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Biochemical markers of bone turnover - uses and limitations

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Bone turnover markers of resorption and formation are released during the process of bone remodelling. These markers have been extensively studied in a number of therapeutic trials of osteoporosis during the past decade. This has led to better understanding of their physiology, clinical applications and possible ways to optimize analytical techniques. Bone markers can complement the results of bone mineral density in the management of osteoporosis, but their use in clinical practice is challenged by pre-analytical and analytical variability. This review will discuss different types of bone markers, their limitations, use in different metabolic bone diseases and current recommendations from the International Osteoporosis Foundation and the International Federation of Clinical Chemistry and Laboratory Medicine bone marker standards working group.
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... Moreover, low BMI is an important risk factor for increased bone loss in postmenopausal women, which further increases the risk of postoperative fractures [57]. Bone turnover markers (BTMs) highlight delicate balance between bone formation and resorption [58][59][60]. Procollagen type I N propeptide (PINP) is a marker of bone formation, and cross-linked C-telopeptides of type I collagen (bCTx) is considered a marker of bone resorption [59,61]. It has been found inversely associated between BMD and serum levels of PINP [62]. ...
... Bone turnover markers (BTMs) highlight delicate balance between bone formation and resorption [58][59][60]. Procollagen type I N propeptide (PINP) is a marker of bone formation, and cross-linked C-telopeptides of type I collagen (bCTx) is considered a marker of bone resorption [59,61]. It has been found inversely associated between BMD and serum levels of PINP [62]. ...
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Objective: Percutaneous vertebroplasty (PVP) and kyphoplasty (PKP) have been widely used to treat osteoporotic vertebral compression fractures (OVCF), but the risk of vertebral re-fracture after PVP/PKP remains controversial. This study aims to investigate the incidence and risk factors of vertebral re-fracture after PVP/PKP. Methods: Relevant literatures published up to November 2021 were collected from PubMed, Embase and Web of Science. A meta-analysis was performed to extract data associated with risk factors of SVCF following the PRISMA guidelines. Also, pooled odds ratio (OR) or weighted mean difference (WMD) with 95% confidence interval (CI) was calculated. Results: A total of 23 studies, encompassing 9372 patients with OVCF, met the inclusion criteria. 1255 patients (13.39%) suffered re-fracture after PVP/PKP surgery. A total of 22 studies were from Eastern Asia and only 1 study was from Europe. Female sex (OR = 1.34, 95%CI 1.09-1.64, P = 0.006), older age (WMD = 2.04, 95%CI 0.84-3.24, P = 0.001), lower bone mineral density (BMD, WMD = - 0.38, 95%CI - 0.49-0.26, P < 0.001) and bone cement leakages (OR = 2.05, 95% CI 1.40-3.00, P < 0.001) increased the risk of SVCF. The results of subgroup analysis showed the occurrence of re-fracture was significantly associated with gender (P = 0.002), age (P = 0.001) and BMD (P < 0.001) in Eastern Asia. Compared with the unfractured group, anterior-to-posterior vertebral body height ratio (AP ratio, WMD = 0.06, 95%CI 0.00-0.12, P = 0.037) and visual analog scale score (VAS, WMD = 0.62, 95%CI 0.09-1.15, P = 0.022) were higher in the refracture group, and kyphotic angle correction ratio (Cobb ratio, WMD = - 0.72, 95%CI - 1.26-0.18, P = 0.008) was smaller in Eastern Asia. In addition, anti-osteoporosis treatment (OR = 0.40, 95% CI 0.27-0.60, P < 0.001) could be a protective factor. Conclusion: The main factors associated with re-fracture after PVP/PKP are sex, age, bone mineral density, AP ratio, Cobb ratio, VAS score, bone cement leakage and anti-osteoporosis treatment, especially in Eastern Asia.
