Loading dose ibandronate versus standard oral ibandronate in patients with bone metastases from breast cancer.

INTRODUCTION: In this phase II trial, the efficacy and safety of loading-dose I.V. ibandronate in patients with breast cancer with bone metastases were evaluated. PATIENTS AND METHODS: Thirty-four patients were randomized to receive a loading dose of 12 mg I.V. ibandronate on day 1 then oral ibandronate 50 mg daily (arm A), or standard oral therapy of 50 mg ibandronate daily from day 1 (arm B). The primary end point was percentage change in serum C-terminal crosslinking telopeptide of type I collagen (S-CTX) from baseline by day 5 of study. Secondary/exploratory end points included percentage change in other bone turnover markers (N-terminal cross-linking telopeptides of type I collagen [NTX], procollagen type I N propeptide, bone alkaline phosphatase) and change in average bone pain score. RESULTS: There was a significantly greater reduction in S-CTX at day 5 in arm A compared with arm B (median difference, 15.82%; P = .005). There was also a significantly greater reduction in urine NTX/creatinine at day 5 (P = .009) and at the end of weeks 1 to 8 (averaged; P = .006). Average bone pain score was lower in arm A at the end of 8 weeks (P = .012). There were no additional adverse events after administration of 12 mg I.V. loading dose of ibandronate. CONCLUSION: A 12-mg dose of I.V. ibandronate rapidly reduced markers of bone turnover and can be administered without additional toxicity.

Effects of Src kinase inhibition by saracatinib (AZD0530) on bone turnover in advanced malignancy in a Phase I study.

Saracatinib (AZD0530) is an orally active once-daily Src kinase inhibitor which modulates key signaling pathways in cancer cells. In a Phase I study in patients with advanced solid malignancies resistant to standard treatment we assessed the effect of saracatinib on bone turnover. Fifty-one patients were randomized into three parallel groups to receive saracatinib 50, 125 or 175 mg/day. After a single dose followed by a 7-day washout, patients received once-daily doses for 21 days. Bone turnover markers were measured in serum and urine samples collected before dosing on days 1, 2, 3, 17 and 28. Samples were available at baseline and more than one other time point for 44 patients. Bone resorption markers were significantly decreased by saracatinib. Serum cross-linked C-terminal telopeptide of type I collagen (sCTX) changed in the 50, 125 and 175 mg/day groups by -36% (95% CI -58, -4), -64% (95% CI -75, -48) and -75% (95% CI -83, -61), respectively, at day 28. Urinary cross-linked N-terminal telopeptide of type I collagen/creatinine ratio (uNTX/Cr) changed in the 50, 125 and 175 mg/day groups by; -13% (95% CI -33, 13), -48% (95% CI -59, -34) and -50% (95% CI -62, -35), respectively, at day 28. The significant decreases in bone resorption markers indicate that suppression of Src kinase inhibits osteoclast activity in patients with advanced cancer. This result suggests that saracatinib may have therapeutic benefit in metastatic bone disease.

Effect of stopping risedronate after long-term treatment on bone turnover.

CONTEXT: Determining how quickly bisphosphonate treatment effects begin to regress is crucial when considering termination of treatment. OBJECTIVE: Our objective was to assess the effects of 1 yr discontinuation of risedronate use in postmenopausal women with osteoporosis who had previously received risedronate for 2 or 7 yr. DESIGN AND SETTING: Before initiation of the current study, placebo/5-mg-risedronate patients had received placebo for 5 yr and risedronate for 2 yr, whereas 5-mg-risedronate patients had received risedronate for a total of 7 yr. Risedronate was then discontinued for 1 yr (yr 8). PATIENTS: Postmenopausal women with osteoporosis who had previously completed the 3-yr Vertebral Efficacy with Risedronate Therapy MultiNational (VERT-MN) pivotal trial, plus a 2-yr extension comparing risedronate or placebo for a total of 5 yr, followed by 2 yr of open-label risedronate treatment were enrolled in these trial extensions. MAIN OUTCOME MEASURES: Evaluations included changes in type I collagen cross-linked N-telopeptide (NTX)/creatinine (Cr) and bone mineral density (BMD) values, fracture incidence, and adverse events. RESULTS: After 1 yr of risedronate discontinuation, NTX/Cr levels increased toward baseline in both patient groups vs. the values at the end of yr 7. In both treatment groups, off-treatment total hip and femoral trochanter BMD values decreased, whereas lumbar spine and femoral neck BMD were maintained or slightly increased. The adverse event profiles were similar between the two treatment groups during yr 8. CONCLUSIONS: One year of discontinuation of risedronate treatment in patients who had received 2 or 7 yr of risedronate therapy led to increases in NTX/Cr levels toward baseline and decreases in femoral trochanter and total hip BMD.

