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  • DKK-1 a potential biomarker and therapeutic target in Osteogenesis Imperfecta

Osteogenesis imperfecta (OI), also known as brittle bone disease, is a rare hereditary bone disorder with an estimated incidence of about 1 in 10,000 to 1 in 20,000 (1). It is characterized by low bone mass, increased bone fragility and recurrent fractures. The condition results from mutations that disrupt the synthesis and post-translational modification of type I collagen. Recent research indicates that the severity of OI phenotypes is influenced not only by abnormalities in type I collagen metabolism but also by alterations in osteoblast function (2), although the underlying mechanisms remain unclear. So far, none of the current available treatments have shown an overall efficacy in treating OI, thus demonstrating the unmet clinical need for managing OI (3). A recent study in mice has shown that  DKK1-antisense treatment can improve bone mechanical strength, restore the expression of osteogenic genes, stimulate osteogenesis, and suppress osteoclastogenesis in OI mice (3).

 

The Wnt/β-catenin pathways plays a key role in the regulation of osteogenesis. Dickkopf-1 (DKK-1) is a direct inhibitor of Wnt/β-catenin signaling by binding with high affinity to LRP5/LRP6 and Kremen proteins, inhibiting osteoblast function and bone formation. It is a soluble protein secreted in the bone microenvironment and can be detected in the circulation. In a recent study researchers measured DKK-1 concentrations in children with OI and examined its association with bone mineral density (BMD), fracture frequency, bone turnover markers, and the underlying genetic mutations of OI (4).

DKK-1 a potential biomarker and therapeutic target in Osteogenesis Imperfecta                                      

Key findings:

– concentrations were significantly higher in children with OI compared to healthy children

– DKK-1 is closely correlated to the skeletal phenotype of children with OI

– DKK-1 may become a novel biomarker and a potential therapeutic target of OI

 

Biomedica´s high quality human DKK-1 ELISA cat. no. BI-20413

 

Related Products: SCLEROSTIN ELISA (BI-20492), BIOACTIVE SCLEROSTIN ELISA (BI-20472)

 

Correlation of serum DKK1 level with skeletal phenotype in children with osteogenesis imperfecta.  Wang Y et al., J Endocrinol Invest. 2024

Abstract

Purpose: We aim to detect serum DKK1 level of pediatric patients with OI and to analyze its relationship with the genotype and phenotype of OI patients.

Methods: A cohort of pediatric OI patients and age-matched healthy children were enrolled. Serum levels of DKK1 and bone turnover biomarkers were measured by enzyme-linked immunosorbent assay. Bone mineral density (BMD) was measured by Dual-energy X-ray absorptiometry. Pathogenic mutations of OI were detected by next-generation sequencing and confirmed by Sanger sequencing.

Results: A total of 62 OI children with mean age of 9.50 (4.86, 12.00) years and 29 healthy children were included in this study. The serum DKK1 concentration in OI children was significantly higher than that in healthy children [5.20 (4.54, 6.32) and 4.08 (3.59, 4.92) ng/mL, P < 0.001]. The serum DKK1 concentration in OI children was negatively correlated with height (r = – 0.282), height Z score (r = – 0.292), ALP concentration (r = – 0.304), lumbar BMD (r = – 0.276), BMD Z score of the lumbar spine and femoral neck (r = – 0.32; r = – 0.27) (all P < 0.05). No significant difference in serum DKK1 concentration was found between OI patients with and without vertebral compression fractures. In patients with spinal deformity (22/62), serum DKK1 concentration was positively correlated with SDI (r = 0.480, P < 0.05). No significant correlation was observed between serum DKK1 concentration and the annual incidence of peripheral fractures, genotype and types of collagen changes in OI children.

Conclusion: The serum DKK1 level was not only significantly elevated in OI children, but also closely correlated to their skeletal phenotype, suggesting that DKK1 may become a new biomarker and a potential therapeutic target of OI.

Literature

  1. Osteogenesis imperfecta: an update on clinical features and therapies. Marom R, Rabenhorst BM, Morello R. Eur J Endocrinol. 2020; 83(4):R95-R106. PMID: 32621590.
  2. Osteogenesis Imperfecta: Mechanisms and Signaling Pathways Connecting Classical and Rare OI Types. Jovanovic M, Guterman-Ram G, Marini JC. Endocr Rev. 2022; 43(1):61-90. PMID: 34007986.
  3. Dickkopf-1 (DKK1) blockade mitigates osteogenesis imperfecta (OI) related bone disease. Ko JY, Wang FS, Lian WS, Yang FS, Chen JW, Huang PH, Liao CY, Kuo SJ. Mol Med. 2024; 30(1):66. PMID: 38773377; PMCID.
  4. Correlation of serum DKK1 level with skeletal phenotype in children with osteogenesis imperfecta. Wang Y, Hu J, Sun L, Zhou B, Lin X, Zhang Q, Wang O, Jiang Y, Xia W, Xing X, Li M. J Endocrinol Invest. 2024; 47(11):2785-2795. PMID: 38744806.

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Bone markers are currently used to monitor skeletal diseases and treatments. The proteins Sclerostin and Dickkopf-1 (DKK-1) reflect distinct biological processes and have gained attention as potential biomarkers for bone-related conditions. They may provide valuable information for diagnosis, prognosis, and monitoring of bone diseases and treatments.

Sclerostin and DKK-1 emerging biomarkers for bone disease

Sclerostin and Dickkkopf-1 are two important osteocyte proteins that are involved in the regulation of bone metabolism, particularly through their interactions with the Wnt signaling pathway.

SCLEROSTIN (SOST) is a glycoprotein that is primarily secreted by osteocytes, the most abundant cells in bone tissue. It inhibits Wnt signaling, which is a critical pathway regulating bone formation and remodeling. Sclerostin acts as a negative regulator of bone formation by binding to the LRP5/6 co-receptors (low-density lipoprotein receptor protein), which activate Wnt signaling. By binding to LRP5/6, sclerostin inhibits the interaction between Wnt ligands and the Frizzled receptor, thereby inhibiting Wnt signaling and suppressing bone formation. Inhibition of Sclerostin has led to the development of a novel anabolic therapy for osteoporosis.

DICKKOPF-1 (DKK-1) is a protein that also inhibits the Wnt signaling pathway. DKK-1 binds to the LRP5/6 co-receptors thereby preventing Wnt ligand interaction thus inhibiting bone formation and promoting bone resorption.

The Wnt-signaling pathway is one of the most important pathways controlling bone metabolism. Sclerostin and Dickkopf-1 act as Wnt inhibitors and play a crucial role in controlling bone formation and resorption.

Sclerostin and DKK-1 can easily be measured in blood samples with an ELISA assay

BIOMEDICA offers two kits to measure Sclerostin

Bioactive Sclerostin ELISA cat. no. BI-20472

  • serum, plasma, cell-culture
  • characterized antibodies
  • day test
  • 20µl sample volume
  • sample values provided
  • full validation package

 

The epitope of the monoclonal capture antibody is in loop 2 of the Sclerostin molecule, which is the binding site for the LRP5/6 complex.

All Sclerostin molecules including potential fragments containing this receptor binding region can be detected.

Bioactive Sclerostin ELISA – antibody binding sites

 

Sclerostin ELISA cat. no. BI-20492

 

DKK-1 ELISA cat. no. BI-20413

 

All assays are developed and manufactured by BIOMEDICA

Related Publications

New Emerging Biomarkers for Bone Disease: Sclerostin and Dickkopf-1 (DKK1). Dincel AS, Jørgensen NR; IOF-IFCC Joint Committee on Bone Metabolism (C-BM). Calcif Tissue Int. 2023 Feb;112(2):243-257. doi: 10.1007/s00223-022-01020-9. Epub 2022 Sep 27. PMID: 36165920.

Abstract

A healthy skeleton depends on a continuous renewal and maintenance of the bone tissue. The process of bone remodeling is highly controlled and consists of a fine-tuned balance between bone formation and bone resorption. Biochemical markers of bone turnover are already in use for monitoring diseases and treatment involving the skeletal system, but novel biomarkers reflecting specific biological processes in bone and interacting tissues may prove useful for diagnostic, prognostic, and monitoring purposes. The Wnt-signaling pathway is one of the most important pathways controlling bone metabolism and consequently the action of inhibitors of the pathway such as sclerostin and Dickkopf-related protein 1 (DKK1) have crucial roles in controlling bone formation and resorption. Thus, they might be potential markers for clinical use as they reflect a number of physiological and pathophysiological events in bone and in the cross-talk with other tissues in the human body. This review focuses on the clinical utility of measurements of circulating sclerostin and DKK1 levels based on preanalytical and analytical considerations and on evidence obtained from published clinical studies. While accumulating evidence points to clear associations with a number of disease states for the two markers, and thus, the potential for especially sclerostin as a biochemical marker that may be used clinically, the lack of standardization or harmonization of the assays still hampers the clinical utility of the markers.

 

Therapeutic approaches to activate the canonical Wnt pathway for bone regeneration. Nelson AL, Fontana G, Miclau E, Rongstad M, Murphy W, Huard J, Ehrhart N, Bahney C. J Tissue Eng Regen Med. 2022 Nov;16(11):961-976. doi: 10.1002/term.3349. Epub 2022 Sep 16. PMID: 36112528; PMCID: PMC9826348.

Circulating DKK-1 levels predict disease outcomes and mirror metabolic adaptations in patients with Covid-19

Individuals with low serum levels of DKK1 (Dickkopf-1) are twice as likely to die from Covid-19 than those with high levels according to new research published by Nikolai Jaschke and colleagues in the Journal of Clinical Endocrinology & Metabolism.

The researchers found that circulating DKK1 levels vary in humans and change as a function of time during SARS-CoV-2 infection. The infection promotes metabolic adaptations that resembles fasting, which are mirrored by circulating DKK1 levels.  DKK-1 levels predict disease outcomes in Covid-19 individuals.

The results of the study suggest a potential clinical use of measuring circulating DKK1 as an indicator of disease severity in COVID-19 patients. 

Read more: Circulating Dickkopf1 parallels metabolic adaptations and predicts disease trajectories in patients with Covid-19.

Circulating DKK1 levels were measured  with the DKK-1 ELISA kit from Biomedica

Biomedica, Vienna, Austria, DKK-1 ELISA, catalog #BI-20413, RRID: AB_2922680 

Highlights – DKK-1 ELISA (cat. no. BI-20413)

  • Small sample volume – 20µl serum/well
  • Reliable –international validation guidelines
  • Easy – direct measurement
  • Widely cited in +170 publications

 

Circulating Dickkopf1 parallels metabolic adaptations and predicts disease trajectories in patients with Covid-19.   Full text link

Jaschke NP, Funk AM, Jonas S, Riffel RM, Sinha A, Wang A, Pählig S, Hofmann M, Altmann H, Von Bonin S, Koch T, Spieth P, Tausche K, Akgün K, Rauner M, Kronstein-Wiedemann R, Odendahl M, Tonn T, Göbel A, Hofbauer LC, Rachner TD. J Clin Endocrinol Metab. 2022 Sep 8:dgac514. doi: 10.1210/clinem/dgac514. Epub ahead of print. PMID: 36071553; PMCID: PMC9494396.

Abstract

Context and aims: Coronavirus disease 19 (COVID-19) trajectories show high interindividual variability, ranging from asymptomatic manifestations to fatal outcomes, the latter of which may be fueled by immunometabolic maladaptation of the host. Reliable identification of patients who are at risk of severe disease remains challenging. We hypothesized that serum concentrations of Dickkopf1 (DKK1) indicate disease outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals.

Methods: We recruited hospitalized patients with PCR-confirmed SARS-CoV-2 infection and included 80 individuals for whom blood samples from 2 independent time points were available. DKK1 serum concentrations were measured by ELISA in paired samples. Clinical data were extracted from patient charts and correlated with DKK1 levels. Publicly available datasets were screened for changes in cellular DKK1 expression on SARS-CoV-2 infection. Plasma metabolites were profiled by nuclear magnetic resonance spectroscopy in an unbiased fashion and correlated with DKK1 data. Kaplan-Meier and Cox regression analysis were used to investigate the prognostic value of DKK1 levels in the context of COVID-19.

Results: We report that serum levels of DKK1 predict disease outcomes in patients with COVID-19. Circulating DKK1 concentrations are characterized by high interindividual variability and change as a function of time during SARS-CoV-2 infection, which is linked to platelet counts. We further find that the metabolic signature associated with SARS-CoV-2 infection resembles fasting metabolism and is mirrored by circulating DKK1 abundance. Patients with low DKK1 levels are twice as likely to die from COVID-19 than those with high levels, and DKK1 predicts mortality independent of markers of inflammation, renal function, and platelet numbers.

Conclusion: Our study suggests a potential clinical use of circulating DKK1 as a predictor of disease outcomes in patients with COVID-19. These results require validation in additional cohorts.

Ovarian cancer is one of the most common types of cancer in women. Dickkopf-related protein 1 is a secreted protein postulated as a promising target for cancer immunotherapy. In this first study, researchers investigated the prognostic relevance of blood-based circulating soluble DKK-1 (sDKK-1) in ovarian cancer patients including those with wtBRCA 1/2 status.  The data encourage further evaluation of sDKK1 in ovarian cancer patients, possibly in terms of a therapy monitoring marker or a response predictor for sDKK1-directed targeted therapies.

OVARIAN CANCER & DKK-1 a blood-based biomarker

Learn more: Evaluation of circulating Dickkopf-1 as a prognostic biomarker in ovarian cancer patients. Klotz DM, Link T, Goeckenjan M, Wimberger P, Poetsch AR, Jaschke N, Hofbauer LC, Göbel A, Rachner TD, Kuhlmann JD. Clin Chem Lab Med. 2021 Oct 25. doi: 10.1515/cclm-2021-0504. Epub ahead of print. PMID: 34687595.

 

Check out the Biomedica human DKK-1 ELISA Assay  – measures soluble DKK-1  in human serum

√   CONVENIENT – direct measurement / 20µl serum
√   RELIABLE  – full validation package – developed and manufactured by Biomedica
√  WIDELY Cited in + 170 publications

 

OVARIAN CANCER & DKK-1 a blood-based biomarker

Evaluation of circulating Dickkopf-1 as a prognostic biomarker in ovarian cancer patients.

Abstract

Objectives: Dickkopf-1 (DKK1) is a secreted protein, known for suppressing the differentiation and activity of bone-building osteoblasts by acting as an inhibitor of Wnt-signalling. Soluble DKK1 (sDKK1) has been proposed as prognostic biomarker for a wide range of malignancies, however, clinical relevance of sDKK1 as potential blood-based marker for ovarian cancer is unknown.

Methods: sDKK1 levels were quantified in a cohort of 150 clinically documented ovarian cancer patients by a commercially available DKK1 ELISA (Biomedica, Vienna, Austria).

Results: Median sDKK1 level was significantly elevated at primary diagnosis of ovarian cancer compared to healthy controls (estimated difference (ED) of 7.75 ng/mL (95% CI: 3.01-12.30 ng/mL, p=0.001)). Higher levels of sDKK1 at diagnosis indicated an increased volume of intraoperative malignant ascites (ED 7.08 pmol/L, 95% CI: 1.46-13.05, p=0.02) and predicted suboptimal debulking surgery (ED 6.88 pmol/L, 95% CI: 1.73-11.87, p=0.01). sDKK1 did not correlate with CA125 and higher sDKK1 levels predicted a higher risk of recurrence and poor survival (PFS: HR=0.507, 95% CI: 0.317-0.809; p=0.004; OS: HR=0.561, 95% CI: 0.320-0.986; p=0.044). Prognostic relevance of sDKK1 was partly sustained in wtBRCA patients (PFS: HR=0.507, 95% CI: 0.317-0.809; p=0.004).

Conclusions: This is the first study demonstrating the prognostic relevance of sDKK1 in ovarian cancer patients, including those with wtBRCA 1/2 status. Our data encourage further evaluation of sDKK1 in ovarian cancer patients, possibly in terms of a therapy monitoring marker or a response predictor for sDKK1-directed targeted therapies.

 

Related publications: 

Researchers identified the soluble bone metabolism biomarker DKK-1 to be independently associated with future cardiovascular events, which are primarily driven by increased risk of stroke.

Associations of Serum Dickkopf‐1 and Sclerostin With Cardiovascular Events: Results From the Prospective Bruneck Study.
Klingenschmid G et al., JAHA 2020; Mar 17;9(6):e014816.

Serum DKK-1 can easily be measured by ELISA assay

√ SIMPLE analysis – direct measurement – results in 3.5 h
√ LOW SAMPLE VOLUME – only 20µl sample / well
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Interested in performing a study? Contact us for your special offer :
e-mail, or phone: +43-1-29107-45.

Maintaining strong and healthy bones is crucial for overall well-being. Bones not only provide structural support for the body but also protect vital organs and serve as reservoirs for essential minerals like calcium and phosphorus. Key aspects of bone health include bone density and bone strength.

Osteoporosis is a condition characterized by weakened and fragile bones. It is the most prevalent metabolic bone disorder worldwide and can affect people of all ages, though it is more commonly associated with aging (1). Both men (2) and women can develop osteoporosis, but postmenopausal women are at a higher risk due to declining estrogen levels, which normally help protect bone health (3). Prevention strategies include maintaining a balanced diet and engaging in regular exercise.

Bone remodeling is a continuous, tightly regulated process involving the resorption of old or damaged bone and the formation of new bone tissue. Various hormones and factors influence bone metabolism. The bone cycle encompasses different phases, and markers of bone metabolism can be classified into markers of bone formation, markers of bone resorption, and markers involved in the regulation of bone metabolism.

