Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial

Summary

Findings from this 5-year phase 3 study of postmenopausal women with osteoporosis showed that bazedoxifene was associated with an overall favorable safety and tolerability profile, with no evidence of endometrial or breast stimulation. Overall, the results at 5?years were consistent with those seen at 3?years.

Introduction

We report safety and tolerability findings from a 5-year randomized, double-blind, phase 3 study of bazedoxifene in postmenopausal women with osteoporosis.

Methods

In the core study, healthy postmenopausal women with osteoporosis (N?=?7,492; mean age, 66.4?years) were randomized to daily doses of bazedoxifene 20 or 40?mg, raloxifene 60?mg, or placebo for 3?years. During the 2-year study extension, the raloxifene 60-mg treatment arm was discontinued after the 3-year database was finalized, and subjects receiving bazedoxifene 40?mg were transitioned in a blinded manner to bazedoxifene 20?mg (bazedoxifene 40-/20-mg group) after 4?years. Safety and tolerability data are reported for subjects in the bazedoxifene 20- and 40-/20-mg and placebo groups; efficacy findings are reported elsewhere.

Results

A total of 3,146 subjects in the bazedoxifene 20- and 40-mg and placebo groups were enrolled in the extension study (years 4 and 5). Overall, the 5-year incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar among groups. The incidence of hot flushes and leg cramps was higher with bazedoxifene compared with placebo. Venous thromboembolic events, primarily deep vein thrombosis, were more frequently reported in the bazedoxifene groups compared with the placebo group. Reports of cardiac disorders and cerebrovascular events were few and evenly distributed among groups. Bazedoxifene showed a neutral effect on the breast and endometrium.

Conclusion

Bazedoxifene was associated with an overall favorable safety and tolerability profile in postmenopausal women with osteoporosis over 5?years of therapy, consistent with findings at 3?years.     

Effects of bazedoxifene on bone mineral density,bone turnover,and safety in postmenopausal japanese women with osteoporosis

This randomized, double‐blind, placebo‐controlled, dose‐response late phase 2 study evaluated the efficacy and safety of bazedoxifene in postmenopausal Japanese women 85 years of age or younger with osteoporosis. Eligible subjects received daily treatment with oral doses of bazedoxifene 20 or 40 mg or placebo for 2 years. Efficacy assessments included bone mineral density (BMD) at the lumbar spine and other skeletal sites, bone turnover marker levels, lipid parameters, and incidence of new fractures. Of 429 randomized subjects, 387 were evaluable for efficacy, and 423 were included in the safety analyses (mean age, 64 years). At 2 years, the mean percent changes from baseline in lumbar spine BMD were significantly greater with bazedoxifene 20 and 40 mg (2.43% and 2.74%, respectively) than with placebo (?0.65%, p < .001 for both). Both bazedoxifene doses significantly improved BMD at the total hip, femoral neck, and greater trochanter compared with placebo (p < .001 for all). Decreases in bone turnover markers were observed with bazedoxifene 20 and 40 mg as early as 12 weeks (p < .05 for all) and were sustained throughout the study. Total and low‐density lipoprotein cholesterol levels were significantly decreased from baseline with both bazedoxifene doses compared with placebo (p < .05 for all). Incidences of new vertebral and nonvertebral fractures were similar among the bazedoxifene and placebo groups. Overall, the incidence of adverse events with bazedoxifene 20 and 40 mg was similar to that with placebo. Bazedoxifene significantly improved BMD, reduced bone turnover, and was well tolerated in postmenopausal Japanese women with osteoporosis. © 2011 American Society for Bone and Mineral Research.     

Effects of Bazedoxifene on BMD and Bone Turnover in Postmenopausal Women: 2‐Yr Results of a Randomized,Double‐Blind,Placebo‐, and Active‐Controlled Study

