Value Of Bone Turnover Markers Research Articles

Evidence-based guidelines for the use of biochemical markers of bone turnover in the selection and monitoring of bisphosphonate treatment in osteoporosis: a consensus document of the Belgian Bone Club

Objectives:To review the clinical value of bone turnover markers (BTM), to initiate and/or monitor anti-resorptive treatment for osteoporosis compared with bone mineral density (BMD) and to evaluate suitable BTM and changes in BTM levels for significance of treatment efficiency.Methodology:Consensus meeting generating guidelines for clinical practice after review and discussion of the randomised controlled trials or meta-analyses on the management of osteoporosis in postmenopausal women.Results:Although the correlation between BMD and BTM is statistically significant, BTM cannot be used as predictive markers of BMD in an individual patient. Both are independent predictors of fracture risk, but BTM can only be used as an additional risk factor in the decision to treat. Current data do not support the use of BTM to select the optimal treatment. However, they can be used to monitor treatment efficiency before BMD changes can be evaluated. Early changes in BTM can be used to measure the clinical efficacy of an anti-resorptive treatment and to reinforce patient compliance.Discussion:Determining a threshold of BTM reflecting an optimal long-term effect is not obvious. The objective should be the return to the premenopausal range and/or a decrease at least equal to the least significant change (30%). Preanalytical and analytical variability of BTM is an important limitation to their use. Serum C-terminal cross-linked telopeptide of type I collagen (CTX), procollagen 1 N terminal extension peptide and bone specific alkaline phosphatase (BSALP) appear to be the most suitable.Conclusion:Consensus regarding the use of BTM resulted in guidelines for clinical practice. BMD determines the indication to treat osteoporosis. BTM reflect treatment efficiency and can be used to motivate patients to persist with their medication.

Determinants of Bone Turnover Markers in Healthy Premenopausal Women

Bone turnover markers (BTMs) are widely used for the management of osteoporosis, and the premenopausal reference range is the target value for the treatment of postmenopausal osteoporosis with antiresorbing agents. Three serum BTMs (serum C-telopeptide of type I collagen [CTX], osteocalcin [OC], and N-terminal propeptide of type I procollagen [P1NP]), serum calcium, creatinine, phosphate, magnesium, and follicle-stimulating hormone (FSH) were measured in 638 healthy premenopausal women aged 20-50 years. In 83 women on the contraceptive pill (CP), the levels of the three BTMs adjusted for all confounding factors were 14-26% lower (P < 0.005) than in non-CP users. In 18 women considered perimenopausal for serum FSH levels >30 IU/mL despite having regular menses, BTM levels were significantly higher than in age-matched women. This group of subjects and the women on the CP were excluded from further analysis. The three BTMs significantly decreased with advancing age and were negatively and independently correlated with body mass index (P < 0.001) and serum phosphate. In conclusion, we confirm that CP use is associated with significantly lower BTM values. An increase in BTM concentrations can be observed in perimenopausal women, i.e., women with normal menses but FSH levels >30 IU/mL. BTMs decrease substantially with advancing age, and this appears to be associated with changes in body weight and serum phosphate. New normative ranges for serum OC, CTX, and P1NP were identified; and our findings in general impose a redefinition of the criteria for establishing the normal ranges for BTMs.

The Effects of Recombinant TSH on Bone Turnover Markers and Serum Osteoprotegerin and RANKL Levels

Recently it was found that thyrotropin (TSH) receptors are present both in osteoclast and osteoblast and that TSH can modulate bone remodeling independent of thyroid hormones. The aim of this study was, firstly, to evaluate the effects of acute administration of TSH on bone remodeling markers both in men and in women and, secondly, to evaluate if these effects are mediated by variations in serum osteoprotegerin (OPG) and receptor activator of nuclear factor-KB ligand (RANKL). We studied 30 thyroidectomized patients (10 premenopausal and 10 postmenopausal women, 10 men) affected by thyroid carcinoma on l-thyroxine therapy. Eighty age- and sex-matched subjects were used as controls. A blood sample was drawn from each patient at baseline and 3 and 5 days after recombinant human TSH (rhTSH) administration, in preparation for (131)I whole body scan, to assess serum bone markers and serum OPG and RANKL levels. At baseline, postmenopausal women and men had significantly higher values of bone turnover markers and serum OPG compared to control subjects. In all thyroidectomized patients serum RANKL was lower than in controls. After rhTSH administration, serum N-terminal propeptide of type-I procollagen (PINP), a marker of bone formation, increased significantly in postmenopausal women, while serum RANKL significantly increased after 3 days in postmenopausal patients and men returning to baseline values at day 5. Serum OPG levels did not change significantly. The low serum TSH observed in thyroidectomized patients on l-thyroxine therapy is associated with an increase of bone turnover in postmenopausal women and men that is associated with an increase of OPG and a decrease of serum RANKL levels. The acute TSH administration results in an increase of PINP, an index of osteoblastic activity, associated with an increase of serum RANKL. The lack of this response in premenopausal women suggests an influence of estrogen status on bone reactivity to TSH.

