Incidence Of New Vertebral Fractures Research Articles

Active Rheumatoid Arthritis and Scoliosis: A Mid-Term Cohort Study.

Retrospective cohort study. To elucidate the factors related to progression of scoliosis in patients with rheumatoid arthritis (RA) using longitudinal cohort data. Thirty percent of patients with RA have lumbar scoliosis. However, the effectiveness of current treatment methods in preventing the progression of scoliosis is not well-understood due to a lack of longitudinal studies. We enrolled 180 patients with RA who were followed up for over two years, all of whom underwent standing spinal X-rays. These patients were categorized based on their disease activity score-28 with erythrocyte sedimentation rate (DAS28-ESR) into two groups: those in remission (n=76) and those in non-remission (n=104). We evaluated various radiographic measures, including C7 center sacral vertical line (C7-CSVL), pelvic obliquity, major Cobb angle, and curve location. Fifty-three (29.4%) patients presented progression of scoliosis during a mean follow-up period of 4.8 years. Patients in the non-remission showed larger Cobb angle at baseline and final follow-up, compared to those in remission. The annual progression rate of the curve was also greater in the non-remission group (1.04 degree /year), than in the remission group (0.59 degree /year, P=0.001). There was no difference in the incidence of new vertebral fractures. The presence of a baseline cobb angle of 10 degree or more (OR: 3.14; 95% CI: 1.38-7.13; P=0.006), glucocorticoid use (OR: 2.88; 95% CI: 1.18-7.06; P=0.021), and non-remission at baseline (OR: 2.83; 95% CI: 1.25-6.41; P=0.012) were significant risk factors for progression of scoliosis. RA disease activity is linked to progression of scoliosis in patients with RA. Patients with RA who present with an initial scoliosis of 10 degrees or greater, require glucocorticoids for treatment and are in non-remission at baseline may be at high risk for scoliosis progression.

Romosozumab Efficacy in Postmenopausal Women With No Prior Fracture Who Fulfill Criteria for Very High Fracture Risk

ObjectiveWe evaluated the efficacy of romosozumab in women from FRAME who had no prior fracture but met other criteria for very high fracture risk (VHFR). MethodsIn FRAME, postmenopausal women received romosozumab or placebo for 12 months (year 1) followed by denosumab for 12 months (year 2). In this post hoc analysis, we applied the following criteria from the American Association of Clinical Endocrinology to define VHFR: lumbar spine or total hip T-score <−3.0 and/or Fracture Risk Assessment Tool probability of major osteoporotic fracture >30% or hip fracture >4.5% to women with no fracture history at baseline (no fracture-VHFR [NF-VHFR]). Incidence of new vertebral, clinical, and nonvertebral fractures and mean bone mineral density (BMD) percentage change from baseline were assessed at years 1 and 2. ResultsOf the 7180 women in FRAME, 2825 were included in the NF-VHFR subgroup analysis. At year 1, romosozumab versus placebo reduced the incidence of new vertebral fracture (relative risk reduction [RRR]: 76%), clinical fracture (RRR: 60%), and nonvertebral fracture (RRR: 54%) (all P <.05). This fracture reduction was maintained through year 2 in women receiving the romosozumab-to-denosumab sequence versus the placebo-to-denosumab sequence for new vertebral, clinical, and nonvertebral fractures (RRR: 77%, 54%, and 46%, respectively; all P <.05). The mean BMD changes in both treatment groups were similar to those in the overall FRAME population at years 1 and 2. ConclusionRomosozumab significantly reduced vertebral, clinical, and nonvertebral fracture risk and increased the BMD more than placebo in women at VHFR.

The Impact of Persistent Low Weight Status on the Occurrence of Vertebral Fractures: A Nationwide Population-Based Cohort Study.

Although, being underweight is commonly associated with osteoporosis and sarcopenia, its association with vertebral fractures (VFs), is less well researched. We investigated the influence of cumulative, chronic periods of low weight and changes in body weight on VF development. We used a nationwide, population-based database with data on people (> 40 years) who attended three health screenings between January 1, 2007, and December 31, 2009 to assess the incidence of new VFs. Cox proportional hazard analyses were used to establish the hazard ratios (HRs) for new VFs based on the degree of body mass index (BMI), the cumulative numbers of underweight participants, and temporal change in weight. Of the 561,779 individuals in this analysis, 5,354 (1.0%) people were diagnosed three times, 3,672 (0.7%) were diagnosed twice, and 6,929 (1.2%) were diagnosed once. The fully adjusted HR for VFs in underweight individuals was 1.213. Underweight individuals diagnosed only once, twice, or three times had an adjusted HR of 0.904, 1.443, and 1.256, respectively. Although the adjusted HR was higher in adults who were consistently underweight, there was no difference in those who experienced a temporal change in body weight. BMI, age, sex, and household income were significantly associated with VF incidence. Low weight is a risk factor for VFs in the general population. Given the significant correlation between cumulative periods of low weight and the risk of VFs, it is necessary to treat underweight patients before a VF to prevent its development and other osteoporotic fractures.

