Sclerostin a biomarker in renal pediatric bone disease
The Biomedica SCLEROSTIN ELISA Assay Kit (# BI-20492) was utilized in a recent publication assessing the associations between serum and bone sclerostin levels and biomarkers of bone turnover and bone histomorphometry. Read more: Sclerostin, Osteocytes, and Wnt Signaling in Pediatric Renal Osteodystrophy.
Sclerostin a biomarker in renal pediatric bone disease
Sclerostin, Osteocytes, and Wnt Signaling in Pediatric Renal Osteodystrophy. Laster M. et al., Nutrients. 2023 Sep 25;15(19):4127. doi: 10.3390/nu15194127. PMID: 37836411; PMCID: PMC10574198 . link to full text
Abstract
The pathophysiology of chronic kidney disease-mineral and bone disorder (CKD-MBD) is not well understood. Specific factors secreted by osteocytes are elevated in the serum of adults and pediatric patients with CKD-MBD, including FGF-23 and sclerostin, a known inhibitor of the Wnt signaling pathway. The molecular mechanisms that promote bone disease during the progression of CKD are incompletely understood. In this study, we performed a cross-sectional analysis of 87 pediatric patients with pre-dialysis CKD and post-dialysis (CKD 5D). We assessed the associations between serum and bone sclerostin levels and biomarkers of bone turnover and bone histomorphometry. We report that serum sclerostin levels were elevated in both early and late CKD. Higher circulating and bone sclerostin levels were associated with histomorphometric parameters of bone turnover and mineralization. Immunofluorescence analyses of bone biopsies evaluated osteocyte staining of antibodies towards the canonical Wnt target, β-catenin, in the phosphorylated (inhibited) or unphosphorylated (active) forms. Bone sclerostin was found to be colocalized with phosphorylated β-catenin, which suggests that Wnt signaling was inhibited. In patients with low serum sclerostin levels, increased unphosphorylated “active” β-catenin staining was observed in osteocytes. These data provide new mechanistic insight into the pathogenesis of CKD-MBD and suggest that sclerostin may offer a potential biomarker or therapeutic target in pediatric renal osteodystrophy.
Related Literature
FGF-23 and sclerostin in serum and bone of CKD patients. Lima F, Monier-Faugere MC, Mawad H, David V, Malluche HH. Clin Nephrol. 2023 May;99(5):209-218. doi: 10.5414/CN111111. PMID: 36970967; PMCID: PMC10286735. (Biomedica Sclerostin ELISA Assay Kit, cat. no. BI-20492 citation)
Sclerostin and Dickkopf-1 in renal osteodystrophy. Cejka D, Herberth J, Branscum AJ, Fardo DW, Monier-Faugere MC, Diarra D, Haas M, Malluche HH. Clin J Am Soc Nephrol. 2011 Apr;6(4):877-82. doi: 10.2215/CJN.06550810. Epub 2010 Dec 16. PMID: 21164019; PMCID: PMC3069382. (Biomedica Sclerostin ELISA Assay Kit, cat. no. BI-20492 citation)
Type 2 diabetes mellitus (T2DM) is characterized by a persistent state of elevated blood sugar levels and glucose intolerance, resulting from the body´s incomplete response to insulin, accompanied by an increase in insulin production and a subsequent insulin deficiency. Individuals suffering from T2DM have an increased risk of cardiovascular disease (CVD). High glucose levels, insulin resistance, and chronic inflammation, contribute to endothelial dysfunction (ED) and atherosclerosis (1). ED refers to an impairment of the endothelium, the inner lining of blood vessels, which play an important role in regulating vascular health.
Sclerostin is associated with endothelial dysfunction in patients with type 2 diabetes
Sclerostin is a protein known primarily for its role in bone metabolism. It has also been identified of being linked to endothelial dysfunction in individuals diagnosed with type 2 diabetes (2). Sclerostin is predominantly secreted by osteocytes, cells that are embedded in the bone. However, vascular endothelial cells have also been observed to produce sclerostin leading to the discovery of its significant anti-calcifying role (3).
Sclerostin is associated with endothelial dysfunction in patients with type 2 diabetes: In an investigation in individuals with T2DM, researchers measured endothelial dysfunction by digital thermal monitoring (2). This method is a valid and noninvasive technique to evaluate endothelial function using temperature change on finger as a surrogate measure of the magnitude of vascular reactivity index (VRI) (4) . Serum Sclerostin levels were measured in the T2DM cohort with the Biomedica ELISA. The prospective cross-sectional study revealed that serum sclerostin levels are positively associated with endothelial dysfunction measured in patients with T2DM.
