Response Of Bone Turnover Markers Research Articles

Ethanol alters the relationship between IGF-1 and bone turnover in male macaques.

Insulin-like growth factor 1 (IGF-1) influences bone turnover. Transient decreases in IGF-I levels and/or bioavailability may contribute to the detrimental effects of alcohol on bone. The goals of this non-human primate study were to i) evaluate the 20-h response of bone turnover markers to ethanol consumption and ii) assess how ethanol consumption influences the relationship between IGF-1 and these markers. Osteocalcin (bone formation), carboxyterminal cross-linking telopeptide of type 1 collagen (CTX, bone resorption), IGF-1, and IGF binding protein 1 (IGFBP-1) were measured in plasma from male rhesus macaques (N = 10, 8.4 ± 0.3 years) obtained at 12:00, 16:00, and 06:00 h during two phases: pre-ethanol (alcohol-naïve) and ethanol access. During the ethanol access phase, monkeys consumed 1.5 g/kg/day ethanol (4% w/v) beginning at 10:00 h. Osteocalcin and CTX were lower, and the ratio of osteocalcin to CTX was higher at each time point during ethanol access compared to the pre-ethanol phase. Pre-ethanol marker levels did not vary across time points, but markers varied during ethanol access. IGF-1 levels, but not IGFBP-1 levels, varied during the pre-ethanol phase. In contrast, IGF-1 levels were stable during ethanol access but IGFBP-1 levels varied. There were positive relationships between IGF-1 and turnover markers during the pre-ethanol phase, but not during ethanol access. In conclusion, chronic ethanol consumption reduces levels of bone turnover markers and blocks the normal positive relationship between IGF-1 and turnover markers and alters the normal relationship between IGF-1 and IGFBP-1. These findings support the hypothesis that chronic alcohol consumption leads to growth hormone/IGF-1 resistance.

Quantitative prediction of bone mineral density by using bone turnover markers in response to antiresorptive agents in postmenopausal osteoporosis: A model-based meta-analysis.

This study aimed to predict time course of bone mineral density (BMD) by using corresponding response of bone turnover markers (BTMs) in women with postmenopausal osteoporosis under antiresorptive treatments. Data were extracted from literature searches in accessible public database. Time courses of percent change from baseline in serum C-telopeptide of type 1 collagen (sCTX) and N-telopeptide of type 1 collagen were described by complex exponential onset models. The relationship between BTM changes and BMD changes at lumbar spine and total hip was described using a multiscale indirect response model. The dataset included 41 eligible published trials of 5 US-approved antiresorptive agents (alendronate, ibandronate, risedronate, zoledronic acid and denosumab), containing over 28 800 women with postmenopausal osteoporosis. The time courses of BTM changes for different drugs were differentiated by maximal effect and onset rate in developed model, while sCTX responses to zoledronic acid and denosumab were captured by another model formation. Furthermore, asynchronous relationship between BTMs and BMD was described by a bone remodelling-based semimechanistic model, including zero-order production and first-order elimination induced by N-telopeptide of type 1 collagen and sCTX, separately. After external and informative validations, the developed models were able to predict BMD increase using 1-year data. This exploratory analysis built a quantitative framework linking BTMs and BMD among antiresorptive agents, as well as a modelling approach to enhance comprehension of dynamic relationship between early and later endpoints among agents in a certain mechanism of action. Moreover, the developed models can offer predictions of BMD from BTMs supporting early drug development.

Bone turnover marker response in patients on second line agents for osteoporosis - what is the significance of non-suppression?

Bone turnover marker response in patients on second line agents for osteoporosis - what is the significance of non-suppression?

Use of bone turnover markers in the management of osteoporosis.

