hypertension were each associated with higher odds of AAC4. Coexistence of low serum fetuin-A levels and heavy smoking, elevated fibroblast growth factor 23 levels or low serum dickkopf-1 levels were associated with higher odds of AAC4. Similar results were obtained for 789 men with GFR60 mL/min/1.73 m(2). Similar results were obtained when severe AAC was defined as AAC score3 or AAC5. Thus, lower serum fetuin-A levels are associated with severe AAC, suggesting that poor calcification inhibitory potential contributes to vascular calcification, independently of renal impairment.

There are large regional differences in the incidence of hip fracture in Germany. These differences were unexpected and do not follow a north-to-south or an east-to-west gradient. But they are of high socioeconomic importance and cannot be explained by geographic location, the age structure of the population, and only to a small extent by the regulation of specific medication. The most important complications and the major cost factors of osteoporosis are fractures. In order to develop strategies for fracture prevention, knowledge about different incidence rates and possible causes is necessary. In order to detect persistent differences in the incidence of hip fractures between the former eastern and western states of Germany, structured diagnostic data of patients hospitalized between 2000 and 2011 were used to determine the regional incidence of hip fractures in the individual federal states of Germany. To account for error due to repeated admissions and double registrations, the frequency of fractures was corrected by a factor of 0.89. Our analysis of the 10-year period from 2000 to 2011 did not confirm the difference between eastern and western Germany reported in the national literature, or the north-south gradient for Germany as reported in several European publications. We found significant differences in the incidence of fractures in adjacent territorial states such as Schleswig-Holstein and Mecklenburg-Western Pomerania or Saxony and Thuringia. Particularly, high incidence rates over the entire period were noted in the city-states of Hamburg, Berlin, and Bremen. The reason for such differences is still unclear and, thus, the consequences of urbanization must be considered to explain diverse incidence rates. In general, the investigation of causes should be based on the use of a multivariate model that takes additional factors such as specific drug use, socioeconomic aspects, environmental aspects, education, and health care into account. There are large regional differences in the incidence of hip fracture in Germany. These differences were unexpected and do not follow a north-to-south or an east-to-west gradient. But they are of high socioeconomic importance and cannot be explained by geographic location, the age structure of the population and only to a small extent by the regulation of specific medication.

While their negative impact on bone health is well established, the effects of aromatase inhibition (AI) on Wnt inhibitors and osteoprotegerin (OPG) are unknown. The aim of the study was to investigate the effects of AI on serum levels of sclerostin, DKK-1 and OPG, as well as their associations with PINP and CTX as markers of bone turnover and bone mineral density (BMD) assessed by DXA.We conducted a prospective longitudinal analysis of 70 postmenopausal women with hormone receptor-positive early breast cancer (BC) treated with anastrozole. All measurements were performed at baseline, 12 and 24 months of treatment. We measured the association of the investigated variables with circulating bone turnover markers, as well as with the BMD.After 24 months of AI therapy, sclerostin and OPG concentrations increased from 29.5 pmol/l (SD = 15.1) and 6.8 pmol/l (SD = 2.2) at baseline to 43.2 pmol/l (SD = 20.6) (p0.001) and 7.4 pmol/l (SD = 2.2) (p = 0.028), respectively. DKK-1 levels decreased from 34.3 pmol/l (SD = 13.5) at baseline to 29.7 pmol/l (SD = 12.3) at the 24-month visit (p = 0.005). Sclerostin levels significantly correlated with PTH, OPG and BMD of the lumbar spine, while DKK-1 correlated with the BMD of the femoral neck and of the total hip.The observed increase in sclerostin levels indicates a central role of osteocytes in bone turnover in women with BC.