A previous cross-sectional study in patients with T2DM, with/without cardiovascular disease, determined Sclerostin levels and its expression by RT-qPCR and immunohistochemistry in calcified and non-calcified artery of the lower limb from T2D. Serum Sclerostin was measured with an ELISA from Biomedica. Moreover, in vitro experiments were performed in vascular smooth muscle cells under calcifying conditions investigating the cardioprotective function of Sclerostin (5). The study provided evidence that supports the protective function of Sclerostin in the development of vascular calcification. The findings suggest that Sclerostin could potentially reduce the susceptibility to atherosclerosis by decreasing atherosclerotic plaque formation and underscore the significance of the bone-vascular axis when developing therapeutic strategies for treating impaired bone metabolism or vascular diseases (5).
Features and Benefits when measuring Sclerostin with the Biomedica ELISA kits
November is “Diabetes Awareness Month” raising attention to this fast growing and life-threating epidemic. Patients suffering from diabetes have a risk of additional health complications, including heart disease, strokes, and diabetic kidney disease (DKD). People who develop DKD mostly have few symptoms in the early stage of the disease, although the risk of developing severe kidney damage is very high. High blood sugar levels may damage the small blood vessels in the kidney leading to kidney damage, kidney failure, and high blood pressure (1).
FGF23 and Sclerostin – novel biomarkers in diabetic kidney disease
Traditionally, the bone is regarded as a structural organ that gives the human body support and facilitates physical movement. However, bone is also a source of various hormones including fibroblast growth factor 23 and sclerostin that play an important role in regulating glucose metabolism and DKD (2).
FGF23 and Sclerostin – novel biomarkers in diabetic kidney disease
Fibroblast growth factor 23 (FGF23) is a bone-derived protein that regulates phosphate metabolism, by inhibiting renal phosphate reabsorption. There is increasing evidence that FGF23 plays a role in type 2 diabetes (T2DM), as FGF23 levels are elevated in these patients, even in individuals with preserved kidney function when compared to the general population (3). Phosphate independent effects on FGF23 following glucose loading were shown in a recent study demonstrating that FGF23 is associated with glucose, insulin and proinsulin levels, as well as obesity (4 ). Furthermore, FGF23 has also been shown to be associated with the development of gestational diabetes mellitus (5).
Sclerostin is a protein that is produced by bone cells that inhibits bone formation. Recent research suggests that Sclerostin also plays a role in lipid and glucose metabolism as serum sclerostin is negatively associated with insulin sensitivity as measured in obese, but not lean women (5). Sclerostin levels have also been shown to be increased in individuals with prediabetes (6).
FGF23 and Sclerostin can reliable by measured with conventional ELISA assays from BIOMEDICA.
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
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.
Decrease of bone biomarker Sclerostin in women with anorexia nervosa during nutrition therapy – indication of reduced bone loss
Anorexia nervosa (AN) is an eating disorder and has one of the highest mortality rates of any mental illness. It affects roughly 2.9 million people and many experience bone loss and increased fracture risk. In a 3-year prospective study, Swedish researchers looked into the long-term effects of nutrition therapy. They investigated bone and mineral metabolism and biomarkers young women with AN. Their results showed that body mass index (BMI) and fat mass was increased. The regulatory bone biomarker Sclerostin decreased during nutrition therapy and further over 3 years, indicating reduced bone loss.
Svedlund A, Pettersson C, Tubic B, Ellegård L, Elfvin A, Magnusson P, Swolin-Eide D. J Bone Miner Metab. 2022 Aug 12. doi: 10.1007/s00774-022-01359-x. Epub ahead of print. PMID: 35960382.
Abstract
Introduction: Anorexia nervosa (AN) increases the risk of impaired bone health, low areal bone mineral density (aBMD), and subsequent fractures. This prospective study investigated the long-term effects of bone and mineral metabolism on bone and biomarkers in 22 women with AN.
Materials and methods: Body composition and aBMD were measured by dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography. Total and free 25-hydroxyvitamin D (25OHD), C-terminal collagen cross-links (CTX), osteocalcin, bone-specific alkaline phosphatase (BALP), leptin, sclerostin, and oxidized/non-oxidized parathyroid hormone (PTH) were analyzed before and after 12 weeks of intensive nutrition therapy and again 3 years later. An age-matched comparison group of 17 healthy women was recruited for the 3-year follow-up.