Biomarkers of bone regulation

Protein biomarkers are frequently utilized in clinical research and practice to evaluate bone health and monitor the effectiveness of osteoporosis treatments. Some of these biomarkers offer insights into the regulatory processes governing bone metabolism and turnover. Measuring these markers can help assess overall bone health. Key regulatory biomarkers include:

Sclerostin (SOST): Produced by osteocytes, the bone cells embedded within bone tissue, sclerostin is a bone-specific inhibitor of the Wnt signaling pathway. It negatively influences bone formation by promoting osteoclastogenesis and increasing bone resorption. Elevated levels of sclerostin may indicate reduced bone formation.

Dickkopf-1 (DKK-1): Similar to sclerostin, DKK-1 inhibits Wnt signaling, which is essential for bone formation. Increased serum DKK-1 levels can promote bone resorption, potentially signaling suppressed bone formation.

The Wnt signaling pathway is one of the most vital mechanisms regulating bone metabolism. Sclerostin and Dickkopf-1 function as inhibitors of Wnt signaling and are essential in the regulation of bone formation and resorption.

Wnt signaling pathway

 

Receptor Activator of Nuclear Factor-Kappa B Ligand (RANKL): A critical regulator of osteoclast development and activation, RANKL promotes bone resorption by stimulating osteoclast activity. It is secreted by osteocytes and plays a central role in osteoclast formation.

Osteoprotegerin (OPG): Serving as a decoy receptor for RANKL, OPG modulates bone resorption. The ratio of OPG to RANKL influences bone remodeling processes, with alterations potentially impacting bone strength.

Fibroblast Growth Factor 23 (FGF23): This hormone regulates phosphate balance and vitamin D metabolism. Abnormal FGF23 levels are linked to bone disorders such as hypophosphatemic rickets, which can impair bone health.

 

These biomarkers can easily be measured in human blood samples with an ELISA assay

Biomedica ELISA Kit

Example of a Biomedica ELISA Kit

 

Sclerostin (SOST) ELISA  (BI-20492)

    • Most internationally referenced Sclerostin ELISA with more than 320 citations
    • Low sample volume – 20µl / well
    • Full validation package

 

Bioactive Sclerostin ELISA (BI-20472)

    • Targets the receptor binding region
    • Full validation package
    • Low sample volume – 20 µl of serum/plasma per well 

 

Dickkopf-1 (DKK-1) ELISA  (BI-20413)

    • Widely cited +180 publications
    • Direct measurement
    • Validated following international quality guidelines

 

Osteoprotegerin (OPG) ELISA (BI-20403)

    • most referenced human OPG ELISA in +280 citations
    • day test, ready to use color coded reagents
    • controls included

 

Free soluble RANKL ELISA (BI-20462)

    • Highly sensitive  – measurable concentrations in healthy subjects
    • Only assay measuring free, uncomplexed soluble RANKL
    • Cited in over +320 citations 

 

FGF23 c-terminal multi-matrix ELISA (BI-20702)

    • for serum and plasma samples
    • full validation package 
    • cited in +60 publications

 

FGF23 intact ELISA (BI-20700)

    • for serum and plasma samples
    • full validation package
    • one-step ELISA

 

Literature 

  1. Bone Health and Osteoporosis Prevention and Treatment. Muñoz M, Robinson K, Shibli-Rahhal A.Clin Obstet Gynecol. 2020 Dec;63(4):770-787. doi: 10.1097/GRF.0000000000000572. PMID: 33017332.
  2. Osteoporosis in men. Lancet Diabetes Endocrinol. Vilaca T, Eastell R, Schini M. 2022 Apr;10(4):273-283. doi: 10.1016/S2213-8587(22)00012-2. Epub 2022 Mar 2. PMID: 35247315.
  3. Postmenopausal Osteoporosis: A Review of Latest Guidelines. Subarajan P, Arceo-Mendoza RM, Camacho PM. Endocrinol Metab Clin North Am. 2024 Dec;53(4):497-512. doi: 10.1016/j.ecl.2024.08.008. Epub 2024 Oct 5. PMID: 39448132.

We are excited to be soon attending the ECTS Congress in Innsbruck, Austria from May 23-26, 2025. Meet us at our banner exhibition “Biomedica´s Bone Marker ELISAs” and explore our kits including SCLEROSTIN, OPG, RANKL, FGF23, PERIOSTIN, and many others.

We look forward to connecting with you!

Join us at ECTS 

Click here for more information about the congress.

The ECTS 2025 Congress is recognized as the premier annual gathering in Europe dedicated to this field. The congress offers a comprehensive and engaging scientific program that covers the most recent advances, challenges, and debates related to bone and calcified tissues. The program aims to unite researchers,  clinicians, and health professionals, showcasing their latest research.

Biomarkers in Bone Biology
Bone cells produce biomarkers throughout the process of bone remodeling. These biomarkers are valuable for evaluating bone diseases and serve as potential therapeutic targets. They can be readily identified in serum and plasma samples using immunoassay techniques.

A recent review by Fernández-Villabrille S et al.,  Novel Biomarkers of Bone Metabolism explores some emerging biomarkers in mineral and bone metabolism like:

Receptor Activator of NFkappa B lingand (RANKL), Osteoprotegerin (OPG), Sclerostin (SOST), Dickkopf-1 (DKK-1), Periostin (POSTN) and others.

 

BIOMEDICA offers quality Bone Marker ELISA assay kits: 

-Sclerostin ELISA (SOST; cat.no. BI-20492)  

-OPG ELISA (Osteoprotegerin; cat.no. BI-20403)  

-RANKL ELISA (soluble RANKL; cat.no. BI-20462)  

-DKK-1 ELISA (Dickkopf-1; cat.no. BI-20413)  

-FGF23 intact ELISA (Fibroblast growth factor-23 intact; cat.no. BI-20700) 

-FGF23 C-terminal ELISA  (Fibroblast growth factor-23 C-terminal; cat.no. cat.no. BI-20702) 

-PERIOSTIN ELISA (POSTN, BI-20433) 

-NT-proCNP ELISA (NT-C-type natriuretic peptide, BI-20812)

 

 TRUSTED – cited in over 1300 publications

  • Kit validations follows international quality guidelines
  • Developed & manufactured by Biomedica in Austria

 

About SCLEROSTIN

Sclerostin (SOST), primarily produced by osteocytes, is regarded as a key regulator of bone formation. It functions as a soluble antagonist of the Wnt signaling pathway. Inhibition of this pathway results in bone resorption, whereas activation of Wnt signaling stimulates bone formation.

About PERIOSTIN

Periostin (POSTN) is an extracellular matrix protein predominantly expressed in the periosteum, the membrane covering the outer surface of bones that plays a role in bone growth. It is involved in various processes, including bone biology, tissue repair, cancer, cardiovascular and respiratory conditions, as well as in numerous inflammatory conditions such as asthma.

Osteoporosis is a bone disease characterized by progressive loss of bone density, leading to an increased risk of fractures, particularly in the hip, spine, and wrist. It occurs when the balance between bone resorption and bone formation is disrupted, often due to factors such as aging, hormonal changes (especially post-menopause in women), nutritional deficiencies (such as calcium and vitamin D), sedentarism, and certain medications or medical conditions (1).

The prevalence of osteoporosis among older adults is significant: it is estimated that over 200 million people suffer from osteoporosis worldwide, with about one in three women and one in five men over the age of 50 experiencing an osteoporotic fracture in their lifetime (1). Osteoporosis represents a major public health concern due to its impact on mobility, quality of life, and healthcare costs associated with fracture management and treatment. Surprisingly, in women over 45 years of age, osteoporosis accounts for more days in hospital than may other diseases, including diabetes, myocardial infarction and breast cancer (3).

Bone Health and Osteoporosis

How can Osteoporosis be prevented ?

Regular exercise and a healthy diet, including the intake of key nutrients like Vitamin D and Calcium, are some key factors that can help in preventing the disease (2).

–Calcium: a healthy adult body contains around 1 kg of calcium, 99% of which is deposited in bone and teeth (4). Good sources of calcium include dairy products, leafy green vegetables, fortified foods, and fish with bones (1).

–Vitamin D: vitamin D plays an important role in regulating calcium and maintaining bone health. Although vitamin D influences various aspects of bone and calcium metabolism, one of its most important functions is the regulation of the efficiency of intestinal calcium (Ca) absorption (5).

The primary source of vitamin D is sunlight; it is synthesized in the skin. The form of vitamin D produced in the skin is known as vitamin D3 (cholecalciferol), while the dietary forms can be either vitamin D3 or a closely related plant-derived compound called vitamin D2 (ergocalciferol). Only a limited number of foods are naturally high in vitamin D. Dietary sources include fatty fish like salmon, sardines, and mackerel, as well as eggs, liver, and in some regions, fortified products such as margarine, dairy items, and cereals. For more information on sources on vitamin D and Vitamin D recommendations : https://www.osteoporosis.foundation/vitamin-d-recommendations.

-Other potentially risk factors for osteoporosis are smoking, alcohol consumption, low or excessive phosphorus intake, protein deficiency or a high-protein diet, excessive consumption of coffee, a sedentary lifestyle or lack of mobility, and insufficient exposure to the sun (6). 

Role of the human skeleton

The human skeleton provides support and structure for the body, protecting vital organs like the brain and heart. It is an important component of the musculoskeletal system, enabling movement. The skeleton also produces blood cells in its bone marrow and stores essential minerals like calcium. The skeleton is  constantly remodeled throughout life, with old bone being broken down and replaced by new tissue to maintain bone mass. This ongoing process of bone resorption and growth is called bone metabolism.

Bone remodeling

Bone remodeling is a continuous and regulated process where various specialized cells primarily osteoclasts breaking down old bone tissue, and osteoblasts building new bone, are involved. These cells constantly interact via factors like osteoprotegerin (OPG) and RANKL (receptor activator of nuclear factor kappa-B ligand) to maintain a healthy balance between bone resorption and bone formation. Imbalances in this process can lead to bone diseases like osteoporosis.  

Bone cells act as endocrine cells, influencing other organs. Osteocytes, the most common bone cell type embedded within the bone, are key regulators of bone formation. They play an important role in bone remodelling and release specific biomarkers such as sclerostin (SOST), fibroblast growth factor 23 (FGF23), and Dickkopf-1 (DKK-1).

 

Biomedica offers a range of ELISA kits to measure bone biomarkers in serum, plasma, and cell cultures

SCLEROSTIN (SOST; cat.no. BI-20492)

OPG  (Osteoprotegerin; cat.no. BI-20403)

RANKL  (soluble RANKL; cat.no. BI-20462)

DKK-1  (Dickkopf-1; cat.no. BI-20413)

FGF23 intact (Fibroblast growth factor-23, intact; cat.no. BI-20700)

FGF23 C-terminal  (Fibroblast growth factor-23, C-terminal; cat.no. cat.no. BI-20702)

PERIOSTIN  (POSTN, BI-20433)

 

User-friendly - convenient - reliable - ready-to-use ELISA kit

  • TRUSTED – cited in over 1200 publications
  • Kit validations follows international quality guidelines
  • Developed & manufactured by Biomedica in Austria

 

Literature

  1. Assessment of osteoporosis at the primary health-care level. WHO Scientific Group Technical Report. Kanis J. 2007  [Accessed 22.02.2019];
  2. The clinician’s guide to prevention and treatment of osteoporosis. LeBoff M et al. Osteoporos Int 33, 2049–2102 (2022).
  3. The prevalence of vertebral deformity in european men and women: the European Vertebral Osteoporosis Study. O’Neill TW et al., J Bone Miner Res, 1996. 11(7): p. 1010-8.
  4. Physiology of Calcium Homeostasis: An Overview. Matikainen N et al., Endocrinol Metab Clin North Am. 2021; 50(4):575-590. PMID: 34774235.
  5. Vitamin D-Mediated Regulation of Intestinal Calcium Absorption . Fleet JC. Nutrients. 2022 Aug 16;14(16):3351. PMID: 36014856.
  6. Osteoporosis – risk factors, pharmaceutical and non-pharmaceutical treatment. Tański W et al., Eur Rev Med Pharmacol Sci. 2021; 25(9):3557-3566. PMID: 34002830.

 

Kidney dysfunction causes disruptions in bone and mineral metabolism and changes in the regulators of the renal-bone axis through various mechanisms. Studies have demonstrated that fibroblast growth factor 23 (FGF23) and inflammatory markers rise, while iron status may decline (1, 2). In healthy individuals, FGF23 is regulated by phosphate, Vitamin D (1,25(OH)2D), and parathyroid hormone (PTH). However in the early stages of chronic kidney disease (CKD), FGF23 levels begin to increase even before plasma phosphate levels increase (3).

Thus, CKD causes disruptions in bone and mineral metabolism that also includes the regulatory hormones, resulting chronic kidney disease-mineral bone disorder (CKD-MBD).

Bone biomarkers in early renal impairment

A recent study investigated the effects of Vitamin D supplementation in a cohort of healthy community-dwelling older people. Baseline blood concentrations of bone regulatory markers including Sclerostin (SOST), Dickkopf-related Protein 1 (DKK1); Osteoprotegerin (OPG) and soluble RANKL (sRANKL), Fibroblast growth factor 23 (intact and c-terminal FGF23) and TNF-alpha, Interleukin-6 (IL-6) were analysed. The results showed that SOST, cFGF23, iFGF23, PTH and TNF-alpha were elevated in the group of individuals with early kidney impairment compared to those with normal kidney function. Following Vitamin D supplementation, only cFGF23, 25(OH)D, and IL-6 showed differences between the groups.

The study identified alterations in the renal bone-axis that occur prior to clinical monitoring of patients. Early diagnosis in the initial stages of renal impairment may offer opportunities for preventing the progression of renal disease and chronic kidney disease-mineral bone disorder (CKD-MBD).

Learn more: Alterations in regulators of the renal-bone axis, inflammation and iron status in older people with early renal impairment and the effect of vitamin D supplementation. Christodoulou M et al., Age Ageing. 2024; 53(5):afae096. doi: 10.1093/ageing/afae096. PMID: 38770543.

Bone biomarkers in early renal impairment

Biomedica offers quality ELISA Assay Kits for bone regulatory biomarkers

Sclerostin (SOST; cat.no. BI-20492)

Bioactive Sclerostin (bioSOST; cat. no. BI-20472)

OPG  (Osteoprotegerin; cat.no. BI-20403)

RANKL (soluble RANKL; cat.no. BI-20462)

DKK-1  (Dickkopf-1; cat.no. BI-20413)

FGF23 intact  (Fibroblast growth factor-23 intact; cat.no. BI-20700)

FGF23 C-terminal  (Fibroblast growth factor-23 C-terminal; cat.no. cat.no. BI-20702)

 

Key Features

  • TRUSTED – cited in over 1000 publications
  • Kit validations follows international quality guidelines
  • Ready to use standards and controls included
  • Developed & manufactured by Biomedica in Austria

 

Literature

  1. Iron Deficiency Anemia in Chronic Kidney Disease. Gafter-Gvili A, Schechter A, Rozen-Zvi B. Acta Haematol. 2019;142(1):44-50. doi: 10.1159/000496492. Epub 2019 Apr 10. PMID: 30970355.
  2. Iron-Deficiency Anemia in CKD: A Narrative Review for the Kidney Care Team. Hain D, Bednarski D, Cahill M, Dix A, Foote B, Haras MS, Pace R, Gutiérrez OM. Kidney Med. 2023 May 25;5(8):100677. doi: 10.1016/j.xkme.2023.100677. PMID: 37415621; PMCID: PMC10319843.
  3. The bone-renal axis in early chronic kidney disease: an emerging paradigm. Danziger J. Nephrol Dial Transplant. 2008 Sep;23(9):2733-7. doi: 10.1093/ndt/gfn260. Epub 2008 May 9. PMID: 18469306.

 

Breast cancer is the most prevalent cancer among women globally. Enhancing our knowledge of how breast cancer develops, progresses, and metastasizes could aid in decreasing the risk and impact of the disease. Circulating proteins in serum or plasma can serve as biomarkers of cancer progression and prognosis while also serving as potential therapeutic targets. Enhancing our understanding on how cancers originate, grow and spread could aid in lowering the risk and impact of the disease. Recent research on cancer markers has highlighted novel protein biomarkers and promising therapeutic targets in breast cancer:

PERIOSTIN, NEUROPILIN-1, SEMAPHORIN 4D, and LEUCINE-RICH ALPHA-2-GLYCOPROTEIN. These proteins can be easily detected in human serum and plasma using ELISA assays.

Novel Biomarkers in Breast Cancer

PERIOSTIN (alternative names: POSTN, OSF-2, OSF2, PDLPN, PN)

Periostin is a matricellular protein that plays a significant role in various physiological and pathological processes, including tissue remodeling, inflammation, and wound healing. In the context of breast cancer, periostin has garnered attention due to its involvement in tumorigenesis, progression, and the tumor microenvironment.

Role of Periostin in Breast Cancer

Tumor Microenvironment: Periostin is often overexpressed in the extracellular matrix (ECM) of breast tumors (1). It interacts with various cells in the tumor microenvironment, including cancer-associated fibroblasts, immune cells, and endothelial cells, promoting tumor growth and metastasis. A recent study has demonstrated that Periostin drives extracellular matrix degradation, stemness, and chemoresistance in triple-negative breast cancer cells by activating specific signaling pathways (2).

Cell Signaling: Periostin can activate multiple signaling pathways that contribute to cancer progression. It is known to bind to integrins on the surface of cancer cells, which can lead to enhanced cell survival, proliferation, and migration. This signaling also supports processes such as epithelial-to-mesenchymal transition (EMT), a critical step in cancer metastasis.

Metastasis: Elevated levels of periostin have been associated with increased metastasis in breast cancer. Studies have indicated that higher periostin expression correlates with the aggressive behavior of breast cancer cells, particularly in triple-negative breast cancer (TNBC), which is known for its poor prognosis (3).

