Cumulative Incidence Of Fracture Research Articles

Fractures are common within 18 months following first-line R-CHOP in older patients with diffuse large B-cell lymphoma

AbstractDiffuse large B-cell lymphoma (DLBCL) and osteoporotic fracture are both more common in older patients. Exposure to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) is likely to increase the risk of fracture, but evidence is lacking to define fracture incidence in this group. Data on consecutive patients with DLBCL aged ≥70 years treated with 1 to 8 cycles of full or attenuated R-CHOP were retrospectively collected across 10 UK centers (2009-2019). Patients were followed up from starting R-CHOP for a minimum of 6 months and censored at 18 months; at last follow-up if <18 months; or at progression or death. Of 877 patients identified, 148 were excluded: 121 had progression or died before 6 months; 23 had follow-up <6 months. Across 729 remaining patients, the median age was 77 years, and 68% had an Eastern Cooperative Oncology Group performance status of 0 to 1. Eighty-one fractures occurred within 18 months of follow-up; 42 were symptomatic, including 30 requiring hospital attendance or admission. The cumulative fracture incidence was 6.2% (95% confidence interval [CI], 4.7-8.2) at 6 months; 9.7% (95% CI, 7.8-12.1) at 12 months; and 11.4% (95% CI, 9.3-14.0) at 18 months. Multivariate analysis identified a predisposing history (osteoporosis, osteopenia, prior fracture, and rheumatoid arthritis [RhA]), DLBCL bone involvement at baseline, and receipt of prephase steroids as independent risk factors for fracture. There is a clinically relevant fracture risk and significant associated morbidity in older patients receiving R-CHOP. Careful attention to bone health is warranted in older patients receiving R-CHOP. Randomized studies are required to better define the most effective strategies to reduce fracture risk.

Incidence of fractures in patients with type 1 diabetes mellitus-a retrospective study with 4420 patients.

The aim of this study was to investigate the incidence of fracture in patients with type 1 diabetes mellitus (T1DM). This study is based on the German Disease Analyzer database and included 4258 adult individuals with a T1DM diagnosis documented between January 2000 and December 2015 in 1203 general practices in Germany. Individual matching of T1DM and non-diabetic patients was performed. The cumulative incidence of new fractures was shown for up to 10years after the index date using Kaplan-Meier curves. Cox proportional hazard models (dependent variable: incident fracture) were used to estimate the effect of T1DM on fracture incidence, as well as the effect of predefined variables on fracture incidence. After 10years of follow-up, the cumulative fracture incidence was 18.4% for T1DM patients and 9.9% for non-diabetic patients (p < 0.001). A strong association between T1DM and fractures was found (HR, 2.01 (95% CI, 1.70-2.38) p < 0.001) in both female and male patients. Significant differences between T1DM and non-diabetes patients were found in lower leg/ankle, foot and toe, shoulder/upper arm, and rib(s), sternum and thoracic spine fractures. A significant association between higher age and fracture incidence was observed in T1DM patients. In summary, we found that patients with T1DM have a twofold increased fracture rate compared with healthy controls. Furthermore, fractures were associated with increased age and high HbA1c values.

Evaluating the Performance of the WHO International Reference Standard for Osteoporosis Diagnosis in Postmenopausal Women of Varied Polygenic Score and Race.

Background: Whether the bone mineral density (BMD) T-score performs differently in osteoporosis classification in women of different genetic profiling and race background remains unclear. Methods: The genomic data in the Women’s Health Initiative study was analyzed (n = 2417). The polygenic score (PGS) was calculated from 63 BMD-associated single nucleotide polymorphisms (SNPs) for each participant. The World Health Organization′s (WHO) definition of osteoporosis (BMD T-score ≤ −2.5) was used to estimate the cumulative incidence of fracture. Results: T-score classification significantly underestimated the risk of major osteoporotic fracture (MOF) in the WHI study. An enormous underestimation was observed in African American women (POR: 0.52, 95% CI: 0.30–0.83) and in women with low PGS (predicted/observed ratio [POR]: 0.43, 95% CI: 0.28–0.64). Compared to Caucasian women, African American, African Indian, and Hispanic women respectively had a 59%, 41%, and 55% lower hazard of MOF after the T-score was adjusted for. The results were similar when used for any fractures. Conclusions: Our study suggested the BMD T-score performance varies significantly by race in postmenopausal women.

Risk of Fracture Following Front Line R-CHOP Immunochemotherapy in Older Patients with Diffuse Large B Cell Lymphoma Is Common