Incidence, Risk Factors, and Outcomes of Symptomatic Bone Cement Displacement following Percutaneous Kyphoplasty for Osteoporotic Vertebral Compression Fracture: A Single Center Study.

Retrospective. Symptomatic bone cement displacement (BCD) is a rare complication following percutaneous kyphoplasty (PKP) interventions for osteoporotic vertebral compression fracture (OVCF). This study aimed to investigate the incidence and the outcomes of symptomatic BCD comprehensively and identify its risk factors. The clinical data of patients treated with PKP for OVCF between January 2012 and December 2020 were extracted. Patients who developed BCD following PKP during follow-up were divided into the symptomatic and asymptomatic groups. Patients who did not develop BCD were assigned to the control group. Univariate and multiple logistic regression analyses were used to compare the three clinical groups' features to assess the independent risk factors for the symptomatic and asymptomatic groups. A total of 896 patients were enrolled. Twenty-one patients (2.3%) were identified as having symptomatic BCD following PKP for OVCF, and 35 (3.9%) developed asymptomatic BCD. Compared with the control group, the symptomatic and asymptomatic groups had a higher incidence of anterior leakage, intravertebral vacuum cleft (IVC) signs, and a lower cement distribution score. The symptomatic group had a lower relative cross-sectional area (rCSA) of the paraspinal muscle (PSM), higher PSM fatty degeneration, and higher kyphotic angle (at the last follow-up) than the asymptomatic and control groups. For outcomes, the symptomatic group had a higher VAS/ODI score and a higher incidence of new vertebral fractures compared with the asymptomatic and control groups. Anterior leakage (OR: 1.737, 95% CI: 1.215-3.300), the IVC sign (OR: 3.361, 95% CI: 1.605-13.036), the cement distribution score (OR: 0.476, 95% CI: 0.225-0.904), PSM rCSA (OR: 0.953, 95% CI: 0.917-0.992), and PSM fatty degeneration (OR: 1.061, 95% CI: 1.005-1.119) were identified as independent risk factors for the symptomatic group. Anterior leakage (OR: 1.839, 95% CI: 1.206-2.803), the IVC sign (OR: 2.936, 95% CI: 1.174-9.018), and cement distribution score (OR: 0.632, 95% CI: 0.295-0.858) were independent risk factors for the asymptomatic group. The incidence of symptomatic BCD is 2.3% in patients treated with PKP. Anterior leakage, the IVC sign, and the distribution score were independent risk factors for BCD, and paraspinal muscle degeneration was a specific risk factor for symptomatic BCD. Symptomatic BCD can lead to poor outcomes.

Efficacy and safety of the biosimilar denosumab candidate (Arylia) compared to the reference product (Prolia®) in postmenopausal osteoporosis: a phase III, randomized, two-armed, double-blind, parallel, active-controlled, and noninferiority clinical trial

Background/objectiveOsteoporosis is a global health concern with an increasing prevalence worldwide. Denosumab is an antiresoptive agent that has been demonstrated to be effective and safe in osteoporotic patients. This study aimed to compare the efficacy and safety of the biosimilar denosumab candidate (Arylia) to the originator product (Prolia®) in postmenopausal osteoporotic patients.MethodsIn this randomized, double-blind, active-controlled, noninferiority trial, postmenopausal osteoporotic patients received 60 mg of subcutaneous Arylia or Prolia® at months 0, 6, and 12 and were followed up for 18 months. The primary endpoint was the noninferiority of the biosimilar product to the reference product in the percentage change of bone mineral density (BMD) in 18 months at the lumbar spine (L1-L4), total hip, and femoral neck. The secondary endpoints were safety assessment, the incidence of new vertebral fractures, and the trend of bone turnover markers (BTMs).ResultsA total of 190 patients were randomized to receive either biosimilar (n = 95) or reference (n = 95) denosumab. In the per-protocol (PP) analysis, the lower limits of the 95% two-sided confidence intervals of the difference between Arylia and Prolia® in increasing BMD were greater than the predetermined noninferiority margin of − 1.78 at the lumbar spine, total hip, and femoral neck sites (mean differences [95% CIs] of 0.39 [− 1.34 to 2.11], 0.04 [− 1.61 to 1.69], and 0.41 [− 1.58 to 2.40], respectively). The two products were also comparable in terms of safety, new vertebral fractures, and trend of BTMs.ConclusionThe efficacy of the biosimilar denosumab was shown to be noninferior to that of the reference denosumab, with a comparable safety profile at 18 months.Trial registrationClinicalTrials.gov, NCT03293108; Registration date: 2017–09-19.