Prevention of aromatase inhibitor-induced bone loss using risedronate: the SABRE trial.

PURPOSE To investigate the management of bone health in women with early breast cancer (EBC) who were scheduled to receive anastrozole. PATIENTS AND METHODS Postmenopausal women with hormone receptor-positive EBC were assigned to one of three strata by risk of fragility fracture. Patients with the highest risk (H) received anastrozole 1 mg/d plus risedronate 35 mg/wk orally. Patients with moderate-risk (M) were randomly assigned in a double-blind manner to anastrozole and risedronate (A + R) or to anastrozole and placebo (A + P). Patients with lower-risk (L) received anastrozole (A) alone. Calcium and vitamin D were recommended for all patients. Lumbar spine and total hip bone mineral density (BMD) were assessed at baseline, 12 months, and 24 months. Results At 24 months, in the M group, treatment with A + R resulted in a significant increase in lumbar spine and total hip BMD compared with A + P treatment (2.2% v -1.8%; treatment ratio, 1.04; P < .0001; and 1.8% v -1.1%; treatment ratio, 1.03; P < .0001, respectively). In the H stratum, lumbar spine and total hip BMD increased significantly (3.0%; P = .0006; and 2.0%; P = .0104, respectively). Patients in the L stratum showed a significant decrease in lumbar spine BMD (-2.1%; P = .0109) and a numerical decrease in total hip BMD (-0.4%; P = .5988). Safety profiles for anastrozole and risedronate were similar to those already established. CONCLUSION In postmenopausal women at risk of fragility fracture who were receiving adjuvant anastrozole for EBC, the addition of risedronate at doses established for preventing and treating osteoporosis resulted in favorable effects in BMD during 24 months.

Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: a randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial.

Src is a nonreceptor tyrosine kinase thought to be essential for osteoclast function and bone resorption. We investigated the effect of the orally available Src inhibitor saracatinib (AZD0530) on bone turnover in healthy men. The study was part of a randomized, double-blind, placebo-controlled multiple-ascending-dose phase I trial of saracatinib. Fifty-nine healthy men (mean age 34.6 years) were divided into five cohorts; four with 12 subjects and one with 11 subjects, and randomized within each cohort in the ratio 3:1 to receive a single dose of saracatinib or placebo, respectively, followed 7 to 10 days later with daily doses for a further 10 to 14 days. Dosing levels of saracatinib ascended by cohort (60 to 250 mg). Markers of bone turnover were measured predose and 24 and 48 hours after the initial single dose and immediately before and 24 and 48 hours and 10 to 14 days after the final dose. Data from 44 subjects were included in the analysis. There was a dose-dependent decrease in bone resorption markers [serum cross-linked C-telopeptide of type I collagen (sCTX) and urinary cross-linked N-telopeptide of type I collagen normalized to creatinine (uNTX/Cr)]. At a dose of 250 mg (maximum tolerated dose), sCTX decreased by 88% [95% confidence interval (CI) 84-91%] and uNTX/Cr decreased by 67% (95% CI 53-77%) from baseline 24 hours after the final dose. There was no significant effect on bone formation markers. There were no significant adverse events. We conclude that inhibition of Src reduces osteoclastic bone resorption in humans. Saracatinib is a potentially useful treatment for diseases characterized by increased bone resorption, such as metastatic bone disease and osteoporosis.