Introduction Diffuse large B cell lymphoma (DLBCL) and osteoporotic fracture are commoner in older patients (pts). Steroids and chemotherapy are recognised as a risk factor (RF) for fragility-related fracture and its associated morbidity. A small randomised trial (RCT) (Westin 2013) showed bisphosphonates stabilize bone mineral density (including all ages / histologies) in NHL pts. Despite this, there is a lack of data defining the specific incidence and fracture risk in older DLBCL pts post R-CHOP. We aimed to better define this risk in this specific cohort. Methods Data on consecutive DLBCL pts ≥70 years (y) treated with R-CHOP were retrospectively collected across 7 UK centres (2009-2019). Follow up was censored in 07/2019. All pts had untreated, de novo DLBCL or untreated transformed (to DLBCL) indolent B cell NHL. PTLD, HIV and pre-treated NHL pts were excluded. All pts received 1-9 cycles of full or attenuated R-CHOP with curative intent. Pts were excluded if they had progressive disease (PD) or died &lt; 6 months (m) of cycle 1 R-CHOP (RCHOP1). A detailed anonymised database included ECOG performance status (PS), body mass index (BMI), history of osteoporosis / osteopenia, documented steroid pre-phase, vitamin D supplementation, calcium and alkaline phosphatase levels, and sites of bone DLBCL involvement. Fractures at diagnosis (DLBCL-related/unrelated) and pre diagnosis were collected. Fractures (including bone site) occurring during 18m from RCHOP1 were identified from radiology records. Pts were followed for a minimum of 6m and censored at 18m from RCHOP1, or at their last follow up if &lt; 18m or at PD or death if between 6-18m. Baseline pt characteristics were descriptive. Survival analyses were performed using Kaplan Meier methods and Cox regression with comparisons between categories using the log-rank test. Time to event analyses were measured from RCHOP1 until fracture event. Primary end point was 18m cumulative fracture incidence censoring pts at death or relapse. Univariable and multivariable analyses (UVA; MVA) of potential influencing RFs for fracture was assessed by Cox regression (Final stepwise model; p=0.1 for inclusion). Results Of 589 pts identified, 92 pts had PD or died prior to 6m and were excluded. 20 pts were excluded due to short follow up. Across 477 pts, the median age was 77 (range 70-93) y. 66% had an ECOG PS 0-1. The median cycles given was 6 (range 1-9). 27.3% received pre-phase steroids. The median BMI was 25.5 (range 14.2-48.1). 8.1% had a fracture prior to DLBCL, and 9.1% had a history of osteopenia or osteoporosis. 5.7% were current smokers, 3% had rheumatoid arthritis, 13.5% had type (T) 2 diabetes (DM), and 4.5% had a history of excess alcohol. At baseline, 25.2% had PET or CT-assessed cortical bone involvement. Overall, there were 52 fractures, including 50 within 18m follow up. Cumulative fracture incidence was 6.3% (95% confidence interval (CI) 4.4 - 8.9) at 6m, 9.5% (95% CI 7.1 - 12.6) at 12m and 11.5% (95% CI 8.8 - 14.9) at 18m (Fig A). 6 pts had multiple fracture sites (2; n=5, 3; n=1). 32 (62%) had vertebral fracture(s). Thoracic (34% 20/59) and lumbar vertebral (27% 16/59) were dominant sites (Fig C). 7/52 fractures were at the site of DLBCL involvement, 17/52 were at a different site from initial bone DLBCL involvement, 27/52 were in pts without bone involvement and 1/52 was unknown. Univariable RFs included female sex (hazard ratio (HR) 1.89 (95% CI 1.05 - 3.28)), known osteopenia or osteoporosis (HR 2.64 (95% CI 1.32 - 5.29)), DLBCL-related fracture at diagnosis (HR 4.05 (95% CI 2.07 - 7.92) (Fig B). Initial bone involvement was only associated with an increased risk in pts with a DLBCL-related baseline fracture (95% CI HR 4.56 (2.27 - 9.17)) (Table 1). MVA showed that DLBCL-related baseline fracture (HR 4.32 (1.97 - 9.47)) was the only significant independent RF for fracture with low BMI (p=0.051) and smoking history (p=0.052) of borderline significance (Table 2). Conclusions This is the largest series to date to show there is a clinically relevant fracture risk in older DLBCL pts specifically receiving R-CHOP in early follow up. Our data have limitations inherent to a retrospective study including the potential for unknown confounders, missing data, and medical record misinterpretation. Prospective data is required to validate RFs identified which could enable targeting a high-risk population. An RCT is needed to determine the value of prophylactic intervention(s) in high risk pts. Figure Disclosures Gibb: Takeda: Research Funding. Collins:Gilead: Consultancy, Honoraria. Eyre:Janssen: Honoraria; Abbvie: Honoraria; Gilead: Consultancy, Honoraria, Other: commercial research support; Roche: Honoraria.

OR03-5 Fractures during Bisphosphonate Therapy after Orthotopic Liver Transplantation: Incidence and Predictors

