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See detailTreatment of osteoporosis in men.
Kaufman, JM; Reginster, Jean-Yves ULg; Boonen, S et al

in BONE (2013), 53(1), 134-44

SUMMARY: Aspects of osteoporosis in men, such as screening and identification strategies, definitions of diagnosis and intervention thresholds, and treatment options (both approved and in the pipeline ... [more ▼]

SUMMARY: Aspects of osteoporosis in men, such as screening and identification strategies, definitions of diagnosis and intervention thresholds, and treatment options (both approved and in the pipeline) are discussed. INTRODUCTION: Awareness of osteoporosis in men is improving, although it remains under-diagnosed and under-treated. A European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) workshop was convened to discuss osteoporosis in men and to provide a report by a panel of experts (the authors). METHODS: A debate with an expert panel on preselected topics was conducted. RESULTS AND CONCLUSIONS: Although additional fracture data are needed to endorse the clinical care of osteoporosis in men, consensus views were reached on diagnostic criteria and intervention thresholds. Empirical data in men display similarities with data acquired in women, despite pathophysiological differences, which may not be clinically relevant. Men should receive treatment at a similar 10-year fracture probability as in women. The design of mixed studies may reduce the lag between comparable treatments for osteoporosis in women becoming available in men. [less ▲]

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See detailHigh-throughput quantification of the mechanical competence of murine femora - A highly automated approach for large-scale genetic studies
Ruffoni, Davide ULg; Kohler, T.; Voide, R. et al

in BONE (2013), 55(1), 216-221

Animal models are widely used to gain insight into the role of genetics on bone structure and function. One of the main strategies to map the genes regulating specific traits is called quantitative trait ... [more ▼]

Animal models are widely used to gain insight into the role of genetics on bone structure and function. One of the main strategies to map the genes regulating specific traits is called quantitative trait loci (QTL) analysis, which generally requires a very large number of animals (often more than 1000) to reach statistical significance. QTL analysis for mechanical traits has been mainly based on experimental mechanical testing, which, in view of the large number of animals, is time consuming. Hence, the goal of the present work was to introduce an automated method for large-scale high-throughput quantification of the mechanical properties of murine femora. Specifically, our aims were, first, to develop and validate an automated method to quantify murine femoral bone stiffness. Second, to test its high-throughput capabilities on murine femora from a large genetic study, more specifically, femora from two growth hormone (GH) deficient inbred strains of mice (B6-lit/lit and C3.B6-lit/lit) and their first (F1) and second (F2) filial offsprings. Automated routines were developed to convert micro-computed tomography (micro-CT) images of femora into micro-finite element (micro-FE) models. The method was experimentally validated on femora from C57BL/6J and C3H/HeJ mice: for both inbred strains the micro-FE models closely matched the experimentally measured bone stiffness when using a single tissue modulus of 13.06 GPa. The mechanical analysis of the entire dataset (n = 1990) took approximately 44 CPU hours on a supercomputer. In conclusion, our approach, in combination with QTL analysis could help to locate genes directly involved in controlling bone mechanical competence. (C) 2013 Elsevier Inc. All rights reserved. [less ▲]

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See detailStrain-adaptive in silico modeling of bone adaptation - A computer simulation validated by in vivo micro-computed tomography data
Schulte, Friederike A.; Zwahlen, Alexander; Lambers, Floor M. et al

in BONE (2013), 52(1), 485-492

Computational models are an invaluable tool to test different mechanobiological theories and, if validated properly, for predicting changes in individuals over time. Concise validation of in silico models ... [more ▼]

Computational models are an invaluable tool to test different mechanobiological theories and, if validated properly, for predicting changes in individuals over time. Concise validation of in silico models, however, has been a bottleneck in the past due to a lack of appropriate reference data. Here, we present a strain-adaptive in silico algorithm which is validated by means of experimental in vivo loading data as well as by an in vivo ovariectomy experiment in the mouse. The maximum prediction error following four weeks of loading resulted in 2.4% in bone volume fraction (BV/TV) and 8.4% in other bone structural parameters. Bone formation and resorption rate did not differ significantly between experiment and simulation. The spatial distribution of formation and resorption sites matched in 55.4% of the surface voxels. Bone loss was simulated with a maximum prediction error of 12.1% in BV/TV and other bone morphometric indices, including a saturation level after a few weeks. Dynamic rates were more difficult to be accurately predicted, showing evidence for significant differences between simulation and experiment (p<0.05). The spatial agreement still amounted to 47.6%. In conclusion, we propose a computational model which was validated by means of experimental in vivo data. The predictive value of an in silico model may become of major importance if the computational model should be applied in clinical settings to predict bone changes due to disease and test the efficacy of potential pharmacological interventions. (C) 2012 Elsevier Inc. All rights reserved. [less ▲]