Osteoporosis is an increasingly common health concern in postmenopausal women. In a 2‐yr phase III study, bazedoxifene prevented bone loss, reduced bone turnover, and was well tolerated in early postmenopausal women with normal or low BMD. Introduction : Bazedoxifene is a novel selective estrogen receptor modulator that has increased BMD and bone strength in experimental models, without stimulating breast or uterus. This 24‐mo, randomized, double‐blind study assessed the efficacy and safety of three doses of bazedoxifene compared with placebo and raloxifene in the prevention of postmenopausal osteoporosis. Materials and Methods : Healthy postmenopausal women with a BMD T‐score at the lumbar spine or femoral neck between –1.0 and ?2.5 or clinical risk factors for osteoporosis were randomly assigned to one of five groups: bazedoxifene 10, 20, or 40 mg/d, placebo, or raloxifene 60 mg/d. All women received elemental calcium. Efficacy outcomes included changes from baseline through 24 mo in BMD of the lumbar spine, hip, femoral neck, and femoral trochanter and biomarkers of bone metabolism. Results : The intent‐to‐treat population included 1434 women (mean age, 58 yr; mean time from last menstrual period, 11 yr). All doses of bazedoxifene and raloxifene prevented bone loss, whereas in the placebo group, there was significant loss of BMD at all skeletal sites. Mean differences in percent change in lumbar spine BMD from baseline to 24 mo relative to placebo were 1.08 ± 0.28%, 1.41 ± 0.28%, 1.49 ± 0.28%, and 1.49 ± 0.28% for 10, 20, and 40 mg bazedoxifene and 60 mg raloxifene, respectively (p < 0.001 for all comparisons). Comparable BMD responses were observed at other body sites. Significant and comparable decreases in serum osteocalcin and C‐telopeptide levels from baseline and relative to placebo with active treatment were observed as early as 3 mo and were sustained through study conclusion (p < 0.001). Overall incidences of adverse events, serious adverse events, and discontinuations caused by adverse events were similar between groups. The most common adverse events included headache, infection, arthralgia, pain, hot flush, and back pain. Conclusions : Treatment with bazedoxifene prevented bone loss and reduced bone turnover equally as well as raloxifene and was generally well tolerated in postmenopausal women with normal/low BMD.     

Vitamin D status in relation to obesity, bone mineral density, bone turnover markers and vitamin D receptor genotypes in healthy Saudi pre- and postmenopausal women

Summary

The various factors that may contribute to vitamin D deficiency or insufficiency were examined among healthy Saudi pre- and postmenopausal women. Vitamin D deficiency was highly prevalent among studied Saudi women with obesity, poor sunlight exposure, poor dietary vitamin D supplementation and age as the main risk factors.

Introduction

The various factors that may contribute to vitamin D deficiency or insufficiency in relation to bone health among Saudi women are not known. The main objectives of the present study were to determine the factors influencing vitamin D status in relation to serum 25-hydroxyvitamin D (25(OH)D), intact parathyroid hormone (PTH), bone turnover markers (BTMs), bone mineral density (BMD), and vitamin D receptor genotype (VDR) in healthy Saudi pre- and postmenopausal women.

Methods

A total number of 1,172 healthy Saudi women living in the Jeddah area were randomly selected and studied. Anthropometric parameters, socioeconomic status, sun exposure index together with serum levels of 25(OH)D, calcitriol, intact PTH, Ca, PO4, Mg, creatinine, albumin, and biochemical BTMs were measured. BMD was measured by a dual energy X-ray absorptiometry and VDR genotypes were also determined.

Results

About 80.0% of Saudi women studied exhibited vitamin D deficiency (serum 25(OH)D?<?50.0?nmol/L) with only 11.8% of all women were considered with adequate vitamin D status (serum 25(OH)D?>?75?nmol/L). Secondary hyperparathyroidism was evident in 18.5% and 24.6% in pre- and postmenopausal women with 25(OH)D?<?50?nmol/L. Serum 25(OH)D was lower (P?<?0.001) and intact PTH higher (P?<?0.001) in the upper quintiles of body mass index (BMI) and waist-to-hip ratio (WHR). Multiple linear regression analysis showed that BMI, sun exposure index, poor dietary vitamin D supplementation, WHR, and age were independent positive predictors of serum 25(OH)D values.

Conclusions

Vitamin D deficiency is highly prevalent among healthy Saudi pre-and postmenopausal women and largely attributed to obesity, poor exposure to sunlight, poor dietary vitamin D supplementation, and age.     

Use of risedronate to prevent bone loss following a single course of glucocorticoids: findings from a proof-of-concept study in inflammatory bowel disease

Summary

We performed a randomised controlled trial (RCT) to determine whether risedronate 35 mg once weekly prevents bone loss following an 8-week reducing course of prednisolone given for an exacerbation of inflammatory bowel disease (IBD). The greatest change in bone mineral density (BMD) was at Ward’s triangle (WT), which fell by 2.2% in the placebo group, compared with a reduction of 0.8% in the risedronate group.

Introduction

Whether bisphosphonates can prevent bone loss associated with intermittent glucocorticoid (GC) therapy is unknown, reflecting the difficulty in performing RCTs in this context.

Method

To explore the feasibility of RCTs to examine this question, lumbar spine (LS; L2–4) and hip dual X-ray absorptiometry (DXA) scans were performed in 78 patients commencing a GC therapy course for a relapse of IBD. They were then randomised to receive placebo or risedronate 35 mg weekly for 8 weeks, after which the DXA scan was repeated.