Comparative Efficacy of Three Minimally Invasive Procedures for Kümmell's Disease: A Systematic Review and Network Meta-Analysis.

BackgroundPercutaneous vertebroplasty (PVP), percutaneous kyphoplasty (PKP), and bone-filling mesh containers(BFC) are three viable minimally invasive techniques that have been used to treat Kümmell’s disease(KD). However, there is still debate as to which is safer and more effective. This study summarized the pros and cons of the three techniques in the treatment of KD through network meta-analysis(NMA).MethodsAll eligible published clinical control studies comparing PVP, PKP, and BFC for KD up to December 2021 were collected by online search of Cochrane Library, PubMed, Embase, CNKI, Wanfang Database, and Chinese biomedical literature database. Data were extracted after screening, and Stata 16.0 software was used to perform the network meta-analysis.ResultsFour randomized controlled trials (RCTs) and 16 retrospective case-control studies (CCTs) with a total of 1114 patients were included. The NMA results showed no statistical difference between the 3 procedures in terms of improving patients’ clinical symptoms. PKP was most likely to be the most effective in correcting kyphosis, while BFC was likely to be the most effective in managing the occurrence of cement leakage. No statistical differences were found in the incidence of new vertebral fractures in adjacent segments.ConclusionsRanking analysis showed that BFC has the highest likelihood of being the optimal procedure for the treatment of KD, based on a combined assessment of effectiveness in improving patients’ symptoms and safety in the occurrence of adverse events.

Denosumab versus romosozumab for postmenopausal osteoporosis treatment

Denosumab and romosozumab, a recently approved new drug, are effective and widely known molecular-targeted drugs for postmenopausal osteoporosis treatment. However, no studies have directly compared their therapeutic effects or safety in postmenopausal osteoporosis. This retrospective observational registry study compared the efficacy of 12-month denosumab or romosozumab treatment in postmenopausal osteoporosis patients. The primary outcome was the change in bone mineral density (BMD) at the lumbar spine. Secondary outcomes included BMD changes at the total hip and femoral neck, changes in bone turnover markers, and adverse events. Propensity score matching was employed to assemble patient groups with similar baseline characteristics. Sixty-nine patients each received either denosumab or romosozumab for 12 months. The mean 12-month percentage change from baseline in lumbar spine BMD was 7.2% in the denosumab group and 12.5% in the romosozumab group, indicating a significant difference between the groups. The percentage changes in BMD at both the total hip and femoral neck were also significantly higher at 12 months in the romosozumab group than in the denosumab group. In denosumab patients, bone formation and bone resorption markers were significantly decreased at 6 and 12 months from baseline. In the romosozumab group, the bone formation marker was significantly increased at 6 months and then returned to baseline, while the bone resorption marker was significantly decreased at both time points. Adverse events were few and predominantly minor in both groups, with no remarkable difference in the incidence of new vertebral fractures. Romosozumab showed a higher potential for improving BMD than denosumab in this clinical study of postmenopausal osteoporosis patient treatment.

Cancer Treatment–Induced Bone Loss and Role of Denosumab in Nonmetastatic Prostate Cancer: A Narrative Review