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See detailTrabecular bone adapts to long-term cyclic loading by increasing stiffness and normalization of dynamic morphometric rates
Lambers, Floor M.; Koch, Kathleen; Kuhn, Gisela et al

in BONE (2013), 55(2), 325-334

Bone has the ability to adapt to external loading conditions. Especially the beneficial effect of short-term cyclic loading has been investigated in a number of in vivo animal studies. The aim of this ... [more ▼]

Bone has the ability to adapt to external loading conditions. Especially the beneficial effect of short-term cyclic loading has been investigated in a number of in vivo animal studies. The aim of this study was to assess the long-term effect (>10 weeks) of cyclic mechanical loading on the bone microstructure, bone stiffness, and bone remodeling rates. Mice were subjected to cyclic mechanical loading at the sixth caudal vertebra with 8 N or 0 N (control) three times per week for a total period of 14 weeks. Structural bone parameters were determined from in vivo micro-computed tomography (micro-CT) scans performed at week 0, 4, 6, 8, 10, 12, and 14. Mechanical parameters were derived from micro-finite element analysis. Dynamic bone morphometry was calculated using registration of serial micro-CT scans. Bone volume fraction and trabecular thickness increased significantly more for the loaded group than for the control group (p = 0.006 and p = 0.002 respectively). The trabecular bone microstructure adapted to the load of 8 N in approximately ten weeks, indicated by the trabecular bone volume fraction, which increased from 16.7% at 0 weeks to 21.6% at week 10 and only showed little change afterwards (bone volume fraction of 21.5% at 14 weeks). Similarly bone stiffness - (at the start of the experiment 649 N/mm) - reached 846 N/mm at 10 weeks in the loaded group and was maintained to the end of the experiment (850 N/mm). At 4 weeks the bone formation rate was 32% greater and the bone resorption rate 22% less for 8 N compared to 0 N. This difference was significantly reduced as the bone adapted to 8 N, with 8 N remodeling rates returning to the values of the 0 N group at approximately 10 weeks. Together these data suggest that once bone has adapted to a new loading state, the remodeling rates reduce gradually while maintaining bone volume fraction and stiffness. (C) 2013 Elsevier Inc. All rights reserved. [less ▲]

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See detailMineralization kinetics in murine trabecular bone quantified by time-lapsed in vivo micro-computed tomography
Lukas, Carolin; Ruffoni, Davide ULg; Lambers, Floor M. et al

in BONE (2013), 56(1), 55-60

Trabecular bone is a highly dynamic tissue due to bone remodeling, mineralization and demineralization. The mineral content and its spatial heterogeneity are main contributors to bone quality. Using time ... [more ▼]

Trabecular bone is a highly dynamic tissue due to bone remodeling, mineralization and demineralization. The mineral content and its spatial heterogeneity are main contributors to bone quality. Using time-lapsed in vivo micro-computed tomography (micro-CT), it is now possible to resolve in three dimensions where bone gets resorbed and deposited over several weeks. In addition, the gray values in the micro-CT images contain quantitative information about the local tissue mineral density (TMD). The aim of this study was to measure how TMD increases with time after new bone formation and how this mineralization kinetics is influenced by mechanical stimulation. Our analysis of changes in TMD was based on an already reported experiment on 15-week-old female mice (C57BL/6), where in one group the sixth caudal vertebra was mechanically loaded with 8 N, while in the control group no loading was applied. Comparison of two consecutive images allows the categorization of bone into newly formed, resorbed, and quiescent bone for different time points. Gray values of bone in these categories were compared layer-wise to minimize the effects of beam hardening artifacts. Quiescent bone in the control group was found to mineralize with a rate of 8 +/- 1 mgHA/cm(3) per week, which is about half as fast as observed for newly formed bone. Mechanical loading increased the rate of mineral incorporation by 63% in quiescent bone. The week before bone resorption, demineralization could be observed with a drop of TMD by 36 +/- 4 mgHA/cm(3) in the control and 34 +/- 3 mgHA/cm(3) in the loaded group. In conclusion, this study shows how time-lapsed in vivo micro-CT can be used to assess changes in TMD of bone with high spatial and temporal resolution. This will allow a quantification of how bone diseases and pharmaceutical interventions influence not only microarchitecture of trabecular bone, but also its material quality. (C) 2013 Elsevier Inc. All rights reserved. [less ▲]