Results

For LS BMD, there was no change in the placebo group (0.1?±?0.4, p?=?0.9), but there was an increase after risedronate (0.8?±?0.4, p?=?0.04; mean%?±?SEM by paired Student’s t test). There were small decreases in both groups at the total hip (?0.5?±?0.3, p?=?0.04; ?0.5?±?0.3, p?<?0.05, placebo and risedronate, respectively). At WT, BMD fell after placebo (?2.2?±?0.5, p?=?0.001) but not risedronate (?0.8?±?0.5, p?=?0.09; p?=?0.05 for between-group comparison).

Conclusion

RCTs can be used to examine whether bisphosphonates prevent bone loss associated with intermittent GC therapy, providing metabolically active sites such as WT are employed as the primary outcome.     

Circulating activin-A is elevated in postmenopausal women with low bone mass: the three-month effect of zoledronic acid treatment

Summary

Activin-A is expressed in bone and seems to regulate osteoclastogenesis. In this study, serum activin-A was increased in postmenopausal women with low bone mass and was positively correlated to age and negatively to lumbar spinal bone mineral density (BMD). Serum activin-A levels did not change 3 months after zoledronic acid infusion.

Introduction

The aims of the study were to evaluate prospectively the circulating activin-A levels in postmenopausal women with low bone mass and explore possible correlations with clinical and laboratory data, as well as the 3-month effect of zoledronic acid infusion.

Methods

Postmenopausal women with low bone mass assigned to receive zoledronic acid infusion (Patients, n?=?47) and age-matched, postmenopausal women with normal bone mass (Controls, n?=?27) were recruited on an outpatient basis. Main outcome measurement was serum activin-A levels.

Results

Serum activin-A was higher in patients at baseline compared to controls (p?<?0.001) and activin-A in the serum of patients and controls was positively correlated with age (Spearman’s coefficient of correlation [rs]?=?0.325; p?=?0.005) and negatively with lumbar spinal (LS) BMD (rs?=??0.425; p?<?0.001). In multiple linear regression analysis, only age (B?=?8.93; 95 % CI?=?4.39–13.46; p?<?0.001) was associated with serum activin-A levels at baseline, independent from group (patients or controls), previous anti-osteoporotic treatment, LS BMD and follicle-stimulating hormone. Circulating activin-A levels were not affected 3 months after zoledronic acid infusion.

Conclusions

Serum activin-A is increased in postmenopausal women with low bone mass compared with postmenopausal women with normal bone mass and is positively correlated to age and negatively to LS BMD.     

Effects of morning vs. evening teriparatide injection on bone mineral density and bone turnover markers in postmenopausal osteoporosis

Summary

A 12-month morning teriparatide (TPTD) administration resulted in a larger increase in the lumbar spine bone mineral density (BMD) than the evening application. The results indicate that the response of bone cells to teriparatide treatment depends on dosing time.

Introduction

The aim of this study was to assess the long-term effects of the morning vs. the evening teriparatide administration on BMD and bone turnover markers (BTMs) in postmenopausal osteoporosis.

Methods

Fifty women with established postmenopausal osteoporosis were randomized to 12-month treatment with 20?μg of TPTD, administered daily in the morning or in the evening. The BMD and serum concentrations of C-terminal telopeptide of type I collagen, N-terminal propeptide of type I procollagen (PINP), and tartrate-resistant acid phosphatase isoform 5b (TRAP 5b) were measured at baseline, after 6 and 12?months. General linear model-repeated measurements were used to analyze the data.

Results

After 12?months, the lumbar spine BMD grew markedly (p?<?0.001) with a significantly greater increase in the morning arm compared to the evening arm (9.1% vs. 4.8%, respectively, p?<?0.05). The BMD at the distal radius significantly decreased (p?<?0.001), with no differences between the arms. The BMD at proximal femur did not change significantly. After 6 months, the BTMs were significantly increased compared with baseline (p?<?0.001). The increases in the evening arm vs. the morning arm, however, were more pronounced in PINP (+358% vs. +215%, respectively) and in TRAP 5b (+70% vs. +37%, respectively) (both p?<?0.05).

Conclusion

12-month morning administration of TPTD resulted in a larger increase in the lumbar spine BMD than the evening application. The timing of TPTD administration may be important for its efficacy.     