... Osteoporosis, which is the severe form of low BMD, is a disorder with no obvious specific symptoms and is usually misdiagnosed so that accurate dealing with osteoporosis is often reactionary to harmful fractures. 26,27 So, accurate diagnosis of osteoporosis is the key stone for treatment and discovering patients vulnerable to fractures. 28,29 This work studies the possibility to use serum markers for early diagnosis of low BMD instead of measuring the bone minerals by DEXA, which is an accurate simple means of diagnosis but is too costly to be widely recommended and is not available, especially in poor communities. ...
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Context: Bone remodeling comprises balanced coupling of bone formation and resorption, and low bone mineral density (BMD) demonstrates high rates of bone resorption. Osteoporosis is a chronic asymptomatic disease with fragile bones and impending risk of fractures mediated by minor trauma. Whereas bone mineralization and integrity are determined by calcium and vitamin D, specific serum markers such as bone specific alkaline phosphatase (ALP) and osteocalcin (OC) play a vital role in bone formation. Materials and methods: Serum calcium, vitamin D, ALP, and OC levels were measured in 2,145 Saudi students aged 18-22 years at Umm Al-Qura University. The BMD was measured by dual-energy X-ray absorptiometry (DEXA), and the findings were statistically evaluated. The following statistics were utilized in the analysis: the SPSS software was used to record, tabulate, and statistically evaluate the results. Results: Low BMD cases accounted for 27.46% of all cases investigated, with considerably higher serum calcium, bone-specific ALP, and OC levels compared to control cases, but significantly lower serum vitamin D levels. In low BMD instances, there was no association between serum markers and DEXA findings. Conclusion: Serum indicators by themselves may be useful for screening and predicting patients at risk of osteoporosis, as well as assessing treatment response. The combination of serum markers and DEXA measures is more effective in detecting low BMD.
... In addition, bone turnover markers (BTMs) are parameters that were also widely measured in metabolic bone diseases, including osteoporosis, to evaluate the severity of the disease. Because of the significance in studying the bone health, numerous assays were developed and are currently available [2]. ...
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Serum P1NP, one of the important biomarkers for bone turnover, is commonly used for the prediction of bone fracture and the prognosis of osteoporosis after therapy. We developed a P1NP chemiluminescence assay and evaluated changes in bone metabolism markers in lung transplant patients. The screened 2 P1NP antibodies with constructed antigens and α-1 chain antigens expressed by the Corynebacterium glutamate expression system were applied into assay development. The assay performance was evaluated to examine the reliability. A normal Q-Q plot was used to establish male reference interval. Changes of bone metabolism markers before and after lung transplantation in 19 patients were evaluated. The linear factor R of P1NP reagent was greater than 0.99. The limit of detection was 3.32 ng/ml. The precision of the three batches of P1NP reagents was lower than 8%. Method comparison with Roche P1NP reagent showed that the correlation coefficient R² was 0.91. In the monitoring of bone mass in a short time, bone metabolism markers can better indicate the change of bone mass, while the traditional bone mineral density detection is lagging behind the bone metabolism markers. P1NP and β-CrossLap to bone mass change in patients after lung transplantation, and P1NP and β-CrossLap are very good clinical markers for bone mass monitoring.
Article
This study aimed to investigate whether changes in the bone turnover markers (BTMs) during teriparatide therapy for osteoporotic vertebral compression fractures could reflect therapeutic effects by analyzing the relationship between clinical and radiological features and BTMs. A total of 33 patients with 51 osteoporotic vertebral compression fracture segments were included. Plain radiographs and BTM levels were evaluated at the pretreatment and at 3 months after teriparatide treatment. Based on serial vertebral compression ratio analysis, the progression of fracture was defined as a vertebral compression ratio decrease of ≥10%, relative to the pretreatment values. All segments were divided into 2 groups: the “maintain” group with 32 (62.7%) segments and the “progression” group with 19 (37.3%) segments. After the teriparatide treatment, serum osteocalcin and serum C-terminal telopeptide of type I collagen levels (P = .028 and .008, respectively), and change amounts of them were significantly larger, increasing (P = .001) in the progression group. The vitamin D (25OH-D) levels were significantly lower (P = .038) in the progression group; however, the relative changes in the 25OH-D levels between the 2 groups, before and after the treatment, were not significantly different (P = .077). The parathyroid hormone (PTH) levels were reduced by the teriparatide treatment in both groups, while the decrease in PTH concentration after the treatment was significantly more pronounced in the progression group (P = .006). Significant increase in the osteocalcin and serum C-terminal telopeptide of type I collagen levels and a simultaneous decrease in the PTH levels during the teriparatide treatment suggest that clinicians should assume the progression of fracture.
