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Summary Rebound-associated vertebral fractures may follow treatment discontinuation of highly potent reversible bone antiresorptives, resulting from the synergy of rapid bone resorption and accelerated microdamage accumulation in trabecular bone. Introduction The purposes of this study are to characterize rebound-associated vertebral fractures following the discontinuation of a highly potent reversible antiresorptive therapy based on clinical observation and propose a pathophysiological rationale. Methods This study is a case report of multiple vertebral fractures early after discontinuation of denosumab therapy in a patient with hormone receptor-positive non-metastatic breast cancer treated with an aromatase inhibitor. Results Discontinuation of highly potent reversible bone antiresorptives such as denosumab may expose patients to an increased fracture risk due to the joined effects of absent microdamage repair during therapy followed by synchronous excess activation of multiple bone remodelling units at the time of loss-of-effect. We suggest the term rebound-associated vertebral fractures (RVF) for this phenomenon characterized by the presence of multiple new clinical vertebral fractures, associated with either no or low trauma, in a context consistent with the presence of high bone turnover and rapid loss of lumbar spine bone mineral density (BMD) occurring within 3 to 12 months after discontinuation (loss-of-effect) of a reversible antiresorptive therapy in the absence of secondary causes of bone loss or fractures. Unlike atypical femoral fractures that emerge from failure of microdamage repair in cortical bone with long-term antiresorptive treatment, RVF originate from the synergy of rapid bone resorption and accelerated microdamage accumulation in trabecular bone triggered by the discontinuation of highly potent reversible antiresorptives. Conclusions Studies are urgently needed to i) prove the underlying pathophysiological processes suggested above, ii) establish the predictive criteria exposing patients to an increased risk of RVF, and iii) determine appropriate treatment regimens to be applied in such patients.

Summary The FREEDOM study and its Extension provide long-term information about the effects of denosumab for the treatment of postmenopausal osteoporosis. Treatment for up to 8 years was associated with persistent reduction of bone turnover, continued increases in bone mineral density, low fracture incidence, and a favorable benefit/risk profile. Introduction This study aims to report the results through year 5 of the FREEDOM Extension study, representing up to 8 years of continued denosumab treatment in postmenopausal women with osteoporosis. Methods Women who completed the 3-year FREEDOM study were eligible to enter the 7-year open-label FREEDOM Extension in which all participants are scheduled to receive denosumab, since placebo assignment was discontinued for ethical reasons. A total of 4550 women enrolled in the Extension (2343 long-term; 2207 cross-over). In this analysis, women in the long-term and cross-over groups received denosumab for up to 8 and 5 years, respectively. Results Throughout the Extension, sustained reduction of bone turnover markers (BTMs) was observed in both groups. In the long-term group, mean bone mineral density (BMD) continued to increase significantly at each time point measured, for cumulative 8-year gains of 18.4 and 8.3 % at the lumbar spine and total hip, respectively. In the cross-over group, mean BMD increased significantly from the Extension baseline for 5-year cumulative gains of 13.1 and 6.2 % at the lumbar spine and total hip, respectively. The yearly incidence of new vertebral and nonvertebral fractures remained low in both groups. The incidence of adverse and serious adverse events did not increase over time. Through Extension year 5, eight events of osteonecrosis of the jaw and two events of atypical femoral fracture were confirmed. Conclusions Denosumab treatment for up to 8 years was associated with persistent reductions of BTMs, continued BMD gains, low fracture incidence, and a consistent safety profile.

This multicenter trial evaluated zoledronic acid versus placebo in men with osteoporosis for a primary end point of new morphometric vertebral fracture over 24 months. Zoledronic acid was associated with a significantly reduced risk of vertebral fracture. Osteoporosis is an important cause of morbidity and mortality among men. 1 , 2 Among persons older than 50 years of age, approximately 40% of all osteoporotic fractures worldwide occur in men. 3 Mortality after osteoporotic fracture is higher among men than among women. 2 , 4 Previous studies involving men with osteoporosis have focused on the surrogate outcomes of bone mineral density and bone-turnover markers, 5 – 9 but data from double-blind, randomized studies assessing antifracture efficacy are lacking. In addition, given the low awareness of the disease, 10 the development of guidelines for the detection and treatment of osteoporosis in men has been limited. 11 Hence, there . . .