The use of a point of care device for monitoring the bone resorption biomarker urinary N-telopeptide in cancer patients with bone metastases.

Type I collagen is the major constituent of bone and its breakdown products are increasingly used as sensitive markers of bone resorption. The N-terminal peptide-bound crosslinks of type I collagen (NTX) can be measured in urine and is useful for the monitoring of patients with metastatic bone disease. Studies have shown that raised NTX levels in metastatic bone disease correlate with an increased risk of complications and pathological fracture. The development of accurate and instantaneous point of care devices (POCD) would facilitate patient treatment and avoid delays in awaiting results from specialist laboratories. This study assesses the clinical performance of a single use POCD (OSTEOMARK NTx Point of Care Rx Home Use) to monitor NTX levels in patients with metastatic bone disease. NTX was measured in duplicate in 136 urine samples from patients attending clinic with metastatic bone disease using the POCDs. In our centre the frequency of bisphosphonate treatment is dependent on the NTX level, which is categorised into three groups (0-50, 50-100 and >100 nmol BCE/mmol creatinine). We used these categories to compare the clinical performance of the POCDs to that of a laboratory immunoassay. From a total of 272 devices, 231 (84.9%) successfully recorded a value in nM BCE/mM creatinine. Statistical analysis of the measure of agreement between POCD and laboratory assay found moderate agreement between the two assays (kappa 0.508). Out of the 72 samples with a laboratory assay value of <50, 53 (73.6%) were found to be within the same group recorded by POCD. From the 20 samples with a laboratory assay value of >100, 19 (95.0%) were found to be within the same category using POCDs. The measurement of urinary NTX by POCD appears to be a viable option for the monitoring of metastatic cancer patients. Whilst POCDs appear to record higher values than laboratory assays, the correlation between devices is good and with further research the NTX categories could be modified to accommodate this variation.

Prevention of anastrozole-induced bone loss with monthly oral ibandronate during adjuvant aromatase inhibitor therapy for breast cancer.

PURPOSE: The aromatase inhibitor anastrozole is a highly effective well-tolerated treatment for postmenopausal endocrine-responsive breast cancer. However, its use is associated with accelerated bone loss and an increase in fracture risk. The ARIBON trial is a double-blind, randomized, placebo-controlled study designed to evaluate the impact of bisphosphonate treatment on bone mineral density (BMD) in women taking anastrozole. EXPERIMENTAL DESIGN: BMD was assessed in 131 postmenopausal, surgically treated women with early breast cancer at two U.K. centers. Of these, 50 patients had osteopenia (T score -1.0 to -2.5) at either the hip or lumbar spine. All patients were treated with anastrozole 1 mg once a day and calcium and vitamin D supplementation. In addition, osteopenic patients were randomized to receive either treatment with ibandronate 150 mg orally every month or placebo. RESULTS: After 2 years, osteopenic patients treated with ibandronate gained +2.98% (range -8.9, +19.9) and +0.60% (range -9.0, +6.9) at the lumbar spine and hip, respectively. Patients treated with placebo, however, lost -3.22% (range -16.0, +4.3) at the lumbar spine and -3.90% (range -12.3, +7.2) at the hip. The differences between the two treatment arms were statistically significant at both sites (P < 0.01). At 12 months, urinary n-telopeptide, serum c-telopeptide, and serum bone-specific alkaline phosphatase levels declined in patients receiving ibandronate (30.9%, 26.3%, and 22.8%, respectively) and increased in those taking placebo (40.3%, 34.9%, and 37.0%, respectively). CONCLUSIONS: Monthly oral ibandronate improves bone density and normalizes bone turnover in patients treated with anastrozole.

Biomarkers of bone health and osteoporosis risk.