Background Members of the urokinase-type plasminogen activator (uPA) system including uPA, its receptor uPAR and the plasminogen activator inhibitor 1 (PAI-1) play an important role in tumour invasion and progression in a variety of tumour types. Since the majority of clear cell renal cell carcinoma (ccRCC) shows distant metastasis at time of diagnosis or later, the interplay of uPA, uPAR and PAI-1 might be of importance in this process determining the patients’ outcome. Methods Corresponding pairs of malignant and non-malignant renal tissue specimens were obtained from 112 ccRCC patients without distant metastasis who underwent tumour nephrectomy. Tissue extracts prepared from fresh-frozen tissue samples by detergent extraction were used for the determination of antigen levels of uPA, uPAR and PAI-1 by ELISA. Antigen levels were normalised to protein concentrations and expressed as ng per mg of total protein. Results Antigen levels of uPA, uPAR, and PAI-1 correlated with each other in the malignant tissue specimens (rs=0.51-0.65; all P

Parathyroid cancer has a poor mid-term prognosis, often because of local recurrence, observed in half of all patients. Modern diagnostic workup increasingly enables a preoperative diagnosis of parathyroid cancer. There is limited evidence that more comprehensive oncologic surgery can reduce the risk of local recurrence. This study aims to identify the best specific surgical approach in parathyroid cancer. This observational cohort study comprises 19 consecutive patients who had undergone oncologic or nononcologic resection for parathyroid cancer. Baseline parameters were compared by using univariate analysis; outcomes were assessed by χ 2 testing and Kaplan–Meier statistics. Fifteen of 19 patients were primarily operated on in our tertiary center between 1996 and 2013, and four were referred for follow-up because of their cancer diagnosis. Patient cohorts defined by histologic R-status were comparable for established risk factors: sex, calcium levels, low-risk/high-risk status, and presence of vascular invasion. Oncologic resections were performed in 13 of 15 patients primarily treated in the center and 0 of 4 treated elsewhere (χ 2 = 5.6; p

ObjectiveMedical management of primary hyperparathyroidism (PHPT) is important in patients for whom surgery is inappropriate. We aimed to describe clinical profiles of adults with PHPT receiving cinacalcet.DesignA descriptive, prospective, observational study in hospital and specialist care centres.MethodsFor patients with PHPT, aged 23–92 years, starting cinacalcet treatment for the first time, information was collected on dosing pattern, biochemistry and adverse drug reactions (ADRs). Initial cinacalcet dosage and subsequent dose changes were at the investigator's discretion.ResultsOf 303 evaluable patients with PHPT, 134 (44%) had symptoms at diagnosis (mostly bone pain (58) or renal stones (50)). Mean albumin-corrected serum calcium (ACSC) at baseline was 11.4 mg/dl (2.9 mmol/l). The reasons for prescribing cinacalcet included: surgery deemed inappropriate (35%), patient declined surgery (28%) and surgery failed or contraindicated (22%). Mean cinacalcet dose was 43.9 mg/day (s.d., 15.8) at treatment start and 51.3 mg/day (31.8) at month 12; 219 (72%) patients completed 12 months treatment. The main reason for cinacalcet discontinuation was parathyroidectomy (40; 13%). At 3, 6 and 12 months from the start of treatment, 63, 69 and 71% of patients, respectively, had an ACSC of ≤10.3 mg/dl vs 9.9% at baseline. Reductions from baseline in ACSC of ≥1 mg/dl were seen in 56, 63 and 60% of patients respectively. ADRs were reported in 81 patients (27%), most commonly nausea. A total of 7.6% of patients discontinued cinacalcet due to ADRs.ConclusionsReductions in calcium levels of ≥1 mg/dl was observed in 60% of patients 12 months after initiation of cinacalcet, without notable safety concerns.