Summary Remaining lifetime and absolute 10-year probabilities for osteoporotic fractures were determined by gender, age, and BMD values. Remaining lifetime probability at age 50 years was 20.2% in men and 51.3% in women and increased with advancing age and decreasing BMD. The study validates the elements required to populate a Swiss-specific FRAX® model. Introduction Switzerland belongs to high-risk countries for osteoporosis. Based on demographic projections, burden will still increase. We assessed remaining lifetime and absolute 10-year probabilities for osteoporotic fractures by gender, age and BMD in order to populate FRAX® algorithm for Switzerland. Methods Osteoporotic fracture incidence was determined from national epidemiological data for hospitalised fractured patients from the Swiss Federal Office of Statistics in 2000 and results of a prospective Swiss cohort with almost 5,000 fractured patients in 2006. Validated BMD-associated fracture risk was used together with national death incidence and risk tables to determine remaining lifetime and absolute 10-year fracture probabilities for hip and major osteoporotic (hip, spine, distal radius, proximal humerus) fractures. Results Major osteoporotic fractures incidence was 773 and 2,078 per 100,000 men and women aged 50 and older. Corresponding remaining lifetime probabilities at age 50 were 20.2% and 51.3%. Hospitalisation for clinical spine, distal radius, and proximal humerus fractures reached 25%, 30% and 50%, respectively. Absolute 10-year probability of osteoporotic fracture increased with advancing age and decreasing BMD and was higher in women than in men. Conclusion This study validates the elements required to populate a Swiss-specific FRAX® model, a country at highest risk for osteoporotic fractures.

SummaryTrabecular bone score (TBS) assesses bone quality in the lumbar spine using dual-energy X-ray absorptiometry (DXA) scans. In postmenopausal women with osteoporosis, denosumab significantly improved TBS independently of bone mineral density (BMD). This practical technique may have a role in managing patients with osteoporosis.IntroductionTBS, a gray-level texture index determined from lumbar spine DXA scans, correlates with bone microarchitecture and enhances assessment of vertebral fracture risk independently of BMD. In the FREEDOM study, denosumab increased BMD and reduced new vertebral fractures in postmenopausal women with osteoporosis. This retrospective analysis explored the effect of denosumab on TBS and the association between TBS and BMD in FREEDOM.MethodsPostmenopausal women with lumbar spine or total hip BMD T-score <−2.5 and −4.0 or higher at both sites received placebo or denosumab 60 mg subcutaneously every 6 months. TBS indices were determined from DXA scans at baseline and months 12, 24, and 36 in a subset of 285 women (128 placebo, 157 denosumab) who had TBS values at baseline and ≥1 postbaseline visit.ResultsBaseline characteristics were comparable between treatment groups; mean (SD) lumbar spine BMD T-score was −2.79 (0.64), and mean (standard deviation [SD]) TBS was 1.200 (0.101) overall. In the placebo group, BMD and TBS increased by ≤0.2% or decreased from baseline at each visit. In the denosumab group, progressive increases from baseline at 12, 24, and 36 months were observed for BMD (5.7, 7.8, and 9.8%) and TBS (1.4, 1.9, and 2.4%). Percentage changes in TBS were statistically significant compared with baseline (p < 0.001) and placebo (p ≤ 0.014). TBS was largely unrelated to BMD, regardless of treatment, either at baseline or for annual changes from baseline (all r2 ≤ 0.06).ConclusionsIn postmenopausal women with osteoporosis, denosumab significantly improved TBS independently of BMD.

SummaryReference values for radius and tibia strength using multiple-stack high-resolution peripheral quantitative computed tomography (HR-pQCT) with homogenized finite element analysis are presented in order to derive critical values improving risk prediction models of osteoporosis. Gender and femoral neck areal bone mineral density (aBMD) were independent predictors of bone strength.IntroductionThe purpose was to obtain reference values for radius and tibia bone strength computed by using the homogenized finite element analysis (hFE) using multiple stacks with a HR-pQCT.MethodsMale and female healthy participants aged 20–39 years were recruited at the University Hospital of Bern. They underwent interview and clinical examination including hand grip, gait speed and DXA of the hip. The nondominant forearm and tibia were scanned with a double and a triple-stack protocol, respectively, using HR-pQCT (XCT II, SCANCO Medical AG). Bone strength was estimated by using the hFE analysis, and reference values were calculated using quantile regression. Multivariable analyses were performed to identify clinical predictors of bone strength.ResultsOverall, 46 women and 41 men were recruited with mean ages of 25.1 (sd 5.0) and 26.2 (sd 5.2) years. Sex-specific reference values for bone strength were established. Men had significantly higher strength for radius (mean (sd) 6640 (1800) N vs. 4110 (1200) N; p < 0.001) and tibia (18,200 (4220) N vs. 11,970 (3150) N; p < 0.001) than women. In the two multivariable regression models with and without total hip aBMD, the addition of neck hip aBMD significantly improved the model (p < 0.001). No clinical predictors of bone strength other than gender and aBMD were identified.ConclusionReference values for radius and tibia strength using multiple HR-pQCT stacks with hFE analysis are presented and provide the basis to help refining accurate risk prediction models. Femoral neck aBMD and gender were significant predictors of bone strength