Periostin as a Potential Biomarker: Due to its association with poor outcomes and aggressive disease, periostin has been investigated as a potential biomarker for breast cancer. Its expression levels in tumor tissues or serum may provide insights into disease progression and treatment responses. Epithelial periostin expression is correlated with poor survival in patients with invasive breast carcinoma (3). High serum levels of Periostin have been demonstrated to be associated with poor survival in breast cancer (4).

Therapeutic Target: Given its role in promoting cancer progression, periostin presents a potential therapeutic target. Inhibition of periostin signaling may offer a novel strategy for treating aggressive breast cancer subtypes by disrupting the supportive tumor microenvironment (5).

Conclusion: Periostin plays a multifaceted role in breast cancer, affecting tumor growth, metastasis, and the tumor microenvironment. Its involvement in key molecular pathways and its potential utility as a biomarker make it a significant focus of ongoing research. Targeting periostin could open new avenues for therapy, particularly in aggressive forms of breast cancer, ultimately aiming to improve patient outcomes. Further studies are needed to fully elucidate its mechanisms and to evaluate its efficacy as a therapeutic target in clinical settings.

Periostin can reliably be measured in human blood samples with a conventional ELISA assay developed and manufactured by BIOMEDICA.

PERIOSTIN ELISA (cat. no. BI-20433)

  • EASY – ready to use calibrators & controls included
  • RELIABLE – validated according to international quality guidelines
  • LOW sample volume- 10 µl / sample
  • TRUSTED – widely cited

 

An in-depth characterization of the Biomedica Periostin ELISA has been published here: Characterization of a sandwich ELISA for the quantification of all human periostin isoforms. Gadermaier E et al., J Clin Lab Anal. 2018; 32(2):e22252.

 

Novel Biomarkers in Breast Cancer

NEUROPILIN-1 (alternative names: NRP1, BDCA4, CD304, NP1, NRP, VEGF165R)

Neuropilin-1 (NRP1) is a transmembrane protein that has emerged as an important player in breast cancer biology. It is involved in various cellular processes, including cell signaling, survival, and migration, and has been implicated in cancer progression and metastasis (6).

Role of Neuropilin-1 in Breast Cancer

Tumor Growth and Survival: Neuropilin-1 (NRP1) is expressed in both cancer cells and the surrounding stromal cells within the tumor microenvironment. It has been linked to enhanced cell survival and proliferation, contributing to tumor growth. Elevated NRP1 expression has been associated with aggressive breast cancer subtypes, such as triple-negative breast cancer (TNBC) (6). A recent study has demonstrated that high NRP1 expression is associated with shorter relapse- and metastasis-free survival specifically in ER-negative BrCa cohorts (7).

Angiogenesis: NRP1 plays a critical role in angiogenesis, the formation of new blood vessels from existing ones, which is crucial for tumor growth and metastasis. By interacting with vascular endothelial growth factor (VEGF) and its receptors, NRP1 promotes endothelial cell proliferation and migration, facilitating the tumor’s ability to establish a blood supply (8).

Metastasis: Neuropilin-1 expression has been shown to be associated with lymph node metastasis in breast cancer tissues (9). Increased levels of NRP1 in breast cancer have been correlated with a higher propensity for metastasis. Studies have shown that NRP1 facilitates the migration of cancer cells to distant sites, contributing to the spread of the disease and poorer patient outcomes.

Potential Biomarker: In breast cancer patients, soluble Neuropilin-1 has shown to be an independent marker of poor prognosis in early breast cancer (10). In addition NRP-1 has also been shown to be a potential biomarker of prognosis and invasive-related parameters in other cancers such as liver and colorectal cancer (11).

Therapeutic Target: Given its involvement in tumor growth, angiogenesis, and metastasis, NRP1 is being explored as a therapeutic target. Strategies to inhibit NRP1 function or block its signaling pathways could offer new avenues for breast cancer treatment, particularly for patients with aggressive or metastatic disease (12).

Conclusion: Neuropilin-1 is a significant factor in the biology of breast cancer, influencing tumor growth, metastasis, and interactions within the tumor microenvironment. Its role in promoting angiogenesis and facilitating aggressive cellular behaviors makes it an important target for ongoing research. Targeting NRP1 could provide new therapeutic approaches for breast cancer, potentially improving outcomes for patients, especially those with more aggressive forms of the disease. Further studies are needed to clarify its mechanisms and evaluate targeted therapies in clinical settings.

Neuropilin-1 (NRP1) can reliably be measured in human blood samples with a conventional ELISA assay developed and manufactured by BIOMEDICA.

Total soluble NEUROPILIN-1 ELISA (cat. no. BI-20409)

  • EASY – ready to use calibrators & controls included
  • RELIABLE – validated according to international quality guidelines
  • LOW sample volume- 10 µl / sample
  • TRUSTED – for citations click here

 

The Biomedica human NRP-1 ELISA is described in this following publication: Characterization of a sandwich ELISA for quantification of total human soluble neuropilin-1. Gadermaier E, Tesarz M, Wallwitz J, Berg G, Himmler G. J Clin Lab Anal. 2019; 33(7):e22944. doi: 10.1002/jcla.22944. PMID: 31219204.

 

Novel Biomarkers in Breast Cancer

SEMAPHORIN 4D (alternative names: Sema4D, C9orf164, SEMAJ, CD100, BB18, GR3, CD100, COLL4)

Semaphorin 4D (Sema4D) is a member of the semaphorin family of proteins, which are known for their roles in cell signaling, axon guidance, and immune regulation (13). In the context of breast cancer, Sema4D has garnered attention for its involvement in tumor growth, metastasis, and the tumor microenvironment.

About Semaphorin 4D in Breast Cancer

Tumor Growth and Progression: Sema4D can influence the behavior of cancer cells, promoting survival and proliferation. It may also aid in the establishment of a supportive tumor microenvironment. In a study researchers have shown that Sema4D was expressed at higher levels in breast cancer cell lines compared with the normal human breast epithelial cell lines (14).

Angiogenesis: Sema4D is involved in the formation of new blood vessels (angiogenesis), which is vital for tumor growth. It can modulate the activity of endothelial cells, thereby supporting the vascularization of tumors (14).

Immune Evasion: Sema4D can affect the immune response to tumors. It may contribute to the suppression of T-cell responses, allowing cancer cells to evade immune detection and destruction.

Metastasis: The expression of Sema4D has been linked to increased metastatic potential in breast cancer. It may facilitate the migration and invasion of cancer cells to distant sites in the body. In a recent study researchers have found that Semaphorin 4D promotes skeletal metastasis in breast cancer (15).

A decreased expression of semaphorin 4D and plexin-B in breast cancer has been shown to be associated with recurrence and poor prognosis in a breast cancer cohort (16).

Biomarker Potential: Research suggests that Sema4D levels could serve as a potential biomarker for breast cancer progression and prognosis, although further studies would be needed to establish its clinical utility.

The potential link between Sema4D and estrogen receptor signaling was proposed in a study measuring circulating Sema4D plasma levels at primary diagnosis and in a follow-up sample 12 months after surgery in a cohort of 46 pre- and postmenopausal women with primary estrogen receptor positive breast cancer receiving adjuvant tamoxifen. The finding potentially represents an additional mechanism of the bone-protective properties of tamoxifen (17).

Therapeutic Targeting:  Due to its involvement in various aspects of cancer biology, Sema4D is being explored as a potential therapeutic target. Inhibiting its function might help in reducing tumor growth and improving the effectiveness of existing treatments. A study demonstrated that a Sema4D antibody in combination with either CTLA-4 or PD-1 blockade enhanced rejection of tumors or tumor growth delay, resulting in prolonged survival with either treatment (18).

Conclusion: Sema4D plays a multifaceted role in breast cancer pathology, influencing tumor growth, metastasis, and immune interactions. Ongoing research is essential to fully understand its mechanisms and to explore its potential as a target for therapeutic intervention.

Soluble SEMAPHORIN 4D ELISA (cat. no. BI-20405)

  • EASY – ready to use calibrators & controls included
  • RELIABLE – first validated according to international quality guidelines
  • LOW sample volume- 10 µl / sample – no predilution!
  • Reference values for healthy individuals provided

 

An in-depth characterization of the Biomedica Semaphorin 4D ELISA has been published here: A high-sensitivity enzyme immunoassay for the quantification of soluble human semaphorin 4D in plasma. Laber, A., Gadermaier, E., Wallwitz, J., Berg, G., Himmler, G., 2019. Anal. Biochem. 574, 15–22.  PMID: 30879960

 

Novel Biomarkers in Breast Cancer

LEUCINE-RICH ALPHA-2-GLYCOPROTEIN (alternative names: LRG, LRG1, HMFT1766) 

Leucine-rich alpha-2-glycoprotein (LRG) is a protein that has been studied in various diseases, including cancer. It is known for its involvement in inflammation and immune responses. In the context of breast cancer, LRG has attracted interest for its potential role as a biomarker and its involvement in the tumor microenvironment. For more information on LRG-1 as a prognostic marker for breast cancer survival please click here

LRG ELISA Assay Highlights (cat. no. BI-LRG)

  • CONVENIENT – ready to use reagents and controls included
  • RELIABLE – rigorously validated following international quality guidelines
  • EASY – results available in 3 hours

 

Related products

DKK-1 (Dickkopf-1) ELISA kit (cat. no. BI-20413) 

  • Direct measurement – no sample pre-dilution
  • Day test – all reagents included
  • Widely cited +180 references!

 

Literature 

  1.  Expression of periostin in breast cancer cells. Ratajczak-Wielgomas K, Grzegrzolka J, Piotrowska A, Matkowski R, Wojnar A, Rys J, Ugorski M, Dziegiel P. Int J Oncol. 2017; 51(4):1300-1310. doi: 10.3892/ijo.2017.4109.
  2. Periostin drives extracellular matrix degradation, stemness, and chemoresistance by activating the MAPK/ERK signaling pathway in triple-negative breast cancer cells. Wu J, Li J, Xu H, Qiu N, Huang X, Li H. Lipids Health Dis. 2023; 16;22(1):153. doi: 10.1186/s12944-023-01912-1.
  3. Epithelial periostin expression is correlated with poor survival in patients with invasive breast carcinoma. Kim GE, Lee JS, Park MH, Yoon JH. PLoS One. 2017; 21;12(11):e0187635. doi: 10.1371/journal.pone.0187635. PMID: 29161296..
  4. High serum levels of periostin are associated with a poor survival in breast cancer. Rachner TD et al., Breast Cancer Res Treat. 2020; 180(2):515-524.
  5. Development of an engineered peptide antagonist against periostin to overcome doxorubicin resistance in breast cancer. Oo KK, Kamolhan T, Soni A, Thongchot S, Mitrpant C, O-Charoenrat P, Thuwajit C, Thuwajit P. BMC Cancer. 2021; 14;21(1):65. doi: 10.1186/s12885-020-07761-w.
  6. Neuropilin1, a novel independent prognostic factor and therapeutic target in triple-negative breast cancer. Wang H, Zhang YN, Xu DQ, Huang JG, Lv D, Shi XY, Liu JY, Ren HW, Han ZX. Neoplasma. 2020; 67(6):1335-1342. doi: 10.4149/neo_2020_191127N1223. PMID: 32657612.
  7. Neuropilin-1 is over-expressed in claudin-low breast cancer and promotes tumor progression through acquisition of stem cell characteristics and RAS/MAPK pathway activation. Tang YH, Rockstroh A, Sokolowski KA, Lynam LR, Lehman M, Thompson EW, Gregory PA, Nelson CC, Volpert M, Hollier BG. Breast Cancer Res. 2022; 25;24(1):8. doi: 10.1186/s13058-022-01501-7. PMID: 35078508.
  8. Endothelial VEGFR Coreceptors Neuropilin-1 and Neuropilin-2 Are Essential for Tumor Angiogenesis. Benwell CJ, Johnson RT, Taylor JAGE, Price CA, Robinson SD. Cancer Res Commun. 2022 Dec 14;2(12):1626-1640. doi: 10.1158/2767-9764.CRC-22-0250. PMID: 36970722; PMCID: PMC10036134.
  9. Neuropilin-1 expression is associated with lymph node metastasis in breast cancer tissues. Seifi-Alan M, Shams R, Bandehpour M, Mirfakhraie R, Ghafouri-Fard S. Cancer Manag Res. 2018 Jul 11;10:1969-1974. doi: 10.2147/CMAR.S169533. PMID: 30022855; PMCID: PMC6045910.
  10. Soluble Neuropilin-1 is an independent marker of poor prognosis in early breast cancer. Rachner TD, Kasimir-Bauer S, Goebel A, Erdmann K, Hoffmann O, Rauner M, Hofbauer LC, Kimmig R, Bittner AK. J Cancer Res Clin Oncol. 2021; 147(8):2233-2238. doi: 10.1007/s00432-021-03635-1. PMID: 33884469.
  11. Neuropilin-1 as a Potential Biomarker of Prognosis and Invasive-Related Parameters in Liver and Colorectal Cancer: A Systematic Review and Meta-Analysis of Human Studies. Fernández-Palanca P, Payo-Serafín T, Fondevila F, Méndez-Blanco C, San-Miguel B, Romero MR, Tuñón MJ, Marin JJG, González-Gallego J, Mauriz JL. Cancers (Basel). 2022 Jul 15;14(14):3455. doi: 10.3390/cancers14143455. PMID: 35884516.
  12. SPECT and near-infrared fluorescence imaging of breast cancer with a neuropilin-1-targeting peptide. Feng GK, Liu RB, Zhang MQ, Ye XX, Zhong Q, Xia YF, Li MZ, Wang J, Song EW, Zhang X, Wu ZZ, Zeng MS.J Control Release. 2014; 28;192:236-42. doi: 10.1016/j.jconrel.2014.07.039. PMID: 25058570.
  13. Semaphorin 4D as a guidance molecule in the immune system. Kuklina E. Int Rev Immunol. 2021;40(4):268-273. doi: 10.1080/08830185.2021.1905807. PMID: 33787446.
  14. The role of semaphorin 4D in tumor development and angiogenesis in human breast cancer. Jiang H, Chen C, Sun Q, Wu J, Qiu L, Gao C, Liu W, Yang J, Jun N, Dong J. Onco Targets Ther. 2016 Sep 26;9:5737-5750. doi: 10.2147/OTT.S114708. PMID: 27729799; PMCID: PMC5045906.
  15. Semaphorin 4D Promotes Skeletal Metastasis in Breast Cancer. Yang YH, Buhamrah A, Schneider A, Lin YL, Zhou H, Bugshan A, Basile JR.PLoS One. 2016; 11(2):e0150151. doi: 10.1371/journal.pone.0150151. PMID: 26910109.
  16. Reduced expression of semaphorin 4D and plexin-B in breast cancer is associated with poorer prognosis and the potential linkage with oestrogen receptor. Malik MF, Ye L, Jiang WG. Oncol Rep. 2015 Aug;34(2):1049-57. doi: 10.3892/or.2015.4015. Epub 2015 May 28. PMID: 26035216.
  17. Plasma levels of Semaphorin 4D are decreased by adjuvant tamoxifen but not aromatase inhibitor therapy in breast cancer patients. Göbel, A., Kuhlmann, J.D., Link, T., Wimberger, P., Link-Rachner, C., Thiele, S., Dell’Endice, S., Furesi, G., Breining, D., Rauner, M., Hofbauer, L.C., Rachner, T.D., 2019. Journal of Bone Oncology, 16: 100237. PMID: 31011525
  18. Semaphorin4D Inhibition Improves Response to Immune-Checkpoint Blockade via Attenuation of MDSC Recruitment and Function. Clavijo PE, Friedman J, Robbins Y, Moore EC, Smith E, Zauderer M, Evans EE, Allen CT. Cancer Immunol Res. 2019; 7(2):282-291. doi: 10.1158/2326-6066.CIR-18-0156. PMID: 30514791.

September is Blood Cancer Awareness Month raising awareness about the various types of blood cancers, including leukemia, lymphoma, myeloma, and other hematologic malignancies. The goal of this month-long initiative is to educate the public about the signs, symptoms, and the risks that are associated with these cancers, as well as the importance of early detection and treatment.

Some cancer treatments may lead to bone loss and increases the risk of osteoporosis and fractures. Learn more about the impact of intensive chemotherapy and glucocorticoid treatment on bone remodeling markers in children with acute lymphoblastic leukemia in the study described below (1).

The campaign also focuses on highlighting the latest advancements in blood cancer research and treatment, emphasizing that ongoing research is essential for improved outcomes and quality of life for patients.

September is Blood Cancer Awareness Month

Acute lymphoblastic leukemia (ALL) is a type of cancer that affects the blood and bone marrow. ALL is the most common cancer in children. Intensive chemotherapy has improved the 5-year survival rate for ALL patients up to 90%. However, this improved survival has resulted in long-term complications associated with chemotherapy, including negative effects on bone health including osteopenia/osteoporosis, osteonecrosis, and increased fragility fractures.

Skeletal health relies on a balance between bone resorption and bone formation

The health of the skeleton relies on a balance between bone resorption and bone formation, a process known as “bone remodeling,” which is regulated by the RANKL/RANK/osteoprotegerin (OPG) and Wnt/β-catenin signaling pathways.

Currently, there is a lack of data regarding the impact of intensive chemotherapy on bone remodeling markers in children with ALL. In a recent study, researchers in Italy investigated the role of bone remodeling markers in children with acute lymphoblastic leukemia after intensive chemotherapy and glucocorticoid (GC) treatment (1). The bone remodeling markers such as RANKL, OPG and the WNT signaling molecules Sclerostin and DKK-1 were also measured with ELISA kits from BIOMEDICA.