AbstractBone loss is an important complication of prostate cancer and its associated treatments, especially androgen-deprivation therapy (ADT). There is a 5 to 10 times increased loss of bone mineral density (BMD) in men receiving ADT with yearly 4 to 13% BMD loss. The risk of fracture increases yearly by 5 to 8% with ADT. ADT associated bone loss of 10 to 15% of BMD doubles the risk of fractures. Hence, BMD evaluation through dual-energy X-ray absorptiometry and evaluation of individual fracture risk assessed before initiating ADT. The use of vitamin D, calcium, bisphosphonates, and denosumab has shown improved bone health in men with prostate cancer receiving ADT. Denosumab 60 mg is approved to increase bone mass in men at high risk for fractures receiving ADT for nonmetastatic prostate cancer. Denosumab has shown improvement of 5.6% BMD at 2 years in nonmetastatic prostate cancer patients, with significant improvements seen at the total hip, femoral neck, and distal third of the radius. Denosumab has shown a 62% decreased incidence of new vertebral fractures at 36 months. Furthermore, denosumab delays the onset of bone metastases in high-risk nonmetastatic prostate cancer patients. Denosumab can be preferred over other bone modifying agents owing to several advantages, such as subcutaneous administration and no requirement of hospitalization, no dose modifications in renal impairment and less incidence of acute phase anaphylactic reactions. We review the available evidence of denosumab for managing bone loss in nonmetastatic prostate cancer patients. The relevant articles used in this narrative review were obtained through general search on google and PubMed using the key terms “non-metastatic prostate cancer,” “denosumab,” “bone loss,” “bone mineral density,” “fracture,” “CTIBL,” and “chemotherapy induced bone loss.”

Romosozumab: a Review of Efficacy, Safety, and Cardiovascular Risk.

Authors review the safety and efficacy of romosozumab for the treatment of osteoporosis as demonstrated in three phase III clinical trials and offer insights into the potential cardiovascular risk associated with its use. Incidence of new vertebral fracture is dramatically reduced with 12months of romosozumab use in comparison to both placebo and active bisphosphonate control groups in patients with postmenopausal osteoporosis. Significant non-vertebral anti-fracture benefit was also demonstrated in patients with more severe osteoporosis. Numerical increases in cardiovascular events call into question the safety of romosozumab use, particularly in patients with cardiovascular history or at high cardiovascular risk. Romosozumab has impressive anti-fracture effects in postmenopausal women with high risk for fragility fracture. Despite no significant differences in baseline cardiovascular risk factors between groups, a numerical increase in serious cardiovascular adverse events was demonstrated with romosozumab in randomized trials with no discernable etiology. Until more real-world evidence is available, romosozumab should not be used in patients with a recent cardiovascular event and should be used cautiously in patients with high cardiovascular risk. Romosozumab's place in therapy is likely patients with severe postmenopausal osteoporosis and low cardiovascular risk.

Vertebroplasty Increases the Incidence Of New Vertebral Compression Fractures Compared To Conservative Management

Abstract Background Vertebral osteoporotic fractures are a major cause of morbidity and disability among the elderly population.This study sought to compare the incidence of new vertebral fractures in patients treated by vertebroplasty with that of those managed conservatively, while also assessing the potential risk factors contributing to the occurrence of these fractures. Materials and Methods The details of a total of 121 eligible subjects with radiologically proven osteoporotic vertebral fractures were retrieved from our archive between January 2010 and September 2019 and divided, based on the treatment method, into percutaneous vertebroplasty (PVP) (n = 60) and nonsurgical treatment (n = 61). The included subjects’ clinical data, demographic profiles, and imaging findings on plain radiography, CT, and MRI scans performed at baseline and within 24 months following treatment were reviewed and documented. Results The difference in the incidence of new fractures was statistically significant (p = 0.001), with rates of 70% (n = 32) in the vertebroplasty group and 30% (n = 14) in the conservatively treated cases reported at a median follow-up time point of approximately 4 months. The presence of liver disease (p = 0.037), a history of transplantation (p = 0.003), the use of steroids (p = 0.023), a low-bone mineral density (BMD) score (p = 0.023), and a higher number of fractures on baseline imaging (p = 0.013) were associated with a greater risk of subsequent vertebral fractures. Conclusions The incidence of acute fractures after PVP is higher than that among patients treated conservatively. Decision-making regarding the adoption of this intervention should take into consideration the risk factors leading to a greater risk of subsequent vertebral fractures, such as a higher number of fractures at baseline imaging, low-BMD score, patient comorbidities, and steroid use.

In Memoriam: Uri A. Liberman, 1935-2022.

In Memoriam: Uri A. Liberman, 1935-2022.

