Changes In Bone Turnover Markers Research Articles

New drugs for osteoporosis therapy: a review of the clinical trials phase 2 and 3

SUMMARY Osteoporosis is a chronic disease with increasing incidence that predominantly occurs in female population. There are evidences that bisphosphonates, selective estrogen receptor modulators, denosumab, teriparatide and strontium renalate, prevent vertebral fractures while alendronate, risedronate, zoledronic acid, denosumab and strontium renalate prevent hip fractures. Although these drugs are effective in osteoporosis treatment, their use is limited by their side-effects and low-adherence. The aim of this review article was to compare efficacy of new drugs for osteoporosis currently in phase 2 and 3 clinical trials. After reviewing 57 articles available on PubMed and Scopus databases that evaluated efficacy of osteoporosis medications, 10 papers, that fulfilled the review criteria, were selected for the analysis. Finally, the efficacy of five drugs was compared. Efficacy was evaluated by the values of bone mineral density (BMD) and bone turnover markers (BTM). In all the analyzed articles the BMD increased and changes of BTM were noted. The highest increase of lumbar BMD from the baseline values was achieved after six months of subcutaneous application of 20 μg/day teriparatide (11.3%). The lowest increase of BMD in the same region was recorded after six months of risedronate therapy 100 mg per os once monthly (2.1%). From ten selected articles, only one has reported data about fracture risk.

Changes in bone mineral density, bone turnover markers, and vertebral fracture risk reduction with once weekly teriparatide

Objective:We aimed to evaluate the surrogacy of bone mineral density and bone turnover markers for incident vertebral fracture using data from 237 patients treated with once weekly 56.5 μg teriparatide or placebo.Methods:This analysis was conducted using data from the Teriparatide Once-Weekly Efficacy Research trial, a randomized, double-blind, placebo-controlled trial for patients with severe osteoporosis in Japan. A total of 237 subjects (placebo group, n = 130; teriparatide group, n = 107) were assessed at baseline and at 72 weeks. Main outcome measures included estimation of the treatment effects of once weekly teriparatide on vertebral fracture risk reduction using percentage changes in lumbar bone mineral density and bone turnover markers.Results:The percentage change in lumbar bone mineral density was 6.69% in the teriparatide group compared with 0.28% in the placebo group (p < 0.01). One incident vertebral fracture occurred in the teriparatide group compared with 16 in the placebo group. The unadjusted and adjusted hazard ratios of the teriparatide group compared with the placebo group were 0.07 (95% confidence interval: 0.01 to 0.56) and 0.64 (95% confidence interval: 0.06 to 6.36), respectively. The proportion of treatment effect explained by changes in lumbar bone mineral density was 83% (Freedman’s method) and 66% (Chen’s method). There were no notable changes in hazard ratios if we adjusted for bone turnover markers.Conclusions:Most of the vertebral fracture risk reduction with once weekly 56.5 μg teriparatide is explained by changes in lumbar bone mineral density rather than changes in bone turnover markers.

Once-weekly teriparatide treatment on osteoporosis

Teriparatide (human PTH 1-34) transiently stimulate both bone formation and bone resorption and subsequently bone formation markers increased. The changes in bone turnover markers 24 h after each injection of once-weekly 56.5μg teriparatide were constant for 24 weeks. Once-weekly injections of teriparatide increased bone mineral density by 8.1% at the lumbar spine and reduced the risk of new vertebral fracture with a relative risk reduction of 80% compared to placebo for the patients with osteoporosis. Significant vertebral fracture risk reductions were also observed in the patients with high risk for fracture such as higher age, low bone mineral density, or sever vertebral fracture grade. Once-weekly teriparatide improved cortical bone parameters at proximal femur, may have the potential to prevent hip fracture. The duration of teriparatide treatment was limited. Therefore subsequent treatment for osteoporosis should be need. Bisphosphonates seem to be a useful choice as a subsequent treatment to once-weekly teriparatide.