Osteoporosis is a common public health problem that is often undertreated and underdiagnosed. The clinical management of osteoporosis is often reactionary to devastating fracture events. Bone turnover markers may improve the ease and rapidity at which osteoporosis is monitored and treated. Bone turnover markers are biochemical byproducts of bone formation or bone resorption. The clinical use of bone turnover markers is limited by significant preanalytical variability. Effective interpretation of bone turnover markers requires a detailed understanding of the variables that can affect their responses to osteoporosis treatment and monitoring. Progress is continuously being made on the standardization of bone turnover markers. The literature on the response of bone turnover markers to unique clinical situations is expanding. Data for evidence-based reference intervals for bone turnover markers has increased. Variables that affect the appropriate timing of lab draws like diurnal variation, postprandial status, exercise and alcohol use have been described. Studies examining the expected response of bone turnover markers to treatments of osteoporosis and other medications that affect bone health continue to increase. Bone turnover markers have clinical utility in the comprehensive evaluation of osteoporosis. When interpreted with caution and with a good understanding of their natural variability, bone turnover markers provide information that supplements osteoporosis management and provides useful clinical information about conditions that alter bone turnover.

Response of bone turnover markers to raloxifene treatment in postmenopausal women with osteopenia.

We used two methods of identifying women who reached the target for raloxifene treatment with bone turnover markers. Both approaches identified women that responded to treatment but did not fully agree and may be complementary. The change in bone turnover markers (BTMs) in response to osteoporosis therapy can be assessed by a decrease beyond the least significant change (LSC) or below the mean of the reference interval (RI). We compared the performance of these two approaches in women treated with raloxifene. Fifty postmenopausal osteopenic women (age 51-72years) were randomised to raloxifene or no treatment for 2years. Blood samples were collected for the measurement of BTM. The LSC for each marker was calculated from the untreated women and the RI obtained from healthy premenopausal women (age 35-40years). Bone mineral density (BMD) was measured at the spine and hip. There was a decrease in BTM in response to raloxifene treatment, percentage change at 12weeks: C terminal telopeptide of type I collagen (CTX) -39% (95% CI -48 to -28) and N terminal propeptide of type I procollagen (PINP) -32% (95% CI -40 to -23) P < 0.001. The proportion of women classified as responding to treatment using LSC at 12weeks was as follows: CTX 38% and PINP 52% and at 48weeks CTX 60% and PINP 65%. For the RI approach, the proportion of women classified as responding to treatment at 12 weeks was CTX and PINP 38 % and at 48 weeks CTX 40% and PINP 45%. There was a significant difference in the change in spine BMD in the raloxifene-treated group compared to the no-treatment group at week 48: difference 0.031g/cm(2) (95% CI 0.016 to 0.046, P < 0.001). The two approaches identified women that reached the target for treatment using BTM. Both LSC and RI criteria appear useful in identifying treatment response, but the two approaches do not fully overlap and may be complementary.

Response of Bone Turnover Markers and Cytokines to High-Intensity Low-Impact Exercise.

Low-impact, high-intensity interval exercise (HIE) was used to investigate the postexercise response in bone turnover markers and cytokines. Twenty-three recreationally active males (21.8 ± 2.4 yr) performed one HIE bout on a cycle ergometer at 90% maximum workload. The total duration of the exercise was 12 min and included six 1-min high-intensity exercise intervals separated by 1-min rest intervals. Blood samples were collected before exercise, 5 min, 1 h, and 24 h after exercise and were analyzed for serum levels of anti- and pro-inflammatory cytokines (interleukin 10 [IL-10], interleukin 6 [IL-6], interleukin 1-alpha [IL-1α], interleukin 1-beta [IL-1β], and tumor necrosis factor alpha [TNF-α]) and markers of bone formation (bone alkaline phosphatase [BAP], osteoprotegerin [OPG]) and resorption (amino-terminal cross-linking propeptide [NTX], receptor activator of NF-κB ligand [RANKL]). There was a significant (P < 0.05) time effect for all bone turnover markers. Post hoc analysis showed that BAP, OPG, and RANKL significantly increased from baseline to 5 min after exercise (10.9%, 13.5%, and 34.2%, P < 0.05). At 1 h after exercise, only BAP was significantly higher than baseline (9.5%, P = 0.010) and remained higher than baseline at 24 h (10.9%, P = 0.001). NTX was significantly lower than baseline 24 h after exercise (-14.6%, P = 0.046). Significant (P < 0.05) time effects were also observed for IL-1α, IL-1β, IL-6, and TNF-α, with all four significantly increasing 5 min after exercise and returning to baseline levels 1 h after exercise. The postexercise changes in bone formation markers correlated positively with the anti-inflammatory cytokine (IL-10) and negatively with the pro-inflammatory cytokines while NTX correlated positively with a pro-inflammatory cytokine, TNF-α (P < 0.05). These results suggest that HIE stimulates a response in bone turnover markers and cytokines and that a correlation exists between immune and skeletal responses to this form of exercise. This type of exercise may benefit individuals for whom high-impact exercise might be contraindicated.