Comparative cost-effectiveness of bazedoxifene and raloxifene in the treatment of postmenopausal osteoporosis in Europe, using the FRAX algorithm

Summary

Bazedoxifene and raloxifene were evaluated in the treatment of postmenopausal osteoporosis from health economic perspective in Europe. Based on a computer-based algorithm calculating efficacy of the treatments, bazedoxifene appears to be a cost-effective strategy compared to raloxifene, particularly in patients at high fracture risk.

Introduction

The purpose of this study was to compare cost-effectiveness of bazedoxifene and raloxifene in eight European countries: Belgium, France, Germany, Ireland, Italy, Spain, Sweden, and the UK.

Methods

The Fracture Risk Assessment Tool, which is a computer-based algorithm to calculate fracture probability using clinical risk factors alone or with bone mineral density, was incorporated in a Markov Tunnel model to evaluate cost-effectiveness of bazedoxifene 20 or 40 mg vs. raloxifene 60 mg in postmenopausal osteoporotic women. The efficacy of bazedoxifene and raloxifene for vertebral and non-vertebral fractures was measured as a function of the 10-year probability of a major osteoporotic fracture. The model estimated the incremental cost-effectiveness ratio and net monetary benefit (NMB) from a healthcare perspective, given the willingness to pay €30,000.

Results

In postmenopausal osteoporotic women, bazedoxifene was a cost saving strategy compared to raloxifene in the countries studied. The median NMB of bazedoxifene compared to raloxifene increased monotonically with the 10-year fracture probability. In general, the median NMB became greater than 0 in women with 10-year probabilities of a major osteoporotic fracture between 5 and 10 % or above. The impact on results by varying the assumptions in the model was examined in sensitivity analysis.

Conclusion

Bazedoxifene appears to be a cost-effective strategy compared to raloxifene for the treatment of postmenopausal osteoporotic women in Europe, particularly in patients at high fracture risk.     

Effects of anti-resorptive agents on trabecular bone score (TBS) in older women

Summary

We evaluated the longitudinal effects of anti-resorptive agents (534 treated women vs. 1,150 untreated) on lumbar spine bone mineral density (BMD) and trabecular bone score (TBS). TBS was responsive to treatment in women over age 50. The treatment-related increase in TBS was less than the increase in BMD, which is consistent with bone texture preservation.

Introduction

In addition to inducing an increase in BMD, anti-resorptive agents also help to preserve bone architecture. TBS, a new gray-level texture measurement, correlates with 3D parameters of bone micro-architecture independent of BMD. Our objective was to evaluate the longitudinal effects of anti-resorptive agents on lumbar spine BMD and TBS.

Methods

Women (≥50 years), from the BMD program database for the province of Manitoba, Canada, who had not received any anti-resorptive drug prior to their initial dual X-ray absorptiometry (DXA) exam were divided into two groups: untreated, those without any anti-resorptive drug over the course of follow-up, and treated, those with a non-estrogen anti-resorptive drug (86 % bisphosphonates, 10 % raloxifene, and 4 % calcitonin). Lumbar spine TBS was calculated for each lumbar spine DXA examination. Changes in TBS and BMD between baseline and follow-up (mean follow-up 3.7 years), expressed in percentage per year, were compared between the two groups.

Results

A total of 1,150 untreated women and 534 treated women met the inclusion criteria. Only a weak correlation was seen between BMD and TBS in either group. Significant intergroup differences in BMD change and TBS change were observed over the course of follow-up (p?<?0.001). Similar mean decreases in BMD and TBS (?0.36 %/year and ?0.31 %/year, respectively) were seen for untreated subjects (both p?<?0.001). Conversely, treated subjects exhibited a significant mean increase in BMD (+1.86 %/year, p?<?0.002) and TBS (+0.20 %/year, p?<?0.001).

Conclusion

TBS is responsive to treatment with non-estrogen anti-resorptive drug therapy in women over age 50. The treatment-related increase in TBS is less than the increase in BMD, which is consistent with bone texture preservation.     

Comparative effects of teriparatide and ibandronate on spine bone mineral density (BMD) and microarchitecture (TBS) in postmenopausal women with osteoporosis: a 2-year open-label study

Summary

Treatment effects over 2 years of teriparatide vs. ibandronate in postmenopausal women with osteoporosis were compared using lumbar spine bone mineral density (BMD) and trabecular bone score (TBS). Teriparatide induced larger increases in BMD and TBS compared to ibandronate, suggesting a more pronounced effect on bone microarchitecture of the bone anabolic drug.

