Biochemical markers of bone turnover for the clinical assessment of metabolic bone disease

There is not yet an ideal marker of bone formation, but circulating BGP is the most satisfactory at present. New developments include the use of sheep BGP64 and human BGP85 as an immunogen and monoclonal antibodies, which may recognize fragments of BGP released during resorption. The specific measurement of bone alkaline phosphatase and the assay of procollagen fragments and of other noncollagenous bone-related proteins will allow a more precise assessment of the complex osteoblastic functions in normal and pathologic conditions. Finding a sensitive and specific marker of resorption is a challenge because all constituents of bone matrix are likely to be degraded into minute peptides during osteoclastic bone resorption. The measurement of pyridinium crosslinks and possibly of tartrate-resistant acid phosphate by a bone-specific monoclonal antibody are the most tangible improvements in this area. These markers need to be validated by comparison with data obtained by direct measurement of bone turnover on iliac crest biopsy. It should be remembered, however, that circulating markers reflect the overall activity of the whole skeleton, including the cortical, subcortical, and trabecular envelopes, which have different remodeling rates in normal and abnormal states. A circulating marker will not detect a specific defect of the cellular activity of one compartment of bone if the summated turnover of the skeleton is unchanged. Conversely, bone histomorphometry is limited to a small area of the trabecular envelope but allows detection of a specific defect at the cellular level. These differences should be kept in mind, as there is growing evidence that, for example, bone mass and bone turnover of osteoporotic patients before and during treatment vary in different appendicular/axial and cortical/trabecular compartments. Finally, a single marker might be valuable in some diseases and not in others (such as serum BGP in Paget's disease of bone). Despite these difficulties, significant advances have been made in the last few years in the bone marker field. In the future, the development of a battery of several bone-specific markers that indicate various aspects of the complex mechanisms of bone formation, resorption, and mineralization is likely to provide new tools for the diagnosis and management of bone diseases.     

骨质疏松患者部分骨代谢指标测定的临床意义

目的 研究血清Ⅰ型胶原氨基末端肽(NTx)和Ⅰ型胶原羧基末端肽(CTx)等指标的检测对于中老年骨质疏松患者的意义. 方法 对165例中老年患者行双能X线骨密度检查,同时检测其血清NTx、CTx、骨型碱性磷酸酶(BAP)、Ⅰ型前胶原氨基末端肽(PINP)、骨钙素(BGP)、白细胞介素6(IL-6)及肿瘤坏死因子α(TNFα),100例体检人员作为对照. 结果 骨质疏松患者BGP和IL-6明显高于对照组(P＜0.05)而TNF-α则与对照组无显著差异.骨质疏松组血清BAP和PINP显著低于对照组和骨量减少组(P＜0.05),NTx及CTx则显著高于对照组和骨量减少组(P＜0.05);而骨量减少组NTx、CTx明也显高于对照组(P＜0.05). 结论 血清NTx和CTx可作为骨吸收的特异性指标,对骨质疏松患者的诊断和疗效评估均具有重要意义.     

Metabolic bone disease in primary biliary cirrhosis at presentation

Metabolic bone disease, particularly osteoporosis, is a complication of advanced primary biliary cirrhosis, but the extent of the problem is unclear. We present 33 patients who were investigated for bone disease at the time of diagnosis of their liver disease and who had received no prior treatment likely to influence their bones. Iliac crest bone biopsy showed no patient with osteoporosis, and mild osteomalacic changes in 1 patient. Slight elevations in appositional rate, osteoid volume, and resorption surface were compatible with a state of high bone turnover. Photon absorptiometry revealed a low forearm bone mineral content in 3 of 25 patients, calcium absorption was below normal in 14 of 24 patients, and there was evidence of fat malabsorption in 11 of 25 patients. Five patients also had low serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. Thus, little evidence of significant metabolic bone disease was found in this group by these methods, but abnormalities were seen, such as poor calcium absorption, that may predispose to its later development.     

Metabolic bone disease and bone quality

On the progress of study concerned with pathology of metabolic bone disease such as osteoporosis, it has been known that most of bone strength can be explained by bone volume. As bone volume can be determine by bone mineral density (BMD) with dual-energy X-ray absorptiometry (DXA), it has been widely used for diagnosis of osteoporosis or efficacy of treatment. However, with the advance of bone morphometry, decrease of bone strength or existence of insufficiency fracture is influenced by not only loss of BMD but also deterioration of bone quality especially bone microstructure. In this chapter, we will give an outline of change of bone quality in metabolic bone disease.     