Experimental data show that dickkopf-1 (DKK1) may be involved in the regulation of arterial calcification. However, clinical data on the association between serum DKK1 levels and severity of abdominal aortic calcification (AAC) are scarce.Our aim was to determine the association between serum DKK1 concentration and AAC severity in men.This is a cross-sectional analysis in the STRAMBO cohort.The cohort was recruited from the general population.We examined 1139 male volunteers aged 20 to 87 years. No specific exclusion criteria were used.We collected blood samples and assessed AAC severity on the lateral spine scans obtained by a Discovery A Hologic device using the semiquantitative Kauppila score.We tested the hypothesis that low DKK1 levels are associated with AAC severity in men.In men aged 20 to 60 years, serum DKK1 levels were not associated with other variables. In men aged 60 years and older, lower DKK1 levels were associated with higher odds of severe AAC (AAC score5). After adjustment for confounders, odds of severe AAC increased with decreasing DKK1 levels (odds ratio = 1.42, 95% confidence interval = 1.13-1.79, P.005) and was higher below vs above the median DKK1 level (odds ratio = 2.19, 95% confidence interval = 1.37-3.49, P.005). Heavy smoking, hypertension, ischemic heart disease, and elevated levels of fibroblast growth factor 23 were associated with severe AAC significantly, independently of DKK1 and additively with low DKK1 levels.In older men, lower serum DKK1 levels are associated with severe AAC regardless of age and other potential confounders.

The contribution of the bone marrow microenvironment in myelodysplastic syndrome is controversial. We therefore analyzed the functional properties of primary mesenchymal stromal cells from patients with myelodysplastic syndrome in the presence or absence of lenalidomide. Compared to healthy controls, clonality and growth were reduced across all disease stages. Furthermore, differentiation defects and particular expression of adhesion and cell surface molecules (e.g. CD166, CD29, CD146) were detected. Interestingly, the levels of stromal derived factor 1-alpha in patients' cells culture supernatants were almost 2-fold lower (P

Osteonecrosis of the jaw (ONJ) is a common and potentially severe complication of antiresorptive therapy for bone metastases. However, its occurrence in patients treated for osteoporosis is rare. Although poor oral hygiene and invasive dental procedures have been identified as potential triggers, little is known about the role of other systemic risk factors. We describe a patient who developed ONJ after her first treatment with denosumab, a monoclonal antibody against receptor activator of NF-κB ligand. This patient had several comorbidities that prompted us to assess the German ONJ registry for the incidence of comorbidities in patients with ONJ. In summary, almost half of the patients (35 of 86 [41%]) had 1 or more risk factors thought to increase the risk of ONJ. In conclusion, comorbidities or comedications may increase the susceptibility of developing ONJ during osteoporosis therapy.

Sclerostin is predominantly expressed by osteocytes. Serum sclerostin levels are positively correlated with areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DXA) and bone microarchitecture assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) in small studies. We assessed the relation of serum sclerostin levels with aBMD and microarchitectural parameters based on HR-pQCT in 1134 men aged 20 to 87 years using multivariable models adjusted for confounders (age, body size, lifestyle, comorbidities, hormones regulating bone metabolism, muscle mass and strength). The apparent age-related increase in serum sclerostin levels was faster before the age of 63 years than afterward (0.43 SD versus 0.20 SD per decade). In 446 men aged ≤63 years, aBMD (spine, hip, whole body), trabecular volumetric BMD (Tb.vBMD), and trabecular number (Tb.N) at the distal radius and tibia were higher in the highest sclerostin quartile versus the three lower quartiles combined. After adjustment for aBMD, men in the highest sclerostin quartile had higher Tb.vBMD (mainly in the central compartment) and Tb.N at both skeletal sites (p 0.05 to 0.001). In 688 men aged63 years, aBMD was positively associated with serum sclerostin levels at all skeletal sites. Cortical vBMD (Ct.vBMD) and cortical thickness (Ct.Th) were lower in the first sclerostin quartile versus the three higher quartiles combined. Tb.vBMD increased across the sclerostin quartiles, and was associated with lower Tb.N and more heterogeneous trabecular distribution (higher Tb.Sp.SD) in men in the lowest sclerostin quartile. After adjustment for aBMD, men in the lowest sclerostin quartile had lower Tb.vBMD and Tb.N, but higher Tb.Sp.SD (p 0.05 to 0.001) at both the skeletal sites. In conclusion, serum sclerostin levels in men are strongly positively associated with better bone microarchitectural parameters, mainly trabecular architecture, regardless of the potential confounders.