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See detailAntidepressant medications and osteoporosis
Rizzoli, R; Cooper, C; Reginster, Jean-Yves ULg et al

in BONE (2012), 51

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See detailBisphosphonates and glucocorticoid osteoporosis in men: results of a randomized controlled trial comparing zoledronic acid with risedronate.
Sambrook, P. N.; Roux, C.; Devogelaer, J. P. et al

in BONE (2012), 50

BACKGROUND: We studied 265 men (mean age 56.4years; range 18-83years), among patients enrolled in two arms of a double-blind, 1-year study comparing the effects of zoledronic acid (ZOL) with risedronate ... [more ▼]

BACKGROUND: We studied 265 men (mean age 56.4years; range 18-83years), among patients enrolled in two arms of a double-blind, 1-year study comparing the effects of zoledronic acid (ZOL) with risedronate (RIS) in patients either commencing (prednisolone 7.5mg/day or equivalent) (prevention arm, n=88) or continuing glucocorticoid therapy (treatment arm, n=177). METHODS: Patients received either a single ZOL 5mg infusion or RIS 5mg oral daily at randomization, along with calcium (1000mg) and vitamin D (400-1200IU). Primary endpoint: difference in percentage change from baseline in bone mineral density (BMD) at the lumbar spine (LS) at 12months. Secondary endpoints: percentage changes in BMD at total hip (TH) and femoral neck (FN), relative changes in bone turnover markers (beta-CTx and P1NP), and overall safety. FINDINGS: In the treatment subpopulation, ZOL increased LS BMD by 4.7% vs. 3.3% for RIS and at TH the percentage changes were 1.8% vs. 0.2%, respectively. In the prevention subpopulation, bone loss was prevented by both treatments. At LS the percentage changes were 2.5% vs. -0.2% for ZOL vs. RIS and at TH the percentage changes were 1.1% vs. -0.4%, respectively. ZOL significantly increased lumbar spine BMD more than RIS at Month 12 in both the prevention population (p=0.0024) and the treatment subpopulation (p=0.0232) in men. In the treatment subpopulation, ZOL demonstrated a significantly greater reduction in serum beta-CTx and P1NP relative to RIS at all time-points. In the prevention subpopulation, ZOL significantly reduced beta-CTx at all time-points, and P1NP at Month 3 (p=0.0297) only. Both treatments were well tolerated in men, albeit with a higher incidence of influenza-like illness and pyrexia events post-infusion with ZOL. INTERPRETATION: Once-yearly ZOL preserves or increases BMD within 1year to a greater extent than daily RIS in men receiving glucocorticoid therapy. [less ▲]

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See detailRisk of nonvertebral fractures among elderly postmenopausal women using antidepressants
Rabenda, Véronique ULg; Bruyère, Olivier ULg; REGINSTER, Jean-Yves ULg

in Bone (2012), 51(4), 674-679

Objective: To examine the association between antidepressants, including TCAs, SSRIs, and miscellaneous antidepressants and the risk of nonvertebral fractures among women with osteoporosis. Materials and ... [more ▼]

