Beatrice J. Edwards

Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia

CONTEXT The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin are licensed to treat chemotherapy-associated anemia in patients with nonmyeloid malignancies. Although systematic overviews of trials have identified venous thromboembolism (VTE) risks, none have identified mortality risks with ESAs. OBJECTIVE To evaluate VTE and mortality rates associated with ESA administration for the treatment of anemia among patients with cancer. DATA SOURCES A published overview from the Cochrane Collaboration (search dates: January 1, 1985-April 1, 2005) and MEDLINE and EMBASE databases (key words: clinical trial, erythropoietin, darbepoetin, and oncology), the public Web site of the US Food and Drug Administration and ESA manufacturers, and safety advisories (search dates: April 1, 2005-January 17, 2008). STUDY SELECTION Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer. DATA EXTRACTION Mortality rates, VTE rates, and 95% confidence intervals (CIs) were extracted by 3 reviewers from 51 clinical trials with 13 611 patients that included survival information and 38 clinical trials with 8172 patients that included information on VTE. DATA SYNTHESIS Patients with cancer who received ESAs had increased VTE risks (334 VTE events among 4610 patients treated with ESA vs 173 VTE events among 3562 control patients; 7.5% vs 4.9%; relative risk, 1.57; 95% CI, 1.31-1.87) and increased mortality risks (hazard ratio, 1.10; 95% CI, 1.01-1.20). CONCLUSIONS Erythropoiesis-stimulating agent administration to patients with cancer is associated with increased risks of VTE and mortality. Our findings, in conjunction with basic science studies on erythropoietin and erythropoietin receptors in solid cancers, raise concern about the safety of ESA administration to patients with cancer.

Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research

Bisphosphonates (BPs) are the most commonly used medications for osteoporosis. This ASBMR report provides guidance on BP therapy duration with a risk-benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score, between -2 and -2.5 in FLEX and below -2.5 in HORIZON extension, predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, reassessment of risk should be considered. In women at high risk, for example, older women, those with a low hip T-score or high fracture risk score, those with previous major osteoporotic fracture, or who fracture on therapy, continuation of treatment for up to 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered. The risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with BP therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients. For women not at high fracture risk after 3 to 5 years of BP treatment, a drug holiday of 2 to 3 years can be considered. The suggested approach for long-term BP use is based on limited evidence, only for vertebral fracture reduction, in mostly white postmenopausal women, and does not replace the need for clinical judgment. It may be applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future trials will provide data for formulating definitive recommendations.

Lateral Balance Factors Predict Future Falls in Community-Living Older Adults

OBJECTIVE To prospectively determine the capacity of measures of mediolateral (ML) protective stepping performance, maximum hip abduction torque, and trunk mobility, in order to predict the risk of falls among community-living older people. DESIGN Cross-sectional study. SETTING A balance and falls research laboratory. PARTICIPANTS Medically screened and functionally independent community-living older adult volunteers (N=51). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Measures included: (1) protective stepping responses: percentage of trials with multiple balance recovery steps and sidestep/crossover step recovery patterns, and first step length following motor-driven waist-pull perturbations of ML standing balance; (2) hip abduction strength and axial mobility: (3) peak isokinetic hip abduction joint torque and trunk functional axial rotation (FAR) range of motion; and (4) fall incidence: monthly mail-in reporting of fall occurrences with follow-up contact for 1 year post-testing. One- and 2-variable logistic regression analysis models determined which single and combined measures optimally predicted fall status. RESULTS The single variable model with the strongest predictive value for falls was the use of multiple steps in all trials (100% multiple steps) (odds ratio, 6.2; P=.005). Two-variable models, including 100% multiple steps and either hip abduction torque or FAR variables, significantly improved fall prediction over 100% multiple steps alone. The hip abduction and FAR logistic regression optimally predicted fall status. CONCLUSIONS The findings identify new predictor variables for risk of falling that underscore the importance of dynamic balance recovery performance through ML stepping in relation to neuromusculoskeletal factors contributing to lateral balance stability. The results also highlight focused risk factors for falling that are amenable to clinical interventions for enhancing lateral balance function and preventing falls.