Romosozumab followed by denosumab in Japanese women with high fracture risk in the FRAME trial

This post-hoc analysis of the FRAME study investigated the long-term efficacy and safety of romosozumab followed by denosumab in postmenopausal Japanese women with osteoporosis at high fracture risk. Data from Japanese women with a high fracture risk participating in the international, randomised, double-blind, placebo-controlled, phase 3 FRAME study were analysed. High risk of fracture was defined as ≥ 1 fragility fracture with bone mineral density (BMD) ≤ - 2.5 standard deviations [SD], > 2 prevalent vertebral fractures, prevalent semiquantitative grade 3 vertebral fracture, or lumbar spine BMD < - 3.3 SD. Endpoints included incidence of new vertebral fracture at 12, 24 and 36months and percentage change from baseline in BMD at the lumbar spine, total hip and femoral neck. 187 Japanese subjects at high risk of fracture were enrolled in FRAME. Incidence of new vertebral fractures was lower with romosozumab/denosumab vs. placebo/denosumab at 12, 24 and 36months (relative risk reduction at all timepoints: 84%; p = 0.056). BMD increases at 12, 24 and 36months were greater in subjects receiving romosozumab/denosumab than placebo/denosumab (lumbar spine: 16.3%, 21.5% and 23.2% vs 0.4%, 8.1% and 10.4%; total hip: 4.9%, 7.9% and 8.9% vs 0.4%, 2.8% and 4.1%; femoral neck: 4.8%, 7.6% and 8.1% vs 0.3%, 3.3% and 3.7%, respectively; all p < 0.001 vs placebo/denosumab). Adverse events were generally balanced between groups. Romosozumab/denosumab in Japanese subjects at high risk of fracture resulted in significant BMD gains and numerically lower vertebral fracture rate vs. placebo/denosumab at all timepoints measured.

Early clinical effects, safety, and appropriate selection of bone markers in romosozumab treatment for osteoporosis patients: a 6-month study.

Romosozumab appeared as a new osteoporosis medication in Japan in 2019. It is an anti-sclerostin antibody which increases bone formation and suppresses bone resorption. In this study, we analyzed the actual clinical effects, adverse effects, and the optimal way to evaluate the treatment. Romosozumab was administered as subcutaneous injection of 210mg once every 4weeks. We conducted pre-post study in 185 patients treated for 6months. We focused on the incidence of new vertebral fractures, safety, bone mineral density (BMD) at the spine and total hip, and bone metabolism markers. We evaluated BMD before romosozumab treatment and after 4 to 6months and performed the serum analysis before romosozumab treatment, after 1, 3, and 6months. There was no new fracture during treatment, and there was no fatal adverse event including cardiovascular disease. Since percent changes from baseline of the spine and total hip BMD were 6.34% and 1.53% after 4- to 6-month treatment, the treatment was effective for spine osteoporosis. Tartrate-resistant acid phosphatase 5b (TRACP-5b) and intact type I procollagen N-terminal propeptide (iP1NP) had significant changes during romosozumab treatment (p < 0.05). Percent change from baseline of TRACP-5b and iP1NP after 1month correlated with percent change from baseline of BMD after 4 to 6months of treatment. Romosozumab is effective in preventing fractures and useful for increasing the spine BMD. Also, romosozumab is relatively safe to use. It is especially effective in patients with low baseline spine BMD, high TRACP-5b, and high iP1NP.

Efficacy of denosumab co-administered with vitamin D and Ca by baseline vitamin D status.

In anti-osteoporosis drug trials, vitamin D and calcium (Ca) are common supplements; however, the optimal dose of each is unclear. Using data from the randomized, double-blind, placebo-controlled DIRECT trial, we assessed whether baseline serum 25-hydroxy vitamin D (25[OH]D) level influences the efficacy of denosumab co-administered with vitamin D and Ca. In this prespecified sub-analysis, subjects with primary osteoporosis who received denosumab or placebo, plus vitamin D (≥ 400IU/day) and Ca (≥ 600mg/day), were classified as 25(OH)D deficient (< 20ng/mL), insufficient (≥ 20 to < 30ng/mL), and sufficient (≥ 30ng/mL). Study endpoints included absolute serum 25(OH)D level at baseline, 12months, and 24months; change in serum 25(OH)D and bone mineral density (BMD) status from baseline; and incidence of new vertebral fractures at 24months. In 475 denosumab-treated and 481 placebo-treated subjects, proportions with deficient/insufficient/sufficient 25(OH)D at baseline were 53.1%/37.1%/9.9% and 50.9%/42.0%/7.1%, respectively. Supplementation significantly increased mean serum 25(OH)D levels; at 24months, mean levels were > 30ng/mL (sufficient) in both treatment groups. Increase in BMD over time was higher in the denosumab group vs. placebo group in all three vitamin D status groups. At month 24, denosumab-treated subjects with deficient/insufficient baseline 25(OH)D had a significantly lower risk of new vertebral fracture vs. placebo-treated subjects. Among DIRECT trial subjects supplemented with ≥ 400IU/day of vitamin D and ≥ 600mg/day of Ca, baseline 25(OH)D sufficiency may not influence the efficacy of denosumab in increasing BMD or preventing vertebral fractures.