The assay features of biochemical markers of bone turnover have markedly improved in the past few years. The most sensitive and specific markers of bone formation include serum bone alkaline phosphatase, total osteocalcin (including the intact molecule and the large N-mid fragment) and the procollagen type I N-terminal propeptide assay. Among the various markers of bone resorption, measurements of the urinary excretion of N- and C-terminal cross-linked telopeptides) and of serum C-terminal cross-linked telopeptides are the most sensitive and specific. Markers of bone turnover can be used to predict the rate of bone loss in post-menopausal women and can also be used to assess the risk of fractures. In osteoporosis-treatment studies (with alendronate, risedronate, raloxifene) markers of bone turnover appear even more strongly associated with fracture risk reduction than bone mineral density (BMD). These observations support the use of markers of bone turnover as surrogates for fracture risk reduction, perhaps even more so than BMD. Bone markers can also be used to monitor the efficacy of antiresorptive therapy such as hormone-replacement therapy, raloxifene and bisphosphonates in individual patients. Furthermore, they have also proved to be helpful in monitoring the response to nutritional interventions and have the advantage over BMD in that they provide information about mechanism of effect and changes are often observed much more rapidly.

Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230.

PURPOSE: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (median follow-up, 68 months) has shown that adjuvant anastrozole has superior efficacy and better tolerability than tamoxifen. However, anastrozole reduces circulating estrogen, and low estradiol levels are associated with decreased bone mineral density (BMD) and increased fracture risk. It is therefore important to understand the effects of long-term aromatase inhibitor therapy on BMD. PATIENTS AND METHODS: This prospective substudy of the ATAC trial assessed BMD changes in postmenopausal women with invasive primary breast cancer receiving anastrozole (1 mg/d) or tamoxifen (20 mg/d) as adjuvant therapy for 5 years. Lumbar spine and total hip BMD were assessed at baseline and after 1, 2, and 5 years. RESULTS: One hundred ninety-seven women from the monotherapy arms of the ATAC trial were recruited onto the bone substudy, and 108 were included in the primary analysis. Among anastrozole-treated patients, there was a decrease in median BMD from baseline to 5 years in lumbar spine (-6.08%) and total hip (-7.24%) compared with the tamoxifen group (lumbar spine, +2.77%; total hip, +0.74%). No patients with normal BMD at baseline became osteoporotic at 5 years. CONCLUSION: Anastrozole is associated with accelerated bone loss over the 5-year treatment period. However, although patients with pre-existing osteopenia are likely to require monitoring and bone-protection strategies, patients with normal BMD would not appear to require monitoring beyond the recommendation for healthy postmenopausal women. The effect of anastrozole on bone should be weighed against its superior efficacy and better tolerability profile versus tamoxifen in the main ATAC trial.

Risk factors for vertebral and nonvertebral fracture over 10 years: a population-based study in women.

UNLABELLED: Risk factors may vary for different types of fracture, in particular for vertebral fractures. We followed 367 women >50 yr of age from a population-based cohort for up to 10 yr. Factors that predicted vertebral rather than nonvertebral fractures related to physical weakness, poor health, and weight loss. Similar factors were also associated with greater bone loss at the hip. INTRODUCTION: Many risk factors predict fractures overall, but it is less clear whether certain factors relate to vertebral fractures in particular. The aim of this study was to compare the risk factors for vertebral and nonvertebral fractures. MATERIALS AND METHODS: We carried out a 10-yr prospective population-based study of 375 women who were 50-85 yr of age initially. At baseline, we measured BMD, blood and urine biochemistry, and anthropometric measurements. Medical and lifestyle data were obtained by questionnaire. Incident vertebral fractures were determined for 311 subjects from spinal radiographs at 0, 2, 5, 7, and 10 yr using an algorithm-based qualitative method, and nonvertebral fractures were confirmed radiographically. Relative risks were calculated by Cox regression analysis. RESULTS: During follow-up, 70 subjects sustained one or more nonvertebral fractures and 29 sustained one or more vertebral fractures. Risk factors that predicted both types of fracture included increasing age, decreasing BMD at all sites, prevalent vertebral fracture, and shorter estrogen exposure. For nonvertebral fractures only, the risk factors included low urinary creatinine and less frequent use of stairs. The factors for vertebral fractures included lighter weight, reduced body fat, heavy smoking, lower serum calcium, albumin, and thyroid T(3), weak grip strength, and poor physical capability. In a multivariate model, weight, fat mass, serum calcium and T(3), prevalent vertebral fracture, and physical capability remained significant. Furthermore, grip strength, serum albumin, weight loss, and physical capability were associated with rate of bone loss at the femoral neck, and a fast rate of bone loss was also associated with vertebral fractures. CONCLUSIONS: We conclude that overall frailty, which may consist of general poor health, small or thin body size, and lack of strength and physical capability, predicts vertebral fractures but is not a significant predictor of nonvertebral fractures. Bone loss rates are associated with similar risk factors and also with the incidence of vertebral fractures.