Acute Response Of Bone Metabolism To Various Resistance Exercises In Women

Abstract The study examines the acute response of bone turnover markers to two different single bouts of resistance exercises in women. Serum bone alkaline phosphatase and sclerostin concentration were measured before, 24 and 48 hours after the interventions to detect the dynamics of bone turnover. Subjects performed two exercises and a control experiment without exercise (CONTR) on different occasions, with 3-week breaks between the interventions, in a random order. First exercises protocol had a constant resistance of 75 % 1 RM (ISOF). Second, serial stretch loading (SSL), was isokinetic: velocity of concentric and eccentric phase of the movement was 50 and 40 cm/s, respectively. Short stops were incorporated into both phases of the movement after every 20 mm, resulting in a frequency of the force peaks of 10 Hz in concentric as well as in eccentric phase. Both protocols consisted of 6 sets of 6 repetitions and 2-minute resting periods. The exercises interventions had no statistically significant effect on either bone turnover marker concentration at any of the time points.

Postprandial response of bone turnover markers in patients with Crohn's disease.

To investigate the postprandial response of bone turnover markers in patients with Crohn's disease (CD). Fifty nine patients with CD aged 38 ± 14 years, and 45 healthy individuals matched for age and body mass index were included in the study. All participants underwent an oral glucose tolerance test (OGTT) after an overnight fast and serum levels of the bone resorption marker C-terminal crosslinking telopeptide of type I collagen (CTX-I) and the bone formation marker procollagen type I N propeptide were measured. Activity of the disease was assessed by calculation of the Crohn's disease activity index (CDAI). Serum CTX-I was significantly higher in patients compared to controls (CTX-I: 453 ± 21 pg/mL vs 365 ± 25 pg/mL, P = 0.008), and values were significantly correlated with the activity of the disease (r = 0.435, P = 0.001). Results from OGTT-induced suppression of CTX-I showed two different trends. Patients with more active disease (assessed as CDAI > 150) had a more excessive suppression of CTX-I compared to controls (55% vs 43% P < 0.001), while patients on remission (assessed as CDAI < 150) demonstrated an attenuated CTX-I suppression (30% vs 43% P < 0.001). In line with this, CTX-I suppression after oral glucose load was significantly correlated with the activity of the disease (r = 0.913, P < 0.001). The physiological skeletal response of postprandial suppression of bone resorption is maintained in patients with CD and is strongly dependent to the activity of the disease.

D-25 Free Communication/Poster - Physical Activity Correlates

High impact physical training is beneficial for bone structure and mineralization and typically results in increased levels of bone turnover markers. However, the acute effects of a single exercise session on bone markers are unclear. In adults, inconsistent results have been demonstrated following high impact exercise. In children, there is a paucity of data in this area. PURPOSE: To investigate the acute response of bone turnover markers to an exercise session consisting of high mechanical loading in boys and men. METHODS: Participants underwent a protocol of plyometric jumping exercises (total 144 jumps). Venous blood samples were collected pre, 5 minutes post-, 1 hour post- and 24 hours post-exercise session to measure bone-specific alkaline phosphatase (BAP), amino-terminal cross-linking telopeptide (NTx), osteoprotegrin (OPG) and receptor activator of nuclear factor kb ligand (RANKL). RESULTS: Boys had higher BAP levels, with an increase 24 hours post-exercise (111.9±29.2 vs. 137.6±36.3 μg/L, respectively), which was not observed in the men (31.4±11.1 vs. 33.3±10.5 μg/L, respectively). NTx levels were higher in boys, with a greater increase over time in boys than in men (boys: 48.7±13.7 vs. 58.8±16.7 nM BCE pre- and 24 hours post-exercise, respectively; men: 21.7±5.4 vs. 19.4±5.0 NM BCE pre- and 24 hours post-exercise, respectively). OPG and RANKL levels were similar in boys and men before and after exercise, with no change over 24 hours. CONCLUSIONS: These results indicate that even one session of exercise stimulates bone turnover, as reflected in the increase in both BAP and NTx values, in boys (but not men) within 24 hours.