Introduction: Bone loss is significant within the first 3 to 6 months after orthotopic liver transplantation (OLT) and is associated with high rates of fractures. Incident fractures after OLT are correlated with substantial decreased quality of life. To attempt preventing post-transplant fractures, the cornerstone of therapeutic management is bisphosphonates (BP). Objectives: The main objective of our study was to determine the incidence of fractures during the first three years after a first OLT in patients receiving BP. The secondary objective was to study the predictors of fractures in these patients. Methods: We conducted a retrospective study in a cohort of patients who underwent OLT between January 2012 and September 2016 at our center. All adult recipients who received BP after OLT were included in the study. Clinical, laboratory, bone mineral density (BMD) and fracture data were extracted from electronic medical records. Vertebral and non-vertebral fractures were included and all fractures were confirmed by a radiologist. Results: During the study period, 304 OLT were performed and 158 patients (median age 57 y.o.; 29.8% female) met the inclusion criteria. Prior to OLT, 14 patients (8.9%) met the criteria for osteoporosis (T-score ≤ -2.5) and a total of 24 patients (15.2%) had a past history of fractures (vertebral and non-vertebral). The cumulative incidence of fractures after OLT in patients treated with BP was 19.1% (26 patients) at 36 months, with a median time to first fracture of 6 months (Q1=2, Q3=20 months). Predictive factors of fractures in univariate analyses included: age > 60 y.o. (HR 2.46; 95% CI, 1.14-5.33), new onset diabetes after transplantation (NODAT) (HR 2.38; 95% CI, 1.10-5.15), narcotic use at 6 months after OLT (HR 2.19; 95% CI, 1.00-4.77) and length of hospital stays in the first year (days) (HR 1.01; 95% CI, 1.00-1.01). Previous fragility fracture was not associated with higher risk of post-transplant fracture. Multivariate analysis confirmed that age > 60 y.o. (HR 2.66; 95% CI, 1.23-5.79; p=0.01), narcotic use (HR 2.65; 95% CI, 1.20-5.84; p=0.02) and NODAT (HR 2.68; 95% CI, 1.23-5.84; p=0.01) were significant independent risk factors for fractures. BMD was available before and after transplant in 34 patients and there was a statistically significant decrease in mean absolute BMD (g/cm2) at the femoral neck (-0.07 g/cm2 vs. -0.04 g/cm2; p=0.02) and total hip (-0.07 g/cm2 vs. -0.02 g/cm2; p=0.02) in patients with incident fractures compared to patients without fracture during follow-up. Conclusion: Fractures are a frequent complication after OLT even in patients preemptively treated with BP. Special attention should be paid to BP treated older patients, narcotic users and patients with NODAT in order to prevent fractures after OLT. Further studies are needed to identify the best therapeutic strategy in this population.

Effectiveness of monthly intravenous ibandronate injections in a real-world setting: Subgroup analysis of a postmarketing observational study

ObjectivesThe favorable safety and consistent effectiveness of monthly intravenous (IV) ibandronate injections was demonstrated in a prospective, postmarketing, observational study in Japanese patients with osteoporosis. Here, we present subgroup analyses from the study. MethodsLumbar spine (L2–4) bone mineral density (BMD) gains were assessed in the following subgroups: aged <75 or ≥75 years, absence or presence of vertebral fractures, previous bisphosphonate (BP) treatment, and concomitant versus naïve osteoporosis drug treatment. The cumulative incidence of fractures and relative change in bone turnover markers were also examined. ResultsOf 1062 enrolled patients, 1025 received monthly IV ibandronate 1 mg and were assessed for 12 months. BMD gains with ibandronate were comparable, irrespective of older age or prevalent fractures. Overall, 515 patients (50.2%) had previously received osteoporosis treatment; of these, 166 (16.1%) received other BPs. Mean BMD changes were 3.69% (95% confidence interval [CI], 0.89%–6.50%) in patients previously treated with other BPs, and 4.26% (95% CI, 2.88%–5.64%) in patients who had not received prior osteoporosis treatment. Among the 510 patients (49.7%) concomitantly prescribed active vitamin D drugs, mean BMD changes were 5.74% (95% CI, 2.53%–8.95%) with eldecalcitol versus 3.54% (95% CI, 1.98%–5.10%) with ibandronate alone. The lowest fracture incidence was observed with the combination of ibandronate and eldecalcitol, but differences between the subgroups were not statistically significant. ConclusionsMonthly IV ibandronate demonstrated comparable BMD gains in the patient subgroups analyzed. Concomitant use of ibandronate with eldecalcitol showed a trend of higher BMD gains and lower fracture incidence than ibandronate alone.

The Impact of Roux-en-Y Gastric Bypass on Bone Remodeling Expressed by the P1NP/βCTX Ratio: a Single-Center Prospective Cohort Study.

Bariatric surgery seems to decrease bone mineral density and increase the risk of fatigue fractures. P1NP (bone formation) and βCTX (bone resorption) were recently validated as reference bone turnover markers (BTM). To assess changes in bone remodeling in severely obese patients undergoing Roux-en-Y gastric bypass (RYGB) by using a new composite biomarker, the P1NP/βCTX ratio. We prospectively collected blood samples preoperatively, at 1month and at 1year from 114 consecutive RYGB patients from 12/2012 to 04/2014. Repeated measures ANOVA and multiple regression were used for data analysis. Cumulative incidence of fractures was assessed in 06/2018. The P1NP/βCTX ratio decreased significantly (P < 0.001) from baseline to 1month and 1year (180 ± 6.6, 110 ± 4.1, and 132 ± 5.4). The 1-year P1NP/βCTX ratio did not correlate with BMI or ΔBMI, but inversely correlated with age (r = - 0.23, P = 0.014) and with hsCRP (r = - 0.26, P = 0.009), even after adjustment for age, sex, BMI, and lifestyle, and linearly correlated with albumin (r = 0.2, P = 0.037). At baseline, none of these correlations were detectable. Serum for all time-points was available from > 94% of the patients. At a median follow-up of 4.7years, 8 patients (7.3%) had a bone fracture, all of them traumatic. Following RYGB, bone remodeling increases, with a shift toward degradation. This effect seems to be weight-loss independent and shows a correlation with age,with the level of systemic inflammation, and with nutritional state. The risk of fractures should be assessed systematically in bariatric patients and measures of prevention should be improved accordingly.