The researchers found “higher levels of RANKL and OPG in ALL children compared to the controls, with a balance of RANKL/OPG ratio, whereas the levels of sclerostin and DKK-1, the main inhibitors of osteoblastogenesis, were similar in the two groups of subjects. These results suggest that in our cohort of ALL subjects, the intensive chemotherapy and GCs increased osteoclastic activity and, thereby, bone resorption” (1).

About the RANK/RANKL/OPG system

The receptor-ligand duo, RANK and RANKL are crucial regulators of bone metabolism and osteoclast development. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL. It competitively binds to RANKL and interferes with the interaction of RANKL–RANK, thus blocking bone resorption. Beyond its role as a regulator of bone remodeling, the RANK/RANKL/OPG system has direct effects on the development of tumor cells, as it is implicated in the progression of breast and prostate cancer as well as leukemia.

About the WNT signaling molecules Sclerostin and DKK-1

Sclerostin (SOST) is mainly produced by osteocytes and is considered as the major regulator of bone formation. It is a soluble antagonist of the Wnt signaling pathway. Inactivating this pathway leads to bone degradation, while induction of Wnt signaling promotes bone formation.

Dickkopf-1 (DKK-1) is an extracellular protein. DKK-1 plays a role in the regulation of bone metabolism, and is a secreted inhibitor of the Wnt signaling pathway. DKK-1 inhibits the differentiation of osteoblasts and thereby bone formation. The dysregulation of DKK1 can lead to cancer progression.  

Biomedica offers quality kits for the measurement of these bone biomarkers

-Osteoprotegerin (OPG) ELISA (cat. no. BI-20403)

-Soluble free RANKL ELISA (cat. no. BI-20462)

-Sclerostin (SOST) ELISA (cat.no. BI-20492)

-Bioactive Sclerostin (SOST) ELISA (cat. no. BI-20472)

-DKK-1 (Dickkopf-1) ELISA (cat.no. BI-20413)

 

  • Widely cited in + 1000 publications
  • Validated kits following international quality guidelines

 

Literature

  1. Bone Remodeling Markers in Children with Acute Lymphoblastic Leukemia after Intensive Chemotherapy: The Screenshot of a Biochemical Signature. Muggeo P, Grassi M, D’Ascanio V, Brescia V, Fontana A, Piacente L, Di Serio F, Giordano P, Faienza MF, Santoro N. Cancers (Basel). 2023 Apr 29;15(9):2554. doi: 10.3390/cancers15092554. PMID: 37174020; PMCID: PMC10177249.
  2. The RANK-RANKL-OPG System: A Multifaceted Regulator of Homeostasis, Immunity, and Cancer. Medicina (Kaunas). De Leon-Oliva D, Barrena-Blázquez S, Jiménez-Álvarez L, Fraile-Martinez O, García-Montero C, López-González L, Torres-Carranza D, García-Puente LM, Carranza ST, Álvarez-Mon MÁ, Álvarez-Mon M, Diaz R, Ortega MA. 2023 Sep 30;59(10):1752. doi: 10.3390/medicina59101752. PMID: 37893470; PMCID: PMC10608105.
  3. Understanding the Wnt Signaling Pathway in Acute Myeloid Leukemia Stem Cells: A Feasible Key against Relapses. Biology (Basel). Láinez-González D, Alonso-Aguado AB, Alonso-Dominguez JM. 2023 May 5;12(5):683. doi: 10.3390/biology12050683. PMID: 37237497; PMCID: PMC10215262.

We are present in over 60 countries, ensuring global availability and customer support through partnerships with selected local distributors on almost every continent. Regardless of your location, we are here to help you reach your goals.

With over 30 years of experience, we specialize in developing and manufacturing high-quality ELISA assay kits for biomarkers in clinical research.

Check out our ELISA Assay product brochure

Our ELISA Kits Travel Worldwide – contact us or your local representative 

About us

BIOMEDICA develops and manufactures high quality and widely cited immunoassays for clinical and pre-clinical applications in bone and cardiorenal diseases. For specific biomarkers, Biomedica has become a world-wide leader, e.g. Sclerostin, free sRANKL, OPG, DKK-1, and NT-proCNP.   

All Biomedica ELISA assays are fully validated following international quality guidelines. The assays include ready-to-use serum-based calibrators and controls enabling researchers to collect biologically reliable data.

This year’s ELISA assay highlights  

Cardiac Safety Biomarkers : Rat NT-proBNP, NT-proANP ELISA kits

FGF23  : FGF23 intact , FGF23 (C-terminal) ELISA kits

Cytokines  : VEGF, Angiopoietin-2, IL-6   

Discover our PROMOTION : Take 15% OFF of the human IL-6 ELISA Assay now through end of 2024! Making IL-6 ELISA Kits more affordable!

 

Making IL-6 ELISA Kits More Affordable

Features & Benefits of BIOMEDICA ELISA Assay Kits

  • Highly Specific – many of our kits employ  characterized epitope-mapped antibodies
  • Excellent Quality – our kits are validated according to international quality guidelines (ICH, FDA..)
  • Convenient Use  –offering ready to use and color coded reagents – controls are included in all kits! 

 

Other Products

EZ4U – Cell Proliferation & Cytotoxicity Assay (cat. no. BI-5000) for reliable testing of cell viability in 96-well microtiter plates.

 Features & Benefits EZ4U Assay

-easy and convenient singe-step incubation for use on living cells

-non-radioactive

-cultivation can be continued after cell numbers are determined

-widely cited in more than 240 publications e.g.

July is acknowledged as Bone Cancer and Sarcoma Awareness Month, focusing on increasing awareness about rare and challenging cancers affecting children and adolescents. Sarcoma is a type of cancer that originates in the bones and soft tissues. Soft tissues include muscle, fat, blood vessels, fibrous tissues such as tendons and ligament. More than 70 different subtypes of sarcomas have been reported. However, all sarcomas can be divided into two main groups: soft tissue sarcomas and bone cancers.

Soft Tissue Sarcomas is a rare type of cancer that originates from the growth of cells within the body´s soft tissue. More than 50 different soft tissue sarcomas have been reported (3 ) Soft tissue sarcoma can occur anywhere in the body, but it most frequently develops in arms, legs, and abdomen (4).

Osteosarcoma is the most prevalent type of bone cancer in children and adolescents with and incidence of around 4.4. cases per million children reported each year (1). Genomic alterations, particularly the inactivation of TP53 and RB, are present in most cases of osteosarcoma.

Ewing sarcoma is the second most common bone tumor occurring most frequently in teenagers, with a median age of 15 years. Ewing sarcomas is an aggressive tumor that develops usually in bone, but sometimes in soft tissue, most commonly affecting the lower extremity and pelvis. At diagnosis, up to 25% of patients , commonly found in the lung, bones, and bone marrow (2). This condition is biologically driven by a chromosomal translocation, typically involving the EWS and FLI1 genes.

July is Sarcoma and Bone Cancer Awareness Month

  • 5 Things to Know About Bone Cancer and Sarcoma Awareness Month- link

 

Wnt Signalling molecules Sclerostin (SOST) and Dickkopf-1 (DKK-1) in Sarcoma

 

SCLEROSTIN has been shown to be expressed in bone and cartilage forming skeletal tumors. Sclerostin is widely localized to areas in osteoblastic differentiation and ossification (5). In a study using an osteosarcoma mouse model, the administration of sclerostin resulted in inhibited tumor growth and extended survival periods (6).

DKK-1 is a wnt inhibitor that has been shown to partially improve osteosarcoma survival by upregulating aldehyde-dehydrogenase-1A1, neutralizing reactive oxygen species originating from nutritional stress and chemotherapeutic challenge (7). In a mouse model researches demonstrated the use of a DKK-1 targeting vivo morpholino that reduces tumour progression (7).

FGF23 in uterine sarcoma

Human FGF23 has been shown to be highly expressed in uterine sarcoma highlighting its potential as a biomarker for the diagnosis and prognosis of the disease (8).

Sclerostin, DKK-1 and FGF23 can easily be measured in blood, urine and cell culture supernatants with an ELISA assay.

– Sclerostin ELISA (cat. no. BI-20492)

– DKK-1 ELISA (cat. no. BI-20413)

– FGF23 ELISAs (cat. no. BI-20700, BI-20702)

Literature

  1. Osteosarcoma. Pediatr Blood Cancer. Eaton BR, Schwarz R, Vatner R, Yeh B, Claude L, Indelicato DJ, Laack N. 2021 May;68 Suppl 2:e28352. doi: 10.1002/pbc.28352. Epub 2020 Aug 11. PMID: 32779875.
  2. Ewing sarcoma. Pediatr Blood Cancer. Eaton BR, Claude L, Indelicato DJ, Vatner R, Yeh B, Schwarz R, Laack N. 2021 May;68 Suppl 2:e28355. doi: 10.1002/pbc.28355. PMID: 33818887.
  3. More Than 50 Subtypes of Soft Tissue Sarcoma: Paving the Path for Histology-Driven Treatments. Katz D, Palmerini E, Pollack SM. Am Soc Clin Oncol Educ Book. 2018 May 23;38:925-938. doi: 10.1200/EDBK_205423. PMID: 30231352.
  4. Malignant Soft-Tissue Sarcomas. Hematol Oncol Clin North Am. Brownstein JM, DeLaney TF. 2020 Feb;34(1):161-175. doi: 10.1016/j.hoc.2019.08.022. Epub 2019 Oct 28. PMID: 31739942.
  5. Sclerostin expression in skeletal sarcomas. Shen J, Meyers CA, Shrestha S, Singh A, LaChaud G, Nguyen V, Asatrian G, Federman N, Bernthal N, Eilber FC, Dry SM, Ting K, Soo C, James AW. Hum Pathol. 2016 Dec;58:24-34. doi: 10.1016/j.humpath.2016.07.016. Epub 2016 Aug 3. PMID: 27498059; PMCID: PMC6560186.
  6. Antitumor Effect of Sclerostin against Osteosarcoma. Ideta H, Yoshida K, Okamoto M, Sasaki J, Kito M, Aoki K, Yoshimura Y, Suzuki S, Tanaka A, Takazawa A, Haniu H, Uemura T, Takizawa T, Sobajima A, Kamanaka T, Takahashi J, Kato H, Saito N. Cancers (Basel). 2021 Nov 29;13(23):6015. doi: 10.3390/cancers13236015. PMID: 34885123; PMCID: PMC8656567.
  7. Morpholino-driven blockade of Dkk-1 in osteosarcoma inhibits bone damage and tumour expansion by multiple mechanisms. Pan S, Cesarek M, Godoy C, Co CM, Schindler C, Padilla K, Haskell A, Barreda H, Story C, Poole R, Dabney A, Gregory CA. Br J Cancer. 2022 Jul;127(1):43-55. doi: 10.1038/s41416-022-01764-z. Epub 2022 Mar 11. PMID: 35277659; PMCID: PMC9276700.
  8. Fibroblast Growth Factor 23 is a Potential Prognostic Biomarker in Uterine Sarcoma. Yang L, Cai Y, Wang Y, Huang Y, Zhang C, Ma H, Zhou JG. Technol Cancer Res Treat. 2024 Jan-Dec;23:15330338241245924. doi: 10.1177/15330338241245924. PMID: 38613349; PMCID: PMC11015760.

We are excited to be soon exhibiting at the International Conference on Children’s Bone Health (ICCBH) in Salzburg, Austria from June 22-25, 2024.

Join us at booth number 4 and explore our widely trusted Biomarker ELISA Assay Kits including Fibroblast Growth Factor (FGF23), Sclerostin, Periostin, NT-proCNP, and many others.

We look forward to connecting with you!

Join us at the International Conference on Children’s Bone Health

Click here for more information about the conference for anyone who is interested in 

bone metabolism and bone mass in children, adolescents and young adults.

The ICCBH conference aims to unite researchers, clinicians, health professionals, and others from different fields to gain an understanding of the developing skeleton with regards to childhood health and disease. Latest advancements, innovative therapies, and genetic discoveries will be discussed.

More about Biomarkers in Bone Biology  

Bone cells release biomarkers during bone remodeling. They can be used in assessing bone diseases and represent useful therapeutic targets. Bone biomarkers can easily be detected in serum and plasma samples by immunoassay.  

A recent review by Ponds-Belda OD et al., Mineral Metabolism in Children: Interrelation between Vitamin D and FGF23 focuses on various aspects of FGF23 metabolism in children, reference values,  and other key variables involved in mineral homeostasis. 

BIOMEDICA offers quality kits to measure various bone biomarkers 

Sclerostin ELISA (SOST; cat.no. BI-20492)  

OPG ELISA (Osteoprotegerin; cat.no. BI-20403)  

RANKL ELISA (soluble RANKL; cat.no. BI-20462)  

DKK-1 ELISA (Dickkopf-1; cat.no. BI-20413)  

FGF23 intact ELISA (Fibroblast growth factor-23 intact; cat.no. BI-20700) 

FGF23 C-terminal ELISA (Fibroblast growth factor-23 C-terminal; cat.no. cat.no. BI-20702) 

PERIOSTIN ELISA (POSTN, BI-20433) 

NT-proCNP ELISA (NT-C-type natriuretic peptide, BI-20812)

 TRUSTED – cited in over 1300 publications

  • Kit validations follows international quality guidelines
  • Developed & manufactured by Biomedica in Austria

Machine Learning for Bone Biomarker Profiling in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic, progressive inflammatory disorder which can lead to severe joint damage and disability. In 2019, an estimated 18 million people worldwide were living with this disease (1). Untreated RA can lead to destruction of the joints as well as heart, lung or nervous system problems (2). Skeletal bone loss, referred to as osteopenia or osteoporosis, is a key feature of RA. 

Sclerostin and Dickkopf-1 (DKK-1) are Wnt signaling proteins that are secreted by osteocytes, bone cells embedded in the bone matrix. They are inhibitors of bone formation and play a key role in the pathogeneses of systemic and localized bone loss in RA (3, 4). Serum levels of Sclerostin and DKK-1 have shown to be elevated in patients with RA compared to controls and correlate with bone erosions and inflammation (4, 5, 6). Findings in mice have demonstrated that DKK-1 triggers inflammatory bone degradation and neutralization of DKK-1 protects from systemic bone loss during inflammation (7). Interestingly, blocking the bone destruction molecule Sclerostin with an anti-sclerostin antibody has shown to be effective for the treatment of osteoporosis but may not be safe for patients suffering from inflammatory RA: in a rodent RA model, Weymeyer et al. demonstrated that Sclerostin inhibition did not stop bone loss and worsened clinical RA outcome by promoting TNF-dependent inflammatory joint destruction (8).

Controlling inflammation by biological therapies targeting pro-inflammatory cytokines has shown to have a positive effect in RA patients (5). Interleukin-6 is a key immunomodulatory cytokine that plays an important role in the development of RA. Inhibition of IL-6 has proven to be effective in treating patients with RA (9). A study by Briot et al showed that DKK-1 levels decreased in RA patients treated with an anti-IL-6 inhibitor (6).

Machine Learning for Bone Biomarker Profiling in Rheumatoid Arthritis

A recent cross-sectional study by Adami G et al., with over 1800 enrolled participants diagnosed with RA, Psoriatic Arthritis (PsA), and Systemic Sclerosis (SSc), employed machine learning techniques to assess the capability of biomarker profiles in differentiating RA patients from individuals with PsA and SSc. The Wnt signaling antagonists Sclerostin and Dickkopf-1 (DKK-1) were among the biomarkers measured. The study provided an in-depth understanding into the bone signature of RA that is marked by changes in bone mineral density and by unique biomarker profiles (6). Serum Sclerostin and DKK-1 levels were measured with ELISA assay kits from Biomedica.

SCLEROSTIN ELISA (#BI-20492) and DKK-1 (#BI-20403) ELISA kits

Biomedica´s Sclerostin ELISA Assay

  • TRUSTED – cited in more than 290 publications!
  • QUALITY – validated according to international guidelines
  • EFFICIENT – only 20µl sample / well
  • CONVENIENT – ready to use standards and controls included

 

Biomedica´s DKK-1 ELISA assay 

  • TRUSTED – cited in more than 180 publications!
  • QUALITY – validated according to international guidelines
  • EFFICIENT – only 20µl sample / well
  • CONVENIENT – direct measurement – no sample pre-dilution. Ready to use standards and controls included

 

Also available from Biomedica : Bioactive Sclerostin ELISA (cat. no. BI-20472), Interleukin-6 ELISA (BI-IL6)

 

Complete ready-to use ELISA kits

Complete ready-to use ELISA kits

 

Biomedica- High Quality Guaranteed

Literature

  1. GBD 2019: Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. https://vizhub.healthdata.org/gbd-results
  2. WHO- Rheumatoid arthritis, June 2023
  3. Wnt Signaling and Biological Therapy in Rheumatoid Arthritis and Spondyloarthritis. Cici D, Corrado A, Rotondo C, Cantatore FP. Int J Mol Sci. 2019 Nov 7;20(22):5552. doi: 10.3390/ijms20225552. PMID: 31703281; PMCID: PMC6888549.
  4. Study of correlation of level of expression of Wnt signaling pathway inhibitors sclerostin and dickkopf-1 with disease activity and severity in rheumatoid arthritis patients. Singh A, Gupta MK, Mishra SP.Drug Discov Ther. 2019;13(1):22-27. doi: 10.5582/ddt.2019.01011. PMID: 30880318.
  5. The effect of tocilizumab on bone mineral density, serum levels of Dickkopf-1 and bone remodeling markers in patients with rheumatoid arthritis. Briot K, Rouanet S, Schaeverbeke T, Etchepare F, Gaudin P, Perdriger A, Vray M, Steinberg G, Roux C. Joint Bone Spine. 2015 Mar;82(2):109-15. doi: 10.1016/j.jbspin.2014.10.015. Epub 2014 Dec 31. PMID: 25557658.
  6. Machine learning to characterize bone biomarkers profile in rheumatoid arthritis. Adami G, Fassio A, Rossini M, Benini C, Bixio R, Rotta D, Viapiana O, Gatti D. Front Immunol. 2023 Nov 9;14:1291727. doi: 10.3389/fimmu.2023.1291727. PMID: 38022514; PMCID: PMC10665911.
  7. Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression. Heiland GR, Zwerina K, Baum W, Kireva T, Distler JH, Grisanti M, Asuncion F, Li X, Ominsky M, Richards W, Schett G, Zwerina J. Ann Rheum Dis. 2010 Dec;69(12):2152-9. doi: 10.1136/ard.2010.132852. Epub 2010 Sep 21. PMID: 20858621.
  8. Sclerostin inhibition promotes TNF-dependent inflammatory joint destruction. Wehmeyer C, Frank S, Beckmann D, Böttcher M, Cromme C, König U, Fennen M, Held A, Paruzel P, Hartmann C, Stratis A, Korb-Pap A, Kamradt T, Kramer I, van den Berg W, Kneissel M, Pap T, Dankbar B. Sci Transl Med. 2016 Mar 16;8(330):330ra35. doi: 10.1126/scitranslmed.aac4351. Epub 2016 Mar 16. PMID: 27089204.
  9. Targeting IL-6 or IL-6 Receptor in Rheumatoid Arthritis: What Have We Learned? Avci AB, Feist E, Burmester GR. BioDrugs. 2024 Jan;38(1):61-71. doi: 10.1007/s40259-023-00634-1. Epub 2023 Nov 21. PMID: 37989892; PMCID: PMC10789669.