Impact of the growth hormone replacement on bone status in growth hormone deficient adults

IntroductionGrowth hormone deficiency (GHD) is associated with reduced bone mineral density (BMD). GH replacement has positive effect on BMD but the magnitude of this effect and its mechanism are debated. ObjectivesThe objectives of this study was first, to assess the effect of GH replacement on BMD, and second, to evaluate the effect of GH treatment on bone turnover and microarchitecture and to assess the factors influencing the effect of the therapy on BMD. Patients and MethodsAdult GHD (AO-GHD) and childhood onset GHD (CO-GHD) patients treated with GH using IGF-I normalization GH replacement regimen were prospectively followed during 2years. Lumbar spine (L1–L4) and total femur BMD by Hologic discovery, in the subset of patients also bone turnover markers; osteocalcin and carboxy-terminal collagen crosslinks (CTx) were assessed at baseline and at months 3, 6, 12 and 24, respectively. The trabecular bone score (TBS) derived from lumbar spine DXA by the iNsight® software was assessed in a subset of study population at baseline and months 12 and 24. ResultsIn total, 147 GHD patients (age 35.1years, 84 males/63 females, 43 of childhood onset GHD/104 AO-GHD) were included. BMD of lumbar spine and femur increased significantly during the treatment (14% and 7% increase at 2years, respectively; p<0.0001).Bone markers increased during the first 12months of treatment with subsequent decrease of CTx. At month 24, significant increase in TBS was observed (4%, p=0.02).BMD increase was significantly higher in males (15% increase in males vs. 10% in females, p=0.037) and childhood onset GHD (CO-GHD) patients (13% increase in CO-GHD, p=0.004). ConclusionGH supplementation leads to an increase of BMD with corresponding changes in bone turnover markers and changes in microarchitecture as assessed by trabecular bone score. Positive effect of GH on bone status is more pronounced in males and CO-GHD adults.

Profile of changes in bone turnover markers during once-weekly teriparatide administration for 24 weeks in postmenopausal women with osteoporosis

SummaryChanges in bone turnover markers with weekly 56.5 μg teriparatide injections for 24 weeks were investigated in women with osteoporosis. Changes in bone turnover markers 24 h after each injection of teriparatide were constant. During the 24 week period, bone formation markers increased and baseline bone resorption marker levels were maintained.IntroductionThis study aimed to clarify the changes in bone turnover markers during 24 weeks of once-weekly teriparatide injections in postmenopausal women with osteoporosis.MethodsThe 24 h changes in pharmacokinetics (PK), calcium metabolism, and bone turnover markers (serum osteocalcin, procollagen type I N-terminal propeptide (P1NP), urinary cross-linked N-telopeptide of type I collagen (NTX), deoxypiridinoline (DPD)) after each injection of 56.5 μg teriparatide at the data collection weeks (0, 4, 12, and 24 weeks) were investigated. The changes were evaluated by comparison with the data at 0 h in each data collection week.ResultsSimilar 24 h changes in each parameter after injection of teriparatide were observed in each data collection week. Serum calcium increased transiently, and intact PTH decreased 4–8 h after injection; serum calcium subsequently returned to baseline levels. Calcium and intact PTH levels decreased for 24 weeks. Although serum osteocalcin decreased at 24 h, it was significantly increased at 4 weeks. P1NP decreased transiently and then increased significantly at 24 h. P1NP was significantly increased at 4 weeks. Urinary NTX and DPD were significantly increased transiently and then decreased at 24 h. The urinary DPD level decreased significantly at 4 weeks.ConclusionsTwenty-four hour changes in PK, calcium metabolism, and bone turnover markers showed the same direction and level after once-weekly teriparatide injections for 24 weeks, with no attenuation of the effect over time. After 24 weeks, the bone formation marker, serum osteocalcin, increased significantly, but the serum P1NP, did not. Bone resorption markers decreased or remained the same.