OR13-05 Romosozumab Treatment Lowers the Incidence of New Vertebral Fractures Across All Fracture Severity Grades Among Postmenopausal Women with Osteoporosis

Vertebral fractures (VFx) are the most common type of fracture in postmenopausal osteoporosis (PMO). VFx are generally classified using the Genant grading system as mild (grade 1), moderate (grade 2), or severe (grade 3) according to their degree of compression visualized on spinal x-rays. Regardless of their severity, VFx are associated with significant morbidity and carry the highest subsequent fracture rate of any fragility fracture. We assessed the incidence of new VFx by Genant severity grade in the romosozumab (Romo) vs placebo (Pbo) or alendronate (ALN) arms of the FRAME and ARCH studies, respectively.In FRAME, 7,180 women with PMO were randomized 1:1 to receive monthly Romo 210 mg or Pbo for 12 months followed by biannual denosumab (DMAb) 60 mg (Romo→DMAb or Pbo→DMAb) for 12 months. In ARCH, 4,093 women with PMO and ≥ 1 fracture were randomized 1:1 to receive monthly Romo 210 mg or weekly oral ALN 70 mg for 12 months followed by ALN 70 mg (Romo→ALN or ALN→ALN) for ≥ 12 months. Throughout both studies, lateral radiographs of the spine were assessed for the presence and severity (mild, moderate, or severe) of VFx using the Genant grading at baseline and after 12 and 24 months of treatment.The incidence of new VFx was significantly lower among patients who received Romo during the 12-month double-blind treatment phase in both studies. Over 12 months, the incidence of new VFx was 0.5% Romo vs 1.8% Pbo (P<0.001) in FRAME and 3.2% Romo vs 5.0% ALN (P=0.008) in ARCH. Over 24 months, the incidence of new VFx was 0.6% Romo→DMAb vs 2.5% Pbo→DMAb (P<0.001) in FRAME and 4.1% Romo→ALN vs 8.0% ALN→ALN (P<0.001) in ARCH. Fewer new VFx were observed in the Romo arm of both studies across all fracture severity grades. Specifically, in FRAME, the incidence of mild VFx was 0.2% Romo vs 0.4% Pbo over 12 months and 0.2% Romo→DMAb vs 0.6% Pbo→DMAb over 24 months; the incidence of moderate VFx was 0.1% Romo vs 0.9% Pbo over 12 months and 0.2% Romo→DMAb vs 1.4% Pbo→DMAb over 24 months; and the incidence of severe VFx was 0.2% Romo vs 0.5% Pbo over 12 months and 0.2% Romo→DMAb vs 0.6% Pbo→DMAb over 24 months. Similarly, in ARCH, the incidence of mild VFx was 0.5% Romo vs 1.0% ALN over 12 months and 0.4% Romo→ALN vs 1.4% ALN→ALN over 24 months; the incidence of moderate VFx was 1.3% Romo vs 2.1% ALN over 12 months and 1.8% Romo→ALN vs 3.4% ALN→ALN over 24 months; and the incidence of severe VFx was 1.5% Romo vs 1.9% ALN over 12 months and 1.9% Romo→ALN vs 3.3% ALN→ALN over 24 months.In conclusion, Romo administered over 12 months to women with PMO resulted in reductions in VFx across all fracture severity grades compared with Pbo and standard-of-care ALN. The treatment effect of Romo continued after patients transitioned to an antiresorptive agent. These data will help to foster treatment decisions in postmenopausal women at high risk for VFx.

Assessment of baseline bone turnover marker levels and response to risedronate treatment: Data from a Japanese phase III trial