Determinants of bone turnover marker response to three oral bisphosphonate therapies in postmenopausal osteoporosis: the TRIO study

Determinants of bone turnover marker response to three oral bisphosphonate therapies in postmenopausal osteoporosis: the TRIO study

THU0411 Efficacy of Teriparatide on Osteoporosis in Patients with Rheumatoid Arthritis ~is it Appropriate to Prescribe Teriparatide Together with Biological Agents?

BackgroundAlthough medication of rheumatoid arthritis (RA) has been improved by positive administration of methotrexate and biological agents (BIO) for decades, treatment of concomitant disease in RA patients, such as osteoporosis,...

Periarticular Bone Gain at Proximal Interphalangeal Joints and Changes in Bone Turnover Markers in Response to Tumor Necrosis Factor Inhibitors in Rheumatoid and Psoriatic Arthritis

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are characterized by periarticular bone erosion; periarticular bone formation is a feature in PsA. The effect of anti-tumor necrosis factor-α (TNF-α) on periarticular bone remodeling is unclear in both diseases. Our aim was to assess the response of bone turnover markers (BTM) and hand bone mineral density (BMD) to anti-TNF over 3 years in RA and PsA. We measured serum bone-specific alkaline phosphatase (bone ALP), procollagen type-I N-propeptide (PINP), intact osteocalcin, C-terminal cross-linking telopeptides (CTX-I), urinary N-terminal cross-linking telopeptide of type-I collagen (NTX-I), and free deoxypyridinoline crosslinks (fDPD) at baseline, 1, 12, and 36 months. BMD measurements (hands/spine/hip) were obtained at 3 timepoints. We recruited 62 patients (RA 35; PsA 27). BTM correlated significantly with hand BMD but not with central BMD. Low hand BMD was associated with RA and increased BTM. Following anti-TNF therapy, hip BMD declined while spine and hand BMD were unchanged. Periarticular BMD at proximal interphalangeal (PIP) joints increased while it decreased at metacarpophalangeal joints. Bone ALP increased steadily and was always higher in PsA. PINP and intact osteocalcin increased to a lesser extent, but resorption markers did not change. At baseline, hand BMD was inversely associated with BTM. Bone formation rather than resorption markers better showed the bone response to anti-TNF. Despite a lack of effect on central BMD, the modest effect of anti-TNF on PIP BMD may provide evidence that BTM reflect specifically bone remodeling activity at periarticular sites of inflammation in RA and PsA.

Effect on bone turnover markers of once-yearly intravenous infusion of zoledronic acid versus daily oral risedronate in patients treated with glucocorticoids

Long-term glucocorticoid use is accompanied by rapid bone loss; however, early treatment with bisphosphonates prevents bone loss and reduces fracture risk. The aim of this study was to examine the effects of two bisphosphonates, i.v. zoledronic acid (ZOL) versus oral risedronate (RIS), on bone turnover markers (BTMs) in subjects with glucocorticoid-induced osteoporosis (GIO). Patients were randomly stratified according to the duration of pre-study glucocorticoid therapy [prevention subpopulation (ZOL, n = 144; RIS, n = 144) ≤3 months, treatment subpopulation (ZOL, n = 272; RIS, n = 273) >3 months]. Changes in β-C-terminal telopeptides of type 1 collagen (β-CTx), N-terminal telopeptide of type I collagen (NTx), procollagen type 1 N-terminal propeptide (P1NP) and bone-specific alkaline phosphatase (BSAP) from baseline were measured on day 10 and months 3, 6 and 12. At most time points, there were significantly greater reductions (P < 0.05) in the concentrations of serum β-CTx, P1NP and BSAP and urine NTx in subjects on ZOL compared with RIS in both males and females of the treatment and prevention subpopulations. In pre- and post-menopausal women, there were significantly greater reductions in the concentrations of BTMs with ZOL compared with RIS. At 12 months, ZOL had significantly greater reductions compared with RIS (P < 0.05) for β-CTx, P1NP, BSAP and NTx levels, independent of glucocorticoid dose. Once-yearly i.v. infusion of ZOL 5 mg was well tolerated in different subgroups of GIO patients. ZOL was non-inferior to RIS and even superior to RIS in the response of BTMs in GIO patients. ClinicalTrials.gov, http://clinicaltrials.gov, NCT00100620.