Monitoring of bone turnover markers and bone scintigraphy for teriparatide therapy in bisphosphonate related osteonecrosis of the jaw

Treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) remains an intractable problem in many cases. Recent literatures have shown that the new treatment modality using teriparatide may be beneficial to BRONJ. However, the teriparatide therapy was not effective in all cases. It would be necessary to assess the therapeutic effectiveness of teriparatide with predictable procedures to treat BRONJ. We report here two cases of BRONJ treated by adjunctive teriparatide therapy for 6 months while simultaneously performing the monitoring of changes of bone turnover markers and the quantitative assessment of bone scintigraphy. Six months after the combination of teriparatide and conservative treatment, CT showed evidence of bone regeneration and the intraoral wound was completely healed. Biochemical bone formation markers were monitored at the time points of 0, 1, 3 and 6 months. Almost of all the markers related to the bone formation and resorption revealed an increase during the teriparatide treatment. The uptake area and quantitative value of technetium-99m-methylene diphosphonate showed a reduction after the administration of teriparatide. It was strongly suggested that teriparatide therapy is one of the useful treatments for BRONJ based on monitoring bone turnover results and employing bone scintigraphy.

A report from Fukushima: an assessment of bone health in an area affected by the Fukushima nuclear plant incident

Bone health was assessed for inhabitants of an area affected by the Fukushima nuclear plant incident. Osteoporotic patients, who had been treated with active vitamin D3 and/or bisphosphonate at Soma Central Hospital before the Fukushima incident, were enrolled. Changes in bone turnover markers and bone mineral density were retrospectively analyzed. Serum levels of a bone resorption marker, serum type I collagen cross-linked N-telopeptide were decreased in all the treated groups, whereas those of a bone formation marker, bone-specific alkaline phosphatase, were increased. Accordingly, bone mineral density, estimated by dual-energy X-ray absorptiometry, was increased in the lumbar spine of all groups, but bone mass increase in the proximal femur was detected only in the group treated with the two agents in combination. From the degree of these parameter changes, the antiosteoporotic treatments looked effective and were equivalent to the expected potency of past observations. At this stage, the present study implies that the Fukushima nuclear incident did not bring an acute risk to bone health in the affected areas.

Early detection of bone metabolism changes under different antiepileptic drugs (ED-BoM-AED) – A prospective multicenter study

To determine early changes in bone turnover markers induced by treatment with oxcarbazepine or valproate. In this prospective study, 31 adults with newly diagnosed epilepsy were included who were started on therapy with either oxcarbazepine (OXC, n=16, mean age 45.6 years, 37.5% female) or valproate (VPA, n=15, mean age 42.2 years, 33.3% female). Clinical characteristics were obtained at baseline, after 2 weeks and 3 months. In addition, blood samples were drawn at each visit. Calcium, phosphate, alkaline phosphatase (AP), receptor activator of NF-κB ligand (RANKL), osteoprotegerin (OPG), osteocalcin (OC) and cathepsin K were determined. In OXC treated patients, OPG increased by 0.06 pmol/L (p=0.0004) after 2 weeks and remained elevated by 0.05 pmol/L (p=0.02) after 3 months. Between 2 weeks and 3 months of OXC treatment, OC increased by 1.98 ng/mL (p=0.02). During the first 3 months of OXC treatment, total serum AP increased by 11%±9% (p=0.02). Compared to baseline, serum calcium raised by 0.06 mmol/L (p=0.04) after 2 weeks and by 0.07 mmol/L (p=0.004) after 3 months of OXC treatment. In VPA treated patients, a late OPG increase by 0.07 pmol/L (p=0.007) occurred after 3 months. During the first 3 months of OXC treatment, total serum AP decreased by by 7%±15% (p=0.03). No changes in OC or calcium were seen. RANKL was below detection limit in 16 out of 31 patients (52%) and did not change significantly during treatment. Cathepsin K was below detection limit at baseline in 27 out of 31 patients (87%) and was therefore not further evaluated. Phosphate did not change during treatment. Increased bone turnover can be measured within few weeks of newly started treatment with OXC, while significant changes under VPA treatment occurred only after 3 months. Our data suggest distinct mechanisms of increased bone turnover in different anticonvulsants. These variable mechanisms may require individual prevention and treatment strategies.

