Biomarkers in Rare Bone Diseases
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 FGF23 gene.
FGF23 can reliably be measured with an immunoassay (14).
FGF23 ELISAs (c-term FGF23, cat. no BI-20702) (intact FGF23, cat. no. BI-20700)
- MULTI-USE for serum and plasma samples
- TRUSTED in over 60 citations
FGF23 – Test
Biomarker ELISA assay kits from BIOMEDICA
Complete ready-to use ELISA kits
NT-proCNP ELISA (cat. no. BI-20812)
- CONVENIENT – low sample volume – 20 µl / well
- RELIABLE – validated following international quality guidelines
- TRUSTED – widely cited in over 40 publications (click here for full list)
- MULTI-USE – for human serum and plasma samples; protocols for non-human samples (e.g. rat).
Citations Selection of NT-proCNP ELISA citations related to skeletal disorders:
- Plasma C-Type Natriuretic Peptide: Emerging Applications in Disorders of Skeletal Growth. Espiner E et al.,Horm Res Paediatr. 2018. 90(6):345-357. doi: 10.1159/000496544. PMID: 30844819.
- Rats deficient C-type natriuretic peptide suffer from impaired skeletal growth without early death. Fujii T et al., PLoS One. 2018. 22;13(3):e0194812. doi: 10.1371/journal.pone.0194812. PMID: 29566041.
- Serum NT-proCNP levels increased after initiation of GH treatment in patients with achondroplasia/hypochondroplasia. Kubota T etal., Clin Endocrinol (Oxf). 2016 Jun;84(6):845-50. doi: 10.1111/cen.13025. Epub 2016 Feb 25. PMID: 26814021.
- Acromesomelic dysplasia, type maroteaux caused by novel loss-of-function mutations of the NPR2 gene: Three case reports. Wang W et al., 2016. Am J Med Genet A 170A, 426–434.
- Skeletal overgrowth syndrome caused by overexpression of C-type natriuretic peptide in a girl with balanced chromosomal translocation, t(1;2)(q41;q37.1). Ko J et al., 2015. Am J Med Genet A 167A, 1033–1038.
RANKL ELISA (cat. no. BI-20462)
- Highly sensitive – measurable concentrations in healthy subjects
- Only assay that measures free, uncomplexed, soluble RANK Ligand
- TRUSTED in over 300 citations
- CONVENIENT- ready to use liquid calibrators and controls
- EFFICIENT – low sample volume 20µl / well
- TRUSTED in over 250 citations
Literature
- Genetic approaches to metabolic bone diseases. Hannan FM, Newey PJ, Whyte MP, Thakker RV. Br J Clin Pharmacol. 2019. 85(6):1147-1160. doi: 10.1111/bcp.13803. PMID: 30357886; PMCID: PMC6533455.
- The evolving therapeutic landscape of genetic skeletal disorders. Sabir, A.H., Cole, T. Orphanet J Rare Dis 14, 300 (2019).
- Changes in skeletal dysplasia nosology. Jurcă MC, Jurcă SI, Mirodot F, Bercea B, Severin EM, Bembea M, Jurcă AD. Rom J Morphol Embryol. 2021. 2(3):689-696. doi: 10.47162/RJME.62.3.05. PMID: 35263396; PMCID: PMC9019670.
- Atlas of rare genetic metabolic bone diseases. IOF, 2024.
- Natriuretic peptide regulation of endochondral ossification. Evidence for possible roles of the C-type natriuretic peptide/guanylyl cyclase-B pathway. Yasoda A, Ogawa Y, Suda M, Tamura N, Mori K, Sakuma Y, Chusho H, Shiota K, Tanaka K, Nakao K J Biol Chem.1998. 8;273(19):11695-700. doi: 10.1074/jbc.273.19.11695. PMID: 9565590.
- Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification. Miyazawa T, Ogawa Y, Chusho H, Yasoda A, Tamura N, Komatsu Y, Pfeifer A, Hofmann F, Nakao K. Endocrinology. 2002. 143(9):3604-10. doi: 10.1210/en.2002-220307. PMID: 12193576.
- Optimal management of complications associated with achondroplasia. Ireland PJ, Pacey V, Zankl A, Edwards P, Johnston LM, Savarirayan R Appl Clin Genet. 2014. 7:117-25. doi: 10.2147/TACG.S51485. PMID: 25053890; PMCID: PMC4104450.
- C-type natriuretic peptide regulates endochondral bone growth through p38 MAP kinase-dependent and -independent pathways. Agoston H, Khan S, James CG, Gillespie JR, Serra R, Stanton LA, Beier F BMC Dev Biol. 2007. 7:18. doi: 10.1186/1471-213X-7-18. PMID: 17374144; PMCID: PMC1847438.
- Role of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in bone cell biology. Hofbauer LC, Heufelder AE. J Mol Med (Berl). 2001 Jun;79(5-6):243-53. doi: 10.1007/s001090100226. PMID: 11485016.
- Effect of denosumab on the growing skeleton in osteogenesis imperfecta. Hoyer-Kuhn H, Semler O, Schoenau E.J Clin Endocrinol Metab. 2014. 99(11):3954-5. doi: 10.1210/jc.2014-3072. PMID: 25148238.
- Effect of sclerostin inactivation in a mouse model of severe dominant osteogenesis imperfecta. Marulanda J, Tauer JT, Boraschi-Diaz I, Bardai G, Rauch F. Sci Rep. 2023. 13(1):5010. doi: 10.1038/s41598-023-32221-3. PMID: 36973504; PMCID: PMC10043013.
- Hereditary Metabolic Bone Diseases: A Review of Pathogenesis, Diagnosis and Management. Charoenngam N, Nasr A, Shirvani A, Holick MF.Genes (Basel). 2022. 13(10):1880. doi: 10.3390/genes13101880. PMID: 36292765; PMCID: PMC9601711.
- 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 Measurement and Interpretation of Fibroblast Growth Factor 23 (FGF23) Concentrations. Heijboer AC, Cavalier E Calcif Tissue Int. 2023. 112(2):258-270. doi: 10.1007/s00223-022-00987-9. PMID: 35665817; PMCID: PMC9859838.