Results: Body mass index (BMI) and fat mass increased from baseline to 3 years in women with AN. Sclerostin decreased during nutrition therapy and further over 3 years, indicating reduced bone loss. CTX was elevated at baseline and after 12 weeks but decreased over 3 years. BALP increased during nutrition therapy and stabilized over 3 years. Free 25OHD was stable during treatment but decreased over 3 years. Non-oxidized PTH was stable during treatment but increased over 3 years. Trabecular volumetric BMD in AN patients decreased during the first 12 weeks and over 3 years despite stable BMI and bone biomarkers implying increased BMD.
Conclusion: Our findings highlight the importance of early detection and organized long-term follow-up of bone health in young women with a history of AN.
Keywords: DXA; Eating disorder; Osteoporosis; Sclerostin; Vitamin D
Background: Little is known about the long-term outcome of anorexia nervosa.
Aims: To study the 30-year outcome of adolescent-onset anorexia nervosa.
Method: All 4291 individuals born in 1970 and attending eighth grade in 1985 in Gothenburg, Sweden were screened for anorexia nervosa. A total of 24 individuals (age cohort for anorexia nervosa) were pooled with 27 individuals with anorexia nervosa (identified through community screening) who were born in 1969 and 1971-1974. The 51 individuals with anorexia nervosa and 51 school- and gender-matched controls were followed prospectively and examined at mean ages of 16, 21, 24, 32 and 44. Psychiatric disorders, health-related quality of life and general outcome were assessed.
Results: At the 30-year follow-up 96% of participants agreed to participate. There was no mortality. Of the participants, 19% had an eating disorder diagnosis (6% anorexia nervosa, 2% binge-eating disorder, 11% other specified feeding or eating disorder); 38% had other psychiatric diagnoses; and 64% had full eating disorder symptom recovery, i.e. free of all eating disorder criteria for 6 consecutive months. During the elapsed 30 years, participants had an eating disorder for 10 years, on average, and 23% did not receive psychiatric treatment. Good outcome was predicted by later age at onset among individuals with adolescent-onset anorexia nervosa and premorbid perfectionism.
Conclusions: This long-term follow-up study reflects the course of adolescent-onset anorexia nervosa and has shown a favourable outcome regarding mortality and full symptom recovery. However, one in five had a chronic eating disorder.
Mitchell JE, Peterson CB. N Engl J Med. 2020 Apr 2;382(14):1343-1351. doi: 10.1056/NEJMcp1803175. PMID: 32242359.
Effect of Sclerostin Inhibition on Cardiovascular Safety for the Treatment of Severe Osteoporosis
Osteoporosis is a skeletal disorder characterized by diminished bone strength that is responsible for an increased fracture risk. The glycoprotein sclerostin acts as an inhibitor of bone formation. Therapies directed against this molecule have been developed. A humanized antibody against sclerostin has been approved for the treatment of severe osteoporosis in postmenopausal women in many parts of the world. A recent review by Langdahl BL and colleagues sumarizes the current knowledge of the effect of sclerostin inhibition on cardiovascular safety.
Bovijn J, Krebs K, Chen CY, Boxall R, Censin JC, Ferreira T, Pulit SL, Glastonbury CA, Laber S, Millwood IY, Lin K, Li L, Chen Z, Milani L, Smith GD, Walters RG, Mägi R, Neale BM, Lindgren CM, Holmes MV. Sci Transl Med. 2020 Jun 24;12(549):eaay6570. doi: 10.1126/scitranslmed.aay6570. PMID: 32581134; PMCID: PMC7116615.
Abstract
Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab (210 milligrams per month; 0.09 grams per square centimeter of higher bone mineral density), the SOST genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab) and with a higher risk of myocardial infarction and/or coronary revascularization and major adverse cardiovascular events. The same variants were also associated with increased risk of type 2 diabetes mellitus and higher systolic blood pressure and central adiposity. Together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.