OP0248 Inhibition of Sclerostin with Romosozumab in Postmenopausal Women with Low Bone Mineral Density: Phase 2 Trial Results

BackgroundIn preclinical studies, administration of antibodies that neutralize sclerostin results in increased bone mass and strength.ObjectivesWe report the primary and key secondary endpoints of a phase 2 trial evaluating the...

Celecoxib, a selective cyclooxygenase-2 inhibitor, reduces level of a bone resorption marker in postmenopausal women with rheumatoid arthritis

Celecoxib (CEL), a selective cyclooxygenase-2 (COX-2) inhibitor, has been reported to suppress osteoclastogenesis in vitro, reduce levels of bone resorption markers in ovariectomized (OVX) mice, and prevent bone destruction in rheumatoid arthritis (RA) model mice; however, no clinical data has been reported. Here, we prospectively evaluated the changes in bone turnover markers in RA patients who switched from nonsteroidal anti-inflammatory drugs (NSAIDs) to CEL, to examine the effects of selective COX-2 inhibitor on bone metabolism. RA patients who had been treated with NSAIDs for more than 12weeks were switched to CEL (400mg/day) without any other changes in previously prescribed medications. Urinary type I collagen cross-linked N-telopeptide (uNTX), serum bone alkaline phosphatase (BAP), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and matrix metalloproteinase-3 (MMP-3) were evaluated before switching to CEL and 16weeks later. Significant reductions in uNTX, a bone resorption marker, were observed in 60 female patients (P=0.042), especially in 52 postmenopausal women (P=0.033). However, uNTX level did not significantly change in premenopausal women or in men. There were no significant changes in BAP, a bone formation marker. CRP significantly decreased (P=0.007), while ESR and MMP-3 were unchanged. CEL reduced the levels of a bone resorption marker in postmenopausal RA patients, suggesting that this drug may attenuate the accelerated osteoclastic bone resorption associated with menopause.

The Effects of Season-Long Vitamin D Supplementation on Collegiate Swimmers and Divers

The purpose of this 6-month randomized, placebo-controlled trial was to determine the effect of season-long (September-March) vitamin D supplementation on changes in vitamin D status, which is measured as 25(OH) D, body composition, inflammation, and frequency of illness and injury. Forty-five male and female athletes were randomized to 4,000 IU vitamin D (n = 23) or placebo (n = 22). Bone turnover markers (NTx and BSAP), 25(OH)D, and inflammatory cytokines (TNF-alpha, IL-6, and IL1-β) were measured at baseline, midpoint, and endpoint. Body composition was assessed by DXA and injury and illness data were collected. All athletes had sufficient 25(OH)D (> 32 ng/ml) at baseline (mean: 57 ng/ml). At midpoint and endpoint, 13% and 16% of the total sample had 25(OH)D < 32 ng/ml, respectively. 25(OH)D was not positively correlated with bone mineral density (BMD) in the total body, proximal dual femur, or lumbar spine. In men, total body (p = .04) and trunk (p = .04) mineral-free lean mass (MFL) were positively correlated with 25(OH)D. In women, right femoral neck BMD (p = .02) was positively correlated with 25(OH)D. 25(OH)D did not correlate with changes in bone turnover markers or inflammatory cytokines. Illness (n = 1) and injury (n = 13) were not related to 25(OH)D; however, 77% of injuries coincided with decreases in 25(OH)D. Our data suggests that 4,000 IU vitamin D supplementation is an inexpensive intervention that effectively increased 25(OH)D, which was positively correlated to bone measures in the proximal dual femur and MFL. Future studies with larger sample sizes and improved supplement compliance are needed to expand our understanding of the effects of vitamin D supplementation in athletes.