Effects of denosumab on bone turnover markers in postmenopausal osteoporosis

Denosumab, a fully human monoclonal antibody to RANKL, decreases bone remodeling, increases bone density, and reduces fracture risk. This study evaluates the time course and determinants of bone turnover marker (BTM) response during denosumab treatment, the percentage of denosumab-treated women with BTMs below the premenopausal reference interval, and the correlations between changes in BTMs and bone mineral density (BMD). The BTM substudy of the Fracture REduction Evaulation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Trial included 160 women randomized to subcutaneous denosumab (60 mg) or placebo injections every 6 months for 3 years. Biochemical markers of bone resorption (serum C-telopeptide of type I collagen [CTX] and tartrate-resistant acid phosphatise [TRACP-5b]) and bone formation (serum procollagen type I N-terminal propeptide [PINP] and bone alkaline phosphatase [BALP]) were measured at baseline and at 1, 6, 12, 24, and 36 months. Decreases in CTX were more rapid and greater than decreases in PINP and BALP. One month after injection, CTX levels in all denosumab-treated subjects decreased to levels below the premenopausal reference interval. CTX values at the end of the dosing period were influenced by baseline CTX values and the dosing interval. The percentage of subjects with CTX below the premenopausal reference interval before each subsequent injection decreased from 79% to 51% during the study. CTX and PINP remained below the premenopausal reference interval at all time points in 46% and 31% denosumab-treated subjects, respectively. With denosumab, but not placebo, there were significant correlations between CTX reduction and BMD increase (r = -0.24 to -0.44). The BTM response pattern with denosumab is unique and should be appreciated by physicians to monitor this treatment effectively.

The response of bone turnover markers to lasofoxifene: The PEARL trial

The response of bone turnover markers to lasofoxifene: The PEARL trial

Modulatory effect of farnesyl pyrophosphate synthase (FDPS) rs2297480 polymorphism on the response to long-term amino-bisphosphonate treatment in postmenopausal osteoporosis

ABSTRACTIntroduction: Polymorphisms of genes encoding enzymes of the mevalonate pathway could modulate the response to amino-bisphosphonate treatment in postmenopausal osteoporosis.Research design and methods: A characterisation of 234 Danish osteoporotic postmenopausal women (as part of the Prospective Epidemiological Risk Factors study (PERF)), treated for at least 2 years with amino-bisphosphonates, with respect to the adenosine/cytosine (A/C) rs2297480 farnesyl pyrophosphate synthase (FDPS) gene polymorphism, was carried out by PCR-based enzymatic digestion and quantitative PCR allelic discrimination on genomic DNA extracted from blood leukocytes. The association between these polymorphism genotypes and the response of spine and femur bone mineral density (BMD) and of biochemical bone biomarkers to treatment with amino-bisphosphonates was statistically examined.Results: FDPS polymorphism did not show any relationship to baseline spinal and femoral BMD in Danish postmenopausal women. BMD response to treatment with amino-bisphosphonates was similar in the AA and the AC genotypes, while the CC genotype showed a lower BMD response to 2-year-treatment with amino-bisphosphonates at all examined skeletal sites ( p = 0.60 at the spine and p = 0.59 at the femur). Interestingly, after 2 years of treatment the response of urinary Cross-laps to amino-bisphosphonates treatment was significantly ( p < 0.05) lower in the CC genotype when compared to both the AC and AA genotypes. Even the response of serum osteocalcin was lower in the CC genotype, but without reaching a statistical significance ( p = 0.65).Conclusions: Danish postmenopausal women with osteoporosis bearing the homozygous CC genotype for rs2297480 FDPS polymorphism showed a decreased response of bone turnover markers to amino-bisphosphonate therapy, when compared to the heterozygous AC and to the homozygous AA genotypes. Further investigation on larger and different populations, together with polymorphism functional studies are required to confirm these data.