The glycoprotein Sclerostin is mainly secreted by osteocytes and acts as a negative regulator of bone mass and strength by inhibiting bone formation. Studies have shown that high intensity exercise induces an increase in serum Sclerostin levels suggesting that it may be a key protein involved in muscle and bone interaction. A recent study by Śliwicka E and colleagues https://buff.ly/3qx6V4U evaluated the effects of a marathon race on selected myokines and Sclerostin in male recreational runners. Results show that in response to the marathon run, a complex network of endocrine interactions is initiated. Further research is needed to fully elucidate the long-term impact of prolonged high intensity exercise on the human body. Exercise-induced increase in sclerostin- related finding: https://buff.ly/3atiBA4
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Serum levels of sclerostin reflect altered bone microarchitecture in patients with hepatic cirrhosis. Sclerostin, a glycoprotein secreted mainly by osteocytes, regulates bone mass by decreasing bone formation.
In patients with hepatic cirrhosis, areal bone mineral density (aBMD) is decreased especially at the lumbar spine. aBMD alone can be insufficient to explain increased fracture risk and bone microarchitecture can provide additional information. However, since assessment of bone microarchitecture is complex, biomarkers could help assess fracture risk. In a study of several biomarkers, Wakolbinger et al. found a correlation between sclerostin and altered bone microarchitecture in hepatic cirrhosis https://link.springer.com/article/10.1007/s00508-019-01595-8.
Biomedica´s bioactive sclerostin ELISA measures bioactive sclerostin by using a monoclonal antibody directed at the LRP5/6 binding region, capturing all circulating sclerostin forms containing the free-receptor binding site. It is validated in depth according to FDA quality standards, to ensure the ELISA reliability.
Researchers have identified the soluble WNT pathway inhibitor SCLEROSTIN as an independent risk factor for all-cause #mortality in patients after kidney transplantation. 600 stable renal transplant recipients were followed for all-cause mortality for 3 years.
Sclerostin is an independent risk factor for all-cause mortality in kidney transplant recipients. Zeng S et al., Clin Exp Nephrology (2020). Click link for full text.
√ HIGH QUALITY – fully validated assay according to ICH/FDA/EMEA guidelines √ LOW SAMPLE VOLUME – only 20 µl sample / well √ EASY – convenient ready to use protocol √ MOST REFERENCED Sclerostin ELISA
Also available: Bioactive Sclerostin ELISA https://www.bmgrp.com/product/cardiovascular/biomedica-bioactive-sclerostin-elisa-human-sost/ √ specific antibodies targeting the receptor binging region
The only Sclerostin ELISA that utilizes specific EPITOPE MAPPED ANTIBODIES enabling the analysis of bioactive Sclerostin in clinical samples.
HIGHLY SPECIFIC and DEFINED: capture antibody directed against Sclerostin’s bioactive site. Learn more
RELIABLE: human serum based calibrators and controls, rigorously validated
LOW SAMPLE VOLUME: 20 µl / well
QUICK: total incubation time 3.5 h
First bioactive Sclerostin ELISA for clinical samples
Areas of interest: osteoporosis, cancer induced bone diseases, rheumatoid arthritis, chronic inflammation, kidney diseases, therapy monitoring of anabolic treatment.
For detailed information please click corresponding links:
Background: Circulating serum sclerostin levels are supposed to give a good estimation of the levels of this negative regulator of bone mass within bone. Most studies evaluating total serum sclerostin found different levels in males compared to females and in older compared to younger subjects. Besides an ELISA detecting total sclerostin an ELISA determining bioactive sclerostin has been developed. The aim of this study was to investigate serum levels of bioactive sclerostin in an Austrian population-based cohort.
Methods: We conducted a cross-sectional observational study in 235 healthy subjects. Using the bioactive ELISA assay (Biomedica) bioactive sclerostin levels were evaluated.
Results: Serum levels of bioactive sclerostin were higher in men than in women (24%). The levels correlated positively with age (r = 0.47). A positive correlation could also be detected with body mass index and bone mineral density.
Conclusion: Using the ELISA detecting bioactive sclerostin our results are consistent with data in the literature obtained by different sclerostin assays. The determination of sclerostin concentrations in peripheral blood thus appears to be a robust parameter of bone metabolism.
Human Sclerostin ELISA highlights:
Rigorously validated according to FDA/ICH/EMEA guidelines
Low sample volume
Bioactive Sclerostin ELISA Kit (Human SOST):
Specific antibodies targeting the receptor binding region
Rigorously validated for clinical samples according to FDA/ICH/EMEA guidelines
Low sample volume – 20 µl of serum/plasma per well
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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.
Rath et al., Transl Lung Cancer Res; 2024; 13 (1), 5-15. PMID: 38405004
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 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.