Changes in Bone Turnover Markers and Bone Mass with Reducing Levels of Jumping Exercise Regimens in Female Rats

To date, little is known about the effects of a reduced level of jumping exercise regimens on bone turnover markers and mass. This study investigates the effects of different jumping exercise regimens with varying exercise loads on serum bone turnover markers and bone mass in female rats. A total of 144 female rats aged 12 weeks, were divided into 12 groups as follows: no exercise for 8 (8S) or 32 weeks (32S), or 8 weeks of standard training program (8STP) consisting of 200 jumps per week (200J/w), given at 40 jumps per day (40J/d) for 5 days per week (5d/w) (8STP24E), followed by 24 weeks of exercise at loads of either 10J/d or 20J/d or 40J/d, for either 5d/w, or 3d/w, or 1d/w. Serum osteocalcin, alkaline phosphatase, C-terminal telopeptide of type 1 collagen (1CTP) concentrations, and tibial fat free dry weight were measured. Tibial mass was significantly higher in 8STP than 8S. No changes were evident in serum markers of bone turnover parameters after 8STP. Significant increases in tibial mass were observed in rats that continued to exercise at workloads of 30J/w and above after 8STP. Serum alkaline phosphatase concentrations increase whereas serum 1CTP concentrations decrease in rats given workloads of 40J/w and above. It appears, an exercise load of 30J/w, i.e. 10J/d for 3d/w, was the minimum level of continuous exercise load that was required to maintain the 8STP-induced bone gains. In addition, significant increases in bone mass in young rats following 8STP might not always be reflected by changes in serum levels of osteocalcin, alkaline phosphatase and 1CTP.

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.

Dietary Protein-Induced Increases in Urinary Calcium Are Accompanied by Similar Increases in Urinary Nitrogen and Urinary Urea: A Controlled Clinical Trial

To determine the usefulness of urinary urea as an index of dietary protein intake, 10 postmenopausal women were enrolled in and completed a randomized, double-blind, cross-over feeding trial from September 2008 to May 2010 that compared 10 days of a 45-g whey supplement with 10 days of a 45-g maltodextrin control. Urinary nitrogen, urinary calcium, urinary urea, and bone turnover markers were measured at days 0, 7, and 10. Paired sample t tests, Pearson's correlation statistic, and simple linear regression were used to assess differences between treatments and associations among urinary metabolites. Urinary nitrogen/urinary creatinine rose from 12.3±1.7 g/g (99.6±13.8 mmol/mmol) to 16.8±2.2 g/g (135.5±17.8 mmol/mmol) with whey supplementation, but did not change with maltodextrin. Whey supplementation caused urinary calcium to rise by 4.76±1.84 mg (1.19±0.46 mmol) without a change in bone turnover markers. Because our goal was to estimate protein intake from urinary nitrogen/urinary creatinine, we used our data to develop the following equation: protein intake (g/day)=71.221+1.719×(urinary nitrogen, g)/creatinine, g) (R=0.46, R(2)=0.21). As a more rapid and less costly alternative to urinary nitrogen/urinary creatinine, we next determined whether urinary urea could predict protein intake and found that protein intake (g/day)=63.844+1.11×(urinary urea, g/creatinine, g) (R=0.58, R(2)=0.34). These data indicate that urinary urea/urinary creatinine is at least as good a marker of dietary protein intake as urinary nitrogen and is easier to quantitate in nutrition intervention trials.

Application of a mechanism-based disease systems model for osteoporosis to clinical data

A recently proposed mechanism-based disease systems model for osteoporosis (Schmidt et al., J Pharmacokinet Pharmacodyn 38:873-900, 2011) was applied to clinical data from post-menopausal women (n = 767) receiving various doses of the selective estrogen receptor modulator tibolone. Plasma bone-specific alkaline phosphatase activity and urinary N-telopeptide were used as biomarkers reflecting the activity of osteoblasts (bone forming cells) and osteoclasts (bone removing cells), respectively. These data were analyzed in conjunction with data on osteocalcin and on bone mineral density (BMD) (both lumbar spine and total hip), which reflect the activity of both cell types. While the dynamics of bone turnover markers changes rapidly, closely following changes in the activity of bone cells, changes in BMD are slower and have their own dynamics. Application of the mechanism-based disease systems model to the clinical data allowed for an adequate description of the data and yielded parameter estimates that are consistent with physiological values reported in the literature (Lemaire et al., J Theor Biol 229:293-309, 2004). The fitted model enabled characterization of (i) the critical time scales involved in disease progression, (ii) the dynamics of the system during onset and offset of the therapeutic intervention, and (iii) the distinction between responders and low-responders to tibolone treatment.