Effects of third generation aromatase inhibitors on bone health and other safety parameters: results of an open, randomised, multi-centre study of letrozole, exemestane and anastrozole in healthy postmenopausal women.

Given potential differences between the skeletal and other effects of the third generation aromatase inhibitors (AIs), we conducted an open, randomised Phase I study, comparing the effects of three licensed AIs on bone turnover markers, lipid profiles and adrenal function. Treatment comparisons were undertaken in 90 healthy postmenopausal women with normal bone mineral density who received once daily oral anastrozole (1mg, n=29), letrozole (2.5mg, n=29) or exemestane (25mg, n=32) for 24weeks with a subsequent 12week washout period. All three AIs induced increases in bone resorption markers, but no significant differences were observed in their effects on bone turnover markers. Greater differences were observed in lipid metabolism. Notably, exemestane, but not anastrozole or letrozole, significantly increased the LDL:HDL cholesterol ratio by 12weeks, largely mediated by a decrease in HDL-cholesterol. Further, long-term clinical studies are required to determine the impact, if any, of the differences observed between the AIs

Effect of an aromatase inhibitor on bmd and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230).

UNLABELLED: Aromatase inhibitors reduce estrogen levels in postmenopausal women with breast cancer. Residual estrogen is an important determinant of bone turnover. Adjuvant anastrozole was associated with significant BMD loss and increased bone remodeling, whereas tamoxifen reduced bone marker levels. INTRODUCTION: In the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial after a median follow-up of 68 months, a significant improvement in disease-free survival was observed with anastrozole treatment (hazard ratio [HR], 0.87; 95% CI, 0.78-0.97; p = 0.01). Anastrozole was also associated with tolerability benefits compared with tamoxifen, but with higher fracture rates. The HR of anastrozole compared with tamoxifen after 60 months of treatment was 1.49 (95% CI, 1.25-1.77). MATERIALS AND METHODS: This prospectively designed subprotocol (n = 308) of ATAC assessed changes in BMD and bone turnover markers in postmenopausal women with invasive primary breast cancer receiving anastrozole 1 mg/day, tamoxifen 20 mg/day, or combination treatment with both agents for 5 years. Patients with osteoporosis were excluded (osteopenia permitted at the investigators discretion). Lumbar spine and total hip BMD was assessed at baseline and after 1 and 2 years; bone turnover markers (serum C-telopeptide, urinary N-telopeptide [NTX], free deoxypyridinoline, serum procollagen type-1 N-propeptide, bone alkaline phosphatase [ALP]) were assessed at baseline and after 3, 6, and 12 months. Results were expressed as median percentage change. RESULTS: After 2 years of anastrozole treatment, BMD was lost at lumbar spine (median 4.1% loss) and total hip (median 3.9% loss) sites; increases of 2.2% and 1.2%, respectively, were observed with tamoxifen. After 1 year of anastrozole treatment, increased bone remodeling was observed (NTX, +15%; 95% CI, 3-25%; bone ALP, +20%; 95% CI, 14-25%); decreased bone remodeling was observed with tamoxifen (NTX, -52%; 95% CI, -62% to -33%; bone ALP, -16%; 95% CI, -24% to -11%). CONCLUSIONS: Anastrozole is associated with significant BMD loss and a small increase in bone turnover, whereas tamoxifen (and the combination) is associated with increased BMD and decreased remodeling. These data may explain the increased fracture risk observed with anastrozole treatment in the ATAC trial. The impact of anastrozole on bone should be weighed against its overall superior efficacy and tolerability as observed in the main ATAC trial.