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.
Join us at the International Conference on Children’s Bone Health
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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.
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.
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
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.
Kidney disease is estimated to affect more than 800 million people worldwide (1). Taking action for prevention, early diagnosis and treatment can reduce the risk and the burden of kidney disease.
Role of the kidneys, kidney disease and risk factors
Kidneys are vital organs that regulate fluid balance, blood pressure and produce hormones that stimulate the production of red blood cells . Kidney disease is a condition in which kidneys lose their ability to effectively filter waste products and excess fluids from the blood. Kidney disease commonly leads to a decline in kidney function that may lead to kidney failure, characterized by the complete loss of kidney function. At this stage dialysis or kidney transplantation become the only treatment option.
Kidney problems can emerge suddenly (acute) or gradually over time (chronic). Various conditions, diseases and medications can contribute to acute and chronic kidney problems. Chronic kidney disease (CKD) is characterized by a prolonged period of kidney abnormalities that last for more than three months (2), whereas acute kidney disease – acute kidney injury (AKI) is characterized by a sudden loss of excretory kidney function (3).
Other forms of kidney disease include polycystic kidney disease (PKD) a genetic disorder that leads to kidney enlargement and impaired kidney function over time and glomerulonephritis (GN). GN is a group of diseases characterized by inflammation of the glomeruli, the filtration units of the kidney (4).
The most common risk factors for the development and progression of CKD are diabetes and high blood pressure. Managing blood sugar and blood pressure can help keep kidneys healthy. Other risk factors of CKD include heart disease, obesity, family history and genetic background as well as age, smoking and nutrition (5).
Consequences of kidney disease include heart disease, high blood pressure, bone and mineral disorders, and anemia (6).
Keep Your Kidneys Healthy
Regular exercise, weight control, a balanced diet (7) and sufficient fluid intake are only some of the ways to keep your kidney healthy.
World Kidney Day – about kidney health download here and check out the 6-Step Guide to Protecting Kidney Health here .
BIOMEDICA – Biomarker ELISA kits for clinical research in kidney disease
HIGH QUALITY ASSAYS – Fully validated according to international quality guidelines
Rare Disease Day is a global initiative held on the last day of February. It raises awareness for rare diseases to improve accessibility to medical treatment and representation for individuals diagnosed with rare diseases. It is estimated that around 300 million people worldwide are living with rare diseases.
Rare metabolic bone diseases are caused by genetic disorders that may directly or indirectly have an impact on bone structure or function (1). Other factors like hormones, tumors, diet or certain medications may also lead to abnormal growth and development of the skeleton. Some of the diseases are inherited many caused by genetic mutations. Other bone disorders are not inherited and can develop after birth.In some cases, the precise cause remains unknown.
Rare bone diseases
Rare bone diseases account for 5% of all birth defects and are an important cause of disability worldwide, yet they remain a difficult group of conditions to treat (2). It is estimated that more than 400 developmental abnormalties of the skeletal system exist (3).
The main rare metabolic bone diseases include Hypophosphatemia, Osteogenesis Imperfecta, Tumor-Induced Osteomalacia, X-Linked Hypophashatemia, and other Rare Bone Diseases (Fibrous Dysplasia, Osteopetrosis, High Bone Mass..) (4).
Biomarkers in Rare Bone Diseases
Biomarkers in Rare Bone Diseases provide a way to accelerate medical research by providing valuable insights into disease mechanisms. They play an important role in monitoring disease progression, optimizing treatments. and developing novel therapies.
NT-proCNP
C-natriuretic peptide (CNP) and its receptor, natriuretic peptide receptor-B (NPR-B) are important regulators of endochondral ossification and longitudinal bone growth (5, 6) The discovery and understanding of their physiological functions in promoting longitudinal bone growth have created opportunities for a specific targeted strategy in achondroplasia, the most common form of human dwarfism (7).
RANKL and OPG
Receptor activator of nuclear factor (NF-kappaβ) ligand (RANKL), its cellular receptor, receptor activator of NF-kappaβ (RANK), and the decoy receptor osteoprotegerin (OPG) are part of a cytokine system that regulate bone formation and resorption (8) . Denosumab is a bone anti-resorptive drug, a monoclonal antibody that binds RANKL and disrupts bone resorption. It has been approved for the treatment of osteoporosis and other bone-related disorders. The use of Denosumab in pediatric patients with Osteogenesis Imperfecta (OI), a genetic bone disorder, also known as brittle bone disease, shows decreased fractures and improved bone growth (9). A clinical trial at the National Institutes of Health found that Denosumab, significantly reduced abnormal bone turnover in adults with fibrous dysplasia, a rare disease characterized by weak, oddly shaped, or broke bones.