Dose-Dependent Short-Term Effects of Single High Doses of Oral Vitamin D3 on Bone Turnover Markers

We investigated the short-term effects on bone turnover markers of high doses of vitamin D(3) in order to identify what initial therapeutic dose can be safely administered in vitamin D-deficient subjects. Thirty-seven elderly subjects [mean age 75 ± 3 (SD) years] were consecutively randomized to the administration of a single oral bolus of 600000, 300000, or 100000 IU vitamin D(3). Blood samples were taken at baseline and 1, 3, 7, 14, 30, 60, and 90 days after vitamin D(3) administration. Twenty-four subjects served as controls. No relevant changes in bone turnover markers [C-terminal telopeptides of type I collagen (sCTX) and bone-specific alkaline phosphatase (BAP)] were observed in the controls. In treated patients a dose-dependent effect on sCTX was observed. With the administration of 600,000 IU vitamin D(3) a significant increase of sCTX was observed already at day 1, and it was sustained for 2 months. The changes in sCTX with smaller doses were considerably lower and reached statistical significance only within the first 3 days with the 300,000 IU dose. BAP remained unchanged in patients given 300,000 and 600,000 IU vitamin D(3), while it significantly rose by 15-23 % throughout the observation period in patients given 100,000 IU. Our results indicate that the use of a vitamin D bolus exceeding 100,000 IU may be associated with acute increases of sCTX.

Systematic Review of Bone Health in Older Women Treated with Aromatase Inhibitors for Early‐Stage Breast Cancer

To review data from randomized controlled trials (RCTs) that evaluate adverse bone outcomes in older women using aromatase inhibitors (AIs) for early-stage hormone receptor-positive breast cancer. Systematic review. International RCTs referenced in Medline and EMBASE databases through August 1, 2011. Postmenopausal women with early-stage hormone receptor-positive breast cancer receiving adjuvant endocrine therapy. Fracture rates and changes in bone turnover markers and bone mineral density. Eleven RCTs were identified. The majority of trials included women with a mean age in the 60s; and women aged 75 and older and 80 and older were excluded from two studies. Fracture rates ranged from 0.9% to 11%, with AIs having a 1.5 times higher risk than tamoxifen or placebo. Fracture data were not systematically collected in many of these trials. In a small subpopulation of women, AIs were associated with higher markers of bone turnover and lower bone density. The relationship between age and fracture was not described. AIs are associated with low bone density and high fracture risk in women with a mean age in their early 60s. There is a paucity of data describing the effect of baseline fracture risk factors, particularly age, and the longer-term effects on bone health in older women. Future research is needed regarding baseline fracture risk, interventions, and long-term effects on bone in this vulnerable population to inform management decisions to optimize AI duration and ensure quality of life after breast cancer.

Relationships Between Changes in Bone Mineral Density or Bone Turnover Markers and Vertebral Fracture Incidence in Patients Treated with Bazedoxifene

We analyzed the relationships between bone mineral density (BMD) or bone turnover marker (BTM) changes and vertebral fracture incidence in women treated with bazedoxifene using a post hoc analysis from a 3-year randomized, placebo-controlled study evaluating the effect of bazedoxifene (20 or 40mg) on fracture risk reduction. BMD was assessed at baseline and every 6months for 3years. Osteocalcin and C-telopeptide of type I collagen were assessed at baseline and at 3, 12, and 36months. Vertebral fractures were assessed with a semiquantitative visual assessment. Data were available for 5,244 women, of whom 3,476 were treated with bazedoxifene. Using a logistic regression analysis and the classical Li approach, the proportion of fracture incidence explained by BMD change after 3years of bazedoxifene treatment was 29% for the total hip and 44% for the femoral neck. The proportion of treatment explained by lumbar BMD change could not be quantified accurately because of the significant interaction between treatment and change in BMD. With the same model, the 12-month BTM changes explained up to 29% of the fracture risk reduction observed with the two forms of bazedoxifene. In women treated with bazedoxifene, changes in femoral neck BMD, hip BMD, or BTMs explained a moderate proportion of the fracture risk reduction observed during the 3years of follow-up. However, BMD or BTM changes cannot be recommended for individual monitoring of women treated with bazedoxifene.