Bone markers and current laboratory assays.

Metastasis of cancer to bone leads to significant alterations in normal bone remodelling that are reflected in changes in bone turnover markers. These markers are classically defined as markers of bone resorption or formation; markers of bone resorption are measures of osteoclastic activity, whereas markers of bone formation are measures of osteoblastic activity. Recently, there has been growing interest in the use of these markers in metastatic bone disease (MBD), and an increasing number of studies have investigated the potential use of these markers in diagnosis, monitoring of disease progression and treatment, and prediction of outcome. In this review, we briefly discuss the biology of bone metastases as well as describe the bone turnover markers and their possible role in aiding clinicians in the treatment of patients with MBD.

Changes in bone resorption and vascular endothelial growth factor after a single zoledronic acid infusion in cancer patients with bone metastases from solid tumours.

Zoledronic acid (Zometa, ZOL) is increasingly used to treat tumour-induced bone disease, and is also reported to have antiangiogenic properties in vivo. In this study, we have investigated the correlations between changes in the proangiogenic cytokine, vascular endothelial growth factor (VEGF), and markers of bone resorption in a cohort of patients with metastatic bone disease, following a single infusion of ZOL. Twenty-four consecutive selected cancer patients with scintigraphic and radiographic evidence of bone metastases were treated for the first time with a single infusion of 4 mg ZOL. Patients were considered ineligible if they had received any steroid therapy, radiotherapy, chemotherapy, immunotherapy or haemopoietic growth factors in the 4 weeks before or during the study period. Circulating levels of VEGF and beta crosslinked type I collagen C-telopeptide (betaCTX) were measured at base-line and at 1, 2, 7 and 21 days following ZOL infusion. The majority of our patients (23/24) developed a significant reduction in circulating levels of betaCTX at just 1 day after the single zoledronic acid infusion, median percentage decrease 67.05% (95% CI, 52.39%; 76.27%). This reduction persisted at all following time points in almost all subjects in our patient population (day 2, 95.8%; day 7, 100%; day 21, 91.7%). The median decrease at day 2 was 85.67% (95% CI, 78.23%; 90.16%); at day 7, 67.38% (95% CI, 67.38%; 86.98); and at day 21, 76.89% (95% CI, 35.00%; 83.16%). Moreover, a linear regression model with variance analysis demonstrated a statistically significant correlation between median VEGF and betaCTX circulating levels at each of the time points (1, 2, 7 and 21 days after ZOL infusion). The present work demonstrates that a single infusion of ZOL was able to induce a rapid and long lasting decrease of betaCTX plasma levels in the majority (23/24) of the included cancer patients. Furthermore, we found that there is a correlation between the levels of VEGF and betaCTX following ZOL treatment. Future clinical trials should be designed to prospectively evaluate the prognostic role of reduction of betaCTX and VEGF in response to ZOL to predict clinical and skeletal outcome.

Clinical performance of immunoreactive tartrate-resistant acid phosphatase isoform 5b as a marker of bone resorption.