Introduction

The trabecular bone score (TBS) is an index of bone microarchitecture, independent of bone mineral density (BMD), calculated from anteroposterior spine dual X-ray absorptiometry (DXA) scans. The potential role of TBS for monitoring treatment response with bone-active substances is not established. The aim of this study was to compare the effects of recombinant human 1–34 parathyroid hormone (teriparatide) and the bisphosphonate ibandronate (IBN), on lumbar spine (LS) BMD and TBS in postmenopausal women with osteoporosis.

Methods

Two patient groups with matched age, body mass index (BMI), and baseline LS BMD, treated with either daily subcutaneous teriparatide (N?=?65) or quarterly intravenous IBN (N?=?122) during 2 years and with available LS BMD measurements at baseline and 2 years after treatment initiation were compared.

Results

Baseline characteristics (overall mean ± SD) were similar between groups in terms of age 67.9?±?7.4 years, body mass index 23.8?±?3.8 kg/m², BMD L1–L4 0.741?±?0.100 g/cm², and TBS 1.208?±?0.100. Over 24 months, teriparatide induced a significantly larger increase in LS BMD and TBS than IBN (+7.6 %?±?6.3 vs. +2.9 %?±?3.3 and +4.3 %?±?6.6 vs. +0.3 %?±?4.1, respectively; P?<?0.0001 for both). LS BMD and TBS were only weakly correlated at baseline (r ²?=?0.04) with no correlation between the changes in BMD and TBS over 24 months.

Conclusions

In postmenopausal women with osteoporosis, a 2-year treatment with teriparatide led to a significantly larger increase in LS BMD and TBS than IBN, suggesting that teriparatide had more pronounced effects on bone microarchitecture than IBN.     

BMD improvements after operation for primary hyperparathyroidism

Purpose

This study aims to quantify bone mineral density (BMD) changes following surgery in patients with primary hyperparathyroidism (PHPT) and to assess their relationship with clinical and biochemical variables.

Methods

A historic cohort of 236 PHPT patients with DXA scans pre- and 1-year postoperatively, clinical data, and biochemical data was analyzed.

Results

The mean age was 60 years (range 19–86) and 81 % of the patients were women. A significant postoperative 2.6 % (95 % CI, 2.1; 3.1) increase in lumbar spine BMD was seen. The increase in BMD was positively associated with preoperative plasma PTH (p?=?0.002), Ca²⁺ (p?<?0.001), and alkaline phosphatase (p?=?0.014). Hip BMD increased 1.5 % (1.1; 1.9). The increase in BMD was positively associated with preoperative plasma PTH (p?=?0.005) and Ca²⁺ (p?<?0.001) and inversely associated with plasma creatinine (p?=?0.004) and age (p?=?0.018). Total forearm BMD did not change significantly (?0.2 % (?0.5; 0.1)). An increase in forearm BMD was seen in 38 % of all patients, and the changes were positively associated with plasma PTH (p?<?0.001) and Ca²⁺ (p?=?0.009). In all 91 patients with mild PHPT (plasma Ca²⁺?<?1.45 mmol/l), there was a significant postoperative increase in spine BMD (1.9 % (1.2; 2.7)) and in hip BMD (1.0 % (0.4; 1.6)), but not in the forearm BMD (?0.3 % (?0.7; 0.2)). The postoperative BMD gain was higher in the hip and forearm in patients operated for adenomas compared with patients treated for hyperplasia.

Conclusions

We found significant postoperative BMD improvements both at the hip and the spine. BMD improvements were also significant in mild cases. At all scan sites, there were positive associations between preoperative plasma PTH levels and postoperative BMD increases. The measured BMD changes may mainly be due to a decrease in PTH-induced bone turnover with refilling of the remodeling space.     

Sustained efficacy and safety of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study

Summary  

In this 2-year extension of a 3-year study, bazedoxifene showed sustained efficacy in preventing new vertebral fractures in postmenopausal women with osteoporosis and in preventing non-vertebral fractures in higher-risk women. Bazedoxifene significantly increased bone mineral density and reduced bone turnover versus placebo and was generally safe and well tolerated.     

Characterizing microarchitectural changes at the distal radius and tibia in postmenopausal women using HR-pQCT

Summary

Limited prospective evidence exists regarding bone microarchitectural deterioration. We report annual changes in trabecular and cortical bone microarchitecture at the distal radius and tibia in postmenopausal women. Lost trabeculae with corresponding increase in trabecular thickness at the radius and thinning tibial cortex indicated trabecularization of the cortex at both sites.

Introduction

Osteoporosis is characterized by low bone mass and the deterioration of bone microarchitecture. However, limited prospective evidence exists regarding bone microarchitectural changes in postmenopausal women: a population prone to sustaining osteoporotic fractures. Our primary objective was to characterize the annual change in bone area, density, and microarchitecture at the distal radius and distal tibia in postmenopausal women.