 

Bone Health & Osteoporosis – Biomarkers of Bone Regulation

Maintaining strong and healthy bones is essential for our well-being. Bone not only provides structural support for the body but also protects vital organs and serves as a provider for minerals such as calcium and phosphorus. Bone density and bone strength are key components of bone health.

Osteoporosis is a condition of weakened and fragile bones. It is the most common metabolic bone disease in the world (1) that can affect individuals of various ages, but is more commonly associated with aging. Both men and women can be affected, but postmenopausal women are at higher risk to develop Osteoporosis due to the decline of hormonal estrogen levels which plays a protective role in bone. Prevention of Osteoporosis includes a balanced diet and exercise.

Bone remodeling is a continuous process that is tightly regulated between bone resorption of old or damaged bone and the formation of new bone. Various hormones and factors are involved in bone metabolism. The bone cycle consists of different phases and markers of bone metabolism can be categorized as markers of bone formation, markers of bone resorption and markers of the regulation of  bone metabolism.

Bone Health & Osteoporosis – biomarkers of bone regulation

Protein biomarkers are often used in clinical research or clinical settings to assess bone health and to monitor the effectiveness of Osteoporosis treatments. Some of these biomarkers provide information about the regulatory processes involved in bone metabolism and turnover.

Monitoring these biomarkers can provide information on the overall health of bones. Some of these regulatory biomarkers include:

  • Sclerostin (SOST) – is produced by osteocytes, bone cells embedded in the bone. Sclerostin is a bone specific Wnt pathway inhibitor, that negatively regulates bone formation, by promoting osteoclastogenesis and bone resorption (3). Elevated Sclerostin levels may indicate decreased bone formation.

 

  • Dickkopf-1 (DKK-1) – is like Sclerostin an inhibitor of Wnt signaling, which is crucial for bone formation. Elevated serum DKK-1 promote bone resorption (4). DKK-1 levels may indicated suppressed bone formation.

 

  • Receptor Activator of Nuclear Factor-Kappa B Ligand (RANKL) – is a key regulator of osteoclast activation and formation. RANKL promotes bone resorption by activating the bone osteoclasts. RANKL is secreted by osteocytes and is the most important factor of osteoclast formation (5).  

 

  • Osteoprotegerin (OPG) – is the decoy receptor for RANKL. OPG regulates bone resorption (6). Changes in the OPG / RANKL ratio can affect bone remodeling.

 

 

With advancing age, the human body´s natural capacity to consistently renew bones and maintain their resilience diminishes. This decline is enhanced by conditions like osteoporosis. This poses a significant health concern for the elderly and is becoming a growing economic challenge on society. In an effort to address this problem, scientists are actively seeking novel therapeutic strategies to enhance bone regeneration.

 

Building bone with bioinspired molecules

By employing computer models and simulations, a Dresden-based team created innovative bio-inspired compounds that enhance bone regeneration in mice. These compounds can be incorporated into biomaterials, allowing for their localized introduction into bone defects. These newly developed molecules derive from glycosaminoglycans, which are extended sugar chains like hyaluronic acid or heparin. These molecules could be used to turn-off proteins like DKK-1 and Sclerostin that block bone regeneration that could lead to new and more effective therapies for bone diseases.

DKK-1 and SCLEROSTIN are two important proteins that play significant roles in regulating bone health and development.

DKK-1 (Dickkopf-1) acts as an inhibitor of the Wnt signaling pathway. This pathway is crucial for bone formation. Overexpression of DKK-1 leads to a decrease in bone formation characterized by conditions with impaired bone density and increased fragility, such as osteoporosis.

SCLEROSTIN (SOST) is a Wnt signaling inhibitor and a negative regulator of bone formation. Sclerostin is primarily produced by osteocytes, which are bone cells embedded within the bone matrix.

Sclerostin and DKK-1 can be measured in human serum samples with an ELISA assay.

 

Biomedica´s DKK-1 ELISA assay (cat. no. BI-20413)

  • 20µl sample volume
  • Widely cited
  • No sample dilution
  • Fully validated

 

Biomedica´s Sclerostin ELISA assay (cat. no. 20492)

  • The internationally most referenced Sclerostin ELISA!
  • Rigorously validated according to FDA/ICH/EMEA guidelines
  • 20µl sample volume

 

also available: Bioactive Sclerostin ELISA (cat. no. BI-20472)

Rational engineering of glycosaminoglycan-based Dickkopf-1 scavengers to improve bone regeneration. Ruiz-Gómez G, Salbach-Hirsch J, Dürig JN, Köhler L, Balamurugan K, Rother S, Heidig SL, Moeller S, Schnabelrauch M, Furesi G, Pählig S, Guillem-Gloria PM, Hofbauer C, Hintze V, Pisabarro MT, Rademann J, Hofbauer LC. Biomaterials. 2023 Jun;297:122105. doi: 10.1016/j.biomaterials.2023.122105. Epub 2023 Mar 31. PMID: 37031548.

Abstract

The WNT signaling pathway is a central regulator of bone development and regeneration. Functional alterations of WNT ligands and inhibitors are associated with a variety of bone diseases that affect bone fragility and result in a high medical and socioeconomic burden. Hence, this cellular pathway has emerged as a novel target for bone-protective therapies, e.g. in osteoporosis. Here, we investigated glycosaminoglycan (GAG) recognition by Dickkopf-1 (DKK1), a potent endogenous WNT inhibitor, and the underlying functional implications in order to develop WNT signaling regulators. In a multidisciplinary approach we applied in silico structure-based de novo design strategies and molecular dynamics simulations combined with synthetic chemistry and surface plasmon resonance spectroscopy to Rationally Engineer oligomeric Glycosaminoglycan derivatives (REGAG) with improved neutralizing properties for DKK1. In vitro and in vivo assays show that the GAG modification to obtain REGAG translated into increased WNT pathway activity and improved bone regeneration in a mouse calvaria defect model with critical size bone lesions. Importantly, the developed REGAG outperformed polymeric high-sulfated hyaluronan (sHA3) in enhancing bone healing up to 50% due to their improved DKK1 binding properties. Thus, rationally engineered GAG variants may represent an innovative strategy to develop novel therapeutic approaches for regenerative medicine

The process of aging is linked to physiological changes, which include a decline in bone mass and renal function. In a recent study, researchers investigated the effects of Vitamin D supplementation on bone metabolism and bone biomarkers in patients with and without renal impairment.

Effects of Vitamin D on Bone Markers in Kidney Disease

The study incorporated 379 patients with a mean age of > 70 years who were supplemented with various doses of vitamin D ranging from 12000 IU to 48,000 IU/month for a period of one year.

The biomarkers Sclerostin (SOST), Dickkopf-1 (DKK-1), Osteoprotegerin (OPG), and soluble RANKL (sRANKL) were measured with ELISA assays from BIOMEDICA.

Learn more: Early renal impairment affects hormonal regulators of calcium and bone metabolism and Wnt signalling and the response to vitamin D supplementation in healthy older adults. Christodoulou M et al., J Steroid Biochem Mol Biol. 2023. 229:106267. doi: 10.1016/j.jsbmb.2023.106267. 

About the BIOMEDICA bone marker ELISA kits

Sclerostin (SOST) ELISA  (BI-20492)

  • Most referenced Sclerostin ELISA + 250 citations
  • Low sample volume – 20µl / well
  • Validated following international guidelines

 

Dickkopf-1 (DKK-1) ELISA  (BI-20413)

 

Osteoprotegerin (OPG) ELISA (BI-20403)

  • most referenced human OPG ELISA in +245 citations
  • day test, ready to use color coded reagents
  • controls included

 

Free soluble RANKL ELISA (BI-20462)

  • Cited in over + 290 publications

 

FGF23 intact ELISA (BI-20700)

 

FGF23 c-terminal ELISA (BI-20702)

 

All assays are developed and manufactured by BIOMEDICA

Related publications

Fibroblast growth factor 23 (FGF23) and early chronic kidney disease in the elderly. Chudek J et al., Nephrol Dial Transplant. 2014 Sep;29(9):1757-63. doi: 10.1093/ndt/gfu063. 

Effectiveness and safety of vitamin D in relation to bone health. Cranney A et al., Evid Rep Technol Assess (Full Rep). 2007 Aug;(158):1-235. PMID: 18088161; PMCID: PMC4781354.

Biomedica features FGF23 ELISA – intact and C-terminal – assays

Meet us at the OSTEOLOGIE Conference taking place from 22-24 June 2023 in Salzburg, Austria! We will exhibit at booth # 36 introducing our novel biomarker ELISA assays to investigate bone and cancer induced bone diseases (e.g. Periostin, Semaphorin 4D, LRG, and others).

Our focus will also be on FGF23, an important regulator of renal phosphate handling, with our FGF23 intact and FGF23 C-terminal ELISA assays.

Drop by – we’d love to see you there!

Related products:

DKK-1 ELISA
OPG ELISA
free sRANKL ELISA
osteomiR – miRNA bone biomarker
FluoBolt Klotho FIA
Testing Services (ELISA, Luminex, miRNA)

 

Bone metastases affect over 1.5 million cancer patients globally, making bones a favored metastatic site for solid tumors (1). The presence of skeletal metastases can significantly reduce the quality of life for individuals with advanced cancer, as weakened bones can cause pain, fractures, and increase the risk of mortality (2, 3).

Bones have numerous important functions which include structural support, mobility, hematopoiesis, and mineral storage (4). The health and performance of our bone tissue are overseen by a range of cell types, which include:

  • Osteoblasts – cells responsible for creating new bone tissue
  • Osteoclasts – cells responsible for breaking down bone tissue
  • Osteocytes –  cells within the bone that monitor mechanical loading and regulate the process of bone remodeling 

 

Bone biology- cancer and bone

Bone biology- cancer and bone

Cancer and Bone – bone a preferred target site for cancer metastasis

Bone is a favored destination for metastasis in specific types of cancer, whereby cancer cells detach from the primary tumor and disseminate throughout the body. Certain cancers, such as breast, prostate, kidney, lung, ovarian, and thyroid, are especially prone to spread to bone (5).

Cancer and  Bone – the RANK/RANKL/OPG system

The RANK/RANKL/OPG system (receptor activator of the nuclear factor-κB ligand/ Osteoprotegerin) was identified more than 20 years ago and remains a widely researched topic until this day. The interaction between RANK and RANKL is essential for bone metabolism and osteoclast development. OPG acts as a decoy receptor for RANKL. By binding completely to RANKL, OPG obstructs the RANKL-RANK interaction, thereby blocking bone resorption. In addition to its role in regulating bone remodeling, the RANK/RANKL/OPG system is directly implicated in tumor cell development, particularly in the progression of breast and prostate cancer as well as leukemia (6-8).

Inhibiting RANK/RANKL signaling in human cancer

A fully humanized monoclonal antibody has been developed to counteract the effects of RANKL, which has received approval for treating bone loss conditions. The antibody functions by disrupting RANK signaling, preventing osteoclast activation and inhibiting bone resorption (6-8). More recently, inhibiting RANKL has been recognized as a significant checkpoint with the potential to influence anti-tumor response. Consequently, RANKL blockade has a direct impact on bone metastasis. Ongoing clinical and experimental trials are evaluating this emerging therapeutic approach (9).

Studies analyzing serum levels of OPG and RANKL

Serum concentrations of both OPG and soluble RANKL can be accessed via an enzyme-linked immunosorbent assay (ELISA). The predictive value of RANKL/OPG serum levels and disseminated tumor cells in breast cancer patients without metastasis was investigated in 509 patients with primary, nonmetastatic breast cancer. The results demonstrated that RANKL serum levels were significantly elevated in patients who developed bone metastases (10). A different study highlighted the role of OPG as a marker of breast cancer risk in women with a BRCA1 mutation. The authors suggested that OPG levels could be associated with disease risk, potentially serving as a marker for breast cancer risk and improving existing risk prediction models by identifying women at high risk of developing the disease (11).

How are circulating serum levels of Osteoprotegerin and soluble RANKL measured?

Both markers can easily be measured with a conventional ELISA assay.

 

– Widely cited in + 450 publications (citations for OPG, and RANKL)

– Extensively validated ELISA assays following international quality guidelines

High Quality ELISA kits – Developed & Manufactured by Biomedica

Related ELISA kits:  DKK-1, Sclerostin, IL-6, VEGF, Angiopoietin-2

References

  1. Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. Florencio-Silva R, Sasso GR, Sasso-Cerri E, Simões MJ, Cerri PS. Biomed Res Int. 2015;2015:421746. doi: 10.1155/2015/421746. Epub 2015 Jul 13. PMID: 26247020; PMCID: PMC4515490.
  2. Understanding the Bone in Cancer Metastasis. Fornetti J, Welm AL, Stewart SA. J Bone Miner Res. 2018 Dec;33(12):2099-2113. doi: 10.1002/jbmr.3618. Epub 2018 Nov 26. PMID: 30476357.
  3. Bone as a Preferential Site for Metastasis. JBMR Plus. Sowder ME, Johnson RW. 2019 Jan 15;3(3):e10126. doi: 10.1002/jbm4.10126. PMID: 30918918; PMCID: PMC6419612.
  4. Cancer to bone: a fatal attraction. Weilbaecher KN, Guise TA, McCauley LK. Nat Rev Cancer. 2011 Jun;11(6):411-25. doi: 10.1038/nrc3055. Epub 2011 May 19. PMID: 21593787; PMCID: PMC3666847.
  5. Bone metastasis: mechanisms, therapies, and biomarkers. Clézardin P, Coleman R, Puppo M, Ottewell P, Bonnelye E, Paycha F, Confavreux CB, Holen I. Physiol Rev. 2021 Jul 1;101(3):797-855. doi: 10.1152/ physrev.00012.2019. Epub 2020 Dec 24. PMID: 33356915.
  6. The Roadmap of RANKL/RANK Pathway in Cancer. Casimiro S, Vilhais G, Gomes I, Costa L. Cells. 2021 Aug 4;10(8):1978. doi: 10.3390/cells10081978. PMID: 34440747; PMCID: PMC8393235.
  7. RANKL biology: bone metabolism, the immune system, and beyond. Ono T, Hayashi M, Sasaki F, Nakashima T. Inflamm Regen. 2020 Feb 7;40:2. doi: 10.1186/s41232-019-0111-3. PMID: 32047573; PMCID: PMC7006158.
  8. RANKL and RANK in Cancer Therapy. Physiology (Bethesda). Onji M, Penninger JM. 2023 May 1;38(3):0. doi: 10.1152/physiol.00020.2022. Epub 2022 Dec 6. PMID: 36473204.
  9. The Role of the RANKL/RANK Axis in the Prevention and Treatment of Breast Cancer with Immune Checkpoint Inhibitors and Anti-RANKL. Simatou A, Sarantis P, Koustas E, Papavassiliou AG, Karamouzis MV. Int J Mol Sci. 2020 Oct 14;21(20):7570. doi: 10.3390/ijms21207570. PMID: 33066388; PMCID: PMC7590202.
  10. Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer. Rachner TD, Kasimir-Bauer S, Göbel A, Erdmann K, Hoffmann O, Browne A, Wimberger P, Rauner M, Hofbauer LC, Kimmig R, Bittner AK. Clin Cancer Res. 2019 Feb 15;25(4):1369-1378. doi: 10.1158/1078-0432.CCR-18-2482. Epub 2018 Nov 13. PMID: 30425091.
  11. Delineating the role of osteoprotegerin as a marker of breast cancer risk among women with a BRCA1 mutation. Park SS, Uzelac A, Kotsopoulos J. Hered Cancer Clin Pract. 2022 Apr 13;20(1):14. doi: 10.1186/s13053-022-00223-3. PMID: 35418083; PMCID: PMC9008947.

 

Biomarkers & Bone Health – ELISA Kits for Clinical Research

Bone remodeling is a continuous process that removes bone and replaces it with newly synthesized bone. This bone turnover process preserves the mechanical function of the human skeleton.