Association between Baseline Values of Bone Turnover Markers and Bone Mineral Density and Their Response to Raloxifene Treatment in Japanese Postmenopausal Women with Osteoporosis

It has been well established that raloxifene improves bone turnover, increases bone mineral density (BMD), and reduces the risk of fractures. However, it remains obscure which patients are more likely to respond to treatment with raloxifene in patients with postmenopausal osteoporosis. The purpose of this study was to investigate associations between baseline values of BMD and bone turnover markers (BTMs) and changes of those values after 1-year treatment with raloxifene. Sixty-eight Japanese postmenopausal women with untreated osteoporosis were selected for this study, among whom 58 patients (mean age 70.40 +/- 9.2 years) completed this study. Lower baseline values of BMD at the lumbar spine, the femoral neck, and the distal radius were significantly correlated with greater increases of BMD at those corresponding sites after 1-year treatment with raloxifene. On the other hand, higher baseline values of bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx) were significantly correlated with greater reductions of BAP and NTx, respectively, after 1-year treatment with raloxifene. Although longer and larger studies with fracture endpoints are needed, our findings suggest that baseline values of BMD and BTMs can be used to predict subsequent skeletal response to raloxifene therapy in Japanese postmenopausal women with osteoporosis.

Biochemical markers of bone turnover may predict progression to osteoporosis in osteopenic women: the JPOS Cohort Study

We evaluated the value of bone turnover markers, including osteocalcin (OC) and bone-specific alkaline phosphatase in the serum, and type I collagen C-terminal telopeptide and free and total deoxypyridinoline (tDPD) in the urine of fasting patients, in an attempt to predict which osteopenic women [i.e., those with > or = 70% and <80% of the young adult mean (YAM) bone mineral density (BMD)] would progress to the osteoporosis level of BMD (<70% of YAM). Of the 1153 women without defects in bone metabolism who completed the 3-year follow-up, 147, 161, and 144 women were judged by dual X-ray absorptiometry to be osteopenic from baseline measurements of BMD in the spine (LS), hip (TH), and distal radius (DR), respectively. Progression to the osteoporotic level of BMD was noted for 23.8%, 16.1%, and 12.5% of the subjects with osteopenia of the LS, TH, and DR, respectively, while most of them were in the lower half of the osteopenic level of BMD at baseline. Among the subjects in this lower-level osteopenia category, a significantly higher OC level was observed for the subjects with osteoporosis progression at the LS than those without. The subjects with progression at DR showed a significantly higher tDPD level. The association between OC level and disease progression remained unchanged after adjustments for age, body size, and BMD at baseline. The subjects in the upper one-third category of OC levels showed a 6.4 fold greater risk of progression at LS (95% confidence interval, 1.8-23.1) compared with those in the lower one-third category after the adjustments for age, body size, and BMD at baseline. Receiver operating characteristics analysis showed that the area under the curve was 0.716 for the OC level in the prediction of osteoporosis progression at LS. The levels of OC and tDPD may be useful in predicting which osteopenic women will progress to osteoporosis.

Biochemical markers of bone turnover in patients with localized and metastasized prostate cancer

To evaluate and compare the value of several markers of bone turnover in different stages of prostate cancer, as bone metastases are a common feature in this disease, and for assessing bone metastases both bone formation and bone resorption markers are diagnostic. The prospective study included 219 men, i.e. 129 undergoing radical retropubic prostatectomy (RRP) and 25 with bone metastases due to prostate cancer, and 65 with benign urological disorders who served as controls. Before any treatment the concentrations of alkaline phosphatase (ALP), osteocalcin, serum C-terminal telopeptide of type I collagen (S-CTX) and tartrate-resistant acid phosphatase type 5b (TRACP5b) were determined. Men undergoing RRP were divided into those with lymph node-negative, localized (pT3, 101) and lymph node-positive (28) disease, after histological examination. The controls had the lowest marker levels while patients with bone metastases due to prostate cancer had the highest levels, with significance for ALP, osteocalcin and TRACP5b. Patients with lymph node-positive cancer had significantly high serum levels of TRACP5b and ALP but not for osteocalcin and S-CTX. Bone turnover markers represent a new diagnostic tool in prostate cancer; the present data show that both bone resorption and bone formation are crucial for detecting bone metastases in prostate cancer. The value of bone turnover markers in high-risk patients should be evaluated in a longitudinal study.