Methods

Distal radius and tibia were measured using high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 1 year later in 51 women (mean age?±?SD, 77?±?7 years) randomly sampled from the Saskatoon cohort of the Canadian Multicentre Osteoporosis Study (CaMos). We used repeated measures analysis of variance (ANOVA) with Bonferroni adjustment for multiple comparisons to characterize the mean annual change in total density, cortical perimeter, trabecular and cortical bone area, density, content, and microarchitecture. Significant changes were accepted at P?<?0.05.

Results

At the distal radius in women without bone-altering drugs, total density (?1.7 %) and trabecular number (?6.4 %) decreased, while trabecular thickness (+6.0 %), separation (+8.6 %), and heterogeneity (+12.1 %) increased. At their distal tibia, cortical area (?4.5 %), density (?1.9 %), content (?6.3 %), and thickness (?4.4 %) decreased, while trabecular area (+0.4 %) increased.

Conclusions

The observed loss of trabeculae with concomitant increase in trabecular size at the distal radius and the declined cortical thickness, density, and content at the distal tibia indicated a site-specific trabecularization of the cortical bone in postmenopausal women.     

IL-17A-mediated sRANK ligand elevation involved in postmenopausal osteoporosis

Summary

The role of proinflammatory IL-17 cytokine was studied in postmenopausal bone loss between 31 osteopenic and 41 osteoporotic women. The effect of serum IL-17A, soluble receptor activator of NF-κB (sRANK) ligand, and osteoprotegerin (OPG) levels on lumbar bone mineral densities was measured. The results demonstrated an increased IL-17A-mediated sRANK ligand elevation in postmenopausal osteoporotic bone loss.

Introduction

IL-17 proinflammatory cytokine is a new inducer of bone loss. Postmenopausal osteoporosis represents a cross talk between estrogen deprivation and increased immune reactivity. The role of IL-17 was studied in the bone loss of postmenopausal osteoporosis.

Methods

Serum IL-17A, sRANK ligand, and OPG levels were investigated on bone mineral densities (BMDs) in the total lumbar (L1–L4) region in 18 pre- and 72 postmenopausal women. IL-17A, sRANK ligand, OPG levels, and BMDs were measured with enzyme-linked immunosorbent assay (ELISA) and dual-energy X-ray absorptiometry (DXA).

Results

Increased serum IL-17A, sRANK ligand, and OPG levels were demonstrated in postmenopausal osteoporotic women compared to osteopenic women (3.65?±?0.61 vs 3.31?±?0.43 ng/ml for IL-17A, P?<?0.007; 2.88?±?0.84 vs 2.49?±?0.61 ng/ml for sRANK ligand, P?<?0.027; and 1.43?±?0.07 vs 1.39?±?0.07 ng/ml for OPG, P?<?0.038). In postmenopausal women, IL-17A levels correlated inversely with total lumbar BMDs (P?<?0.008, r?=??0.279) and positively with sRANK ligand levels (P?<?0.0001, r?=?0.387) or the ratio of sRANK ligand and OPG (P?<?0.013, r?=?0.261), but did not with OPG levels alone.

Conclusion

Increased IL-17A levels are involved in postmenopausal osteoporosis, playing a role in the bone-resorpting processes.     

Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis

Summary

Vertebral fractures are a major adverse consequence of osteoporosis. In a large placebo-controlled trial in postmenopausal women with osteoporosis, strontium ranelate reduced vertebral fracture risk by 33% over 4 years, confirming the role of strontium ranelate as an effective long-term treatment in osteoporosis.

Introduction

Osteoporotic vertebral fractures are associated with increased mortality, morbidity, and loss of quality-of-life (QoL). Strontium ranelate (2 g/day) was shown to prevent bone loss, increase bone strength, and reduce vertebral and peripheral fractures. The preplanned aim of this study was to evaluate long-term efficacy and safety of strontium ranelate.

Methods

A total of 1,649 postmenopausal osteoporotic women were randomized to strontium ranelate or placebo for 4 years, followed by a 1-year treatment-switch period for half of the patients. Primary efficacy criterion was incidence of patients with new vertebral fractures over 4 years. Lumbar bone mineral density (BMD) and QoL were also evaluated.

Results

Over 4 years, risk of vertebral fracture was reduced by 33% with strontium ranelate (risk reduction?=?0.67, p?<?0.001). Among patients with two or more prevalent vertebral fractures, risk reduction was 36% (p?<?0.001). QoL, assessed by the QUALIOST®, was significantly better (p?=?0.025), and patients without back pain were greater (p?=?0.005) with strontium ranelate than placebo over 4 years. Lumbar BMD increased over 5 years in patients who continued with strontium ranelate, while it decreased in patients who switched to placebo. Emergent adverse events were similar between groups.

