Bone Related Biochemical Examinations Research Articles

Bone and bone related biochemical examinations. Hormone and hormone related substances. Parathyroid hormone

Parathyroid hormone (PTH) is the most important hormone to maintain serum calcium levels. PTH acts directly on bone by stimulating both bone resorption and bone formation with the reactive excess in the former when it acts continuously. PTH also acts on renal tubule to promote urinary excretion of phosphate as well as production active vitamin D (1,25 [OH] 2D) . 1,25 [OH] 2D has been also suggested to have some unique and direct action on the bone. Measurement of intact-PTH is essential for optimal management of bone abnormalities in patients with primary hyperparathyroidism, secondary hyperparathyroidism, and chronic kidney disease. The newer PTH assays ; whole-PTH and bio-intact PTH assay, use an antibody that binds the region including the first amino acid is present, making it specific for the complete molecule, (1-84)-PTH. Recently, a new molecular form of PTH has been reported, which cannot be detected by these newer PTH assays.

Bone and bone related biochemical examinations. Significance of measurement of serum calcium, phosphorus, alkaline phosphatase, corrected calcium and urine calcium

Classical clinical calcium endocrinology was built on measurements of serum Ca, P and alkaline phosphatase as well as urinary Ca. Serum Ca, the most strictly maintained biological constant, occupies the central role among them, controlling PTH secretion and bone metabolism. Ca is strongly bound to proteins especially albumin, so that total serum Ca values are sometimes misleading, necessitating the use of corrected or ionized Ca. Serum Pi rises early in renal insufficiency, playing an important role in vascular calcification. Growth hormone and thyroid hormone functions are also reflected on serum P. Serum alkaline phosphatase especially the bone-specific type is also important for the evaluation of bone dynamics such as growth and tumor metastasis. These classical datasets should be reevaluated in the light of actions of new compounds such as calcimimetics, P-binders, bisphosphonates, vitamin D derivatives, cytokines, etc.

Bone and bone related biochemical examinations. Bone and collagen related metabolites. Measurement and clinical role of OPG

Osteoprotegerin (OPG) has been identified as a novel cytokine that specifically inhibits osteoclastogenesis. OPG acts as a soluble decoy receptor that inhibits the binding of receptor activator of NF-kappaB ligand (RANKL) to its receptor RANK and thus inhibits the proliferation and activation of osteoclasts. Human serum OPG can now be easily measured using a sandwich-type ELISA kit, and the roles of OPG in various diseases have been revealed by clinical studies. These clinical studies have demonstrated that OPG plays an important role in not only metabolic bone diseases but also other diseases such as coronary artery disease, vascular calcification, chronic renal failure and malignancy. Furthermore, OPG may be a useful and novel marker related to the progression or mechanisms of these diseases.

Bone and bone related biochemical examinations. Bone and collagen related metabolites. Tartrate-resistant acid phosphatase (TRACP)

Tartrate-resistant acid phosphatase (TRACP) is a well-known marker for bone resorption, but it is not enough for clinical use in specificity of bone and instability in serum. Tartrate-resistant acid phosphatase type 5b (TRACP-5b) is an osteoclast-produced enzyme and was reported the clinical performance of a novel fragments absorbed immunocapture enzyme assay. TRACP-5b have smaller day-to-day and diurnal variation than those of urinary bone resorption markers and show the usefulness as promising markers in monitoring the treatment for osteoporosis.

Bone and bone related biochemical examinations. Bone and collagen related metabolites. Bone-specific alkaline phosphatase

Research has long been conducted to elucidate the association between bone and alkaline phosphatase (ALP). ALP-labeled monoclonal antibodies developed in recent years represent a significant advance in the evaluation of bone quality by making bone-specific ALP (BAP) available for standard quantitative measurement. While BAP yields variable results depending on the assay used, the enzyme immunoassay (EIA) or immunoradiometric assay (IRMA), it has enabled the risk of fracture, as well as the efficacy of pharmacological intervention, to be predicted to a certain degree, through evaluation of a parameter other than bone mass. In this regard, BAP is assumed not only to reflect bone strength, but also to serve as an index for bone quality, quite apart from bone mass. Thus, quantitative measurement of BAP currently represents the most effective means available for clinical evaluation of bone quality.

Bone and bone related biochemical examinations. Bone and collagen related metabolites. Receptor activator of NF-kappaB ligand (RANKL)

Identification of RANKL (receptor activator of NF-kappaB ligand), RANK (receptor activator of NF-kappaB) and OPG (osteoprotegerin) revealed the mechanisms regulating osteoclast differentiation and function. RANKL-RANK signaling is essential for the physiological osteoclast development and plays a major role in the pathological bone destruction. RANKL is a transmembrane protein, but soluble form (sRANKL) is circulated in blood stream. Change of sRANKL concentration was observed in several bone diseases. This paper reviews the potential of sRANKL measurement as a marker of bone diseases.

Bone and bone related biochemical examinations. Bone and collagen related metabolites. Structure and metabolisms of collagen

Collagens are the most abundant proteins in mammals. They are the major structural proteins in bone as well as other organs. The synthesis of collagens is regulated by numerous growth factors, cytokines and hormones. The higher structure of collagen is derived from the series of biosynthesis including its characteristic primary amino acid structure and post-translational modifications. The degradation products of collagen have been utilized as markers for bone turnover.