Objective: To examine the association between antidepressants, including TCAs, SSRIs, and miscellaneous antidepressants and the risk of nonvertebral fractures among women with osteoporosis. Materials and methods: This study was a post-hoc analysis of pooled data from two international, phase III, randomized, placebo-controlled, double-blind studies (the Spinal Osteoporosis Therapeutic Intervention [SOTI] and TReatment Of Peripheral OSteoporosis [TROPOS]). A nested case-control study was performed in the placebo treated population. Adjusted logistic regression models were used to estimate the risk of nonvertebral fracture associated with the use of antidepressants. Results: After 3. years of follow-up, 391 nonvertebral fractures cases were identified and matched to 1955 controls. Compared with non-users of antidepressants, antidepressants use was associated with an increased risk of nonvertebral fractures (adjusted OR=1.64; 95%CI, 1.03-2.62]). Particularly, there was a 2-fold risk increase (95%CI, 1.07-3.79) of nonvertebral fracture for current users of SSRIs and a 2.1-fold risk increase for subjects who were current users of TCAs (95%CI, 1.02-4.30). Among patients categorized as recent or past users, none of the classes of antidepressants were statistically associated with increased risk of nonvertebral fracture. Conclusions: Our findings confirm that both SSRIs and TCAs increase the risk of nonvertebral fracture in current users. © 2012 Elsevier Inc. [less ▲]

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See detailThe different contributions of cortical and trabecular bone to implant anchorage in a human vertebra
Ruffoni, Davide ULg; Wirth, Andreas J.; Steiner, Juri A. et al

in BONE (2012), 50(3), 733-738

The quality of the pen-implant bone and the strength of the bone-implant interface are important factors for implant anchorage. With regard to pen-implant bone, cortical and trabecular compartments both ... [more ▼]

The quality of the pen-implant bone and the strength of the bone-implant interface are important factors for implant anchorage. With regard to pen-implant bone, cortical and trabecular compartments both contribute to the load transfer from the implant to the surrounding bone but their relative roles have yet to be investigated in detail. However, this knowledge is crucial for the better understanding of implant failure and for the development of new implants. This is especially true for osteoporotic bone, which is characterized by a deterioration of the trabecular architecture and a thinning of the cortical shell, leading to a higher probability of implant loosening. The aim of this study was to investigate the relative biomechanical roles of cortical and trabecular bone on implant pull-out stiffness in human vertebrae. The starting point of our investigation was a micro-computed tomography scan of an adult human vertebra. The cortical shell was identified and an implant was digitally inserted into the vertebral body. Pull-out tests were simulated with micro-finite element analysis and the apparent stiffness of the system with various degrees of shell thickness and bone volume fraction was computed. Our computational models demonstrated that cortical bone, although being very thin, plays a major role in the mechanical competence of the bone-implant construct. (C) 2011 Elsevier Inc. All rights reserved. [less ▲]

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See detailNitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase.
Stresing, Verena; Fournier, Pierrick G; Bellahcene, Akeila ULg et al

in Bone (2011), 48(2), 259-66

Nitrogen-containing bisphosphonates (N-BPs) are widely used to block bone destruction associated with bone metastasis because they are effective inhibitors of osteoclast-mediated bone resorption. More ... [more ▼]

Nitrogen-containing bisphosphonates (N-BPs) are widely used to block bone destruction associated with bone metastasis because they are effective inhibitors of osteoclast-mediated bone resorption. More specifically, once internalized by osteoclasts, N-BPs block the activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway. In addition to their antiresorptive activity, preclinical evidence shows that N-BPs have antiangiogenic properties. However, the exact reasons for which N-BPs inhibit angiogenesis remain largely unknown. Using different angiogenesis models, we examined here the effects of zoledronate, risedronate and three structural analogs of risedronate (NE-58025, NE-58051 and NE-10790) with lower potencies to inhibit FPPS activity. Risedronate and zoledronate were much more potent than NE-compounds at inhibiting both endothelial cell proliferation in vitro and vessel sprouting in the chicken egg chorioallantoic membrane (CAM) assay. In addition, only risedronate and zoledronate inhibited the revascularization of the prostate gland in testosterone-stimulated castrated rats. Moreover, as opposed to NE-compounds, risedronate and zoledronate induced intracellular accumulation of isopentenyl pyrophosphate (IPP) in endothelial cells by blocking the activity of the IPP-consuming enzyme FPPS. Thus, these results indicated that N-BPs inhibited angiogenesis in a FPPS-dependent manner. However, drug concentrations used to inhibit angiogenesis, both in vitro and in the CAM and prostate gland assays, were high. In contrast, a low concentration of risedronate (1 muM) was sufficient to inhibit blood vessel formation in the ex vivo rat aortic ring assay. Moreover, NE-58025 (which had a 7-fold lower potency than risedronate to inhibit FPPS activity) was as effective as risedronate to reduce angiogenesis in the rat aortic ring assay. In conclusion, our results suggest that low concentrations of N-BPs inhibit angiogenesis in a FPPS-independent manner, whereas higher drug concentrations were required to inhibit FPPS activity in vivo. [less ▲]