Previous immunoassays developed for the measurement of serum tartrate-resistant acid phosphatase (TRACP) have lacked specificity for osteoclastic TRACP, TRACP 5b, or have not shown satisfactory clinical performance. The aim of this study was to evaluate the clinical performance of a novel immunocapture activity assay for TRACP 5b, in comparison to telopeptide fragments of type I collagen. Within-subject variability and the effect of feeding on TRACP 5b and telopeptides of type I collagen were assessed in 20 healthy premenopausal women. Diurnal variation of TRACP 5b and serum beta C-terminal cross-linked telopeptide of type I collagen (sbetaCTX) was assessed in 12 healthy postmenopausal women. Renal clearance was assessed in 19 end stage renal failure patients undergoing routine haemodialysis. Response to antiresorptive treatment and calcium supplementation was assessed in osteoporotic postmenopausal women treated with alendronate and calcium (n = 16) or with calcium alone (n = 7) for 24 weeks.Within-subject variability (CVi) of TRACP 5b was 6.6%, lower than CVi of urinary and serum telopeptides. TRACP 5b decreased by 2.4 +/- 0.8%, in response to feeding (P < 0.05) compared to 7.0 +/- 2.6% to 7.9 +/- 3.7% for urinary telopeptides (P < 0.05 to < 0.01) and 8.5 +/- 1.7% to 17.8 +/- 2.6% for serum telopeptides (P < 0.0001). The amplitude of the diurnal rhythm for TRACP 5b was small compared to that of sbetaCTX, 14 +/- 4% vs. 137 +/- 14%. Haemodialysis did not have a significant effect on TRACP 5b but reduced sbetaCTX by 46 +/- 4% (P < 0.0001). In response to alendronate, TRACP 5b decreased by 39 +/- 4% compared to 49 +/- 4% to 69 +/- 5% for urinary telopeptides and 75 +/- 8% for sbetaCTX. We conclude that TRACP 5b shows an attenuated response to antiresorptive therapy in comparison with other markers of bone resorption, but that this may be offset by lower biological variability. TRACP 5b may provide useful additional information about bone resorption.

Absence of marked seasonal change in bone turnover: a longitudinal and multicenter cross-sectional study.

UNLABELLED: The effect of season on bone turnover is controversial. No information is available on seasonality of new serum markers of bone resorption. In this study, we have been unable to confirm findings of a marked wintertime increase in bone formation and resorption within the general population. Seasonality was assessed by cosinor analysis. INTRODUCTION: We investigated the effect of season on seven markers of bone turnover in a longitudinal study (six men and six premenopausal women; age, 24-44 years) and a separate large population-based multicenter European study (n = 2780 women, Osteoporosis and Ultrasound Study [OPUS]). MATERIALS AND METHODS: Measurements included serum Crosslaps, procollagen type I N-terminal propeptide (PINP), osteocalcin (OC), and the N-telopeptide fragment of type I collagen in urine (NTX). Seasonality was assessed by cosinor analysis with Hotelling's T2 test. RESULTS: Serum 25(OH) vitamin D showed a marked seasonal rhythm. There was no significant seasonal component for any marker of bone turnover in the longitudinal analysis (cosinor analysis, p > 0.05). The percentage of within subject variance accounted for by any seasonal trend was very small for all markers (less than 2.5%). Less than 1% of the between-person variance was accounted for by seasonality in the cross-sectional analysis for all markers (n = 2780). There was a small but statistically significant summertime increase in OC and PINP in the healthy postmenopausal population after exclusions based on disease or medication use (remaining n = 1226, amplitudes 5.6% and 5.4%, respectively, p < 0.001). CONCLUSIONS: We have been unable to confirm findings of a marked wintertime increase in bone formation and resorption within the general population. The absence of marked seasonality was irrespective of age, menopausal status, reported supplemental Vitamin D intake, age or geographical location. The small but statistically significant summertime increase in bone formation in this and other studies is unlikely to confound clinical interpretation of these measurements.

Biochemical markers of bone turnover and fracture prediction.

Low bone mineral density is a strong risk factor for fractures in the older woman. Biochemical markers of bone turnover may predict fracture risk independently of bone mineral density. High levels of bone resorption markers are associated with increased risk of fracture in both retrospective and prospective studies, although the evidence for bone formation markers and fracture risk is equivocal. For example, the risk of fracture is increased up to two-fold in women with elevated levels of several markers of bone resorption. Prediction models have been developed to predict the 10-year risk of fracture using bone mineral density and biochemical markers of bone turnover and these could prove very useful in clinical practice.