Pharmacovigilance and reporting oversight in US FDA fast- track process: bisphosphonates and osteonecrosis of the jaw

More than half of all serious adverse reactions are identified 7 or more years after a drug receives approval from the US Food and Drug Administration (FDA). In 2002, 9 months after the intravenous bisphosphonate zoledronic acid received regulatory approval for marketing, the FDA received reports of nine patients with cancer, who were treated with zoledronic acid, who unexpectedly developed osteonecrosis of the jaw. During the next 2 years, three oral surgeons described 104 patients with cancer with osteonecrosis of the jaw in the medical literature and identified intravenous bisphosphonate therapy as being common to the care of these patients. In subspecialty medical, radiology, and dental journals, case reports and case series described clinical features of osteonecrosis of the jaw in patients with cancer who were treated with bisphosphonates. Manufacturer-sponsored epidemiological studies reported the first estimates of the incidence of this toxic effect, ranging from 0.1% to 1.8%. By contrast, independent epidemiological efforts from clinicians and the International Myeloma Foundation reported incidence estimates between 5% and 10%. Between 2003 and 2005, warnings about the risks of bisphosphonate-associated osteonecrosis were disseminated by national regulatory agencies, the manufacturers of bisphosphonates, and the International Myeloma Foundation. From 2006, independent clinical recommendations for diagnosis, prevention, and treatment of this toxic effect have been disseminated by manufacturers, national regulatory authorities, the International Myeloma Foundation, and medical specialty organisations. Furthermore, independent efforts by pharmaceutical manufacturers, dental and medical professionals, a non-profit organisation (the International Myeloma Foundation), patients, and regulatory authorities has led to the rapid identification and dissemination of safety information for this serious adverse reaction. Better coordination of safety-related pharmacovigilance initiatives is now needed.

Barriers and Solutions to Osteoporosis Care in Patients with a Hip Fracture

As the population ages, orthopaedic surgeons are treating an escalating number of patients who have a hip fracture. The total number of hip fractures worldwide was estimated to be 1.7 million in 1990 and is projected to climb to 6.3 million in 2050 1,2. The number of men and women with disabilities directly related to these fractures is reaching epidemic proportions. Even small increases in lifespan will lead to large increases in the rate of hip fracture because the risk of hip fracture increases exponentially with age 3. Approximately 50% of women who sustain a hip fracture lose the ability to walk normally, and complications directly related to the fracture cause a 20% increase in mortality during the six months after the fracture 4-7. In the United States, substantial resources are needed for both acute and long-term treatment of hip fractures. It has been estimated that these costs range from seven to ten billion dollars annually 8. Osteoporosis is the major cause of hip fractures in older adults. Although there are pharmacologic agents available to both prevent and treat osteoporosis, the identification of the appropriate population to target for therapy remains elusive. One of the major problems in averting rapidly increasing numbers of hip fractures has been the underrecognition of osteoporosis by physicians. One recent study revealed that only 5% of patients with osteoporosis or multiple risk factors for it were properly diagnosed and treated for the condition, 12% had signs and symptoms but were undiagnosed, and 5% were diagnosed but not treated 9. The remaining 78% of the patients were neither diagnosed nor treated. In 2000, a retrospective cohort study of 1162 postmenopausal women with a distal radial fracture found that only 2.8% underwent bone-mineral-density testing and only 22.9% received …

Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs?

PURPOSE Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. METHODS We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. RESULTS Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non-orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non-orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. CONCLUSION AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.

Prior fractures are common in patients with subsequent hip fractures.