Noninvasive techniques for assessing skeletal changes in inflammatory arthritis: bone biomarkers

PURPOSE OF REVIEW: Inflammatory arthritis diseases including rheumatoid arthritis (RA) are characterized by systemic bone loss and increased risk of osteoporosis and local joint bone erosion. Clinical and biologic parameters of disease activity and inflammation and radiologic findings are poorly sensitive for assessing skeletal changes. More specific biologic markers reflecting systemic quantitative and dynamic changes of bone turnover represent promising adjunctive tools. RECENT FINDINGS: More specific and well-characterized biochemical assays especially for type I collagen-based bone resorption markers have been recently developed. Prospective studies indicate that increased levels of some biochemical markers of bone resorption are associated with a more rapid progression of joint destruction in patients with early RA, independently of disease activity and inflammation parameters. This increased bone resorption associated with local bone erosion is likely to be mediated by changes in the balance of the OPG/RANK-L system (receptor activator of nuclear factor kappaB-ligand and osteoprotegerin) as suggested by the significant association of this ratio in serum and long-term radiologic progression. Besides their well-documented response to bisphosphonate treatment used as adjuvant therapy in patients with glucocorticoid-induced osteoporosis, bone markers may be useful to assess potential beneficial effects of new disease-modifying antirheumatic drugs on systemic bone loss and on progression of joint damage. SUMMARY: Recent evidence suggests that biochemical markers of bone resorption may be useful to predict progression of joint damage in RA. Together with new biochemical markers of cartilage turnover, they are likely to play a major role in assessing effects of treatment on joint damage. Their value in assessing systemic and local bone abnormalities should be explored in other inflammatory arthritis diseases such as ankylosing spondylarthritis.     

Clinical value of the measurement of bone remodelling markers in primary hyperparathyroidism

This study was performed in order to evaluate the clinical usefulness of the measurement of total serum alkaline phosphatase activity (AP), serum osteocalcin (BGP) and urinary hydroxyproline (OHPr) in assessing bone remodelling in primary hyperparathyroidism. Thirty-two patients with primary hyperparathyroidism were included in the study. No statistically significant differences were observed between the mean values of Z-scores obtained for each marker. Furthermore, an inverse correlation was found between percentage of bone mineral content at the distal radius and both BGP (r = -0.57; p less than 0.05) and AP (r = -0.49; p less than 0.05). The results obtained demonstrate that, contrary to other metabolic bone diseases (e.g. Paget's disease of bone), all three markers examined may be used in clinical practice to evaluate the entity of skeletal turnover in primary hyperparathyroidism.     

Biochemical markers of bone turnover

Recent developments in biomarkers in many fields of medicine have expanded the array of tools health care providers can use today for disease management. Essentially, biomarkers assist clinicians today in four main ways: screening, diagnosis, assessment of severity or risk, and monitoring of, or deciding on, treatment (1). Surrogate markers known as biochemical markers of bone turnover have been used for decades in the management of diseases of the skeleton. Historically, bone biomarkers required 24-h urine collections, lacked accuracy and reliability, and were cumbersome to use. More recently, they have been shown to be effective surrogates for assessments of treatment response and efficacy in osteoporosis. Although used extensively in research and development and in metabolic bone disease clinics, they are still infrequently used tools for osteoporosis management in clinical practice. Today they have been incorporated into the assessment and management of a variety of diseases of bone including complex metabolic bone disorders, osteoporosis, Paget's disease of bone, and skeletal metastases. Developments in the last decade have greatly enhanced their performance characteristics. A variety of tests and assays are now widely available and significantly more accurate and reliable measures of bone metabolism have been developed. However, techniques and assays vary substantially. In order to maximize their clinical usefulness, an understanding of their strengths and weaknesses, factors that influence them, and knowledge of their unique intricacies is crucial for the ordering physician during the decision-making process. As the field continues to develop, more specific markers and standardization of measurement techniques will enhance reliability, which facilitate their use in practice. The aim of this review is to increase knowledge of the variety of tests available, their potential and limitations, and current best practice for practitioners and researchers, focusing primarily on their use in the management of osteoporosis.     