Conclusion

In this 4- and 5-year study, strontium ranelate is an effective and safe treatment for long-term treatment of osteoporosis in postmenopausal women.     

Effect of once-yearly zoledronic acid on the spine and hip as measured by quantitative computed tomography: results of the HORIZON Pivotal Fracture Trial

Summary

Changes in bone mineral density and bone strength following treatment with zoledronic acid (ZOL) were measured by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA). ZOL treatment increased spine and hip BMD vs placebo, assessed by QCT and DXA. Changes in trabecular bone resulted in increased bone strength.

Introduction

To investigate bone mineral density (BMD) changes in trabecular and cortical bone, estimated by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA), and whether zoledronic acid 5 mg (ZOL) affects bone strength.

Methods

In 233 women from a randomized, controlled trial of once-yearly ZOL, lumbar spine, total hip, femoral neck, and trochanter were assessed by DXA and QCT (baseline, Month 36). Mean percentage changes from baseline and between-treatment differences (ZOL vs placebo, t-test) were evaluated.

Results

Mean between-treatment differences for lumbar spine BMD were significant by DXA (7.0%, p?<?0.01) and QCT (5.7%, p?<?0.0001). Between-treatment differences were significant for trabecular spine (p?=?0.0017) [non-parametric test], trabecular trochanter (10.7%, p?<?0.0001), total hip (10.8%, p?<?0.0001), and compressive strength indices at femoral neck (8.6%, p?=?0.0001), and trochanter (14.1%, p?<?0.0001).

Conclusions

Once-yearly ZOL increased hip and spine BMD vs placebo, assessed by QCT vs DXA. Changes in trabecular bone resulted in increased indices of compressive strength.     

Impaired trabecular and cortical microarchitecture in daughters of women with osteoporotic fracture: the MODAM study

Summary

We investigated the familial resemblance of bone microarchitecture parameters between postmenopausal mothers with fragility fracture and their premenopausal daughters using high-resolution peripheral quantitative computed tomography (HR-pQCT). We found that daughters of women with fracture have lower total volumetric bone mineral density (vBMD), thinner cortices, and impaired trabecular microarchitecture at the distal radius and tibia, compared to controls.

Introduction

Familial resemblance of areal bone mineral density (aBMD) in mothers and daughters has been widely studied, but not its morphological basis, including microarchitecture.

Methods

We compared aBMD, vBMD, bone size, and bone microarchitecture at the distal radius and tibia assessed by HR-pQCT in mothers and their premenopausal daughters. We included 115 women aged 43?±?8 years whose mothers had sustained a fragility fracture and 206 women aged 39?±?9 years whose mothers had never sustained a fragility fracture.

Results

Women whose mothers had fracture had significantly (p?<?0.05) lower aBMD at the lumbar spine, total hip, femoral neck, mid-distal radius, and ultradistal radius compared to controls. In similar multivariable models, women whose mothers had a fracture had lower total vBMD at the distal radius (?5 %, 0.3 standard deviation [SD]; p?<?0.005) and distal tibia (?7 %, 0.4 SD; p?<?0.005). They also had lower cortical thickness and area at the distal radius (?5 %, 0.3 SD and ?4 %, 0.2 SD, respectively; p?<?0.005) and at the distal tibia (?6 %, 0.3 SD and ?4 %, 0.3SD, respectively; p?<?0.005). Trabecular vBMD was lower at the distal radius (?5 %, 0.3 SD; p?<?0.05) and tibia (?8 %, 0.4 SD; p?<?0.005), with a more spaced and heterogeneous trabecular network (4 and 7 % at the radius and 5 and 9 %, at the tibia, p?<?0.05, for Tb.Sp and Tb.Sp.SD, respectively).

Conclusion

Premenopausal daughters of women who had sustained fragility fracture have lower total and trabecular vBMD, thinner cortices, as well as impaired trabecular microarchitecture at the distal radius and tibia, compared with premenopausal daughters of women without fracture.     

Maintenance of antifracture efficacy over 10?years with strontium ranelate in postmenopausal osteoporosis

Summary

In an open-label extension study, BMD increased continuously with strontium ranelate over 10?years in osteoporotic women (P?P?Introduction Strontium ranelate has proven efficacy against vertebral and nonvertebral fractures, including hip, over 5?years in postmenopausal osteoporosis. We explored long-term efficacy and safety of strontium ranelate over 10?years.