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See detailPotential cost-effectiveness of denosumab for the treatment of postmenopausal osteoporotic women.
Hiligsmann, Mickaël ULg; Reginster, Jean-Yves ULg

in BONE (2010), 47

Denosumab has recently been shown to be safe and to significantly reduce the risk of vertebral, hip and non-vertebral fractures in the "Fracture REduction Evaluation of Denosumab in Osteoporosis every ... [more ▼]

Denosumab has recently been shown to be safe and to significantly reduce the risk of vertebral, hip and non-vertebral fractures in the "Fracture REduction Evaluation of Denosumab in Osteoporosis every 6Months" (FREEDOM) Trial. Besides the clinical profile of a new drug, it becomes increasingly important to assess whether the drug represents good value for money. This study aims to examine the potential cost-effectiveness of denosumab in the treatment of postmenopausal osteoporotic women. An updated version of a validated Markov microsimulation model was used to estimate the cost (euro2009) per quality-adjusted life-year (QALY) gained of a 3-year denosumab treatment compared with no treatment. The model was populated with cost and epidemiological data for Belgium from a health-care perspective and the base-case population was defined from the FREEDOM Trial. The effect of denosumab after treatment cessation was conservatively assumed to decline linearly over 1year. Uncertainty was investigated using one-way and probabilistic sensitivity analyses. In particular, additional analyses were performed in populations (over 60years) where osteoporosis medications are currently reimbursed in many European countries, i.e. with bone mineral density (BMD) T-score</=-2.5 or prevalent vertebral fracture. In the base-case analysis, the cost per QALY gained of denosumab compared with no treatment was estimated at euro28,441. This value decreased to euro15,532 and to euro11,603 for women with a BMD T-score of -2.5 or prevalent vertebral fracture, respectively. Additional analyses showed that the cost-effectiveness of denosumab fall below commonly accepted threshold of euro30,000per QALY gained for women with a BMD T-score </=-2.5 or prevalent vertebral fracture, over the entire age range examined (60-80years). The results were robust under a wide range of plausible assumptions. In conclusion, this study suggests, on the basis of currently available data, that denosumab is cost-effective compared with no treatment for postmenopausal Belgian women with low bone mass and who are similar to patients included in the FREEDOM Trial. In addition, denosumab was found to be cost-effective in population currently reimbursed in Europe with T-score</=-2.5 or prevalent vertebral fracture, aged 60years and above. Additional data are needed on the relative cost-effectiveness compared with other anti-osteoporotic agents and on the long-term safety of denosumab. [less ▲]

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See detailCost-effectiveness of strontium ranelate versus risedronate in the treatment of postmenopausal osteoporotic women aged over 75 years.
Hiligsmann, Mickaël ULg; Bruyère, Olivier ULg; Reginster, Jean-Yves ULg

in Bone (2010), 46(2), 440-6

OBJECTIVE: To estimate the cost-effectiveness of strontium ranelate in the treatment of postmenopausal osteoporotic women aged over 75 years. MATERIALS AND METHODS: A validated Markov microsimulation ... [more ▼]