Article
Background: Bone turnover markers (BTMs) have been studied for application in clinical medicine. However, BTMs in children are challenging, and few studies explore these BTMs in children. The application of BTMs is complicated mainly due to pre-analytical factors, variable reference intervals of age- and sex-related BTMs for adolescents and children in different regions and laboratories. Therefore, laboratory testing of BTMs is critical for understanding pediatric bone development and metabolism, which provides additional information about bone development and diseases. Methods: Literature search was conducted using the MeSH term "child" combined with the terms that bone turnover markers such as "osteocalcin," "Procollagen type I N-terminal propeptide," "procollagen type I C-terminal propeptide," "osteocalcin," "N-terminal cross-linked telopeptide," and "C-terminal cross-linked telopeptide," Several databases including Web of Science, Google Scholar, and PubMed were searched to obtain the relevant studies. Results: BTMs represent the combined effects of skeletal development, growth, and remodeling in children, which can be used in clinical pediatrics to assist in the diagnosis and prognosis of bone metabolic disorders. Conclusion: BTMs are clearly helpful for diagnosis and monitoring of bone growth and development as well as bone metabolic disorders.
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Purpose: Simvastatin is a prodrug of the potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. The main purpose of the current study is to assess the accurate function of simvastatin on osteoporosis of extremity bones in aging rats. Materials and methods: Fifty 15-month-old SD rats were divided into five groups (four simvastatin groups and one control group). The rats in four simvastatin groups were fed with different doses of simvastatin (5, 10, 20, and 40 mg/kg/d, respectively) for 3 months, whereas the rats in control group were fed the equal physiological saline. Calcium (Ca), phosphorus (P), and the lipid spectrum in serum were measured. Biochemical markers of bone metabolism, osteocalcin (OC), and tartrate-resistant acid phosphatase (Trap-5b), were analyzed using ELISA. The content of adipocytes in bone marrow was analyzed by histological staining. Finally, the bone quality of the femur and tibia were evaluated using dual-energy X-ray absorptiometry (DEXA), peri-quantity CT (pQCT), and the 3-point bending biomechanical test. Results: Simvastatin reduced serum triglycerides (TG), and 10 mg/kg/d of simvastatin significantly reduced the content of adipocytes in bone marrow compared to the control group. However, statistically significant differences between the simvastatin groups and the control group were not found in the CA, P, OC, Trap-5b, or the evaluation indexes of bone quality from DEXA, pQCT, and biomechanical tests. Conclusion: Simvastatin could not prevent osteoporosis of the extremity bones in aging rats.
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Studies on the effect of sulfated polysaccharides from seaweed on bone regeneration have increased in recent years. However, there is no consensus on how to use them and their real effectiveness in that process. Thereby, we carried out a systematic review to answer the question “Do the sulfated polysaccharides from seaweeds promote osteogenesis?”. Searches were performed in Pubmed, Scopus, and Web of Knowledge databases. A total of 599 articles were selected, resulting in 14 eligible studies. Results showed that the sulfated polysaccharides from seaweeds increase the osteogenic markers evaluated. Nevertheless, due to the lack of standardization on protocols used, the results should be cautiously interpreted. In addition, studies using animal models are still scarce, and the results with cellular models cannot always be extrapolated to systems that are more complex. Despite the study limitations, the use of sulfated polysaccharides appears to promote in vitro osteogenesis and enhance bone regeneration.