Bone turnover biomarkers, e.g. markers of bone formation and bone resorption, have been used during the last decade to monitor bone diseases and to monitor their treatment.

Many of these markers are secreted by osteoblasts and osteoclasts and include regulators of bone turnover e.g. receptor activator of NF-kB ligand (RANKL) and osteoprotegerin (OPG).  

Though RANKL and OPG  play an integral role in bone turnover, they do not reflect the activity of osteocytes, the most abundant cell type in the bone.

Osteocytes are cells that regulate bone remodeling. They secrete proteins – bone regulation markers – that include Sclerostin (SOST), Dickkopf-1 (DKK-1), and Fibroblast growth factor  (FGF23). These markers reflect the osteocyte activity.

The above listed biomarkers circulate and can be measured in serum and plasma allowing the investigation of complex interactions between the bone and their relationship with other organs.

BIOMEDICA ELISA KITS – Biomarkers & Bone Health

check out our Bone Biomarker Brochure

ELISA Assay Kit Highlights

+ EASY – ready to use calibrators & controls included (color-coded reagents)
+FULL VALIDATION PACKAGE – assays are optimized for clinical samples
+ HIGH QUALITY GUARANTEED – results you can rely on
+ WIDELY CITED in 1500 + publications

Biomedica – Complete ready-to-use ELISA kits for superior performance and reproducibility

RELATED PRODUCTS

Osteoprotegerin (OPG) ELISA , soluble RANKL ELISA, Periostin ELISA, DKK-1 ELISA ,  Sclerostin ELISA

FGF23 ELISA , IL-6 ELISA  ,  VEGF ELISA ,  Angiopoietin-2 ELISA

MICRORNA  Analysis 

osteomiR®– bone miRNA biomarkers highlights:

  • Novel minimally invasive biomarkers to detect high imminent fracture-risk in osteoporosis
  • 19 individual bone-related biomarkers with distinct information content

RELATED PUBLICATIONS

Novel biological markers of bone: from bone metabolism to bone physiology. Rheumatology (Oxford). Chapurlat RD, Confavreux CB. 2016; 55(10):1714-25.

Abstract

Biochemical markers of bone turnover have been used for decades in the management of bone diseases, to assess the prognosis of these conditions and to monitor treatments. The new markers, however, also reflect specific physiological mechanisms in the bone or other organs. Periostin may be more specific to the periosteum; cathepsin K is an osteoclastic enzyme that may be involved in the cardiovascular system and joints; Dickkopf-1 is involved in bone formation and vascular calcification; sclerostin is a major regulator of bone formation in response to mechanical loading and may also play a role in chronic kidney disease bone and mineral disorder; sphingosine-1-phosphate is a lipid mediator interacting with bone resorption. Some of the bone markers are in fact hormones produced by the bone that affect various physiological and pathological functions in other organs. Thus, osteocalcin is produced by osteoblasts and participates in the regulation of insulin sensitivity and fertility in men. Fibroblast growth factor 23 is produced by osteocytes to regulate phosphorus and 1,25(OH)2D3, but it also plays a major role in the adverse consequences of declining renal function, in particular with respect to the myocardium. Micro RNAs are single-stranded RNAs that regulate several pathways, including the development timing, organogenesis, cell apoptosis, proliferation and differentiation. Their serum concentration may reflect the links between bone physiology and certain conditions in other organs, for example, the cardiovascular system.

Bones have many important biological functions. Bone biomarkers have gained attention in clinical research for the assessment of bone-related diseases. Some of the biomarker proteins have been found to represent useful targets for therapeutic antibodies.

Biomarkers in Bone Biology

Function of the human skeleton

The human skeletal system gives the body it´s structure and helps to protect and support the internal organs. It forms a part of the muscular-skeletal systems that helps the body to move. Throughout our lifetime, the human skeleton undergoes constant remodeling. This dynamic process, degrading bone and replacing it with new tissue maintains bone mass. The continuous cycle of bone resorption and bone growth is also known as bone metabolism.

Bone remodeling

Bone remodeling is a tightly regulated process performed by hormones, cell-signaling molecules, and bone cells. These specific bone cells are osteoclasts, osteoblasts, and osteocytes. The cells are in constant communication with each other through secreted factors, such as osteoprotegerin, RANKL, and sclerostin. These regulatory systems keep the bone remodeling balanced. Imbalances in bone metabolism can lead to bone diseases.

Role of RANKL, RANK, and OPG in bone biology

 Bones are broken down by osteoclasts and rebuilt by osteoblasts.

RANKL receptor activator is a mediator of bone resorption and OPG acts as a decoy receptor.

 

Osteoprotegerin (OPG) is produced by osteoblasts, cells that synthesize bone. OPG is a decoy receptor and binds to RANKL, antagonizing its binding to RANK.

RANKL (receptor activator of nuclear factor kappa-B ligand) is secreted by osteoblasts and binds to the RANK receptor on osteoclast precursor and mature osteoclast cells. RANKL stimulates bone resorption.

 

Role of Sclerostin, FGF23, DKK-1, and Periostin in bone biology

 

Bone biomarkers

 

Biomarkers in Bone Biology

 

Bone cells have been reported to have endocrine functions that affect multiple organs. The most abundant cell type in the bone are osteocytes residing within the bone matrix and comprising 90% to 95% of the bone cells. Osteocytes play a significant role in the regulation of osteogenesis, releasing osteocyte-related biomarkers such as sclerostin (SOST), fibroblast growth factor 23 (FGF23), and Dickkopf-1 (DKK-1).

Sclerostin (SOST) is mainly produced by osteocytes and is considered as the major regulator of bone formation. More recently, Sclerostin has been shown to stimulate the osteocyte synthesis of fibroblast growth factor-23, potentially contributing to the regulation of phosphate homeostasis.

Fibroblast growth factor 23 (FGF23) is a hormone that is mainly secreted by osteocytes and osteoblasts. It regulates phosphate and vitamin D levels and functions as a central endocrine hormone regulating phosphate balance.

Dickkopf-1 (DKK-1) is an extracellular protein. DKK-1 plays a role in the regulation of bone metabolism, as it inhibits the differentiation of osteoblasts.

Periostin (POSTN) is an extracellular matrix protein that is preferentially expressed in the periosteum, a membrane covering the outer surface of bones which is responsible for growth.  Periostin has functions in osteology, tissue repair, oncology, cardiovascular and respiratory diseases, and in a variety of  inflammatory settings (e.g. asthma).

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  • widely cited in over 1100 publications
 

 

Sclerostin ELISA (cat.no. BI-20492)

OPG ELISA (cat.no. BI-20403)

RANKL ELISA (cat.no. BI-20462)

FGF23 intact ELISA (cat.no. BI-20700)

FGF23 C-terminal ELISA (cat.no. BI-20702)

DKK-1 ELISA (cat.no. BI-20413)

PERIOSTIN ELISA (cat.no. BI-20433)

 

RELATED LITERATURE

A Review of the Potential Application of Osteocyte-Related Biomarkers, Fibroblast Growth Factor-23, Sclerostin, and Dickkopf-1 in Predicting Osteoporosis and Fractures. Ramli FF, Chin KY. Diagnostics (Basel). 2020 Mar 6;10(3):145. doi: 10.3390/diagnostics10030145. PMID: 32155909; PMCID: PMC7151094.

Sclerostin Directly Stimulates Osteocyte Synthesis of Fibroblast Growth Factor-23. Wijenayaka AR, Yang D, Ormsby RT, Bonewald LF, Atkins GJ. Calcif Tissue Int. 2021 Jul;109(1):66-76. doi: 10.1007/s00223-021-00823-6. Epub 2021 Feb 22. PMID: 33616712.

Biology of the RANKL-RANK-OPG System in Immunity, Bone, and Beyond. Front Immunol. Walsh MC, Choi Y.2014 Oct 20;5:511. doi: 10.3389/fimmu.2014.00511. PMID: 25368616; PMCID: PMC4202272.

The Osteocyte: New Insights. Robling AG, Bonewald LF. Annu Rev Physiol. 2020 Feb 10;82:485-506. doi: 10.1146/annurev-physiol-021119-034332. PMID: 32040934; PMCID: PMC8274561.

 

 

Osteoporosis Awareness – 

Worldwide around 200 million women have osteoporosis. Osteoporosis is a disease that weakens bone. Bones become fragile and porous.  From the outside, the osteoporotic bone is shaped like normal bone. However, the inside of the bone loses density and becomes weak. The risk of fractures become greater with age, due to the loss of minerals like calcium and phosphate. Osteoporosis most often affects bones in the hip, the spine and the wrist. Factors that influence bone health are nutrition, exercise and hormonal factors. Osteoporosis cannot be cured but delayed through early intervention and biomarker research has identified proteins that may help to identify patients at risk.

 

BIOMEDICA offers ELISA kits to measure Bone Biomarkers in human serum or plasma samples:

 

Osteoprotegerin (OPG) ELISA  , DKK-1 ELISA ,  Sclerostin ELISA , soluble RANKL ELISA and others…

IL-6 ELISA  , VEGF ELISA ,  Angiopoietin-2 ELISA

 How can you prevent Osteoporosis?

Osteoporosis prevention includes a balanced diet, containing sufficient amounts of calcium and vitamin D and regular exercise.

Exercises to protect or reduce your chance of fracture include regular weight-bearing exercise (eg. weight lifting or resistance training) or any kind of activity that carries your own body weight (e.g. walking, running, climbing stairs, dancing).

A healthy and balanced diet with the recommended daily amounts of calcium are important for bone health. Read more about “Good for your bone foods .

Related literature

 The Effectiveness of Physical Exercise on Bone Density in Osteoporotic Patients.

Benedetti MG, Furlini G, Zati A, Letizia Mauro G. Biomed Res Int. 2018. 23;2018:4840531. PMID: 30671455. Link to full text

Abstract

Physical exercise is considered an effective means to stimulate bone osteogenesis in osteoporotic patients. The authors reviewed the current literature to define the most appropriate features of exercise for increasing bone density in osteoporotic patients. Two types emerged: (1) weight-bearing aerobic exercises, i.e., walking, stair climbing, jogging, and Tai Chi. Walking alone did not appear to improve bone mass; however it is able to limit its progressive loss. In fact, in order for the weight-bearing exercises to be effective, they must reach the mechanical intensity useful to determine an important ground reaction force. (2) Strength and resistance exercises: these are carried out with loading (lifting weights) or without (swimming, cycling). For this type of exercise to be effective a joint reaction force superior to common daily activity with sensitive muscle strengthening must be determined. These exercises appear extremely site-specific, able to increase muscle mass and BMD only in the stimulated body regions. Other suggested protocols are multicomponent exercises and whole body vibration. Multicomponent exercises consist of a combination of different methods (aerobics, strengthening, progressive resistance, balancing, and dancing) aimed at increasing or preserving bone mass. These exercises seem particularly indicated in deteriorating elderly patients, often not able to perform exercises of pure reinforcement. However, for these protocols to be effective they must always contain a proportion of strengthening and resistance exercises. Given the variability of the protocols and outcome measures, the results of these methods are difficult to quantify. Training with whole body vibration (WBV): these exercises are performed with dedicated devices, and while it seems they have effect on enhancing muscle strength, controversial findings on improvement of BMD were reported. WBV seems to provide good results, especially in improving balance and reducing the risk of falling; in this, WBV appears more efficient than simply walking. Nevertheless, contraindications typical of senility should be taken into account.

 

Exercise for the prevention of osteoporosis in postmenopausal women: an evidence-based guide to the optimal prescription.

Daly RM, Dalla Via J, Duckham RL, Fraser SF, Helge EW.Braz J Phys Ther. 2019.23(2):170-180. PMID: 30503353. Full text link

Abstract

Background: Osteoporosis and related fragility fractures are a global public health problem in which pharmaceutical agents targeting bone mineral density (BMD) are the first line of treatment. However, pharmaceuticals have no effect on improving other key fracture risk factors, including low muscle strength, power and functional capacity, all of which are associated with an increased risk for falls and fracture, independent of BMD. Targeted exercise training is the only strategy that can simultaneously improve multiple skeletal and fall-related risk factors, but it must be appropriately prescribed and tailored to the desired outcome(s) and the specified target group.

Objectives: In this review, we provide an overview of the general principles of training and specific loading characteristics underlying current exercise guidelines for the prevention of osteoporosis, and an update on the latest scientific evidence with regard to the type and dose of exercise shown to positively influence bone mass, structure and strength and reduce fracture risk in postmenopausal women.

Back to school – sports training has positive outcomes

Strength training for children and adolescents enhances bone health

Strength training for children and adolescents is becoming more important as part of sport training and after-school fitness programs. Consequently, health problems due to inactivity, sedentary lifestyle and being overweight have resulted in increased interest in strength and resistance training (1). Today there is ample evidence that youth resistance training is safe and effective and improves motor skills, reduces fat mass, and enhances bone health. In addition, various performance markers such as muscle strength, power and overall health also improve (2-5). In adults, weight-bearing impact exercise such as jumping or hopping in addition to strength training can improve bone health. Among these, resistance training is the most promising intervention to maintain or increase bone mass and density (5, 6). 

Subsequently, measuring serum bone related biomarkers can be helpful in understanding normal and pathological processes that reflect bone cell activities in the skeleton.

Check out Biomedica´s high quality bone marker ELISA kits: Sclerostin,  RANKL, OPG,  DKK-1,  FGF23 (C-terminal), FGF23 intact and other 

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References on strength training for children and adoloscents 

  1. Resistance Training for Children and Adolescents.
    Stricker PR, Faigenbaum AD, McCambridge TM; COUNCIL ON SPORTS MEDICINE AND FITNESS Pediatrics. 2020. 145(6):e20201011. doi: 10.1542/peds.2020-1011.
  2. Performance – and health-related benefits of youth resistance training – Leistungs- und gesundheitsbezogene Wirkungen von Krafttraining mit Heranwachsenden.
    H.Chaabene H et al., 2020. Sports Orthopaedics and Traumatology; 36: 231-240.
  3. Strength training for children and adolescents: benefits and risks.
    Barbieri D, Zaccagni L. Coll Antropol. 2013. 37 Suppl 2:219-25. PMID: 23914510.
  4. Strength training for children and adolescents.
    Faigenbaum A. 2000. Clinics in Sports Medicine; 593-619.
  5. Exercise and Sports Science Australia (ESSA) position statement on exercise prescription for the prevention and management of osteoporosis.
    Beck BR, Daly RM, Singh MA, Taaffe DR. J Sci Med Sport. 2017;20:438–445. 
  6. Effects of Resistance Exercise on Bone Health.
    Hong AR, Kim SW. Endocrinol Metab (Seoul). 2018. 33(4):435-444. doi: 10.3803/EnM.2018.33.4.435. PMID: 30513557; PMCID: PMC6279907.

 

RELATED LITERATURE

Youth Resistance Training: The Good, the Bad, and the Ugly-The Year That Was 2017.
Faigenbaum AD. Pediatr Exerc Sci. 2018. 1;30(1):19-24. doi: 10.1123/pes.2017-0290. PMID: 29424264.

Abstract

The good news is that a growing body of evidence recognizes resistance training as foundational to long-term physical development. Original research and reviews published in 2017 conclude that early exposure to developmentally appropriate resistance training can improve markers of health, increase muscular fitness, enhance physical literacy, and reduce the risk of injury in young athletes. Although the papers discussed in the commentary add to our understanding of the pleiotropic benefits of youth resistance training, they also raise concerns. As measures of muscular strength and power have been found to track from childhood to adulthood, the bad news is that youth with low levels of muscular fitness tend to become weak adults who are at increased risk for functional limitations and adverse health outcomes. Furthermore, global participation in youth resistance training is falling far short of public health recommendations, and these ugly trends will likely impact the health and well-being of future generations. A change in current attitudes and common practices is urgently needed to educate parents, practitioners, and clinicians about the potential benefits of resistance training for all children and adolescents, not only young athletes.

Metabolic syndrome: Operational definitions and aerobic and resistance training benefits on physical and metabolic health in children and adolescents.

Leister KR, Cilhoroz BT, Rosenberg J, Brown EC, Kim JY Diabetes Metab Syndr. 2022. 16(6):102530. doi: 10.1016/j.dsx.2022.102530. PMID: 35709585.

Watch this on how kids can get stronger muscles:   “Top 10 Kids Exercises To Get Stronger Muscles”

Strength training for children and adolescents enhances bone health

 

UK study suggests protective effect of Vitamin D supplementation on bone metabolism

Vitamin D plays an important role in bone mineralization. It helps the body to effectively absorb calcium which is essential to good bone health. The most common way for the body to produce vitamin D is through sunlight. As we get older the natural production of vitamin D decreases. Thus, elderly people either need to take vitamin D supplements or focus on eating foods that contain vitamin D. In a recent study, UK researchers investigated the effect of vitamin D supplementation in older people for 12 months. They looked into changes in markers of bone metabolism, bone mineral density, and bone mineral content . The results suggest a protective effect of supplementation on bone metabolism. Read more: Vitamin D Supplementation for 12 Months in Older Adults Alters Regulators of Bone Metabolism but Does Not Change Wnt Signaling Pathway Markers.

 

Biomedica offers a wide range of high quality ELISA Kits for bone markers.


The following Wnt signaling and regulatory bone markers were measured in this study:

Sclerostin, OPG, RANKL, DKK-1, FGF23 intact, FGF23 (C-terminal)

 

Related publications

Vitamin D Supplementation for 12 Months in Older Adults Alters Regulators of Bone Metabolism but Does Not Change Wnt Signaling Pathway Markers.
Christodoulou M, Aspray TJ, Piec I, Washbourne C, Tang JC, Fraser WD, Schoenmakers I; VDOP Trial Group. JBMR Plus. 2022 Mar 24;6(5):e10619. doi: 10.1002/jbm4.10619. PMID: 35509637; PMCID: PMC9059470.

