Denosumab treatment lapses, discontinuation, and off-treatment fracture risk: A retrospective study of patients with osteoporosis in a real-world clinical setting.

INTRODUCTION: The purpose of this study was to retrospectively examine predictors of fracture risk when adult patients experienced a denosumab treatment lapse or discontinuation in a real-world clinic setting. MATERIALS AND METHODS: Eligible patients were adults who had received ≥2 doses of denosumab at an academic health center in the United States. Demographics, treatment doses, reasons for missed doses, and fractures, were collected retrospectively from electronic health records, from an 8-year period (2010-2018). The number of times each patient incurred a treatment lapse, defined as ≥240 days between two doses (excluding lapse due to discontinuation, death, or transfer of care) was computed. The occurrence of denosumab discontinuation (excluding discontinuation due to death or transfer of care), whether the patient initiated alternative therapy, and the reason for each lapse and discontinuation were collected. Cox proportional hazards models assessed characteristics associated with risk of fracture and treatment discontinuation. A logistic regression model was used to determine if cumulative amount of time off medication (i.e., cumulative lapse time) was associated with a higher likelihood of incurring a fracture. RESULTS: We included 534 patients: 95 % White, 86 % women, 33 % tobacco users, 13 % diagnosed with diabetes, median age 69 years (Interquartile Range (IQR): 62-77), and median Body Mass Index (BMI) 25 kg/m2 (IQR: 22-28). Thirty-six percent of patients incurred 250 lapses; 10 % discontinued therapy. Dental problems/procedures and logistical barriers were the most common reasons for lapses and discontinuations. Nineteen percent (n = 103) incurred a total of 190 fractures; of these, 121 were osteoporotic, 50 were vertebral. Risk of any, osteoporotic, and vertebral fractures were associated with off-treatment status (hazard ratio [HR] = 1.7, p = 0.043; HR = 2.0, p = 0.026; and HR = 4.2, p = 0.001, respectively) and older age (HR = 1.3, p = 0.015; HR = 1.5, p = 0.001; and HR = 1.8, p = 0.005, respectively). Older age was associated with higher risk of discontinuation (HR = 1.4, p = 0.022). There was a non-significant trend of a nonlinear association between incurring a fracture and cumulative lapse time (p = 0.087). CONCLUSION: Denosumab treatment lapses are common, and off-treatment status may be associated with a higher risk of fractures. Clinical teams should proactively identify and address adverse effects and potential logistical barriers to reduce the risk of treatment lapses.

Discontinuation/Interruption of Warfarin Therapy in Patients with Nonvalvular Atrial Fibrillation.

BACKGROUND: Use of warfarin is standard of care for stroke prevention in patients with atrial fibrillation (AF). However, AF patients experience high rates of warfarin discontinuation/interruption, resulting in increased health risks and health care costs. As such, it is important to study the rates and predictors of warfarin discontinuation/interruption in this population. OBJECTIVES: To determine (a) rates of warfarin discontinuation and interruption and (b) demographic, clinical, and health care-related factors associated with discontinuation and interruption in patients with nonvalvular AF (NVAF) in the usual clinical practice settings in the United States. METHODS: This retrospective cohort study used the MarketScan Database and included patients (aged ≥ 18 years) with NVAF who were initiated on warfarin. The study period was January 1, 2008, to June 30, 2012. To be included, patients were required to have at least 2 claims with AF diagnosis separated by ≥ 30 days and ≤ 12 months and at least 1 outpatient claim. Warfarin initiation had to occur within 30 days of the AF diagnosis. Patients also had to have continuous enrollment in prescription drug plans from 6 months prior to warfarin use to at least 12 months after warfarin initiation. Patients were followed for 1 year after warfarin initiation. Persistence was defined as warfarin therapy without a gap ≥ 45 days between the end date of the former prescription and the start date of the current prescription or with international normalized ratio (INR) monitoring at least every 42 days. Interruption was defined as a gap in warfarin therapy ≥ 45 days and ≤ 90 days between the end date of the former prescription and the start date of the current prescription and without INR monitoring at least every 42 days. Discontinuation was defined as greater than 90 days without warfarin therapy between the end date of the former prescription and the start date of the current prescription and without INR monitoring at least every 42 days. Chi-square tests were used to analyze categorical variables, and independent samples t-tests were used for continuous variables. Cox proportional hazards regression model was performed to determine factors associated with warfarin discontinuation/interruption, including demographic (e.g., age, gender); clinical (e.g., comorbidities, CHADS2 score); and health care-related (e.g., hospitalizations or emergency room visits) characteristics. Sensitivity analyses were conducted by varying prescription gaps by 7, 14, and 30 days. RESULTS: A total of 58,593 patients with NVAF were included. The mean age was approximately 71 years (SD = 12.00) and mean CHADS2 score was 1.66 (SD = 1.23). The majority of patients were male (60%). During 12 months after warfarin initiation, 45% of patients were persistent with warfarin; 12% had interruption without discontinuation; and 43% had discontinuation. The risk of warfarin interruption or discontinuation was significantly greater in patients who were younger than 65 years (HR = 1.22; 95% CI = 1.19-1.25), lived in the West (HR = 1.07; 95% CI = 1.03-1.11), had history of anemia (HR = 1.10; 95% CI = 1.06-1.14), had history of bleeding (HR = 1.10; 95% CI = 1.06-1.14), or had history of hospitalization or emergency room visits (HR = 1.11; 95% CI = 1.08-1.13). The significant factors associated with interruption and discontinuation were similar. In the sensitivity analyses, the significant factors associated with discontinuation/interruption were similar across different prescription gaps. CONCLUSIONS: In the U.S. clinical practice setting, more than 50% of NVAF patients discontinued or interrupted warfarin within 1 year after initiation. Aged less than 65 years, history of anemia, and history of hospitalization/emergency room visits were associated with increased risk of discontinuation/interruption. Given the high prevalence of warfarin discontinuation/interruption, health care providers should take a more active role in understanding and addressing the reasons behind patient discontinuation/interruption.