OBJECTIVE: To estimate the cost-effectiveness of strontium ranelate in the treatment of postmenopausal osteoporotic women aged over 75 years. MATERIALS AND METHODS: A validated Markov microsimulation model with a Belgian payer's perspective estimated the cost per quality-adjusted life-year (QALY) of a 3-year strontium ranelate treatment compared with no treatment and with the bisphosphonate risedronate. Data on the effect of both treatments on fracture risk were taken from the Cochrane Database of Systematic Reviews. Analyses were performed for postmenopausal women aged 75 and 80 years, either with a diagnosis of osteoporosis (i.e. bone mineral density T-score </=-2.5 SD) or with prevalent vertebral fractures (PVF). Parameter uncertainty was evaluated using both one-way and probabilistic sensitivity analyses. RESULTS: Strontium ranelate was dominant (i.e. more effective and less costly) versus risedronate for women with osteoporosis aged over 75 years and for women with PVF aged 80 years. The cost per QALY gained of strontium ranelate compared with risedronate at 75 years of age was euro11,435 for women with PVF. When compared with no treatment, the costs per QALY gained of strontium ranelate were euro15,588 and euro7,708 at 75 and 80 years of age for women with osteoporosis; the equivalent values were euro16,518 and euro6,015 for women with PVF. Probabilistic sensitivity analyses showed that strontium ranelate was generally more cost-effective than risedronate, in the range of 60% in all cases. CONCLUSION: The results of this study suggest that strontium ranelate is a cost-effective strategy, in a Belgian setting, for the treatment of postmenopausal osteoporotic women aged over 75 years. [less ▲]

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See detailFive years treatment with strontium ranelate reduces vertebral and nonvertebral fractures and increases the number and quality of remaining life-years in women over 80 years of age.
Seeman, Ego; Boonen, Steven; Borgstrom, Frederik et al

in BONE (2010), 46(4), 1038-42

INTRODUCTION: Longevity has resulted in a greater proportion of the population entering a time of life when increasing bone fragility and falls predispose to fractures, particularly nonvertebral fractures ... [more ▼]

INTRODUCTION: Longevity has resulted in a greater proportion of the population entering a time of life when increasing bone fragility and falls predispose to fractures, particularly nonvertebral fractures. Women over 80 years of age constitute 10% of the population but contribute 30% of all fractures and 60% of all nonvertebral fractures. Despite this, few studies have examined antifracture efficacy of treatments in this high-risk group and none has provided evidence for benefits beyond 3 years. MATERIALS AND METHODS: To determine whether strontium ranelate reduces the risk of vertebral and nonvertebral fractures during 5 years, we analyzed a subgroup of 1489 female patients over 80 years of age (mean 83.5+/-3.0 years) with osteoporosis from the SOTI (spinal osteoporosis therapeutic intervention) and TROPOS (treatment of peripheral osteoporosis) studies randomized to strontium ranelate 2 g/d or placebo. All received a supplement of calcium plus vitamin D. RESULTS: By intention to treat, vertebral fracture risk was reduced by 31% (relative risk, RR=0.69; 95% confidence interval, CI 0.52-0.92), nonvertebral fracture risk by 27% (RR=0.73; 95% CI 0.57-0.95), major nonvertebral fracture risk by 33% (RR=0.67; 95% CI 0.50-0.89) and hip fracture risk by 24% (RR=0.76; 95% CI 0.50-1.15, not significant). Treatment was cost-saving as it decreased cost and increased QALYs and life-years. DISCUSSION: Strontium ranelate safely produced a significant reduction in vertebral and nonvertebral fracture risk during 5 years in postmenopausal women over 80 years of age and was cost saving. [less ▲]

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See detailRisk of fracture in women treated with monthly oral ibandronate or weekly bisphosphonates: the eValuation of IBandronate Efficacy (VIBE) database fracture study
Haris, S. T.; Reginster, Jean-Yves ULg; Harley, C. et al

in BONE (2009), 44

The eValuation of IBandronate Efficacy (VIBE) head-to-head database fracture study compared fracture rates between patients treated with monthly ibandronate and weekly oral bisphosphonates (BPs). This ... [more ▼]