Context: Myostatin is expressed mainly in skeletal muscle cells and acts as an inhibitor of muscle growth and differentiation. However, data on the determinants of serum myostatin concentrations in humans are limited. Objective: The aim of the study was to assess the correlates of serum myostatin concentrations in men. Design: We conducted a cross-sectional analysis of the STRAMBO cohort. Setting: Men holding private health insurance coverage with Mutuelle de Travailleurs de la Région Lyonnaise were included in the study. Participants: A total of 1121 male volunteers aged 20–87 yr participated in the study. Interventions: Nonfasting blood samples were collected. Main Outcome Measures: We measured the association of the investigated variables with circulating myostatin levels. Results: Serum myostatin levels increased slightly with age until 57 yr and then decreased. Circulating myostatin levels showed circannual variation, with the highest concentration in spring. In men older than 57 yr, serum myostatin levels decreased across increasing quartiles of body mass index and of total central and peripheral fat mass (P < 0.05 to < 0.001). Serum myostatin levels were positively correlated with serum levels of 25-hydroxycholecalciferol (25OHD), even after adjustment for season. Average myostatin levels were 0.47 sd higher in men with 25OHD above 40 ng/ml, compared with those with 25OHD below 20 ng/ml (P < 0.05). Current smokers had lower myostatin concentration. Neither current physical activity nor serum levels of PTH, testosterone, and 17β-estradiol were associated with myostatin concentrations. Conclusions: In men, circulating myostatin levels show seasonal changes and are associated with age, body mass index, fat mass, smoking, and 25OHD levels.

UNLABELLED: This paper provides a framework for the development of national guidelines for the management of glucocorticoid-induced osteoporosis in men and women aged 18 years and over in whom oral glucocorticoid therapy is considered for 3 months or longer. INTRODUCTION: The need for updated guidelines for Europe and other parts of the world was recognised by the International Osteoporosis Foundation and the European Calcified Tissue Society, which set up a joint Guideline Working Group at the end of 2010. METHODS AND RESULTS: The epidemiology of GIO is reviewed. Assessment of risk used a fracture probability-based approach, and intervention thresholds were based on 10-year probabilities using FRAX. The efficacy of intervention was assessed by a systematic review. CONCLUSIONS: Guidance for glucocorticoid-induced osteoporosis is updated in the light of new treatments and methods of assessment. National guidelines derived from this resource need to be tailored within the national healthcare framework of each country.

Bisphosphonates represent potent antiresorptive drugs that are established for therapy of patients with benign and malignant bone diseases. Zoledronic acid is an iv aminobisphosphonate that is administered annually against osteoporosis. Because of its potency and the parenteral route of administration, zoledronic acid is an alternative to oral bisphosphonates, in particular in elderly patients with multiple comorbidities. The most common side effects include an acute-phase reaction and mild and transient hypocalcemia.Here, we report three cases of seizures that developed after the administration of zoledronic acid.We review case histories and laboratory results of three patients with seizures associated with the administration of zoledronic acid. We discuss their course and comorbidities in the context of the published literature.All three patients were elderly persons with multiple comorbidities, including neurological diseases, that required parenteral bisphosphonates for severe osteoporosis with concurrent contraindications for oral bisphosphonates.We analyze potential mechanisms underlying these seizures in association with zoledronic acid exposure and discuss potential strategies to minimize this risk.

Denosumab is a fully human monoclonal antibody that inhibits bone resorption by neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This phase 3, multicenter, doubleblind study compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone mass. One thousand one hundred eighty-nine postmenopausal women with a T-score