Sclerostin and DKK1 in postmenopausal osteoporosis treated with denosumab

The bone mass benefits of antiresorbers in postmenopausal osteoporosis are limited by the rapid coupling of decreasing bone resorption with bone formation. Wnt signaling is involved in this coupling process during treatment with bisphosphonates, whereas its role during treatment with the anti-receptor activator of NF-κB ligand (RANKL) antibody denosumab is unknown. The study population includes patients participating in a placebo-controlled trial lasting 36 months: 19 women were on placebo and 24 on subcutaneous 60 mg denosumab every 6 months. All measured parameters (serum C-terminal telopeptide of type I collagen [sCTX], serum bone alkaline phosphatase [bAP], Dickkopf-1 [DKK1], and sclerostin) remained unchanged during the observation period in the placebo group. sCTX and bAP were significantly suppressed by denosumab treatment over the entire follow-up. Denosumab treatment was associated with significant (p < 0.05) increases (28% to 32%) in serum sclerostin over the entire study follow-up. Serum DKK1 significantly decreased within the first 6 months with a trend for further continuous decreases, which reached statistical significance (p < 0.05) versus placebo group from the 18th month onward. The changes in DKK1 were significantly and positively related with the changes in sCTX and bAP and negatively with hip bone mineral density (BMD) changes. The changes in sclerostin were significantly and negatively related only with those of bAP. The changes in bone turnover markers associated with denosumab treatment of postmenopausal osteoporosis is associated with significant increase in sclerostin similar to those seen after long-term treatment with bisphosphonates and significant decrease in DKK1. This latter observation might explain the continuous increase over 5 years in BMD observed during treatment of postmenopausal osteoporosis with denosumab.

Changes in bone biomarker concentrations and musculoskeletal symptoms among breast cancer patients initiating aromatase inhibitor therapy and women without a history of cancer

The objectives of this study were to examine: (1) changes in bone formation (osteocalcin) and bone resorption (cross-linked N-telopeptides of bone type I collagen [NTXs]) markers, as well as calcium, phosphorus, and intact parathyroid hormone, over the first 6 months of aromatase inhibitor (AI) therapy among a cohort of breast cancer patients compared with a group of unexposed women without a history of cancer; and (2) whether bone marker changes were associated with musculoskeletal pain. Eligible breast cancer patients (n = 49) and postmenopausal women without a history of cancer (n = 117) were recruited and followed for 6 months. At baseline, 3 months, and 6 months, a questionnaire was administered to assess pain and medication use, and a blood sample was drawn. Results showed that, among the breast cancer patients, calcium concentrations decreased significantly (-7.8% change; p = 0.013) and concentrations of NTXs increased significantly from baseline to 6 months (9.6% change; p = 0.012). Changes were not observed for women in the comparison group. Statistically significant differences in percent change between the breast cancer patients and the women in the comparison group were observed for calcium at 6 months (-7.8% versus 0.0%; p = 0.025), phosphorus at 6 months (-5.1% versus 16.7%; p = 0.003), NTXs at 6 months (9.6% versus -0.7%; p = 0.017), and osteocalcin at 6 months (11.5% versus -3.6%; p = 0.016). No statistically significant associations were observed between bone turnover marker changes and musculoskeletal pain among the breast cancer patients, although baseline NTXs were higher among women with onset or increase in pain compared with those reporting no pain (p = 0.08). Findings from this study suggest that AIs cause changes in bone turnover during the first 6 months of treatment; however, these changes are not associated with musculoskeletal pain. Breast cancer patients initiating AI therapy should be assessed and monitored for fracture risk using known clinical risk factors, including bone density, and managed appropriately.