The eValuation of IBandronate Efficacy (VIBE) head-to-head database fracture study compared fracture rates between patients treated with monthly ibandronate and weekly oral bisphosphonates (BPs). This large study included women ≥45 years old, newly prescribed monthly oral ibandronate or weekly oral alendronate or risedronate, and without malignancy or Paget's disease of bone. The primary analysis included patients who were adherent to treatment during the first 90 days after the index date. The risks of hip, nonvertebral, vertebral and any clinical fracture were compared using Cox proportional hazards models and adjusted for potential confounding factors. A secondary, “intent-to-treat” analysis included all patients who received at least one BP prescription. Sensitivity analyses based on the primary analysis compared patients receiving ibandronate with patients receiving weekly alendronate or risedronate separately, and explored the effect of excluding patients with potential confounding factors from the analysis. Further sensitivity analyses varied the requirement for adherence during the first 90 days after the index date. The primary analysis population included 7345 monthly ibandronate and 56,837 weekly BP patients. Fracture rates after the 12-month observational period were <2% and fracture risk was not significantly different between patients receiving monthly ibandronate or weekly BPs for hip, nonvertebral or any clinical fracture (adjusted relative risk: hip=1.06, p=0.84; nonvertebral=0.88, p=0.255; any clinical fracture=0.82, p=0.052). Ibandronate patients had a significantly lower risk of vertebral fracture than weekly BP patients (adjusted relative risk 0.36, 95% confidence interval 0.18–0.75, p=0.006). In the secondary, “intent-to-treat” analysis, relative risks of fracture were not significantly different between treatment groups for any fracture type. The results of the sensitivity analyses were generally consistent with the primary analysis. This retrospective cohort study found that patients treated with oral monthly ibandronate or weekly BPs (alendronate and risedronate) had similar, low risks of hip fracture, nonvertebral fracture and any clinical fracture. Ibandronate patients had a significantly lower relative risk of vertebral fracture than weekly BP patients; the clinical implications of these findings require further exploration and validation. [less ▲]

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See detailLong-term treatment of postmenopausal osteoporosis with strontium ranelate: Results at 8 years.
Reginster, Jean-Yves ULg; Bruyère, Olivier ULg; Sawicki, A. et al

in BONE (2009), 45

OBJECTIVES: Strontium ranelate 2 g/day has proven efficacy against vertebral and nonvertebral fracture over 5 years in postmenopausal osteoporosis, though many women require longer-term treatment. This ... [more ▼]

OBJECTIVES: Strontium ranelate 2 g/day has proven efficacy against vertebral and nonvertebral fracture over 5 years in postmenopausal osteoporosis, though many women require longer-term treatment. This article describes the efficacy, safety, and tolerability of this agent over 8 years. METHODS: Postmenopausal osteoporotic women having participated in the 5-year efficacy trials SOTI and TROPOS were invited to enter a 3-year open-label extension study. The results presented here focus on patients who received strontium ranelate for 8 years. RESULTS: At the extension baseline, the population treated for 8 years (n=879; 79.1+/-5.6 years) had femoral neck T-score of -2.61+/-0.71. The cumulative incidences of new vertebral and nonvertebral fractures (13.7% and 12.0%, respectively) over years 6 to 8 were non-statistically different from the cumulative incidences in the first 3 years of the original studies (11.5% and 9.6%). Lumbar spine, femoral neck, and total hip bone mineral density (BMD) increased throughout the 8-year period. Annual relative change in BMD was significant at every visit, except the 8-year visit for femoral neck and total hip BMD. Strontium ranelate was safe and well tolerated over 8 years. CONCLUSIONS: Long-term treatment with strontium ranelate 2 g/day in postmenopausal osteoporotic women leads to continued increases in BMD at all sites. The data also provide some evidence for a sustained antifracture efficacy. [less ▲]

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See detailRole of Biochemical Markers of Bone Turnover as Prognostic Indicator of Successful Osteoporosis Therapy
Reginster, Jean-Yves ULg; Collette, Julien ULg; Neuprez, Audrey et al

in BONE (2008), 42

Most of the currently available anti-osteoporosis medications promptly and significantly influence the rate of bone turnover. Biochemical markers of bone turnover now provide a high sensitivity to change ... [more ▼]

Most of the currently available anti-osteoporosis medications promptly and significantly influence the rate of bone turnover. Biochemical markers of bone turnover now provide a high sensitivity to change, allowing the detection of these bone turnover changes within a couple of weeks. Since the anti-fracture efficacy of inhibitors of bone resorption or stimulators of bone formation appears to be largely independent of baseline bone turnover, biochemical markers do not appear to play a significant role in the selection of one particular drug, for an individual patient. However, there are consistent data showing that short-term changes in biochemical markers of bone turnover may be significant predictors of future changes in bone mineral density or fracture reduction, hence suggesting that bone turnover markers play a significant role in the monitoring of anti-osteoporosis therapy. [less ▲]