SummaryA first intravenous dose of bisphosphonates may be associated with an acute-phase response (APR). In bisphosphonate-naïve women with postmenopausal osteoporosis, the characteristics and frequency of APR may differ by compound. Prior bisphosphonate exposure was predictive of APR risk and severity.IntroductionIntravenous (IV) administration of bisphosphonates (BP), such as zoledronate (ZOL) and ibandronate (IBN), may be associated with an APR. The characteristics of APR may differ by compound. The aim of the present study was to evaluate the characteristics of APR (rates, signs and symptoms, severity), in the absence of any preventive measure, after a first IV application of ZOL or IBN in patients naïve or previously exposed to BP in a real-world clinical setting.MethodsThis is an open-label prospective exploratory study with two cohorts of consecutive postmenopausal women with osteoporosis treated with either IV ZOL or IBN at the Department of Osteoporosis of the University Hospital of Berne, Switzerland.ResultsIntravenous BP was administered to 725 women (411 ZOL and 314 IBN). Prior oral or IV BP use was less frequent in the ZOL group (61.8 vs. 71.7%, p = 0.005). In total, 301 women (41.5%) reported the presence of one or more signs or symptoms of APR with rates for ZOL and IBN of 47.7 and 33.4%, respectively (p < 0.001). Corresponding APR rates in the subgroup of BP-naïve patients were 55.6 and 32.4%, respectively (p < 0.001). The leading APR clinical sign was the presence of post-dose myalgia or arthralgia (68.1%). Prior BP exposure was predictive of both APR risk and severity, and lower serum 25-hydroxy vitamin D (25(OH)D) levels were possibly predictive of severity.ConclusionsIn a real-world setting, APR rates with ZOL and IBN may be higher than reported in randomised controlled trials and may differ by compound, prior BP exposure, and serum 25(OH)D levels.

Summary Limited data exist on the efficacy of long-term therapies for osteoporosis. In osteoporotic postmenopausal women receiving denosumab for 7 years, nonvertebral fracture rates significantly decreased in years 4–7 versus years 1–3. This is the first demonstration of a further benefit on fracture outcomes with long-term therapy for osteoporosis. Introduction This study aimed to evaluate whether denosumab treatment continued beyond 3 years is associated with a further reduction in nonvertebral fracture rates. Methods Participants who completed the 3-year placebo-controlled F racture RE duction E valuation of D enosumab in O steoporosis every 6 M onths (FREEDOM) study were invited to participate in an open-label extension. The present analysis includes 4,074 postmenopausal women with osteoporosis ( n  = 2,343 long-term; n  = 1,731 cross-over) who enrolled in the extension, missed ≤1 dose during their first 3 years of denosumab treatment, and continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1–3 of denosumab with that of the fourth year and with the rate during years 4–7 was evaluated. Results For the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab treatment (referent) and 1.36 in the fourth year (rate ratio [RR] = 0.64; 95 % confidence interval (CI) = 0.48 to 0.85, p  = 0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1–3 were compared to years 4–7 in the long-term group (RR = 0.79; 95 % CI = 0.62 to 1.00, p  = 0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip bone mineral density (BMD). Conclusions Denosumab treatment beyond 3 years was associated with a further reduction in nonvertebral fracture rate that persisted through 7 years of continuous denosumab administration. The degree to which denosumab further reduces nonvertebral fracture risk appears influenced by the hip bone density achieved with initial therapy.

Study design: Retrospective data analysis. Objectives: To document fracture characteristics, management and related complications in individuals with traumatic spinal cord injury (SCI). Setting: Rehabilitation centre for SCI individuals. Method: Patients’ records were reviewed. Patients with traumatic SCI and extremity fractures that had occurred after SCI were included. Patient characteristics, fractured bone, fracture localisation, severity and management (operative/conservative), and fracture-related complications were extracted. Results: A total of 156 long-bone fractures in 107 SCI patients (34 women and 73 men) were identified. The majority of patients were paraplegics (77.6%) and classified as American Spinal Injury Association Impairment Scale A (86.0%). Only the lower extremities were affected, whereby the femur (60.9% of all fractures) was fractured more frequently than the lower leg (39.1%). A total of 70 patients (65.4%) had one fracture, whereas 37 patients (34.6%) had two or more fractures. Simple or extraarticular fractures were most common (75.0%). Overall, 130 (83.3%) fractures were managed operatively. Approximately half of the femur fractures (48.2%) were treated with locking compression plates. In the lower leg, fractures were mainly managed with external fixation (48.8%). Conservative fracture management was applied in 16.7% of the cases and consisted of braces or a well-padded soft cast. Fracture-associated complications were present in 13.5% of the cases but did not differ significantly between operative (13.1%) and conservative (15.4%) fracture management. Conclusion: SCI was associated with simple or extraarticular fractures of the distal femur and the lower leg. Fractures were mainly managed operatively with a low complication rate.

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/m 2 , BMD L1–L4 0.741 ± 0.100 g/cm 2 , 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.