Short-term response of bone turnover to low-dose oral contraceptives in exercising women with hypothalamic amenorrhea

Background We examined the response of bone turnover markers and indices of energy status after 2 weeks of oral contraceptive (OC) therapy in premenopausal women with exercise-associated menstrual disturbances (EAMD). Study Design Six women with EAMD received one 28-day cycle of a triphasic OC containing 180–250 mcg norgestimate/25 mcg ethinyl estradiol (EAMD+OC) and six were controls (EAMD controls). Bone turnover markers amino-terminal propeptide of Type I procollagen and serum carboxy-terminal telopeptides of Type I collagen (PINP and SCTX-I) were assessed at baseline and after 2 weeks of OC therapy (EAMD+OC) or after a 30-day monitoring period (EAMD controls). Total triiodothyronine, resting energy expenditure (REE) and dietary intake were assessed as secondary end points. The absolute and percent changes from baseline in the primary and secondary outcomes were evaluated using an analysis of covariance, adjusting for baseline values of the corresponding outcome. Results Compared to EAMD controls, a significant change from baseline was observed in the EAMD+OC group for PINP (mean±SEM, 9.9±6.1 vs. −33.9±9.0 mcg/L; p=.005) and SCTX-I (−0.02±0.11 vs. −0.25±0.07 ng/mL; p=.017), but not osteoprotegerin (−0.53±0.22 vs. 0.20±0.44 pmol/L; p=.429) after 2 weeks (14.7±0.3 days) of OC therapy. Total triiodothyronine levels were elevated in the EAMD+OC group after therapy compared with EAMD controls (19.7±4.1 vs. −8.4±4.9 ng/dL; p=.002); however, no differences between groups were observed for the changes in REE or dietary intake. Conclusion Our data demonstrate that 2 weeks of low-dose OC therapy rapidly reduced markers of bone resorption and formation, without any significant impact on energy status in women with EAMD.

Oral ibandronate preceded by an intravenous (i.v.) ibandronate loading dose in patients with breast cancer and bone metastases or multiple myeloma: phase III results

8060 Background: Ibandronate is the only single nitrogen-containing bisphosphonate with i.v. and oral formulations. In phase III trials of patients with breast cancer and bone metastases both i.v. and oral ibandronate reduced metastatic bone pain and the risk of skeletal-related events. This 12-week trial determined the response of bone turnover markers to a single rapid infusion of i.v. ibandronate followed by daily oral ibandronate treatment. Safety data from 39 patients have been presented earlier.1 Here we discuss the bone turnover marker data of 34 patients. Methods: Patients with advanced multiple myeloma or breast cancer and ≥1 confirmed lytic or mixed bone lesion received a single 15-minute infusion of i.v. ibandronate 6mg followed by oral ibandronate 50mg once daily (n=34). Eligibility criteria included: ≥18 years of age; provided written informed consent; life expectancy ≥6 months, WHO Performance Status of 0, 1 or 2, and adequate renal function (serum creatinine ≤3.0 mg/dL). Cross-linked C-terminal telopeptide of type I collagen in serum (S-CTX), bone specific alkaline phosphatase (S-bALP), the amino-terminal procollagen propeptides of type I collagen (P1NP), and osteocalcin (OC) were measured. Results: Mean (CI) bone turnover marker percent changes are shown in the Table. Conclusions: The combination of an initial infusion of 6mg ibandronate followed by daily oral treatment results in a rapid decrease of S-CTX, a sensitive marker of bone resorption. Initial i.v. doses followed by oral maintenance treatment are undergoing further testing. 1. Früh M, et al. Ann Oncol 2004;15(Suppl. 3):iii49 (Abstract 187P). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Roche Roche