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See detailCreb-1 and Ap-1 Transcription Factors Jund and Fra-2 Regulate Bone Sialoprotein Gene Expression in Human Breast Cancer Cells
Detry, Cédric ULg; Lamour, Virginie ULg; Castronovo, Vincenzo ULg et al

in BONE (2008), 42(2), 422-31

Bone sialoprotein (BSP) expression is detected in a variety of human osteotropic cancers. High expression of BSP in breast and prostate primary carcinomas is associated with progression and bone ... [more ▼]

Bone sialoprotein (BSP) expression is detected in a variety of human osteotropic cancers. High expression of BSP in breast and prostate primary carcinomas is associated with progression and bone metastases development. In this study, we examined the transcriptional regulation of BSP gene expression in MDA-MB-231 and MCF-7 human breast cancer cells compared with Saos-2 human osteoblast-like cells. BSP human promoter deletion analyses delineated a -56/-84 region, which comprises a cAMP response element (CRE) that was sufficient for maximal promoter activity in breast cancer cell lines. We found that the basic fibroblast growth factor response element (FRE) also located in the proximal promoter was a crucial regulator of human BSP promoter activity in Saos-2 but not in breast cancer cells. Promoter activity experiments in combination with DNA mobility shift assays demonstrated that BSP promoter activity is under the control of the CRE element, through CREB-1, JunD and Fra-2 binding, in MDA-MB-231, MCF-7 and in Saos-2 cells. Forskolin, a protein kinase A pathway activator, failed to enhance BSP transcriptional activity suggesting that CRE site behaves as a constitutive rather than an inducible element in these cell lines. Over-expression of JunD and Fra-2 increased BSP promoter activity and upregulated endogenous BSP protein expression in MCF-7 and Saos-2 cells while siRNA-mediated inhibition of both factors expression significantly reduced BSP protein level in MDA-MB-231. Collectively, these data provide with new transcriptional mechanisms, implicating CREB and AP-1 factors, that control BSP gene expression in breast cancer cells. [less ▲]

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See detailThe role of calcium and vitamin D in the management of osteoporosis.
Rizzoli, R.; Boonen, S.; Brandi, M. L. et al

in BONE (2008), 42(2), 246-9

The role of calcium and vitamin D supplementation in the treatment of osteoporosis has been extensively studied. The aim of this paper was to reach, where possible, consensus views on five key questions ... [more ▼]

The role of calcium and vitamin D supplementation in the treatment of osteoporosis has been extensively studied. The aim of this paper was to reach, where possible, consensus views on five key questions relating to calcium and vitamin D supplementation in the management of osteoporosis. Whereas global strategies that target supplementation to the general population could not be justified in terms of efficacy and health economics, there is a clearer rationale for supplementing patients who are at increased risk of osteoporosis and those who have developed osteoporosis, including those already taking other treatments for osteoporosis. The combination of vitamin D with calcium may be beneficial in terms of efficacy and, perhaps, for optimising adherence. [less ▲]

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See detailOsteonecrosis of the jaw and bisphosphonate treatment for osteoporosis.
Rizzoli, Rene; Burlet, Nansa; Cahall, David et al

in BONE (2008), 42(5), 841-7

A potential side effect associated with bisphosphonates, a class of drugs used in the treatment of osteoporosis, Paget's disease and metastatic bone disease, is osteonecrosis of the jaw (ONJ). The ... [more ▼]

A potential side effect associated with bisphosphonates, a class of drugs used in the treatment of osteoporosis, Paget's disease and metastatic bone disease, is osteonecrosis of the jaw (ONJ). The incidence of ONJ in the general population is unknown; this rare condition also may occur in patients not receiving bisphosphonates. Case reports have discussed ONJ development in patients with multiple myeloma or metastatic breast cancer receiving bisphosphonates as palliation for bone metastases. These patients are also receiving chemotherapeutic agents that might impair the immune system and affect angiogenesis. The incidence or prevalence of ONJ in patients taking bisphosphonates for osteoporosis seems to be very rare. No causative relationship has been unequivocally demonstrated between ONJ and bisphosphonate therapy. A majority of ONJ occurs after tooth extraction. Furthermore, the underlying risk of developing ONJ may be increased in osteoporotic patients by comorbid diseases. Treatment for ONJ is generally conservative. [less ▲]

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