Article
Purpose To develop a simple and clinically useful assessment tool for osteoporosis in older women with type 2 diabetes mellitus (T2DM). Methods A total of 601 women over 60 years of age with T2DM were enrolled in this study. The levels of serum sex hormones and bone metabolism markers were compared between the osteoporosis and non-osteoporosis groups. The least absolute shrinkage and selection operator regularization (LASSO) model was applied to generate a risk assessment tool. The risk score formula was evaluated using receiver operating characteristic analysis and the relationship between the risk score and the bone mineral density (BMD) and T-value were investigated. Results Serum sex hormone-binding globulin (SHBG), cross-linked C-telopeptide of type 1 collagen (CTX), and osteocalcin (OC) were significantly higher in the osteoporosis group. After adjustment for age and body mass index (BMI), SHBG was found to be correlated with the T-value or BMD. Then, a risk score was specifically generated with age, BMI, SHBG, and CTX using the LASSO model. The risk score was significantly negatively correlated with the T-value and BMD of the lumbar spine, femoral neck, and total hip (all P<0.05). Conclusion A risk score using age, BMI, SHBG, and CTX performs well for identifying osteoporosis in older women with T2DM.
Chapter
Bone turnover markers are specific enzymes, proteins, and degradation products of the bone tissue produced by osteoblasts and osteoclasts during bone formation and bone resorption, and allow non-invasive, accurate, and repeatable assessment of bone turnover. Bone turnover markers can be combined with bone mineral density to assess fracture risk in osteoporosis management. By measuring bone metabolic status using bone turnover markers, it is possible to select the optimal therapeutic drug in clinical practice. For monitoring osteoporosis therapy, it is necessary to use a bone marker suitable for each drug according to its mechanism of action. Bone markers enable earlier evaluation of therapeutic effects than bone mineral density and contribute to improved treatment adherence. Values of bone turnover markers are affected by biological fluctuations such as diurnal and day-to-day variations, as well as analytical variability. Therefore, it is important to follow the same sample collection and measurement methods. Further, to accurately interpret the results, it is necessary to consider various factors that affect bone marker values. Monitoring osteoporosis therapy with bone turnover markers is useful for the safe and long-term administration of therapeutic drugs for osteoporosis.
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As the definitive reference for clinical chemistry, Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 5th Edition offers the most current and authoritative guidance on selecting, performing, and evaluating results of new and established laboratory tests. Up-to-date encyclopedic coverage details everything you need to know, including: analytical criteria for the medical usefulness of laboratory procedures; new approaches for establishing reference ranges; variables that affect tests and results; the impact of modern analytical tools on lab management and costs; and applications of statistical methods. In addition to updated content throughout, this two-color edition also features a new chapter on hemostasis and the latest advances in molecular diagnostics.
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Bone sialoprotein (BSP) is a phosphorylated glycoprotein with a M(r) of 70-80 kDa that accounts for approximately 5-10% of the noncollagenous proteins of bone. Due to its relatively restricted distribution to mineralized tissues, BSP may serve as a potential marker of bone metabolism. Employing a recently developed RIA, serum BSP was measured in 133 healthy subjects, aged 20-80 yr, and in patients with primary hyperparathyroidism (pHPT; n = 26), Paget's disease of bone (PD; n = 14), untreated multiple myeloma (MM; n = 32), and breast cancer with bone metastases (BC; n = 19). Results were compared to clinical and laboratory data, including serum total alkaline phosphatase as a marker of bone formation, and the urinary cross-links pyridinoline (PYD) and deoxypyridinoline (DPD) as markers of bone resorption. In healthy adults, serum BSP values ranged between 5.0-21.6 ng/mL (5-95% interval), with a median of 10.5 ng/mL (total group). In healthy females, a linear correlation was found between serum BSP and age...
The biological variability of urinary bone resorption markers was measured in 30 healthy and 20 postmenopausal osteoporotic women. The second spot urines were collected at weekly intervals for 5 weeks and urinary pyridinium crosslinks, hydroxyproline, calcium and Ntx were evaluated. Results are discussed in relation to analytical variability, critical difference values and index of individuality. In conclusion monitoring and classifying bone turnover in groups of persons are well established, but the routine use of urinary biochemical bone markers in the individual patient is of limited use.