Abstract
Vitamin D status and supplementation regulates bone metabolism and may modulate Wnt signaling. We studied the response of hormonal regulators of bone metabolism, markers of Wnt signaling and bone turnover and bone mineral density (BMD) and bone mineral content (BMC) in a randomized vitamin D intervention trial (12,000 IU, 24,000 IU, 48,000 IU/mo for 1 year; men and women aged >70 years; n = 379; ISRCTN35648481). Associations with total and free 25(OH)D concentrations were analyzed by linear regression. Baseline vitamin D status was (mean ± SD) 25(OH)D: 40.0 ± 20.1 nmol/L. Supplementation dose-dependently increased total and free 25(OH)D concentrations and decreased plasma phosphate and parathyroid hormone (PTH) (all p < 0.05). The procollagen 1 intact N-terminal (PINP)/C-terminal telopeptide (CTX) ratio, C-terminal fibroblast growth factor-23 (cFGF23), and intact FGF23 (iFGF23) significantly increased with no between-group differences, whereas Klotho was unchanged. 1,25(OH)2D and PINP significantly increased in the 24 IU and 48,000 IU groups. Sclerostin (SOST), osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL), BMD, BMC, and CTX remained unchanged. Subgroup analyses with baseline 25(OH)D <25 nmol/L (n = 94) provided similar results. Baseline total and free 25(OH)D concentrations were positively associated with 1,25(OH)2D, 24,25(OH)2D (p < 0.001), vitamin D binding protein (DBP) (p < 0.05), BMD, and BMC (p < 0.05). Associations with PTH (p <0.001), cFGF23 (p < 0.01), and BAP (p < 0.05) were negative. After supplementation, total and free 25(OH)D concentrations remained positively associated only with 24,25(OH)2D (p < 0.001) and DBP (p < 0.001) and negatively with estimated glomerular filtration rate (eGFR) (p < 0.01). PTH and SOST were significantly associated only with free 25(OH)D. There were no significant relationships with BMD and BMC after supplementation. The decrease in PTH and increase in PINP/CTX ratio suggest a protective effect of supplementation on bone metabolism, although no significant effect on BMD or pronounced changes in regulators of Wnt signaling were found. The increase in FGF23 warrants caution because of its negative association with skeletal and cardiovascular health. Associations of total and free 25(OH)D with biomarkers were similar and known positive associations between vitamin D status and BMD were confirmed. The change in associations after supplementation might suggest a threshold effect. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The role of vitamin D in maintaining bone health in older people.
Hill TR, Aspray TJ. Ther Adv Musculoskelet Dis. 2017 Apr;9(4):89-95. doi: 10.1177/1759720X17692502. Epub 2017 Feb 14. PMID: 28382112; PMCID: PMC5367643.

Abstract
This review summarises aspects of vitamin D metabolism, the consequences of vitamin D deficiency, and the impact of vitamin D supplementation on musculoskeletal health in older age. With age, changes in vitamin D exposure, cutaneous vitamin D synthesis and behavioural factors (including physical activity, diet and sun exposure) are compounded by changes in calcium and vitamin D pathophysiology with altered calcium absorption, decreased 25-OH vitamin D [25(OH)D] hydroxylation, lower renal fractional calcium reabsorption and a rise in parathyroid hormone. Hypovitaminosis D is common and associated with a risk of osteomalacia, particularly in older adults, where rates of vitamin D deficiency range from 10-66%, depending on the threshold of circulating 25(OH)D used, population studied and season. The relationship between vitamin D status and osteoporosis is less clear. While circulating 25(OH)D has a linear relationship with bone mineral density (BMD) in some epidemiological studies, this is not consistent across all racial groups. The results of randomized controlled trials of vitamin D supplementation on BMD are also inconsistent, and some studies may be less relevant to the older population, as, for example, half of participants in the most robust meta-analysis were aged under 60 years. The impact on BMD of treating vitamin D deficiency (and osteomalacia) is also rarely considered in such intervention studies. When considering osteoporosis, fracture risk is our main concern, but vitamin D therapy has no consistent fracture-prevention effect, except in studies where calcium is coprescribed (particularly in frail populations living in care homes). As a J-shaped effect on falls and fracture risk is becoming evident with vitamin D interventions, we should target those at greatest risk who may benefit from vitamin D supplementation to decrease falls and fractures, although the optimum dose is still unclear.

The health effects of vitamin D supplementation: evidence from human studies.
Bouillon R, Manousaki D, Rosen C, Trajanoska K, Rivadeneira F, Richards JB. Nat Rev Endocrinol. 2022 Feb;18(2):96-110. doi: 10.1038/s41574-021-00593-z. Epub 2021 Nov 23. PMID: 34815552; PMCID: PMC8609267.

Abstract
Vitamin D supplementation can prevent and cure nutritional rickets in infants and children. Preclinical and observational data suggest that the vitamin D endocrine system has a wide spectrum of skeletal and extra-skeletal activities. There is consensus that severe vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD) concentration <30 nmol/l) should be corrected, whereas most guidelines recommend serum 25OHD concentrations of >50 nmol/l for optimal bone health in older adults. However, the causal link between vitamin D and many extra-skeletal outcomes remains unclear. The VITAL, ViDA and D2d randomized clinical trials (combined number of participants >30,000) indicated that vitamin D supplementation of vitamin D-replete adults (baseline serum 25OHD >50 nmol/l) does not prevent cancer, cardiovascular events, falls or progression to type 2 diabetes mellitus. Post hoc analysis has suggested some extra-skeletal benefits for individuals with vitamin D deficiency. Over 60 Mendelian randomization studies, designed to minimize bias from confounding, have evaluated the consequences of lifelong genetically lowered serum 25OHD concentrations on various outcomes and most studies have found null effects. Four Mendelian randomization studies found an increased risk of multiple sclerosis in individuals with genetically lowered serum 25OHD concentrations. In conclusion, supplementation of vitamin D-replete individuals does not provide demonstrable health benefits. This conclusion does not contradict older guidelines that severe vitamin D deficiency should be prevented or corrected.

Vitamin D: Production, Metabolism and Mechanisms of Action.
Bikle DD. 2021. Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–. PMID: 25905172.

Excerpt
Vitamin D production in the skin under the influence of sunlight (UVB) is maximized at levels of sunlight exposure that do not burn the skin. Further metabolism of vitamin D to its major circulating form (25(OH)D) and hormonal form (1,25(OH)2D) takes place in the liver and kidney, respectively, but also in other tissues where the 1,25(OH)2D produced serves a paracrine/autocrine function: examples include the skin, cells of the immune system, parathyroid gland, intestinal epithelium, prostate, and breast. Parathyroid hormone, FGF23, calcium and phosphate are the major regulators of the renal 1-hydroxylase (CYP27B1, the enzyme producing 1,25(OH)2D); regulation of the extra renal 1-hydroxylase differs from that in the kidney and involves cytokines. The major enzyme that catabolizes 25(OH)D and 1,25(OH)2D is the 24-hydroxylase; like the 1-hydroxylase it is tightly controlled in the kidney in a manner opposite to that of the 1-hydroxylase, but like the 1-hydroxylase it is widespread in other tissues where its regulation is different from that of the kidney. Vitamin D and its metabolites are carried in the blood bound to vitamin D binding protein (DBP) and albumin–for most tissues it is the free (i.e., unbound) metabolite that enters the cell; however, DBP bound metabolites can enter some cells such as the kidney and parathyroid gland through a megalin/cubilin mechanism. Most but not all actions of 1,25(OH)2D are mediated by the vitamin D receptor (VDR). VDR is a transcription factor that partners with other transcription factors such as retinoid X receptor that when bound to 1,25(OH)2D regulates gene transcription either positively or negatively depending on other cofactors to which it binds or interacts. The VDR is found in most cells, not just those involved with bone and mineral homeostasis (i.e., bone, gut, kidney) resulting in wide spread actions of 1,25(OH)2D on most physiologic and pathologic processes. Animal studies indicate that vitamin D has beneficial effects on various cancers, blood pressure, heart disease, immunologic disorders, but these non-skeletal effects have been difficult to prove in humans in randomized controlled trials. Analogs of 1,25(OH)2D are being developed to achieve specificity for non-skeletal target tissues such as the parathyroid gland and cancers to avoid the hypercalcemia resulting from 1,25(OH)2D itself. The level of vitamin D intake and achieved serum levels of 25(OH)D that are optimal and safe for skeletal health and the non-skeletal actions remain controversial, but are likely between an intake of 800-2000IU vitamin D in the diet and 20-50ng/ml 25(OH)D in the blood.

Testicular Cancer – RANKL inhibition suppresses tumor growth: Testicular cancer is the most commonly diagnosed malignancy in young males. A new study features the use of the Biomedica RANKL ELISA investigating the effects of RANKL (receptor activator of nuclear factor- κB ligand) inhibition in patients with testicular cancer. Despite its high cure rate, patients suffer from serious adverse effects to chemotherapy. Investigating alternative treatments, the scientists demonstrated that the RANKL inhibitor Denosumamb, used to treat osteoporosis, has tumor suppressive properties. As RANKL signaling was recently identified in the testis regulating male reproductive function, an open question remains if RANKL is responsible for the malignant transformation to invasive tumors.

Testicular Cancer – RANKL inhibition suppresses tumor growth

 

RANKL regulates testicular cancer growth and Denosumab treatment has suppressive effects on GCNIS and advanced seminoma.                                                                                                                                        

Andreassen CH, Lorenzen M, Nielsen JE, Kafai Yahyavi S, Toft BG, Ingerslev LR, Clemmensen C, Rasmussen LJ, Bokemeyer C, Juul A, Jørgensen A, Blomberg Jensen M. Br J Cancer. 2022 Apr 13. doi: 10.1038/s41416-022-01810-w. Epub ahead of print. PMID: 35418213.

 

Abstract

Background: Testicular germ cell tumours (TGCTs) have a high sensitivity to chemotherapy and a high cure rate, although with serious adverse effects. In the search for tumour suppressive drugs, the RANKL inhibitor Denosumab, used to treat osteoporosis, came up as a candidate since RANKL signalling was recently identified in the testis.

Methods: Expression of RANKL, RANK and OPG, and the effects of RANKL inhibition were investigated in human TGCTs, TGCT-derived cell-lines, and TGCT-xenograft models. Serum RANKL was measured in TGCT-patients.

Results: RANKL, RANK, and OPG were expressed in germ cell neoplasia in situ (GCNIS), TGCTs, and TGCT-derived cell lines. RANKL-inhibition reduced proliferation of seminoma-derived TCam-2 cells, but had no effect on embryonal carcinoma-derived NTera2 cells. Pretreatment with Denosumab did not augment the effect of cisplatin in vitro. However, inhibition of RANKL in vivo reduced tumour growth exclusively in the TCam-2-xenograft model and Denosumab-treatment decreased proliferation in human GCNIS cultures. In TGCT-patients serum RANKL had no prognostic value.

Conclusions: This study shows that the RANKL signalling system is expressed in GCNIS and seminoma where RANKL inhibition suppresses tumour growth in vitro and in vivo. Future studies are needed to determine whether RANKL is important for the malignant transformation or transition from GCNIS to invasive tumours.

 

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Related products

Osteoprotegerin (OPG) ELISA  , DKK-1 ELISA ,  Sclerostin ELISA ,

IL-6 ELISA  ,  VEGF ELISA ,  Angiopoietin-2 ELISA

 

Related publications

RANKL regulates male reproductive function.

Blomberg Jensen M, Andreassen CH, Jørgensen A, Nielsen JE, Juel Mortensen L, Boisen IM, et al. Nat Commun. 2021;12:1–15. doi: 10.1038/s41467-021-22734-8. PMID: 33893301; PMCID: PMC8065035.

Abstract

Infertile men have few treatment options. Here, we demonstrate that the transmembrane receptor activator of NF-kB ligand (RANKL) signaling system is active in mouse and human testis. RANKL is highly expressed in Sertoli cells and signals through RANK, expressed in most germ cells, whereas the RANKL-inhibitor osteoprotegerin (OPG) is expressed in germ and peritubular cells. OPG treatment increases wild-type mouse sperm counts, and mice with global or Sertoli-specific genetic suppression of Rankl have increased male fertility and sperm counts. Moreover, RANKL levels in seminal fluid are high and distinguishes normal from infertile men with higher specificity than total sperm count. In infertile men, one dose of Denosumab decreases RANKL seminal fluid concentration and increases serum Inhibin-B and anti-Müllerian-hormone levels, but semen quality only in a subgroup. This translational study suggests that RANKL is a regulator of male reproductive function, however, predictive biomarkers for treatment-outcome requires further investigation in placebo-controlled studies.

The RANK-RANKL axis: an opportunity for drug repurposing in cancer?

Peters S, Clézardin P, Márquez-Rodas I, Niepel D, Gedye C. Clin Transl Oncol. 2019;21:977–91. doi: 10.1007/s12094-018-02023-5. Epub 2019 Jan 17. PMID: 30656607.

Abstract

Drug repurposing offers advantages over traditional drug development in terms of cost, speed and improved patient outcomes. The receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) inhibitor denosumab is approved for the prevention of skeletal-related events in patients with advanced malignancies involving bone, including solid tumours and multiple myeloma. Following improved understanding of the role of RANK/RANKL in cancer biology, denosumab has already been repurposed as a treatment for giant cell tumour of bone. Here, we review the role of RANK/RANKL in tumourigenesis, including effects on tumour initiation, progression and metastasis and consider the impact of RANK/RANKL on tumour immunology and immune evasion. Finally, we look briefly at ongoing trials and future opportunities for therapeutic synergy when combining denosumab with anti-cancer agents such as immune checkpoint inhibitors.

Possible link between FSH and RANKL release from adipocytes in men with impaired gonadal function including Klinefelter syndrome .

Juel Mortensen L, Lorenzen M, Jørgensen N, Andersson A-M, Nielsen JE, Petersen LI, et al.Bone. 2019;123:103–14. doi: 10.1016/j.bone.2019.03.022. Epub 2019 Mar 23. PMID: 30914274.

International Trends in the Incidence of Testicular Cancer: Lessons from 35 Years and 41 Countries.

Gurney JK, Florio AA, Znaor A, Ferlay J, Laversanne M, Sarfati D, Bray F, McGlynn KA. Eur Urol. 2019 Nov;76(5):615-623. doi: 10.1016/j.eururo.2019.07.002. Epub 2019 Jul 17. PMID: 31324498; PMCID: PMC8653517.

Development of a 3D-printed testicular cancer model for testicular examination education.

Power RJ, Hearn J, Gillis CJ, Harvey D, French C, Organ M. Can Urol Assoc J. 2021 Apr;15(4):E221-E226. doi: 10.5489/cuaj.6675. PMID: 33007179; PMCID: PMC8021429.

 

How to do a Testicular Self Exam . Testicular Cancer Society

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√  Bone metabilism                                   Osteoprotegerin (OPG), soluble free RANKL (sRANKL)

√  Nephrology & transplant                  Fibroblast growth factor 23 (FGF23 c-terminal and FGF23 intact),
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                                                                              Vanin-1 urine (human, mouse and rat), anti-C4d antibody

 

RELATED CITATIONS

Big Endothelin-1 (BigET-1)

Plasma Big Endothelin-1 Level Predicted 5-Year Major Adverse Cardiovascular Events in Patients With Coronary Artery Ectasia. Cai Z, Wang H, Yuan S, Yin D, Song W, Dou K.Front Cardiovasc Med. 2021 Nov 29;8:768431. doi: 10.3389/fcvm.2021.768431. PMID: 34912865; PMCID: PMC8667227.

Abstract

Background: Coronary artery ectasia (CAE) is found in about 1% of coronary angiography and is associated with poor clinical outcomes. The prognostic value of plasma big Endothelin-1 (ET-1) in CAE remains unknown. Methods: Patients with angiographically confirmed CAE from 2009 to 2015, who had big ET-1 data available were included. The primary outcome was 5-year major adverse cardiovascular events (MACE), defined as a component of cardiovascular death and non-fatal myocardial infarction (MI). Patients were divided into high or low big ET-1 groups using a cut-off value of 0.58 pmol/L, according to the receiver operating characteristic curve. Kaplan-Meier method, propensity score method, and Cox regression were used to assess the clinical outcomes in the 2 groups. Results: A total of 992 patients were included, with 260 in the high big ET-1 group and 732 in the low big ET-1 group. At 5-year follow-up, 57 MACEs were observed. Kaplan-Meier analysis and univariable Cox regression showed that patients with high big ET-1 levels were at increased risk of MACE (9.87 vs. 4.50%; HR 2.23, 95% CI 1.32-3.78, P = 0.003), cardiovascular death (4.01 vs. 1.69%; HR 2.37, 95% CI 1.02-5.48, P = 0.044), and non-fatal MI (6.09 vs. 2.84%; HR 2.17, 95% CI 1.11-4.24, P = 0.023). A higher risk of MACE in the high big ET-1 group was consistent in the propensity score matched cohort and propensity score weighted analysis. In multivariable analysis, a high plasma big ET-1 level was still an independent predictor of MACE (HR 1.82, 95% CI 1.02-3.25, P = 0.043). A combination of high plasma big ET-1 concentrate and diffuse dilation, when used to predict 5-year MACE risk, yielded a C-statistic of 0.67 (95% CI 0.59-0.74). Conclusion: Among patients with CAE, high plasma big ET-1 level was associated with increased risk of MACE, a finding that could improve risk stratification.

Osteoporosis is a disease that weakens bone. When women get older, at the time around menopause, bone loss increases. Poor nutrition, lack of exercise, hormonal changes and other factors influence bone health. Early intervention can delay the development of osteoporosis and novel biomarkers may help to identify people at risk.