High Bone Turnover Markers Predict Poor Outcome in Patients With Bone Metastasis

Bone is a frequent site for metastasis in patients with solid tumors such as breast cancer, prostate cancer, and lung cancer. It may be the first, or even the only, site for metastases in these patients. It is estimated that more than 350,000 patients a year in the United States die with bone metastasis. 1 Bone metastasis is responsible for some of the most devastating complications of malignancy, including pathologic bone fractures, spinal cord compression syndromes, excruciating bone pain, and hypercalcemia. These skeletal metastases can require surgery or radiotherapy to bone, in addition to aggressive analgesic therapy. Furthermore, bone metastases have a major impact on the quality of life and even the survival of these patients. This is clearly illustrated by the authors of the current article, who have reported on patients from the placebo arms of their trials. 2 They found that 143 of 454 patients with bone metastasis from prostate or other solid tumors on the placebo arms of thesetrialsexperiencedpathologicfracturesthroughoutthe 21 months of study. 2 Two hundred forty of these 454 patients required radiotherapy to their bone lesions. The median survival for prostate cancer patients on the placebo arm of the trial was 16.8 months and was only 5.6 months for patients with bone metastasis from other solid tumors. These results demonstrate the extreme toll bone metastasis takes on these patients. Inthisissue,Colemanetalexaminedtheabilityofbone turnover markers to predict negative clinical outcomes in a cohort of almost 2,000 patients with baseline bone metastasisfromprostatecancer,breastcancer,myeloma,orother tumors, who were treated with bisphosphonates. 3 Previous reports of the predictive value of bone turnover markers in these types of patients have been conflicting. However, most of the other studies included much smaller numbers of patients. The overwhelming majority of the patients in the current trial received zoledronate, an extremely potent bisphosphonate. Even patients receiving this very potent bisphosphonate still had progression of their bone disease, experiencing one skeletal-related event per year during the 17 months that they were followed up on. These investigators report on two markers of bone turnover, urinary Ntx (N-telopeptide of collagen type 1) and serum bone-specific alkaline phosphatase (BAP). Ntx is a marker of bone degradation by osteoclasts, and BAP is a marker for bone formation. These markers were chosen because patients with solid tumors and bone metastasis have both increased bone destruction and bone formation. In contrast, patients with myeloma have suppressed bone formation. They found that Ntx levels were better predictors of outcome for these patients than BAP. Patients with hormone refractory prostate cancer had the highest Ntx levels, most likely reflecting the combined effects of increased bone turnover from their metastasis, and bone loss due to low testosterone levels. Furthermore, high levels of Ntx at study entry predicted a poor outcome, and the most recent Ntxlevelwasanevenbetterpredictorforoutcome.Patients with high Ntx levels in their urine had a four- to six-fold increased risk of death and a two-fold increase in the risk of future skeletal events compared with patients with low Ntx levels. Interestingly, once patients were on therapy, Ntx levels did not correlate with tumor burden markers suchasprostate-specificantigeninpatientswithprostate cancer, though it is likely that high Ntx levels reflected increased tumor progression in patients compared with those with low Ntx levels. Furthermore, although Ntx levels reflect bone events, it is reasonable to assume those visceral metastases are also progressing in patients with high Ntx levels. Importantly, high levels of bone resorption markers seem to identify ag roup of patients who are not responding to their current therapy and may need additional antiresorptive therapy as well as changes in their chemotherapy, or may be candidates for trials of novel agents.

Early Changes in Biochemical Markers of Bone Turnover Predict Bone Mineral Density Response to Antiresorptive Therapy in Korean Postmenopausal Women with Osteoporosis