Utilization of Chinese herbal medicine and its association with the risk of fracture in patients with Parkinson's disease in Taiwan

Ethnopharmacological relevanceTraditional Chinese medicine (TCM) has been used for over two thousand years to treat motor impairments corresponding to the clinical manifestations of Parkinson's disease (PD). Aim of the studyThis study aimed to investigate the prescription of Chinese herbal medicine (CHM) for the management of PD and further determine whether CHM can improve motor function and decrease the risk of incident fracture. Materials and methodsPatients older than 40 years newly diagnosed with PD between January 1997 and December 2010 were selected from the National Health Insurance Research Database (NHIRD) and followed up until the end of 2013. We used 1:1 frequency matching by age, sex, index year, and initial diagnostic year to compare the TCM users and non-TCM users. We used a Cox regression model and the Kaplan-Meier method to estimate the risk of developing fracture among the TCM and non-TCM users. ResultsIn total, 7197 patients older than 40 years were newly diagnosed with PD between 1997 and 2010 in Taiwan. Among these patients, 3456 were TCM users, and 3730 were non-TCM users. We compared 2007 PD patients with comparable demographic characteristics and comorbidity profiles between the two cohorts. During the follow-up period, compared with the non-TCM cohort, fewer patients in the TCM cohort had incident fractures (adjusted hazard ratio: 0.5, 95% CI: 0.44–0.56). The cumulative incidence of fracture was lower in the TCM cohort (log-rank test, p < 0.0001). Shi-Chang-Pu (Acorus gramineus Aiton), Yuan-Zhi (Polygala tenuifolia Willd), Bei-Mu (Fritillaria cirrhosa D. Don), Hai-Piao-Xiao (Sepiella maindronide Rochebrune; Sepia esculenta Hoyle), and Tian-Ma (Gastrodia elata Blume) constituted the core Chinese herbal medicine prescriptions used to treat PD patients. ConclusionsThe present study identified the core prescription pattern for the management of PD in Taiwan. Complementary CHM therapy was associated with a reduced risk of fracture in PD patients.

The tamoxifen paradox-influence of adjuvant tamoxifen on fracture risk in pre- and postmenopausal women with breast cancer.

Endocrine treatment of breast cancer may interfere with bone turnover and influence fracture risk. Out of a cohort of almost 5 million patients in total, we identified 5520 women between 18 and 90years of age with breast cancer receiving tamoxifen, matched them with 5520 healthy controls using the Disease Analyzer Database, and investigated the fracture risk. We found a cumulative incidence of fractures of 6.3% in patients aged between 18 and 50years (n = 3634) treated with tamoxifen versus a cumulative incidence of 3.6% in the control group (p < 0.001). As such, the risk of fracture was 75% higher for patients receiving tamoxifen than that for healthy controls (HR 1.75; 95% CI 1.25-2.48). With regard to patients aged between 55 and 90years (n = 7406), the cumulative incidence of fractures in patients treated with tamoxifen was 10.1% compared to 9.3% in the control group (p = 0.740), i.e., there was no significant difference between the two groups (HR 0.97; 95% CI 0.81-1.16). Compared to healthy controls, premenopausal women with breast cancer treated with tamoxifen showed an increased risk of fracture, while postmenopausal women on tamoxifen did not show any risk reduction.

Bone Morbidity and Recovery in Children With Acute Lymphoblastic Leukemia: Results of a Six-Year Prospective Cohort Study.

Osteoporotic fractures are a significant cause of morbidity in acute lymphoblastic leukemia (ALL). Our objective was to determine the incidence and predictors of fractures and recovery from osteoporosis in pediatric ALL over 6 years following glucocorticoid initiation. Vertebral fractures (VF) and vertebral body reshaping were assessed on annual spine radiographs, low-trauma non-VF were recorded at regular intervals and spine bone mineral density (BMD) was captured every 6 months for 4 years and then annually. A total of 186 children with ALL were enrolled (median age 5.3 years; range, 1.3 to 17.0 years). The cumulative fracture incidence was 32.5% for VF and 23.0% for non-VF; 39.0% of children with VF were asymptomatic. No fractures occurred in the sixth year and 71.3% of incident fractures occurred in the first 2 years. Baseline VF, cumulative glucocorticoid dose, and baseline lumbar spine (LS) BMD Z-score predicted both VF and non-VF. Vertebral body reshaping following VF was incomplete or absent in 22.7% of children. Those with residual vertebral deformity following VF were older compared to those without (median age 8.0 years at baseline [interquartile range {IQR}, 5.5 to 9.4] versus 4.8 years [IQR, 3.6 to 6.2], p = 0.04) and had more severe vertebral collapse (median maximum spinal deformity index 3.5 [IQR, 1.0 to 8.0] versus 0.5 [IQR, 0.0 to 1.0], p = 0.01). VF and low LS BMD Z-score at baseline as well as glucocorticoid exposure predicted incident VF and non-VF. Nearly 25% of children had persistent vertebral deformity following VF, more frequent in older children, and in those with more severe collapse. These results suggest the need for trials addressing interventions in the first 2 years of chemotherapy, targeting older children and children with more severe vertebral collapse, because these children are at greatest risk for incident VF and subsequent residual vertebral deformity. © 2018 American Society for Bone and Mineral Research.

Self-Reported Fractures in Dermatitis Herpetiformis Compared to Coeliac Disease.