Effect of exercise as a therapy for osteoporosis on bone metabolism

Exercise affects bone mass most effectively in adolescence depending its property. For postmenopausal women, resistance or high-impact loading training are suggested as preventative exercise against bone loss at the femoral neck. Physical exercise affects the balance of bone turnover. However, there is the discrepancy between studies on bone metabolic markers at present. In my opinion, the proper evaluation of exercise for osteoporosis should focus on prevention of falls.     

Urinary pyridinium crosslinks of collagen Specific markers of bone resorption in metabolic bone disease.

The hydroxypyridinium compounds pyridinoline and deoxypyridinoline are specific constituents of mature skeletal collagens. They are released into the circulation and excreted in the urine. Their measurement in urine is a sensitive index of the extent of ongoing bone resorption. Currently, quantification of collagen crosslinks in urine is achieved by chromatographic techniques, but more convenient immunoassays will make these measurements more widely available in the near future. Clinical applications of hydroxypyridinium markers include numerous metabolic bone disorders such as osteoporosis, primary hyperparathyroidism, Paget's disease of bone, and metastatic bone disease. Urinary pyridinium crosslinks of collagen also show great promise as markers of therapeutic efficacy in bone disorders associated with accelerated bone resorption.     

Use of Bone Turnover Markers in Osteoporosis

Bone metabolism can be assessed by measuring bone turnover markers in serum or urine. Bone turnover markers are substances released from bone during bone turnover. They can be skeletal tissue proteins, collagen fragments, peptides, or enzymes released from bone cells. Bone turnover markers are extensively used in research applications but also as tools for the management of skeletal disorders in clinical practice. Osteoporosis-related applications may include assessment of response to, or deciding on osteoporosis therapy; identification of individuals with increased bone loss, and prediction of risk for fragility fractures. Advancements in the development of assays to measure bone markers has made the measurements available also for clinical practice. The possibility to use them in various aspects of clinical practice has been tested in the recent years and given promising results. Monitoring the efficacy of bone-active drugs is currently the most promising application for bone turnover markers. Some markers, particularly resorption markers may also be useful in identifying individuals who are at high risk for bone loss and future fracture. In this article we discuss some potential applications of currently available bone turnover markers in postmenopausal osteoporosis.     

Bone-derived proteins.

The diagnosis and treatment of metabolic bone disease has been limited by a lack of understanding of bone cell physiology and of suitable markers for various bone cell functions in different diseases. The identification of noncollagenous proteins and their measurement in serum has added to our knowledge. At this stage, of all the bone-derived proteins, bone Gla protein (BGP) is apparently the most useful, but it is best used in conjunction with other tests. The diagnostic usefulness of other noncollagenous proteins, procollagen, and local factors still remains to be documented.     

骨钙素放射免疫测定方法及其临床意义

作者在国内首先制备了骨钙素(BGP)的抗血清,建立了BGP放射免疫测定方法。该抗血清特异性和灵敏度高,其最小检出量IC_(50)为2.5μg/L,批内差异<2.5％,批间差异<10.0％。应用本法测定了338例正常人和100例骨质疏松、糖尿病、卵巢切除、骨肿瘤、慢性肾功能衰竭、佝偻病和甲状旁腺功能亢进症患者血清BGP水平。骨质疏松BGP水平大多数下降,甲状旁腺功能亢进症、骨肿瘤者则明显升高,因此,血清BGP放免测定是骨病、代谢性骨病诊断和研究的一个重要检测手段。     

Non-invasive assessment of bone density in primary biliary cirrhosis.