BackgroundRisedronate increases bone mineral density (BMD) and reduces fracture risk, but treatment response may depend on the baseline state of bone turnover. Data regarding the selection of therapeutic drugs or the prediction of therapeutic effects with baseline levels of bone turnover markers (BTMs) as a reference are insufficient. We hypothesized that when the baseline levels of BTMs are higher, baseline BMD might be lower, changes in BMD at 12 months after risedronate treatment might be higher, and the reduction of fracture incidence might be greater. This study aimed to analyze the data of a phase III clinical trial of risedronate from Japan to investigate the relationships between baseline BTM levels and (1) baseline BMD, (2) changes in BMD at 12 months after the start of treatment, and (3) the incidence of new vertebral fractures. MethodsThis post-hoc analysis included 788 postmenopausal women with osteoporosis whose baseline BTM levels as well as baseline and endpoint BMDs were measured. Relationships between baseline BTM levels and BMD at baseline and 12 months after risedronate treatment and new vertebral fractures were examined. One-way analysis of variance, two-tailed Student's t-test, and Fisher's exact test were used to analyze the data. ResultsBaseline BMD showed a significant upward trend when baseline BTM levels were lower in the analysis by tertiles. New vertebral fractures tended to occur in patients with prevalent vertebral fractures, but the relationship between new fractures and BTM levels was not statistically significant. Regardless of BTM types, BMD percentage increments (%) and increments (g/cm2) with the 12-month treatment were high when pretreatment BTM levels were high (P < 0.0001), and a >5.0% increase in BMD was observed even if baseline BTM levels were within the normal range. A new vertebral fracture occurred in only six patients (0.77%), and there was not enough statistical power to clarify the relationship between baseline BTM levels and fracture risk reduction. ConclusionsWhen pretreatment BTM levels increased, baseline BMD tended to be lower and the increase in BMD with 12-month risedronate treatment was higher. However, BMD could still be increased even if the baseline BTM levels are within the normal range. Combined with available evidence, baseline BTMs may not have an important role in deciding the optimal therapy. To elucidate the relationship between baseline BTM levels and long-term fracture risk, it will be necessary to conduct more large-scale studies with a longer follow-up period in severe osteoporotic patients with a high fracture risk. Mini abstractWe evaluated the significance of baseline bone turnover markers in the response to risedronate treatment. The increase in the bone mineral density (BMD) with the 12-month treatment may be higher when the state of bone turnover at baseline is higher, and BMD could still be increased even if the baseline bone turnover is within the normal range.

Romosozumab or alendronate for fracture prevention in East Asian patients: a subanalysis of the phase III, randomized ARCH study

SummaryRomosozumab, a sclerostin antibody, exerts dual effect to increase bone formation and decrease bone resorption. Among high-risk postmenopausal East Asian women, romosozumab followed by alendronate was associated with lower incidences of fractures vs alendronate alone. Romosozumab demonstrates potential to address an unmet need in osteoporosis management in Asia.IntroductionRomosozumab, a sclerostin antibody, exerts dual effect to increase bone formation and decrease bone resorption. The global ARCH study demonstrated superiority of romosozumab followed by alendronate in reducing fracture risk in high-risk postmenopausal osteoporotic women vs alendronate alone. We report outcomes among ARCH East Asian patients.MethodsIn ARCH, 4093 postmenopausal osteoporotic women with fragility fracture were randomized 1:1 to monthly romosozumab 210 mg or weekly alendronate 70 mg for 12 months, both followed by open-label alendronate. Primary endpoints were incidence of new vertebral fracture (VF) at 24 months and clinical fracture at primary analysis (confirmed fractures in ≥ 330 patients and all patients had opportunity to attend month 24 visit). This post hoc analysis was not powered to detect fracture-rate differences.ResultsThis analysis included 275 patients from Hong Kong, Korea, and Taiwan. Romosozumab followed by alendronate reduced risk of new VFs at 24 months by 60% (P = 0.11) and clinical fractures at primary analysis by 44% (P = 0.15) vs alendronate alone. Romosozumab followed by alendronate significantly increased mean bone mineral density at 24 months from baseline by a further 9.0%, 3.3%, and 3.0% at the lumbar spine, total hip, and femoral neck vs alendronate alone. Adverse event (AE) rates, including positively adjudicated serious cardiovascular AEs (1.6% vs 1.4% at 12 months for romosozumab vs alendronate), were similar across treatment groups.ConclusionsConsistent with the global analysis, romosozumab followed by alendronate was associated with lower incidences of new vertebral, clinical, non-vertebral, and hip fractures vs alendronate alone among East Asian patients.

Investigation of the Influencing Factors on the Incidence of Vertebral Fracture: A Meta-analysis Based on Placebo Data of Randomized Clinical Trials.