Dermatitis herpetiformis (DH) is a cutaneous manifestation of coeliac disease. Increased bone fracture risk is known to associate with coeliac disease, but this has been only scantly studied in DH. In this study, self-reported fractures and fracture-associated factors in DH were investigated and compared to coeliac disease. Altogether, 222 DH patients and 129 coeliac disease-suffering controls were enrolled in this study. The Disease Related Questionnaire and the Gastrointestinal Symptom Rating Scale and Psychological General Well-Being questionnaires were mailed to participants; 45 out of 222 (20%) DH patients and 35 out of 129 (27%) of the coeliac disease controls had experienced at least one fracture (p = 0.140). The cumulative lifetime fracture incidence did not differ between DH and coeliac disease patients, but the cumulative incidence of fractures after diagnosis was statistically significantly higher in females with coeliac disease compared to females with DH. The DH patients and the coeliac disease controls with fractures reported more severe reflux symptoms compared to those without, and they also more frequently used proton-pump inhibitor medication. To conclude, the self-reported lifetime bone fracture risk is equal for DH and coeliac disease. After diagnosis, females with coeliac disease have a higher fracture risk than females with DH.

The Impact of Antihypertensive Medications on Bone Mineral Density and Fracture Risk.

This review summarizes the impact of thiazide diuretics on fracture risk in older hypertensive individuals. We performed a post hoc evaluation of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, a randomized, prospective, double blind hypertension study comparing a thiazide-like diuretic, a calcium channel blocker (CCB), and an angiotensin converting enzyme inhibitor (ACEi). We examined the risk of hip and pelvic fractures during the in-trial period (n=22,180 participants; mean 4.9-year follow-up) and during the post-trial period using national data bases (n=16,622 participants) (mean total follow-up 7.8years). During the trial, participants randomized to the thiazide diuretic versus the CCB or the ACEi had a lower risk of fracture on adjusted analyses (HR 0.79 [95% CI, 0.63, 0.98], p=0.04). Risk of fracture was significantly lower in participants randomized to the diuretic as compared to those randomized to the ACEi (HR 0.75 [95% CI, 0.58, 0.98]; p=0.04), but not significantly different compared to the CCB (HR 0.87 [95% CI, 0.71, 1.09]; p=0.17). Over the entire trial and post-trial period of follow-up, the cumulative incidence of fractures was non-significantly lower in participants assigned to the diuretic vs assignment to the ACEi or the CCB (HR 0.87 [0.74-1.03], p=0.10) and versus each medication separately. These findings establish a benefit for thiazide diuretic treatment for the prevention of fractures versus other commonly used antihypertensive medications using prospective, randomized data. The effects of the thiazide diuretic on bone appear to be long lasting.

Fracture after gastrectomy for gastric cancer: A long-term follow-up observational study

AimGastrectomy is a known risk factor for decreased bone mass. We aimed to evaluate the cumulative incidence and predictive factors of fracture in gastric cancer patients who underwent gastrectomy. MethodWe retrospectively reviewed the records of 1687 patients who underwent gastrectomy for gastric cancer at our hospital between September 1991 and December 2008. The exclusion criteria were stage IV gastric cancer, history of cancer recurrence, medical conditions that cause osteoporosis and high-energy injury. Fractures at sites considered to be associated with osteoporosis were diagnosed radiologically. ResultsIn total, our analysis included the records of 1131 patients. The incidence of postgastrectomy fracture was 42.1 cases per 1000 person-years. Fractures typically occurred within 3.7 ± 0.5 years postoperatively. The cumulative incidence of fracture was 9.1%, 19.7%, and 37.3% by postoperative year 2, 4, and 6, respectively. During the following years, the cumulative incidence increased slowly, up to a final 40.6%. Multivariate analysis showed that older age (hazard ratio, 1.03; 95% confidence interval, 1.01–1.04) and smoking (hazard ratio, 1.35; 95% confidence interval, 1.05–1.73) were significantly associated with fracture, whereas sex, body mass index, percent weight loss, diabetes mellitus, tumour stage, and type of gastrectomy were not. ConclusionThe cumulative incidence of fracture is high in gastric cancer patients who have undergone gastrectomy, and fracture rate is higher during the early postoperative period. Old age and smoking are independent risk factors for postgastrectomy fracture in these patients. More detailed postoperative surveillance and pharmacological intervention should be considered to prevent fracture.

Excellent Outcome of Children with Down Syndrome (DS) and Acute Lymphoblastic Leukemia (ALL) Treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols 00-001 and 05-001