BACKGROUND/AIMS: Low bone mass is an important complication of primary biliary cirrhosis (PBC), resulting in an increased risk of fractures and reduced mobility. In the present study, we sought to determine the frequency of low bone mass in PBC, and its relationship to disease severity and non-invasive markers of bone turnover. METHODS: In 36 women with PBC, bone mineral density of the lumbar spine and hip was assessed by dual emission X-ray absorptiometry. Serum and urinary markers of bone turnover were compared with those from age- and sex-matched controls. RESULTS: Spinal osteopenia (T score, -1.5 to -2.5) was present in 15 of the 36 patients (42%), while six others (16%) had established osteoporosis (T < -2.5). Osteopenia of the femoral neck was found in 17 patients (47%), and osteoporosis in five (14%). The severity of liver disease, as determined by Mayo Clinic R score and histological stage, correlated negatively with both regional bone mineral density and total bone mineral content expressed as a ratio to lean body mass. There was a strong positive correlation between serum levels of the procollagen degradation peptides, PICP and PIIINP (r = 0.65, P < 0.001), and both peptides correlated significantly (P < 0.001) with histological stage and Mayo Clinic R score. Fasting urinary pyridinoline and deoxypyridinoline to creatinine ratios were also significantly raised. CONCLUSIONS: Low bone mass in PBC correlates positively with disease severity, and is associated with a net increase in bone resorption, as assessed by urinary collagen cross-link excretion. These markers of bone turnover may be of value in controlled clinical trials aimed at improving bone mass in PBC.     

Change in biomarkers of osteoporosis in rheumatoid arthritis patients treated with infliximab

A study was made to evaluate bone turn-over in rheumatoid arthritis (RA) patients treated with infliximab. Twenty-two patients with established RA were included. In all patients, biochemical markers of osteoporosis: osteocalcin (BGP), alkaline phosphatase (bone isoenzyme), deoxypyridinoline (Dpd), acute phase proteins (CRP, AGP, ACT, AGP-RC), and interleukin 6 (IL-6) were determined before treatment, at week 30, and at week 46. Two markers (BGP, Dpd) were significantly decreased at both weeks 30 and 46. Moreover, a fall in serum levels of acute phase proteins and IL-6 was seen. The results suggest that anti-TNF treatment with infliximab not only decreases activity of inflammation but also may slow down bone turn-over. Further research is needed to assess its potential in reducing risk of osteoporosis in RA.     

Normal bone turnover in transient hyperphosphatasemia

Transient hyperphosphatasemia of infancy and early childhood (THI) is characterized by a temporary isolated elevation of serum alkaline phosphatase activity (ALP), predominantly its bone or liver isoform, in either sick or healthy children under 5 years of age. Return to normal ALP levels usually occurs within four months. Spontaneous rise of ALP might concern the physician, especially when treating seriously ill children. However, THI is considered a benign biochemical disorder with no clinical consequences. Some existing reports support the hypothesis that THI is a result of increased bone turnover. We present evidence of normal bone turnover in two children with THI. In a one-year-old girl and a boy of the same age, high ALP levels (31 and 109 μkat/L, respectively) were accidentally detected. The children had no signs of metabolic bone disease or of liver disease. The high ALP levels returned to normal in two months, thus fulfilling the diagnosis of THI. In both patients, serum parathyroid hormone and bone turnover markers, serum CrossLaps, and serum osteocalcin were neither elevated, nor did these markers follow the ALP dynamics, thus reflecting normal bone turnover in THI. Children with THI should be spared from extensive investigations and unnecessary vitamin D treatment.     

The role of markers of bone remodeling in multiple myeloma

Osteolytic bone disease is a frequent complication of multiple myeloma, resulting in skeletal complications that are a significant cause of morbidity and mortality. A characteristic feature of myeloma bone disease is that the lesions rarely heal and bone scans are often negative in myeloma patients who have extensive lytic lesions, offering very little in the follow-up of bone disease. X-rays are also of limited value in monitoring bone destruction during anti-myeloma or anti-resorptive treatment. Biochemical markers of bone turnover, such as N- and C-terminal cross-linking telopeptide of type I collagen (NTX, CTX/ICTP, respectively), and newer ones such as the tartrate resistant acid phosphatase isoform 5b, provide information on bone dynamics that in turn may reflect disease activity in bone. Several studies have shown bone markers to be elevated in myeloma patients and reflect the extent of bone disease, while in some of them bone resorption markers correlate with survival. These markers may also be helpful in identifying those patients likely to respond to bisphosphonate treatment, and monitoring the effectiveness of bisphosphonate therapy in the management of myeloma bone disease. This review attempts to summarize the existing data for the role of markers of bone remodeling in assessing the extent of bone destruction in myeloma and monitoring bone turnover during specific anti-myeloma treatment. We also discuss some novel markers that may be of particular interest in the near future.     