Biochemical markers of bone turnover have been suggested to be useful in monitoring the efficacy of antiresorptive therapy. In this study, we investigated the predictive value of bone turnover markers to determine short-term response in bone mineral density (BMD) and to identify nonresponders in 138 postmenopausal women (mean age 58 years) with osteoporosis given with either hormone thearpy (HT) or alendronate. Urinary type I collagen N-telopeptide (NTx) and serum osteocalcin (OC) at baseline, 3, and 6 months after treatment as well as spine and femoral neck BMD at baseline and 12 months were measured. Significant decreases in both NTx and OC were evident in women on treatment with antiresorptive agents as early as 3 months (p<0.01). Percent change of NTx at 3 months correlated with the percent change of spinal BMD at 12 months of treatment. When bone turnover markers were stratified by tertiles, the average rate of lumbar spine BMD gain increased significantly with increasing tertiles of baseline value (p<0.05) and percent change (p<0.05) of urinary NTx at 3 month of treatment. In terms of BMD response, urinary NTx at 3 months decreased significantly more in BMD responders group than in nonresponders group. Logistic regression analysis demonstrated that percent change of NTx at 3 months is an independent predictor to identify BMD nonresponders, defined as those whose BMD gain remained within the precision error range of dual energy X-ray absorptiometer (DXA). We conclude that biochemical markers of bone turnover, especially percent change in urinary NTx levels, can be used to determine BMD response to antiresorptive therapy in Korean postmenopausal women with osteoporosis.

Pharmacological therapy of osteoporosis

The aim of pharmacological therapy for osteoporosis is to prevent osteoporotic fractures. Low bone mineral density, previous fractures, high values of bone turnover markers, and age are the independent risk factors for osteoporotic vertebral fractures. These clinical parameters should be utilized to start and choose the drugs for osteoporosis.

A study of bone turnover markers in prepubertal children with phenylketonuria.

To investigate the effect of low-phenylalanine diets onbone mineralisation status, we compared biochemicalbone formation and resorption markers in prepubertalchildren with phenylketonuria with those of age-mat-ched healthy controls.Dietary phenylalanine (Phe) restriction is the onlyknown strategy of preventing neurological impairmentand mental retardation in patients with phenylketonuria(PKU). In general, most phenylketonuric patients on alow-Phe diet can achieve normal growth and intellectualdevelopment. It is suggested, however, that this form ofdiet may influence bone metabolism, especially inchildhood and adolescence when growth and boneturnover are at their most intensive. Some authors havedescribed decreased bone mineral density and osteope-nia in patients suffering from PKU [1, 2, 3,5].Measurements of bone mineral density (BMD) reflectonly bone mineral status but not the dynamics of boneturnover. Non-invasive biochemical markers whichshow global skeletal activity have lately been developedand validated for the assessment of bone formation andbone resorption processes. Among them, osteocalcin(OC), bone alkaline phosphatase (BALP) and collagentype 1 cross-linked C-telopeptide (CTX) are consideredto be clinically useful. Recently, the novel cytokineosteoprotegerin (OPG), belonging to the tumournecrosis factor receptor family has been established asan endogenous inhibitor of osteoclastogenesis andresorption processes.Our study population consisted of 37 childrenwith PKU under surveillance at the Department ofPaediatrics at the Institute of Mother and Child inWarsaw. Patients were divided into two groups. Thosein group A (n =12; median age 4.5 years; range 3–10years) followed their therapeutic diet strictly and hadmean serum Phe concentrations close to the referencerange (189.4±64.2 lmol/l) and those in group B(n =25; median age 6.0 years; range 3–10 years) did notadhere to their diet and had increased Phe concentra-tions (649.2±140.6 lmol/l). The mean serum Pheconcentration was calculated for the last 3 years of thelife of each patient. Children with PKU were fed with anaminoacid mixture PAM, Milupa-PKU 2 or Phenyl-free. These patients have normal values for calcium andphosphate. Healthy children sent to our laboratory forroutine analytical control (n =27; median age 5.9 years;range 4–9 years) were the reference group. The wholegroup of investigated children was ethnically homoge-nous. Venous blood samples were collected after anovernight fast, centrifuged and serum levels of Phe,calcium and phosphate were determined. Remainingserum samples were frozen and collected for measure-ment of BALP, OC, CTX and OPG. Phe was assayedfluorometrically according to McCaman and Robbins;calcium and phosphate by standard procedures with aCobas Integra analyser (Roche, Switzerland). Serum OCand CTX were measured by immuno-enzymatic ELISAassays (Osteometer, Denmark). For determination ofBALP, the Alkphase-B kit from Metra Biosystems(USA) and for OPG, the kit from Biomedica (Austria)were used. The differences were evaluated by ANOVAwith Bonferroni correction. The significance was set atP <0.05.We observed lower levels of bone formation andbone resorption markers in group A than in group B,but these differences are not statistically significant(Table 1). However, OC, CTX and OPG concentrationswere significantly lower in both groups of PKU childrenin comparison to the healthy age-matched controls.There are only a few papers presenting values of boneturnover markers in PKU subjects. Perez-Duenas et al.[6] observed the same levels of OC and BALP in a groupof younger patients and significantly lower serum BALP