The incidence of vertebral fracture is commonly used as a primary endpoint in randomized clinical trials of pharmaceutical agents for osteoporosis. In order to investigate the impact of ethnic/regional difference in osteoporosis clinical trials on the incidence of vertebral fracture, we examined the correlation between the incidence of vertebral fracture in the placebo group and baseline bone mineral density (BMD), ethnic and regional differences, or other factors by meta-regression analysis. We studied a total of 21 trials involving 28,425 patients treated with placebo, which were identified through MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. A univariate meta-regression showed a significant correlation between the proportion of subjects experiencing new vertebral fracture and the proportion of Caucasian subjects (coefficient = 0.223, [Formula: see text]), and the proportion of subjects with prevalent vertebral fracture (0.161, [Formula: see text]). Baseline lumbar spine BMD did not show significant correlations. As a result of multivariate meta-regression analysis with the factors with [Formula: see text] by the univariate meta-regression, the proportion of subjects with prevalent vertebral fracture was identified as an influencing factor (0.139, [Formula: see text]). The multivariate meta-regression showed that prevalent vertebral fracture was the most important factor to predict subsequent vertebral fracture. In addition, considering the results of the univariate meta-regression analysis, we suggest that the ethnic/regional difference should be considered as one of the important factors that influence the incidence of new vertebral fracture, a primary endpoint of osteoporosis study, when the Caucasian reference range is used in clinical trials.

Influence of Prevalent Vertebral Fracture on the Correlation between Change in Lumbar Spine Bone Mineral Density and Risk of New Vertebral Fracture: A Meta-Analysis of Randomized Clinical Trials.

The correlation between change in bone mineral density (BMD) and the incidence of new vertebral fracture has been drawing attention in regard to evaluation of fracture risk and drug efficacy. We investigated the impact of the prevalence of vertebral fracture on this correlation via a meta-regression analysis with a view to improving evaluation of the correlation. A total of 19 postmenopausal osteoporosis clinical studies involving 62,432 patients in 46 placebo or treatment groups were identified through MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. We performed a multivariate meta-regression analysis to examine the correlation between the percentage change in lumbar spine BMD from baseline at 3years and the proportion of subjects experiencing new vertebral fractures, with or without the proportion of subjects with prevalent vertebral fracture as a covariate. We also analyzed the interaction between the subgroups divided by the proportion of subjects with prevalent vertebral fracture and the percentage change in lumbar spine BMD from baseline at 3years. A multivariate meta-regression analysis showed a significant correlation between the change in lumbar spine BMD and the proportion of subjects experiencing new vertebral fracture, and a lower Akaike information criterion was obtained when the proportion of subjects with prevalent vertebral fracture was added as an explanatory variable. Significant interaction between the proportion of subjects with prevalent vertebral fracture and the change in lumbar spine BMD was shown. The change in lumbar spine BMD, not BMD T-score at one timepoint, had a significant correlation with the incidence of vertebral fracture. The prediction of the fracture risk by change in lumbar spine BMD was improved by adjusting the proportion of subjects with prevalent vertebral fracture in the study population. The difference of prevalence of vertebral fracture among populations should be considered when the association between change in lumbar spine BMD and incidence of vertebral fracture is examined.

Safety and efficacy in actual clinical practice of once-weekly subcutaneous teriparatide for osteoporosis patients with a high fracture risk

ObjectivesTo reassess the safety and efficacy of once-weekly teriparatide 56.5 μg in osteoporosis patients with a high fracture risk. MethodsThis postmarketing observational study was conducted at 72 weeks according to the package insert. Of the 3573 Japanese osteoporosis patients in the safety analysis set, 91.80% were women, the mean age was 78.1 years, and 69.89% had a history of prevalent fragility fractures, indicating that a high proportion of patients at high risk of fracture were enrolled. ResultsPersistence with weekly teriparatide treatment was 59.36%, and 38.95% at 24 and 72 weeks, respectively. Adverse drug reactions (ADRs) were reported in 898 patients (25.13%), and serious ADRs were reported in 26 patients (0.73%). The most frequent ADRs were nausea, vomiting, and headache. The cumulative incidence of new vertebral fractures 72 weeks after the start of treatment was 3.31%. Increases in the bone mineral density were observed in the lumbar spine, femoral neck, and proximal femur. The serum levels of the bone formation markers, procollagen type I N-terminal propeptide and bone-type alkaline phosphatase, increased slightly at 24 weeks and then decreased to baseline levels. At 24 and 72 weeks, the bone resorption markers, serum cross-linked N-terminal telopeptide of type I collagen and urinary cross-linked N-terminal telopeptide of type I collagen, were the same as or slightly lower than at baseline. Visual analogue scale scores for low back pain also decreased. ConclusionsThe present results showed that once-weekly teriparatide may also be useful for osteoporosis patients with a high risk of fracture.