Bone Health & Osteoporosis – what women should know

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Osteoprotegerin (OPG) ELISA  , DKK-1 ELISA ,  Sclerostin ELISA , soluble RANKL ELISA

IL-6 ELISA  , VEGF ELISA ,  Angiopoietin-2 ELISA

Bone Health & Osteoporosis – what women should know

Related publications

The effect of exercise intensity on bone in postmenopausal women (part 2): A meta-analysis.

Kistler-Fischbacher M, Weeks BK, Beck BR. Bone. 2021 Feb;143:115697. doi: 10.1016/j.bone.2020.115697. Epub 2020 Dec 24. PMID: 33357834.

Abstract

Background: Previous reviews have concluded that exercise has only modest effects on bone mineral density (BMD) in postmenopausal women. Despite the well-recognized strong positive relationship between load magnitude and bone response observed from animal research, the majority of human trials have examined the effects of only low to moderate intensity exercise on bone. We speculated that meta-analysing according to intensity may reveal a more potent exercise effect at higher intensity.

Objectives: To determine the effects of low, moderate and high intensity exercise on BMD at the spine and hip in postmenopausal women.

Methods: Electronic databases and reference lists were searched for RCTs that examined the effect of exercise compared to control on DXA-derived lumbar spine, femoral neck or total hip BMD in healthy postmenopausal women. Interventions were classified as low, moderate or high intensity and pooled based on classification. Mean differences (MD) were calculated using random effects models and a risk of bias analysis was undertaken. To determine the effect of different exercise types (resistance and impact training) on BMD outcomes, subgroup analyses for all intensity categories and outcomes were conducted. Separate meta-analyses were undertaken to examine the influence of adding exercise to a bone medication intervention and to examine exercise effects on fracture risk.

Results: Fifty-three trials, testing 63 interventions (19 low, 40 moderate, 4 high intensity) were included. At the lumbar spine, high intensity exercise yielded greater BMD effects (MD = 0.031 g/cm2 95% CI [0.012, 0.049], p = 0.002) than moderate (MD = 0.012 g/cm2 95% CI [0.008, 0.017], p < 0.001) and low intensity (MD = 0.010 g/cm2 95% CI [0.005, 0.015], p < 0.001). Low and moderate intensity exercise was equally effective at the femoral neck (low: 0.011 g/cm2 95% CI [0.006, 0.016], p < 0.001; moderate: 0.011 g/cm2 95% CI [0.007, 0.015], p < 0.001), but no effect of high-intensity exercise was observed. Moderate intensity exercise increased total hip BMD (0.008 g/cm2 95% CI [0.004, 0.012], p < 0.001), but low intensity did not. There were insufficient data to meta-analyse the effect of high intensity exercise at the total hip. Resistance training, potentially in combination with impact training, appears to be the most effective osteogenic stimulus at the spine and hip. Findings from meta-regression analyses were not informative and no influence of exercise on medication efficacy was observed. Risk of bias was mainly low or unclear due to insufficient information reported.

Conclusion: High intensity exercise is a more effective stimulus for lumbar spine BMD than low or moderate intensity, but not femoral neck BMD, however, the latter finding may be due to lack of power. While data from high-intensity exercise interventions are limited, the current comprehensive meta-analysis demonstrates the same positive relationship between load magnitude and bone response in humans that is observed in animal research. Findings have implications for optimal exercise prescription for osteoporosis in postmenopausal women.

Nutrition in the prevention and control of osteoporosis.

Ortega RM, Jiménez Ortega AI, Martínez García RM, Cuadrado Soto E, Aparicio A, López-Sobaler AM. Nutrición en la prevención y el control de la osteoporosis Nutr Hosp. 2021 Jan 13;37(Spec No2):63-66. Spanish. doi: 10.20960/nh.03360. PMID: 32993301.

Abstract

Objective: although osteoporosis develops in advanced stages of life, it must be prevented and stopped from the pediatric age, acting on modifiable factors, especially diet and lifestyle. The objective of this work is to review the latest evidence on nutritional improvements that can help in the prevention and control of the disease. Methods: bibliographic search related to the topic. Results: it is advisable to avoid energy restrictions, especially in postmenopausal women and particularly if they have osteopenia/osteoporosis since, in relation to these pathologies, excess weight may be preferable, rather than underweight. Protein intake higher than the recommended one is beneficial for the bone, provided that the calcium intake is adequate. Excessive intake of sugar and saturated fat should be avoided, but attempts should be made to achieve the nutritional goals set for ω-3 polyunsaturated fatty acids and fiber. It is important to monitor vitamin D status and calcium intake, which is inadequate in high percentages of individuals, as well as improving the contribution of vitamins K, C and group B, and also magnesium, potassium, iron, zinc, copper, fluorine, manganese, silicon and boron, and avoiding the excessive contribution of phosphorus and sodium. Conclusions: osteoporosis is an underdiagnosed pathology and of increasing prevalence. Due to its high morbidity and mortality, prevention is important and, from a nutritional point of view, it is convenient to bring the diet closer to the theoretical ideal. In general, increasing the consumption of dairy products, fish, vegetables and fruits, as well as reducing the consumption of salt, during childhood and throughout life, seems convenient for the bone improvement of most of the population.

Osteoporosis

Compston JE, McClung MR, Leslie WD. Lancet. 2019 Jan 26;393(10169):364-376. doi: 10.1016/S0140-6736(18)32112-3. PMID: 30696576.

 Abstract

Fractures resulting from osteoporosis become increasingly common in women after age 55 years and men after age 65 years, resulting in substantial bone-associated morbidities, and increased mortality and health-care costs. Research advances have led to a more accurate assessment of fracture risk and have increased the range of therapeutic options available to prevent fractures. Fracture risk algorithms that combine clinical risk factors and bone mineral density are now widely used in clinical practice to target high-risk individuals for treatment. The discovery of key pathways regulating bone resorption and formation has identified new approaches to treatment with distinctive mechanisms of action. Osteoporosis is a chronic condition and long-term, sometimes lifelong, management is required. In individuals at high risk of fracture, the benefit versus risk profile is likely to be favourable for up to 10 years of treatment with bisphosphonates or denosumab. In people at a very high or imminent risk of fracture, therapy with teriparatide or abaloparatide should be considered; however, since treatment duration with these drugs is restricted to 18-24 months, treatment should be continued with an antiresorptive drug. Individuals at high risk of fractures do not receive adequate treatment and strategies to address this treatment gap-eg, widespread implementation of Fracture Liaison Services and improvement of adherence to therapy-are important challenges for the future.

The Utility of Biomarkers in Osteoporosis Management.

Garnero P. Mol Diagn Ther. 2017 Aug;21(4):401-418. doi: 10.1007/s40291-017-0272-1. PMID: 28271451.

Abstract

The measurement of bone turnover markers is useful for the clinical investigation of patients with osteoporosis. Among the available biochemical markers, the measurements of serum procollagen type I N-terminal propeptide (PINP) and the crosslinked C-terminal telopeptide (serum CTX) have been recommended as reference markers of bone formation and bone resorption, respectively. The important sources of preanalytical and analytical variability have been identified for both markers, and precise measurement can now be obtained. Reference interval data for PINP and CTX have been generated across different geographical locations, which allows optimum clinical interpretation. However, conventional protein-based markers have some limitations, including a lack of specificity for bone tissue, and their inability to reflect osteocyte activity or periosteal metabolism. Thus, novel markers such as periostin, sclerostin and, sphingosine 1-phosphate have been developed to address some of these shortcomings. Recent studies suggest that the measurements of circulating microRNAs, a new class of marker, may represent early biological markers in osteoporosis. Bone markers have been shown to be a useful adjunct to bone mineral density for identifying postmenopausal women at high risk for fracture. Because levels of bone markers respond rapidly to both anabolic and anticatabolic drugs, they are very useful for investigating the mechanism of action of new therapies and, potentially, for predicting their efficacy to reduce fracture risk.

Biomarkers serve as markers for cancer progression and prognosis and represent promising therapeutic targets. Improving our understanding of how cancers originate, grow and spread may help to reduce the risk and burden of the disease. Cancer biomarker research has identified Neuropilin-1 and Semaphorin 4D  as novel protein markers  and promising  therapeutic targets. These proteins can easily be detected in human serum and plasma by ELISA assay.

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Related publications

Neuropilins Controlling Cancer Therapy Responsiveness. Full text link

Napolitano V, Tamagnone L. Int J Mol Sci. 2019 Apr 25;20(8):2049. doi: 10.3390/ijms20082049. PMID: 31027288. 

Abstract

Neuropilins (NRPs) are cell surface glycoproteins, acting as co-receptors for secreted Semaphorins (SEMAs) and for members of the vascular endothelial growth factor (VEGF) family; they have been initially implicated in axon guidance and angiogenesis regulation, and more recently in cancer progression. In addition, NRPs have been shown to control many other fundamental signaling pathways, especially mediated by tyrosine kinase receptors (RTKs) of growth factors, such as HGF (hepatocyte growth factor), PDGF (platelet derived growth factor) and EGF (epidermal growth factor). This enables NRPs to control a range of pivotal mechanisms in the cancer context, from tumor cell proliferation and metastatic dissemination, to tumor angiogenesis and immune escape. Moreover, cancer treatment failures due to resistance to innovative oncogene-targeted drugs is typically associated with the activity of alternative RTK-dependent pathways; and neuropilins’ capacity to control oncogenic signaling cascades supports the hypothesis that they could elicit such mechanisms in cancer cells, in order to escape cytotoxic stress and therapeutic attacks. Intriguingly, several studies have recently assayed the impact of NRPs inhibition in combination with diverse anti-cancer drugs. In this minireview, we will discuss the state-of-art about the relevance of NRPs as potential predictive biomarkers of drug response, and the rationale to target these proteins in combination with other anticancer therapies.

Semaphorins as emerging clinical biomarkers and therapeutic targets in cancer. Full text link

Mastrantonio R, You H, Tamagnone L. Theranostics. 2021 Jan 15;11(7):3262-3277. doi: 10.7150/thno.54023. PMID: 33537086; PMCID: PMC7847692.

 Abstract

Semaphorins are a large family of developmental regulatory signals, characterized by aberrant expression in human cancers. These molecules crucially control cell-cell communication, cell migration, invasion and metastasis, tumor angiogenesis, inflammatory and anti-cancer immune responses. Semaphorins comprise secreted and cell surface-exposed molecules and their receptors are mainly found in the Plexin and Neuropilin families, which are further implicated in a signaling network controlling the tumor microenvironment. Accumulating evidence indicates that semaphorins may be considered as novel clinical biomarkers for cancer, especially for the prediction of patient survival and responsiveness to therapy. Moreover, preclinical experimental studies have demonstrated that targeting semaphorin signaling can interfere with tumor growth and/or metastatic dissemination, suggesting their relevance as novel therapeutic targets in cancer; this has also prompted the development of semaphorin-interfering molecules for application in the clinic. Here we will survey, in diverse human cancers, the current knowledge about the relevance of semaphorin family members, and conceptualize potential lines of future research development in this field.

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 DKK1 promotes migration and invasion of non-small cell lung cancer via β-catenin signaling pathway. Full text link

Zhang J, Zhang X, Zhao X, Jiang M, Gu M, Wang Z, Yue W Tumour Biol. 2017. 39(7):1010428317703820. doi: 10.1177/1010428317703820. PMID: 28677426.

 Dickkopf-1: A Promising Target for Cancer Immunotherapy. Full text link

Chu HY, Chen Z, Wang L, Zhang ZK, Tan X, Liu S, Zhang BT, Lu A, Yu Y, Zhang G. Front Immunol. 2021 May 20;12:658097. doi: 10.3389/fimmu.2021.658097. PMID: 34093545; PMCID: PMC8174842.

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Leucine-rich α-2-glycoprotein promotes TGFβ1-mediated growth suppression in the Lewis lung carcinoma cell lines. Full text link

Oncotarget. Takemoto N, Serada S, Fujimoto M, Honda H, Ohkawara T, Takahashi T, Nomura S, Inohara H, Naka T. 2015. 10;6(13):11009-22. doi: 10.18632/oncotarget.3557. PMID: 25826092; PMCID: PMC4484435.

Detection of leucine-rich alpha-2-glycoprotein 1-containing immunocomplexes in the plasma of lung cancer patients with epitope-specific mAbs. Abstract link.

Lázár J, Kovács A, Tornyi I, Takács L, Kurucz I. Cancer Biomark. 2021 Nov 1. doi: 10.3233/CBM-210164. Epub ahead of print. PMID: 34744074.

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Paget’s disease of bone is a chronic disease of the skeleton. Healthy bone is remodeled in a lifelong process where mature bone tissue is removed and new bone tissue is formed. In Paget´s disease this process is out of balance which causes bones to grow larger and weaker than normal. Paget´s usually affects just one or a few bones. In some parts of the world it is the second most common bone disorder after osteoporosis. Learn more

 

PAGET´S AWARENESS DAY – 11. January

 

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Related ELISA kits

Osteoprotegerin (OPG) link ; DKK-1 link ; Sclerostin link

Related publications:

Management of Paget’s disease of bone.

Reid IR. Osteoporos Int. 2020 May;31(5):827-837. doi: 10.1007/s00198-019-05259-1. PMID: 31848640. Full text link

 

Abstract link

Paget’s disease is a progressive focal bone condition which can result in pain, low quality of life, deformity and other complications. Disease progression can be halted with potent bisphosphonates, resulting in improvement in both quality of life and pain, and normalisation of scintigraphy, plain radiographs and bone histology. Zoledronate has transformed the treatment of Paget’s disease, producing sustained remissions in almost all patients. Thus, it is now possible to normalise bone cell activity and prevent disease progression at low cost, with one or two intravenous injections of zoledronate, greatly reducing follow-up costs. Patients with Paget’s disease who are symptomatic or at risk of complications should have the opportunity to reap these therapeutic benefits. Potent bisphosphonates are highly effective in halting disease progression in Paget’s disease, but guidelines disagree about treatment indications. The efficacy, safety and low cost of zoledronate recommend its use in any patient who is symptomatic or judged to be at risk of complications from Paget’s disease.

 

Paget’s Disease of Bone.

Gennari L, Rendina D, Falchetti A, Merlotti D. Calcif Tissue Int. 2019 May;104(5):483-500. doi: 10.1007/s00223-019-00522-3. PMID: 30671590. Full text link

 

Abstract link

Paget’s disease of bone (PDB) is a chronic and focal bone disorder, characterized by increased osteoclast-mediated bone resorption and a subsequent compensatory increase in bone formation, resulting in a disorganized mosaic of woven and lamellar bone at one or more affected skeletal sites. As a result, bone pain, noticeable deformities, arthritis at adjacent joints, and fractures can occur. In a small proportion of cases neoplastic degeneration in osteosarcoma, or, less frequently, giant cell tumor has been also described at PDB sites. While recent epidemiological evidences clearly indicate a decrease in the prevalence and the severity of PDB, over the past 2 decades there have been consistent advances on the genetic mechanisms of disease. It is now clear that PDB is a genetically heterogeneous disorder, with mutations in at least two different genes (SQSTM1, ZNF687) and more common predisposing variants. As a counterpart to the genetic hypothesis, the focal nature of lesions, the decline in prevalence rates, and the incomplete penetrance of the disease among family members suggest that one or more environmental triggers may play a role in the pathophysiology of PDB. The exact nature of these triggers and how they might interact with the genetic factors are less understood, but recent experimental data from mice models suggest the implication of paramixoviral infections. The clinical management of PDB has also evolved considerably, with the development of potent aminobisphosphonates such as zoledronic acid which, given as a single intravenous infusion, now allows a long-term disease remission in the majority of patients.

 

Diagnosis and Management of Paget’s Disease of Bone in Adults: A Clinical Guideline.

Ralston SH, Corral-Gudino L, Cooper C, Francis RM, Fraser WD, Gennari L, Guañabens N, Javaid MK, Layfield R, O’Neill TW, Russell RGG, Stone MD, Simpson K, Wilkinson D, Wills R, Zillikens MC, Tuck SP. J Bone Miner Res. 2019 Apr;34(4):579-604. doi: 10.1002/jbmr.3657. PMID: 30803025. Full text link

 

Abstract link  

An evidence-based clinical guideline for the diagnosis and management of Paget’s disease of bone (PDB) was developed using GRADE methodology, by a Guideline Development Group (GDG) led by the Paget’s Association (UK). A systematic review of diagnostic tests and pharmacological and nonpharmacological treatment options was conducted that sought to address several key questions of clinical relevance. Twelve recommendations and five conditional recommendations were made, but there was insufficient evidence to address eight of the questions posed. The following recommendations were identified as the most important: 1) Radionuclide bone scans, in addition to targeted radiographs, are recommended as a means of fully and accurately defining the extent of metabolically active disease in patients with PDB. 2) Serum total alkaline phosphatase (ALP) is recommended as a first-line biochemical screening test in combination with liver function tests in screening for the presence of metabolically active PDB. 3) Bisphosphonates are recommended for the treatment of bone pain associated with PDB. Zoledronic acid is recommended as the bisphosphonate most likely to give a favorable pain response. 4) Treatment aimed at improving symptoms is recommended over a treat-to-target strategy aimed at normalizing total ALP in PDB. 5) Total hip or knee replacements are recommended for patients with PDB who develop osteoarthritis in whom medical treatment is inadequate. There is insufficient information to recommend one type of surgical approach over another. The guideline was endorsed by the European Calcified Tissues Society, the International Osteoporosis Foundation, the American Society of Bone and Mineral Research, the Bone Research Society (UK), and the British Geriatric Society. The GDG noted that there had been a lack of research on patient-focused clinical outcomes in PDB and identified several areas where further research was needed.