SCLEROSTIN
Sclerostin is a secreted protein that decreases bone formation. It binds to LRP-5 receptor on the surface of osteoblasts and consequently interferes with WNT signalling. Genetic sclerostin deficiency leads to increased bone formation and sclerotic bone disorders. Sclerostin inhibition is being evaluated as a potential approach to increase bone mass in Osteogenesis Imperfecta (10).
FGF23
Fibroblast growth factor 23 (FGF23) is a hormone that is produced by bone. It regulates serum phosphate levels by suppressing phosphate reabsorption in the kidney. Excessive actions of FGF23 are responsible for different kinds of hypophosphatemic rickets as found in X-linked hypophosphatemia (XLH) and osteomalacia. XLH is characterized by deformities of the lower limb and short stature. An anti-fibroblast growth factor-23 (FGF23) monoclonal antibody (Burosumab) has been approved as a novel treatment for hypophopshatemic rickets (11).
Measurement of FGF23 is a critical tool to assist in the evaluation and diagnosis of hypophosphatemic conditions (12, 13).
The second most common genetic form of hypophosphatemic rickets after XLH, is autosomal-dominant hypophosphatemic rickets (ADHR). ADHR is caused by specific mutations in the FGF23gene.
FGF23 can reliably be measured with an immunoassay (14).
Determination of FGF23 Levels for the Diagnosis of FGF23-Mediated Hypophosphatemia. Hartley IR, Gafni RI, Roszko KL, Brown SM, de Castro LF, Saikali A, Ferreira CR, Gahl WA, Pacak K, Blau JE, Boyce AM, Salusky IB, Collins MT, Florenzano P. J Bone Miner Res. 2022. 37(11):2174-2185. doi: 10.1002/jbmr.4702. PMID: 36093861; PMCID: PMC9712269.
The enzyme-linked immunosorbent assay (ELISA or EIA) is a laboratory method to detect and quantify the presence of a protein in biological samples (1, 2).
ELISA Assay Principle
When selecting an ELISA kit, researchers are often confronted with the question which assay to choose of the many commercially available kits.
It can be a challenge! Here are a few hints that may help.
HOW TO CHOOSE THE RIGHT ELISA KIT
As a general rule, before purchasing an assay, always read the protocol booklet (instructions for use – IFU or package insert) in detail. This should ensure that the kit will be suitable for your requirements. Check out the following:
1.ANALYTE
Which protein biomarker will you be measuring? Be sure to use the correct term during your search. Some biomarkers have alternative names (e.g. Sclerostin or SOST ELISA (SOST is actually the name for the gene that encodes Sclerostin).
2. SPECIES – SPECIFICITY – CROSS REACTIVITY
Verify if the assay can be used in the respective model such as e.g. human, rat, or mouse. Due to high homology between species, some ELISA kits work both in humans and in different animal species. As an example the biomarker ELISA kit for NT-proANP was developed for human use but due to the high sequence homology between species, the kit is successfully used to measure NT-proANP as a cardiac safety biomarker in various animal models (rat, mouse, rabbit, monkey).
3. SAMPLE TYPE
What is the sample type (matrix) you´ll be using (e.g. serum, EDTA-plasma, heparin-plasma, citrate-plasma, cell culture supernatants, urine..) ?
Verify if the assay is compatible for your sample type: check the package insert and, if available, check if there are validation data showing results (often found on the manufacturers website).
Of note: analysis of some biomarkers in the “wrong” matrix can lead to “false” results due to a matrix effect.
4. SAMPLE VOLUME
Check the amount of sample required per well (calculate volume to measure your samples in duplicates). Low sample volumes and precious samples are often a selection criterium.
5. SENSITIVTY – BIOMARKER CONCENTRATIONS TO BE EXPECTED
Before choosing an assay, look into the validation data of the kit (often documented in the ELISA protocol booklet or in the validation data files).
Reference values and pathological values in serum and/or plasma of the biomarker of interest are sometimes documented as well. These data can be helpful in selecting an appropriate assay. In some cases samples may require a pre-dilution. Therefore, always verify if the dilution buffer (assay buffer) is included in the kit or ask the assay developer for their input.