Bone and bone related biochemical examinations. Hormone and hormone related substances. Calcitonin gene-related peptide (CGRP)

Calcitonin gene-related peptide (CGRP) is secreted from osteoclasts and several cancer cells, as well as from sensory nerve endings innervating blood vessels and bones. A potent vasodilator, CGRP powerfully counteracts hypertensive responses and protects organs from blood pressure-related damage, though it also can precipitate migraine attacks, bronchoconstriction and hypersensitive colon. Because plasma CGRP concentrations are very low, even in patients, it is thought that CGRP functions as local modulator rather than as a circulating hormone. Nevertheless, it is useful to measure plasma CGRP when evaluating the severity of target diseases (e.g., heart failure and sepsis) and when screening or following up patients with neuroendocrine tumors (e.g., medullary thyroid carcinoma). That said, one should understand the biochemical characteristics of CGRP prior to blood sampling, and should use highly sensitive assays that detect only the active form of the molecule.

Bone and bone related biochemical examinations. Bone and collagen related metabolites. Regulatory mechanisms of osteoclast differentiation and function

Osteoclast differentiation is tightly regulated by osteoblasts. Osteoblasts express two cytokines, macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL), essential for osteoclast differentiation. Osteoclast precursors firstly differentiate into mononuclear osteoclasts in response to M-CSF and RANKL. Nuclear factor of activated T cells 1 (NFATc1) is a transcription factor, which is involved in the determination of osteoclast differentiation. The mononuclear osteoclast then fuses each other to form the multinucleated cell. Dendritic cell-specific transmembrane protein (DC-STAMP) plays an important role in the fusion of mononuclear osteoclasts. Osteoclasts recognize bone and form ruffled borders and clear zones on the bone surface (polarization). Polarizing osteoclasts construct active vascular transportation systems to resorb bone efficiently. RANK-TRAF6 (TNF receptor-associated factor 6) -mediated signals key roles in both osteoclast differentiation and function. In this article, I will review the recent findings on osteoclast differentiation and function.

Bone and bone related biochemical examinations. Bone and collagen related metabolites. Osteocalcin (OC)

Osteocalcin is produced by mature osteoblasts and primarily deposited in the extracellular matrix of skeletal tissue. It has been shown that serum osteocalcin is a marker of osteoblastic activity, and the levels reflect the rate of bone formation. The first osteocalcin assays were competitive radioimmunoassays using bovine osteocalcin as a standard, and a new generation of assays was developed to measure the major circulating forms of the protein, which is the intact and the large N-terminal fragment. Since osteocalcin binds to hydroxyapatite crystal after gamma-carboxylation at three residues, increased amounts of immature undercarboxylated osteocalcin might reflect risks for fractures. However, at present, measurement of osteocalcin does not substitute for bone mass measurement and only provide limited clinical values on evaluation of patients with osteoporosis or metabolic bone diseases.

Bone and bone related biochemical examinations. Bone and collagen related metabolites. Urinary and serum NTX as bone resorption markers

Serum (S-) or urinary (U-) type I collagen N-telopeptide (NTX) reflect bone resorption by cathepsin K or matrix metalloproteinase (MMP). In our analysis of 18 patients with serum creatinine (S-Cr) less than 2.0 mg/dL, there was a significant positive correlation between S-NTX and U-NTX (U-NTX = 3.7 x S-NTX-13 [r = 0.84, P<0.0001) ] . Because diurnal and day-to-day variations are large in U-NTX assay, it is recommended that U-NTX be measured in the first or second urine of the day. In contrast, physiological variation in S-NTX is relatively small. However, we should bear in mind that S-NTX is interfered with renal function. Before interpretation of S-NTX, we should estimate glomerular filtration rate by using Cockcroft-Gault formula, especially in elderly patients with low body mass index such as rheumatic patients, whose S-Cr-is in normal ranges Both markers are very useful for estimating the risk of bone fracture and for monitoring therapeutic effects of anti-resorptive agents such as bisphosphonate or selective estrogen receptor modulator.

Bone and bone related biochemical examinations. Bone and collagen related metabolites. Biomarkers for cartilage matrix turnover and destruction in joint diseases

Now, it is becoming known that the mechanisms of cartilage matrix destruction such as roles of degradative enzymes and cytokines. It is important to develop the reliable biomarkers to detect the early stage of cartilage destruction. The biomarker could be useful tool not only to understand the progression of joint destruction in osteoarthritis and rheumatoid arthritis but also to develop new treatment.

Bone and bone related biochemical examinations. Hormone and hormone related substances. The measurement of circulating fibroblast growth factor 23 (FGF-23)

Fibroblast growth factor 23 (FGF-23) is a phosphaturic peptide involving in the development of hypophosphatemic rickets/osteomalacia. FGF-23 assays are known to be useful for the diagnosis of hypophosphatemia. Now three different two-site enzyme-linked immunosorbent assays a C-terminal human FGF23 enzyme-linked immunosorbent assay (ELISA) (Immunotopics, California), an intact human FGF23 ELISA (Immunotopics, California), and another intact human FGF23 ELISA (Kainos Laboratories, Japan) are available for the diagnosis.