▪BackgroundChildren with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are shown to have increased therapy-related morbidity and mortality. Hence, therapy modifications and/or dose-reductions are common treatment strategies for this patient (pt) population. Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols have used same risk-stratified treatment for children with and without DS and ALL.Aim:To define the toxicity profile and outcome of children with DS and de novo ALL treated on DFCI ALL Consortium therapy protocols 00-001 and 05-001 using therapy identical to non-DS patients.Methods:Demographic, clinical and outcome data of DS and non-DS patients enrolled on the DFCI ALL protocols 00-001 (2000-2004) and 05-001 (2005-2011) were analyzed. Risk categorization and protocol therapy have previously been described (J Clin Oncol 2013; 31:1202-10; Lancet Oncol 2015;16:1677-90). On both protocols, DS ALL pts were treated identically to non-DS pts without any dose reduction or modification, except for the option for DS ALL pts to receive 3 doses of leucovorin after IT methotrexate. Fisher’s exact test was used to compare toxicities in the DS and non-DS pts and Gray test was used to compare the cumulative incidence of fracture and osteonecrosis. Overall survival (OS) was defined as time from registration to death. Event-free survival (EFS) was defined as time from registration to first event (defined as induction failure, relapse, second malignant neoplasm (SMN) or death due to any cause). Induction failure and induction death were included as events at time zero. Disease-free survival (DFS) was defined as time from complete remission (CR) to relapse, SMN or death. Pts without an event were censored at the last known follow-up. The Kaplan-Meier method was used for survival estimation and Greenwood’s formula for calculation of 95% confidence interval (CI) of survival estimates. Outcome of DS patients was also examined using Ponte di Legno (PdL) risk group [Low risk (LR) was defined as age at diagnosis ≤ 6 yr. and white cell count < 10X109/L and, remainder as high risk (HR)].(Blood 2014;123:70-7). Two-sided p values <0.05 were considered significant.Results:Of 1286 eligible pts aged 1-18 yrs. with de novo ALL enrolled on protocols 00-001 and 05-001, 38 (3%) had DS. There was no difference in demographic or presenting clinical features between DS and non-DS ALL pts except immunophenotype (absence of T-ALL in DS vs 11.7% in non-DS, p=0.017) and presence of high hyperdiploidy (51-65 chromosomes) (8.8% in DS vs 25.1% in non-DS, p=0.027) (Table 1). Two DS-ALL pts withdrew from the study after achieving CR. There was no difference in the CR rates (DS: 100% vs non-DS: 95.2%, p=0.47) or proportion of pts with low end of induction minimal residual disease (MRD) between DS and non-DS groups (p=0.73). Toxicities were comparable except DS pts had significantly higher rates of ≥Grade 3 mucositis (data available for protocol 05-001 only) (DS: 52.0% vs. non-DS: 12.0%, p<0.001), non-CNS thrombosis/bleed (18.4% vs. 8.2%; p=0.036), and seizure (15.8% vs. 4.7%, p=0.010). DS pts also had marginally higher rate of bacterial and fungal infections (55.3% vs. 41.3%, p=0.096) (Table 2). All 38 DS pts achieved a CR and there were 4 relapses with 1 death due to disease. There were no treatment-related deaths in DS-ALL pts. With a median follow-up of 6.2 yrs. the 5-yr EFS, DFS, and OS of DS pts were similar to non-DS pts (90.7% [81.1-100.0] vs. 83.7% [81.7-85.9]; 90.7% [81.1-100.0] vs. 87.4% [85.5-89.3]; 97.1% [91.8-100.0] vs. 91.4% [89.8-93.0]), with the 95% CI overlapping for each comparison (Figures 1a and 1b). There was no difference in outcomes of DS-ALL PdL LR pts (n=13) compared to PdL HR pts (n=25) (5-yr EFS 90.0% [73.2-100.0]. vs. 91.0% [79.9-100.0]; 5-yr OS 100.0% [100.0-100.0] vs. 95.8% [88.2-100.0]).Conclusion:DS pts treated on DFCI ALL Consortium protocols without dose reduction or modifications achieved similar outcomes to non-DS pts. DS pts had a higher frequency of mucositis, infection, and seizures, but did not experience any treatment-related deaths. Other than a higher risk of thrombotic complications, they did not develop excessive toxicity to asparaginase. The low rates of relapse and toxicity-related mortality support the approach of unified therapy protocol for DS and non-DS ALL pts with emphasis on supportive care interventions to prevent toxicities. [Display omitted] [Display omitted] [Display omitted] DisclosuresAsselin:Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy.

Association of 3 Different Antihypertensive Medications With Hip and Pelvic Fracture Risk in Older Adults

On the basis of observational studies, the use of thiazide diuretics for the treatment of hypertension is associated with reduced fracture risk compared with nonuse. Data from randomized clinical trials are lacking. To examine whether the use of thiazide diuretics for the treatment of hypertension is associated with reduced fracture risk compared with nonuse. Using Veterans Affairs and Medicare claims data, this study examined hip and pelvic fracture hospitalizations in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial participants randomized to first-step therapy with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine besylate), or an angiotensin-converting enzyme inhibitor (lisinopril). Recruitment was from February 1994 to January 1998; in-trial follow-up ended in March 2002. The mean follow-up was 4.9 years. Posttrial follow-up was conducted through the end of 2006, using passive surveillance via national databases. For this secondary analysis, which used an intention-to-treat approach, data were analyzed from February 1, 1994, through December 31, 2006. Hip and pelvic fracture hospitalizations. A total of 22 180 participants (mean [SD] age, 70.4 [6.7] years; 43.0% female; and 49.9% white non-Hispanic, 31.2% African American, and 19.1% other ethnic groups) were followed for up to 8 years (mean [SD], 4.9 [1.5] years) during masked therapy. After trial completion, 16 622 participants for whom claims data were available were followed for up to 5 additional years (mean [SD] total follow-up, 7.8 [3.1] years). During the trial, 338 fractures occurred. Participants randomized to receive chlorthalidone vs amlodipine or lisinopril had a lower risk of fracture on adjusted analyses (hazards ratio [HR], 0.79; 95% CI, 0.63-0.98; P = .04). Risk of fracture was significantly lower in participants randomized to receive chlorthalidone vs lisinopril (HR, 0.75; 95% CI, 0.58-0.98; P = .04) but not significantly different compared with those randomized to receive amlodipine (HR, 0.82; 95% CI, 0.63-1.08; P = .17). During the entire trial and posttrial period of follow-up, the cumulative incidence of fractures was nonsignificantly lower in participants randomized to receive chlorthalidone vs lisinopril or amlodipine (HR, 0.87; 95% CI, 0.74-1.03; P = .10) and vs each medication separately. In sensitivity analyses, when 1 year after randomization was used as the baseline (to allow for the effects of medications on bone to take effect), similar results were obtained for in-trial and in-trial plus posttrial follow-up. These findings from a large randomized clinical trial provide evidence of a beneficial effect of thiazide-type diuretic therapy in reducing hip and pelvic fracture risk compared with treatment with other antihypertensive medications. clinicaltrials.gov Identifier: NCT00000542.