Of note: assays offering high sensitivity offer a different dynamic range than assays with a lower sensitivity. The dynamic range of an assay indicates the range of concentrations over which an assay can accurately quantify the analyte.
6. ASSAY PERFORMANCE – ASSAY VALIDATION
Careful evaluation of the assay´s performance characteristics is important in selecting an ELISA kit.
Choose an assay that has gone through a rigorous validation process. Check out if you can find data on the following performance characteristics:
Accuracy- detection of a protein biomarker in clinical samples.
Dilution linearity and parallelism – recovery of the analyte of interest in diluted samples
Specificity & cross-reactivity – making sure that you detect only the analyte of interest
Precision – within-run and in-between run precision – ensuring precise and reproducible results within an across assay lots
Calibration – ensures consistent performance over the range of the assay of the calibration curve
Sample stability – ensures the stability of the analyte of interest (e.g. exposure of real samples to multiple freeze-thaw cycles, stability at room temperature..).
ELISA Assay – microtiter plate
7. KIT COMPONENTS
Verify if the contents of the ELISA kit includes all the necessary components e.g. controls, assay dilution buffer. Consider storage requirements such as temperature sensitivity and expiration date.
8. CITATIONS & REFERENCES
Check if there are citations on the manufacturers website for the specific ELISA kit. Look into publications and seek feedback from researchers who have used the assay you are considering.
9. PRODUCT ORIGIN
Verify if the kit supplier is the kit manufacturer. More and more kits are repacked and are sold under different names, although it is always the same kit.
ELISA kit manufacturers will more likely give you qualified support as they “know” their product (e.g. availability of additional calibrators, controls, buffers.., technical know-how on the kit..).
10. CUSTOMER SUPPORT
Verify if the kit provider can provide timely and helpful customer service.
Duchenne muscular dystrophy (DMD) is a hereditary neuromuscular disease that leads to progressive muscle fiber degeneration and weakness. There is no cure for this disease and current therapy consists on treatment with glycocorticoids (GC). GC therapy is linked to risk of bone loss and increased fracture risk. Despite their adverse effects GC remain the standard care to slow down disease progression (2).
Steroid therapy and fracture prevention in Duchenne Muscular Dystrophy
This recent study explored factors that are associated with incident fracture risk in glucocorticoid (GC)-treated patients with Duchenne muscular dystrophy (DMD): Risk Factors Associated with Incident Vertebral Fractures in Steroid-treated Males with Duchenne Muscular Dystrophy. Brief, vertical fractures (VF) were prospectively evaluated in 38 males with Duchenne muscular dystrophy at study baseline and 12 months . The authors concluded the following: ” The observation that ≥ 1 prevalent VF and/or non-VF were the strongest predictors of incident VFs at 12 months supports the need for prevention of first fractures in this high-risk setting. Bone age delay, a marker of GC exposure, may assist in the prioritization of patients in efforts to prevent first fractures.”
Steroid therapy and fracture prevention in Duchenne Muscular Dystrophy – The Biomedica IL-6 and Sclerostin ELISA were highlighted in this study.
Purpose: Prevention of fractures is an unmet need in glucocorticoid (GC)-treated Duchenne muscular dystrophy. This study explored factors associated with incident vertebral fractures (VFs) to inform future fracture prevention efforts. Methods: VFs were evaluated prospectively at study baseline and 12 months on lateral spine radiographs in participants aged 4 to 25 years with Duchenne muscular dystrophy. Clinical factors were analyzed for their association with the change in Spinal Deformity Index (sum of the Genant-defined VF grades from T4 to L4) between baseline and 12 months. Results: Thirty-eight males were evaluated (mean ± SD age at baseline 11.0 ± 3.6 years; mean ± SD GC duration at baseline 4.1 ± 3.1 years; 74% ambulatory). Nine of 38 participants (24%) had 17 incident VFs, of which 3/17 VFs (18%) were moderate/severe. Participants with 12-month incident VF had lower mean ± SD baseline lumbar spine areal bone mineral density Z-scores (-2.9 ± 1.0 vs -1.9 ± 1.1; P = .049) and lower total body less head areal bone mineral density Z-scores (-3.1 ± 1.2 vs -1.6 ± 1.7; P = .036). Multivariable linear regression showed that at least 1 VF at baseline (P < .001), a higher number of antecedent non-VF (P < .001), and greater bone age delay at baseline (P = .027) were significant predictors of an increase in the Spinal Deformity Index from baseline to 12 months. Conclusion: The observation that ≥ 1 prevalent VF and/or non-VF were the strongest predictors of incident VFs at 12 months supports the need for prevention of first fractures in this high-risk setting. Bone age delay, a marker of GC exposure, may assist in the prioritization of patients in efforts to prevent first fractures.