Effects of growth hormone (GH) on plasma bone Gla protein in GH-deficient adults

Both deficiency and excess of GH are related to disturbances in calcium metabolism. Bone Gla protein (BGP) is the only specific marker of bone turnover identified in peripheral blood. We, therefore, determined plasma BGP in 21 adult GH-deficient patients treated with biosynthetic human GH in a double blind cross-over study. We also examined 9 patients with acromegaly before and after surgery. The GH-deficient patients had normal initial plasma BGP concentrations, whereas the acromegalic patients had highly significantly increased concentrations (P less than 0.001). During treatment with human GH, plasma BGP (and other nonspecific biochemical markers of bone turnover) increased significantly (P less than 0.001). During placebo treatment plasma BGP showed baseline values. In the acromegalic patients a significant decrease in plasma BGP concentrations was seen 1 week after surgery. The present study suggests that plasma BGP is a useful biochemical marker of the effect of treatment of both GH deficiency and GH excess/disorders.     

Biochemical markers to survey bone turnover

Molecular markers of bone turnover have gained increasing relevance in the evaluation of patients with metabolic bone diseases. Their clinical applications include the assessment of future osteoporotic fracture risk, complementation of bone density measurements, diagnosis of certain metabolic osteopathies, therapeutic decision making, and monitoring of therapeutic efficacy and patient compliance. One should be aware, however, that the results from large epidemiologic or clinical trials are sometimes difficult to translate into the everyday clinical situation. The individual patient often has more than one disease that might affect either bone turnover or the handling of the parameters mentioned (or both). Analytic and biologic variability of bone markers can be significant and also needs to be considered when using these indices. In the scientific setting, conventional and new markers of bone turnover can help to elucidate formerly unknown mechanisms and pathways. Because the development of ever more specific and sensitive markers of bone metabolism is progressing rapidly, we are likely to witness new insights into the pathophysiology of bone diseases in the near future.     

Osteoblast expression of an engineered Gs-coupled receptor dramatically increases bone mass

Osteoblasts are essential for maintaining bone mass, avoiding osteoporosis, and repairing injured bone. Activation of osteoblast G protein-coupled receptors (GPCRs), such as the parathyroid hormone receptor, can increase bone mass; however, the anabolic mechanisms are poorly understood. Here we use "Rs1," an engineered GPCR with constitutive G(s) signaling, to evaluate the temporal and skeletal effects of G(s) signaling in murine osteoblasts. In vivo, Rs1 expression induces a dramatic anabolic skeletal response, with midfemur girth increasing 1,200% and femur mass increasing 380% in 9-week-old mice. Bone volume, cellularity, areal bone mineral density, osteoblast gene markers, and serum bone turnover markers were also elevated. No such phenotype developed when Rs1 was expressed after the first 4 weeks of postnatal life, indicating an exquisite temporal sensitivity of osteoblasts to Rs1 expression. This pathway may represent an important determinant of bone mass and may open future avenues for enhancing bone repair and treating metabolic bone diseases.     

糖皮质激素对狼疮性肾炎患者骨代谢影响的相关性研究

目的　观察狼疮性肾炎患者长期强的松治疗后骨矿含量及骨代谢生化指标的变化。方法　研究对象包括对照组 (A组 ) 2 0例 ,强的松治疗前组 (B组 ) 2 5例 ,强的松治疗后组 (C组 ) 31例 ,用双能X线骨密度仪测定相关部位的骨密度 ,同时测定血钙、磷、碱性磷酸酶、甲状旁腺激素(PTH M )、骨钙素 (BGP)、2 4小时尿钙及尿肌酐。结果　 ( 1)C组病人各部位骨密度较A组和B组明显下降 (P <0 .0 1、P <0 .0 5 ) ;( 2 )C组病人血PTH、尿钙 /肌肝 (Ca/Cr)分别高于A组和B组 (P <0 .0 1) ,血BGP分别低于A组和B组 (P <0 .0 1) ;( 3)C组病人中骨量减少发生率随强的松应用时间的延长而增加。多元逐步法回归分析结果显示 ,腰L2～L4、大转子、ward’s三角区的骨密度仅与强的松应用时间相关 ,与病情活动、CTX冲击、血总蛋白、尿Ca/Cr无关。结论　狼疮性肾炎患者长期强的松治疗后可引起骨量减少或骨质疏松 ,随时间的延长发生率渐增 ,血BGP和PTH是反映继发性骨量减少的敏感性生化指标 ,较骨形态学改变早。