Spine stereotactic radiosurgery for the treatment of multiple myeloma.

OBJECTIVE The objective of this study was to define symptomatic and radiographic outcomes following spine stereotactic radiosurgery (SRS) for the treatment of multiple myeloma. METHODS All patients with pathological diagnoses of myeloma undergoing spine SRS at a single institution were included. Patients with less than 1 month of follow-up were excluded. The primary outcome measure was the cumulative incidence of pain relief after spine SRS, while secondary outcomes included the cumulative incidences of radiographic failure and vertebral fracture. Pain scores before and after treatment were prospectively collected using the Brief Pain Inventory (BPI), a validated questionnaire used to assess severity and impact of pain upon daily functions. RESULTS Fifty-six treatments (in 38 patients) were eligible for inclusion. Epidural disease was present in nearly all treatment sites (77%). Moreover, preexisting vertebral fracture (63%), thecal sac compression (55%), and neural foraminal involvement (48%) were common. Many treatment sites had undergone prior local therapy, including external beam radiation therapy (EBRT; 30%), surgery (23%), and kyphoplasty (21%). At the time of consultation for SRS, the worst, current, and average BPI pain scores at these treatment sites were 6, 4, and 4, respectively. The median prescription dose was 16 Gy in a single fraction. The median clinical follow-up duration after SRS was 26 months. The 6- and 12-month cumulative incidences of radiographic failure were 6% and 9%, respectively. Among painful treatment sites, 41% achieved pain relief adjusted for narcotic usage, with a median time to relief of 1.6 months. The 6- and 12-month cumulative incidences of adjusted pain progression were 13% and 15%, respectively. After SRS, 1-month and 3-month worst, current, and average BPI scores all significantly decreased (p < 0.01). Vertebral fracture occurred following 12 treatments (21%), with an 18% cumulative incidence of fracture at 6 and 12 months. Two patients (4%) developed pain flare following spine SRS. CONCLUSIONS This study reports the largest series of myeloma lesions treated with spine SRS. A rapid and durable symptomatic response was observed, with a median time to pain relief of 1.6 months. This response was durable among 85% of patients at 12 months following treatment, with 91% local control. The efficacy and minimal toxicity of spine SRS is likely related to the delivery of ablative and conformal radiation doses to the target. SRS should be considered with doses of 14-16 Gy in a single fraction for patients with multiple myeloma and limited spinal disease, myelosuppression requiring "marrow-sparing" radiation therapy, or recurrent disease after EBRT.

Sitagliptin and risk of fractures in type 2 diabetes: Results from the TECOS trial.

To examine fracture incidence among participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). We used data from 14 671 participants in the TECOS study who were randomized double-blind to sitagliptin (n = 7332) or placebo (n = 7339). Cumulative fracture incidence rates were calculated and their association with study treatment assignment was examined using multivariable Cox proportional hazards regression. The baseline mean (standard deviation) participant age was 65.5 (8.0) years, diabetes duration was 11.6 (8.1) years and glycated haemoglobin level was 7.2 (0.5)% [55.2 (5.5) mmol/mol], and 29.3% of participants were women and 32.1% were non-white. During 43 222 person-years' follow-up, 375 (2.6%; 8.7 per 1000 person-years) had a fracture; 146 were major osteoporotic fractures (hip, n = 34; upper extremity, n = 81; and clinical spine, n = 31). Adjusted analyses showed fracture risk increased independently with older age (P < .001), female sex (P < .001), white race (P < .001), lower diastolic blood pressure (P < .001) and diabetic neuropathy (P = .003). Sitagliptin, compared with placebo, was not associated with a higher fracture risk [189 vs 186 incident fractures: unadjusted hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.82 to 1.23, P = .944; adjusted HR 1.03, P = .745], major osteoporotic fractures (P = .673) or hip fractures (P = .761). Insulin therapy was associated with a higher fracture risk (HR 1.40, 95% CI 1.02-1.91; P = .035), and metformin with a lower risk (HR 0.76, 95% CI 0.59-0.98; P = .035). Fractures were common among people with diabetes in the TECOS study, but were not related to sitagliptin therapy. Insulin and metformin treatment were associated with higher and lower fracture risks, respectively.

Fracture Incidence in Adult Kidney Transplant Recipients.