2. Emerging therapies for Duchenne muscular dystrophy. Markati T, Oskoui M, Farrar MA, Duong T, Goemans N, Servais L. Lancet Neurol. 2022 Sep;21(9):814-829. doi: 10.1016/S1474-4422(22)00125-9. Epub 2022 Jul 15. PMID: 35850122.
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.
Fibroblast growth factor (FGF23) – is a hormone that regulates phosphate homeostasis and vitamin D metabolism. Abnormal FGF23 levels are associated with disorders affecting bone health e.g. hypophosphatemic rickets (7).
These protein biomarkers can easily be measured in human blood samples with an ELISA assay
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.
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.
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
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.
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.
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.
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.
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.
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.
World Kidney Day – March 9, 2023 – raising awareness of the importance of our kidneys
Around 1 in 10 people suffer from chronic kidney disease (CKD), with more than 800 million individuals being affected worldwide. CKD is a progressive disease in which the kidneys gradually lose their function over time. If detected early, medication and changes in lifestyle may help to prevent or slow down CKD progression.
What are the risk factors for CKD?
Older age (+60 years), diabetes, high blood pressure, heart disease, obesity and some medications are some known risk factors for kidney disease.
How can we keep our kidneys healthy?
Nutrition, exercise, sufficient fluid intake are only some examples on how to keep our kidneys healthy. Valuable information can be found on the following websites :
Purpose of review: Plant-based diets have been used with growing popularity for the treatment of a wide range of lifestyle-related diseases, including diabetes, hypertension, and obesity. With the reinvigoration of the dietary management of chronic kidney disease (CKD) and the use of low protein diets for secondary prevention of CKD to delay or prevent dialysis therapy, there is an increasing interest in the potential role of plant-based diets for these patients.
Recent findings: Recently, a body of evidence related to the role of plant-based diets in preventing CKD has reemerged. Several observational studies have shown that red and processed meat have been associated with increased risk of CKD as well as faster progression in those with preexisting CKD. In several substitution analyses, replacement of one serving of red and/or processed meat has been linked with sizable reductions in CKD risk. Although limited, experimental trials for the treatment of metabolic acidosis in CKD with fruits and vegetables show outcomes comparable to oral bicarbonate. The use of plant-based diets in CKD may have other benefits in the areas of hypertension, weight, hyperphosphatemia, reductions in hyperfiltration, and, possibly, mortality. The risk of potassium overload from plant-based diets appears overstated, mostly opinion-based, and not supported by the evidence. Plant-based diets are generally well tolerated and provide adequate protein intake, including essential amino acids as long as the diet is correctly implemented.
Summary: Plant-based diets should be recommended for both primary and secondary prevention of CKD. Concerns of hyperkalemia and protein inadequacy related to plant-based diets may be outdated and unsupported by the current body of literature. Healthcare providers in general medicine and nephrology can consider plant-based diets as an important tool for prevention and management of CKD.
Chronic kidney disease (CKD) is a major public health problem worldwide. Its prevalence and incidence are increasing, particularly among the ethnic minority populations. Diabetes, hypertension and obesity have been the three major aetiologies for CKD in all developed countries. While diabetes and hypertension remain the major causes of CKD in developing countries, environmental pollution, pesticides, water, analgesic abuse and herbal medications are common causes in these regions. Rapid urbanization and globalization are thought to be the contributing factors to rising prevalence and incidents of CKD. Despite the rising prevalence of CKD, disease awareness remains profoundly low. Worldwide, only 6% of the general population and 10% of the high-risk population are aware of their CKD statuses. Health screenings have been shown to be effective in improving the incidence of ESRD. However, currently there is no effective tool to assess and evaluate the awareness objectively.
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.
+ 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
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
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).
BIOMEDICA OFFERS HIGH QUALITY ELISA KITS FOR BONE BIOMARKERS
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.
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.
√ The internationally most referenced Sclerostin ELISA! √ Extensively validated according to international quality guidelines √ Only 20µl sample / well – low sample volume
References on strength training for children and adoloscents
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.
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.