Treating osteoporosis in patients with prior fractures potentially results in a 50% reduction of risk of future fractures. We retrospectively reviewed 632 patients with incident hip fractures to evaluate (1) the prevalence of prior fractures in incident hip fractures, (2) whether prior fractures led to an increase in the treatment of osteoporosis, and (3) the cost utility of osteoporosis treatment after a prior fracture. The patients were treated at three hospitals from January 2000 to June 2001 and 514 (80%) were women. A minimal trauma fracture was defined as a fracture resulting from a fall while standing or walking or falling from a height less than 4 feet. Two hundred eighty-two patients (45%) with incident hip fractures described a prior minimal trauma fracture. Osteoporosis was diagnosed in 43 (13%) women and three (5%) men. In 107 cases (17%), the incident hip fracture was the second hip fracture. A prior minimal trauma fracture did not increase treatment for osteoporosis. Presuming a 50% reduction in fracture risk with medications, treating the 282 patients with prior minimal trauma fracture would have resulted in a savings of

Functional decline after incident wrist fractures-Study of Osteoporotic Fractures: prospective cohort study

3.5 million. Level of Evidence: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Bisphosphonates and nonhealing femoral fractures: analysis of the FDA Adverse Event Reporting System (FAERS) and international safety efforts: a systematic review from the Research on Adverse Drug Events And Reports (RADAR) project.

Objective To study the effect of an incident wrist fracture on functional status in women enrolled in the Study of Osteoporotic Fractures. Design Prospective cohort study. Setting Baltimore, Minneapolis, Portland, and the Monongahela valley in Pennsylvania, USA Participants 6107 women aged 65 years and older without previous wrist or hip fracture recruited from the community between September 1986 and October 1988. Main outcome measure Clinically important functional decline, defined as a functional deterioration of 5 points in five activities of daily living each scored from 0 to 3 (equivalent to one standard deviation decrease in functional ability). Results Over a mean follow-up of 7.6 years, 268 women had an incident wrist fracture and 41 (15%) of these developed clinically important functional decline. Compared with women without wrist fractures, those with incident wrist fractures had greater annual functional decline after adjustment for age, body mass index, and health status. Occurrence of a wrist fracture increased the odds of having a clinically important functional decline by 48% (odds ratio 1.48, 95% confidence interval 1.04 to 2.12), even after adjustment for age, body mass index, health status, baseline functional status, lifestyle factors, comorbidities, and neuromuscular function. Conclusions Wrist fractures contribute to clinically important functional decline in older women.

Amiodarone-associated Optic Neuropathy: A Critical Review

BACKGROUND In the United States, hip fracture rates have declined by 30% coincident with bisphosphonate use. However, bisphosphonates are associated with sporadic cases of atypical femoral fracture. Atypical femoral fractures are usually atraumatic, may be bilateral, are occasionally preceded by prodromal thigh pain, and may have delayed fracture-healing. This study assessed the occurrence of bisphosphonate-associated nonhealing femoral fractures through a review of data from the U.S. FDA (Food and Drug Administration) Adverse Event Reporting System (FAERS) (1996 to 2011), published case reports, and international safety efforts. METHODS We analyzed the FAERS database with use of the proportional reporting ratio (PRR) and empiric Bayesian geometric mean (EBGM) techniques to assess whether a safety signal existed. Additionally, we conducted a systematic literature review (1990 to February 2012). RESULTS The analysis of the FAERS database indicated a PRR of 4.51 (95% confidence interval [CI], 3.44 to 5.92) for bisphosphonate use and nonhealing femoral fractures. Most cases (n = 317) were attributed to use of alendronate (PRR = 3.32; 95% CI, 2.71 to 4.17). In 2008, international safety agencies issued warnings and required label changes. In 2010, the FDA issued a safety notification, and the American Society for Bone and Mineral Research (ASBMR) issued recommendations about bisphosphonate-associated atypical femoral fractures. CONCLUSIONS Nonhealing femoral fractures are unusual adverse drug reactions associated with bisphosphonate use, as up to 26% of published cases of atypical femoral fractures exhibited delayed healing or nonhealing.