It remains uncertain whether kidney transplant recipients are a high-risk group for fracture. We conducted a cohort study using Ontario, Canada health care databases to estimate the 3-, 5- and 10-year cumulative incidence of nonvertebral fracture (proximal humerus, forearm, hip) in adult kidney transplant recipients between 1994 and 2009, stratifying by sex and age (<50 versus ≥50 years) at transplant. We also assessed the 3-year cumulative incidence of all fracture locations (excluding skull, toes, and fingers) and falls, 10-year cumulative incidence of hip fracture alone, and nonvertebral fracture incidence in recipients compared to nontransplant reference groups matched on age, sex, and cohort entry year. We studied 4821 recipients (median age, 50 years). Among the age and sex strata, female recipients aged 50 years or older had the highest 3-year cumulative incidence of nonvertebral fracture (3.1%; 95% confidence interval [95% CI], 2.1-4.4%). Recipients had a higher 3-year cumulative incidence of nonvertebral fracture (1.6%; 95% CI, 1.3-2.0%) compared to the general population with no previous nonvertebral fracture (0.5%; 95% CI, 0.4-0.6%; P < 0.0001) and nondialysis chronic kidney disease (1.1%; 95% CI, 0.9-1.2%; P = 0.03), but a lower fracture incidence than the general population with a previous nonvertebral fracture (2.3%; 95% CI, 1.9-2.8%; P = 0.007). The 10-year cumulative incidence of hip fracture in all recipients was 1.7% (≥3% defined as high risk in clinical guidelines). Kidney transplant recipients may have a lower fracture risk than previously suggested in the literature. Results inform our understanding of fracture incidence after kidney transplantation and how it compares to nontransplant populations.

Fracture risk in patients with newly diagnosed type 2 diabetes: a retrospective database analysis in primary care

AimsIt is unclear whether fracture risk is increased in newly diagnosed type 2 diabetes patients. In addition, fracture risk of various sites (hip, spine, upper extremity) was analysed. MethodsThe study included 299,104 primary care patients from 1,072 practices who received a first type 2 diabetes diagnosis during the index period (01/2000–12/2013) (Disease Analyser, Germany). Furthermore, 299,104 non-diabetic controls were included after individual matching (1:1) to diabetes cases on age, sex, type of health insurance (private or statutory) and index date (visit at date of first diabetes diagnosis). Cumulative incidence of fractures was estimated for 10years after index date using product-limit methods. Hazard ratios were calculated using Cox regression models adjusting for comorbidity. ResultsCumulative 10-year incidence of any, hip, spine, wrist/hand, forearm, and upper arm/shoulder fractures were 15.4%, 2.9%, 2.6%, 5.1%, 2.3%, and 2.3% in diabetes patients and 13.1%, 2.0%, 2.1%, 4.6%, 2.2%, and 1.7% in controls (log-rank test: all p<0.001, except wrist/hand p=0.56, forearm: p=0.54), respectively. In multivariate Cox regression models, newly diagnosed type 2 diabetes was related to an significantly increased risk of any fracture (adjusted hazard ratio, HR, 95% CI: 1.36, 1.32–1.40), as well as for hip (1.56, 1.45–1.67), spine (1.37, 1.28–1.47), wrist/hand (1.15, 1.03–1.27), forearm (1.12, 1.05–1.20), and upper arm/shoulder (1.61, 1.49–1.74) fractures. ConclusionsAlready few years after diabetes diagnosis, type 2 diabetes patients more frequently experienced overall, hip, spine, and upper extremity fractures, respectively. The underlying mechanisms need to be further explored in order to prevent fractures among patients with type 2 diabetes.

Ten-year incident osteoporosis-related fractures in the population-based Canadian Multicentre Osteoporosis Study — Comparing site and age-specific risks in women and men

BackgroundPopulation-based incident fracture data aid fracture prevention and therapy decisions. Our purpose was to describe 10-year site-specific cumulative fracture incidence by sex, age at baseline, and degree of trauma with/without consideration of competing mortality in the Canadian Multicentre Osteoporosis Study adult cohort. MethodsIncident fractures and mortality were identified by annual postal questionnaires to the participant or proxy respondent. Date, site and circumstance of fracture were gathered from structured interviews and medical records. Fracture analyses were stratified by sex and age at baseline and used both Kaplan–Meier and competing mortality methods. ResultsThe baseline (1995–97) cohort included 6314 women and 2789 men (aged 25–84years; mean±SD 62±12 and 59±14, respectively), with 4322 (68%) women and 1732 (62%) men followed to year-10. At least one incident fracture occurred for 930 women (14%) and 247 men (9%). Competing mortality exceeded fracture risk for men aged 65+years at baseline. Age was a strong predictor of incident fractures especially fragility fractures, with higher age gradients for women vs. men. Major osteoporotic fracture (MOF) (hip, clinical spine, forearm, humerus) accounted for 41–74% of fracture risk by sex/age strata; in women all MOF sites showed age-related increases but in men only hip was clearly age-related. The most common fractures were the forearm for women and the ribs for men. Hip fracture incidence was the highest for the 75–84year baseline age-group with no significant difference between women 7.0% (95% CI 5.3, 8.9) and men 7.0% (95% CI 4.4, 10.3). InterpretationThere are sex differences in the predominant sites and age-gradients of fracture. In older men, competing mortality exceeds cumulative fracture risk.