Doxorubicin-mediated bone loss in breast cancer bone metastases is driven by an interplay between oxidative stress and induction of TGFß.

Breast cancer patients, who are already at increased risk of developing bone metastases and osteolytic bone damage, are often treated with doxorubicin. Unfortunately, doxorubicin has been reported to induce damage to bone. Moreover, we have previously reported that doxorubicin treatment increases circulating levels of TGFß in murine pre-clinical models. TGFß has been implicated in promoting osteolytic bone damage, a consequence of increased osteoclast-mediated resorption and suppression of osteoblast differentiation. Therefore, we hypothesized that in a preclinical breast cancer bone metastasis model, administration of doxorubicin would accelerate bone loss in a TGFß-mediated manner. Administration of doxorubicin to 4T1 tumor-bearing mice produced an eightfold increase in osteolytic lesion areas compared untreated tumor-bearing mice (P = 0.002) and an almost 50% decrease in trabecular bone volume expressed in BV/TV (P = 0.0005), both of which were rescued by anti-TGFß antibody (1D11). Doxorubicin, which is a known inducer of oxidative stress, decreased osteoblast survival and differentiation, which was rescued by N-acetyl cysteine (NAC). Furthermore, doxorubicin treatment decreased Cu-ZnSOD (SOD1) expression and enzyme activity in vitro, and treatment with anti-TGFß antibody was able to rescue both. In conclusion, a combination therapy using doxorubicin and anti-TGFß antibody might be beneficial for preventing therapy-related bone loss in cancer patients.

Anti-transforming growth factor ß antibody treatment rescues bone loss and prevents breast cancer metastasis to bone.

Breast cancer often metastasizes to bone causing osteolytic bone resorption which releases active TGFß. Because TGFß favors progression of breast cancer metastasis to bone, we hypothesized that treatment using anti-TGFß antibody may reduce tumor burden and rescue tumor-associated bone loss in metastatic breast cancer. In this study we have tested the efficacy of an anti-TGFß antibody 1D11 preventing breast cancer bone metastasis. We have used two preclinical breast cancer bone metastasis models, in which either human breast cancer cells or murine mammary tumor cells were injected in host mice via left cardiac ventricle. Using several in vivo, in vitro and ex vivo assays, we have demonstrated that anti-TGFß antibody treatment have significantly reduced tumor burden in the bone along with a statistically significant threefold reduction in osteolytic lesion number and tenfold reduction in osteolytic lesion area. A decrease in osteoclast numbers (p = 0.027) in vivo and osteoclastogenesis ex vivo were also observed. Most importantly, in tumor-bearing mice, anti-TGFß treatment resulted in a twofold increase in bone volume (p<0.01). In addition, treatment with anti-TGFß antibody increased the mineral-to-collagen ratio in vivo, a reflection of improved tissue level properties. Moreover, anti-TGFß antibody directly increased mineralized matrix formation in calverial osteoblast (p = 0.005), suggesting a direct beneficial role of anti-TGFß antibody treatment on osteoblasts. Data presented here demonstrate that anti-TGFß treatment may offer a novel therapeutic option for tumor-induced bone disease and has the dual potential for simultaneously decreasing tumor burden and rescue bone loss in breast cancer to bone metastases. This approach of intervention has the potential to reduce skeletal related events (SREs) in breast cancer survivors.