To explore the relation of changes in measures of bone turnover and changes in bone mineral density (BMD) of the lumbar spine and total hip over 18 months in a double-blinded, randomized trial, comparing the effect of alfacalcidol (101 patients) versus alendronate (100 patients) on BMD in patients who recently started treatment with glucocorticoids for various rheumatic diseases.Associations between changes in serum procollagen type I C-propeptide (P1CP), fasting urine N-terminal telopeptide of type I collagen (NTx), serum calcium, parathyroid hormone (PTH), osteocalcin, and change from baseline in BMD over 18 months were explored with regression and correlation analyses.In both treatment groups, there was a statistically significant decrease in NTx. In the alfacalcidol group there was also a significant increase in P1CP and osteocalcin, in contrast to the alendronate group, but BMD in the alfacalcidol decreased versus an increase in the alendronate group (p0.001). In neither treatment group were changes in biochemical measures correlated with the change in BMD, with the exception of a negative correlation in the alendronate group between changes in total hip BMD and NTx. Use of alendronate resulted in an increased PTH in 27 patients, but the increase in BMD of these patients was not statistically significantly different compared to patients taking alendronate with normal PTH levels.Changes in BMD were not associated with changes in bone measures, with the exception of NTx in the alendronate group. For the patient taking glucocorticoids in clinical practice, the value of serial assessment of bone markers is low; changes in markers are no substitute for changes in BMD. ClinicalTrials.gov number: NCT00138983.

Objectives. The degree of bone loss in patients with psoriatic arthritis (PsA) has not been well-defined. We tested the hypothesis, whether serum levels of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), a pro-apoptotic cytokine and osteoprotegerin (OPG), an anti-osteoclastic cytokine, are associated with changes in biochemical markers of bone turnover or bone mineral density (BMD) in patients with PsA. Methods. In a cross-sectional study, we evaluated biochemical markers of bone turnover, BMD and serum levels of TRAIL and OPG in 116 patients with PsA (mean age: 52±13 yrs). Results. In patients with PsA, osteopenia was present in one-third of women and men, while osteoporosis was more frequent in men (10.2%) than in women (1.75%). Serum levels of TRAIL were significantly higher in patients with PsA (66.1±45.3 pmol/l) compared with controls (50.0±20.1 pmol/l, P

Bisphosphonates are the standard treatment for hypercalcemia of malignancy. We hypothesized that bisphosphonate treatment and the subsequent fall in serum calcium might induce changes in the RANK/RANKL/OPG system, which plays a pivotal role in the regulation of bone resorption. Soluble RANKL and OPG levels were measured in the serum of 15 hypercalcemic patients at baseline and on 5 consecutive days following treatment with the amino-bisphosphonate ibandronate. At day 0, the median soluble OPG level was elevated (p=0.0021) in the hypercalcemic group as compared to normal controls, while the median serum RANKL level was not significantly different. Ibandronate treatment and the resulting decrease (p0.0001) in serum calcium levels did not affect the serum concentrations of OPG, serum RANKL, or the serum RANKL/OPG ratio. In comparison with day 0, these factors did not change significantly at any time-point analyzed.

Increased bone resorption is a hallmark of multiple myeloma and is attributable to osteoclast activation. Recent studies showed that the receptor activator of nuclear factor kappaB ligand (RANKL) is the key mediator of osteoclastogenesis and plays a crucial role in bone destruction in malignant bone disease. We found that human myeloma cells express RANKL and analyzed the association of the RANKL expression with the presence of osteolytic bone disease in patients with multiple myeloma.Flow cytometry was performed on bone marrow samples derived from controls and multiple myeloma patients with or without osteolytic bone lesions on conventional radiography. Plasma cells were identified as CD38++/CD138+ cells. The level of RANKL expression on the surface of bone marrow plasma cells was correlated with the bone status of the patients.The bone marrow plasma cells from controls showed no or only a weak surface expression of RANKL, and the median mean fluorescence index (MFI) was 6. In contrast, expression of RANKL could be detected on bone marrow plasma cells from all of the patients with multiple myeloma, and median MFI was 47. The difference in MFI for RANKL expression of bone marrow plasma cells from controls and myeloma patients was highly significant (P0.0005). Myeloma patients with osteolytic bone lesions showed a significantly higher expression of RANKL (median MFI = 60; range, 16-2494) compared with patients without osteolysis (median MFI = 16; range, 6-229; P0.0005).These results show for the first time that the level of RANKL expression by myeloma cells correlates significantly with osteolytic bone disease.