Methods

Postmenopausal osteoporotic women participating in the double-blind, placebo-controlled phase 3 studies SOTI and TROPOS to 5?years were invited to enter a 5-year open-label extension, during which they received strontium ranelate 2?g/day (n?=?237, 10-year population). Bone mineral density (BMD) and fracture incidence were recorded, and FRAX? scores were calculated. The effect of strontium ranelate on fracture incidence was evaluated by comparison with a FRAX?-matched placebo group identified in the TROPOS placebo arm.

Results

The patients in the 10-year population had baseline characteristics comparable to those of the total SOTI/TROPOS population. Over 10?years, lumbar BMD increased continuously and significantly (P?P?Conclusions Long-term treatment with strontium ranelate is associated with sustained increases in BMD over 10?years, with a good safety profile. Our results also support the maintenance of antifracture efficacy over 10?years with strontium ranelate.     

Higher serum uric acid is associated with higher bone mass, lower bone turnover, and lower prevalence of vertebral fracture in healthy postmenopausal women

Summary

Higher serum uric acid (UA) was associated with higher bone mass, lower bone turnover, and lower prevalence of vertebral fracture in postmenopausal women. Furthermore, UA suppressed osteoclastogenesis and decreased production of reactive oxygen species in osteoclast precursors, indicating UA may have beneficial effects on bone metabolism as an antioxidant.

Introduction

UA is known to play a physiological role as an antioxidant, and oxidative stress has detrimental effects on bone metabolism. In the present study, we investigated the association of serum UA level with the osteoporosis-related phenotypes and its direct effect on bone-resorbing osteoclasts using in vitro systems.

Methods

This is a large cross-sectional study, including 7,502 healthy postmenopausal women. Bone mineral density (BMD) and serum UA concentrations were obtained from all subjects. Data on bone turnover markers and lateral thoracolumbar radiographs were available for 1,023 and 6,918 subjects, respectively. An in vitro study investigated osteoclastogenesis and reactive oxygen species (ROS) levels according to UA treatment.

Results

After adjusting for multiple confounders, serum UA levels were positively associated with BMD at all sites (all p?<?0.001). Compared with the participants in the highest UA quartile, the odds for osteoporosis were 40 % higher in those in the lowest quartile. The serum UA levels were inversely related to both serum C-terminal telopeptide of type I collagen and osteocalcin levels (p?<?0.001 and p?=?0.004, respectively). Consistently, subjects with vertebral fracture had lower serum UA levels, compared with those without it (p?=?0.009). An in vitro study showed that UA decreased osteoclastogenesis in a dose-dependent manner and reduced the production of ROS in osteoclast precursors.

Conclusion

These results provide epidemiological and experimental evidence that serum UA may have a beneficial effect on bone metabolism as an antioxidant in postmenopausal women.     

Association between coronary artery calcification using low-dose MDCT coronary angiography and bone mineral density in middle-aged men and women

Summary

Six hundred sixty-one participants who had at least one cardiac risk factor but were without known coronary heart disease underwent low-dose multidetector computed tomography coronary angiography (MDCT-CA) and dual-energy X-ray absorptiometry. The association between presence of subclinical coronary calcified plaque and low bone mineral density for the middle-aged individual was not significant after multivariate adjustment.

Introduction

Results of previous clinical studies assessing the relationship between osteoporosis and coronary calcification are inconsistent. This study aimed to evaluate the association between subclinical coronary calcification and osteoporosis in middle-aged men, premenopausal women, and postmenopausal women by using low-dose MDCT-CA and bone mineral density (BMD).

Methods

This study enrolled 661 participants with at least one cardiac risk factor but without known coronary artery disease (CAD). All subjects underwent low-dose MDCT-CA and dual-energy X-ray absorptiometry on the same day.

Results

The mean age was 52.2 years for men, 44.8 years for premenopausal women, and 59.1 years for postmenopausal women. The prevalence of calcified plaques between men with normal BMD and low BMD at lumbar spine were significantly different (P?=?0.042). The prevalence of mixed plaque and calcified plaque between pre- and postmenopausal women with normal BMD and low BMD at lumbar spine and femoral neck were not significantly different (P?>?0.05). Possible association between lumbar spine, femoral neck, and total proximal femur BMD and the presence of CAP was evaluated for men, premenopausal women, and postmenopausal women using multivariate logistic regression analysis: results were not significant (P?>?0.05).

Conclusion

Our study demonstrates that the association between the presence of subclinical coronary calcification and low BMD among middle-aged men and women was not significant after controlling for age and other risk factors for CAD and osteoporosis.