Risk Of Atypical Femoral Fractures Research Articles

Abstract P2-18-02: Fractures in women with breast cancer receiving high-dose bisphosphonates to prevent breast cancer metastases as part of the SWOG S0307 trial (ClinicalTrials.gov Identifier: NCT00127205)

Abstract Background: Evidence from randomized trials, including a recent meta-analysis, suggests that adjuvant bisphosphonates can decrease recurrence and death in postmenopausal women with early-stage breast cancer. Bisphosphonates (BP) have been included as adjuvant therapy for postmenopausal breast cancer patients in multiple guidelines. SWOG S0307 compared efficacy of 3 BPs in early stage breast cancer, with no evidence of differences in efficacy on breast cancer outcomes by type of bisphosphonate, either in the overall analysis or subgroups. BPs are generally well tolerated, with a relatively low risk of serious adverse effects. Treatment for hormone sensitive breast cancer frequently includes treatment with an aromatase inhibitor (AI) or ovarian function suppression (OFS), both of which can accelerate bone loss, decrease bone density, and increase fractures. In addition to decreasing breast cancer events, BPs have been shown to decrease fractures in breast cancer patients receiving AIs or OFS. However, concerns have been raised about the risk of atypical femur fractures (AFF), a rare subtype of fragility fractures, which appear to increase with longer BP use (3-100/100,000 person-years) (Shane 2013). This substudy evaluated all fractures occurring in patients enrolled on S0307. Methods: Patients with stage I-III breast cancer who were receiving adjuvant systemic therapy were randomized to receive 3 years of intravenous zoledronic acid (ZA) 4 mg IV given every 4 weeks for the first six months, and then every 3 months for the following 2.5 years, oral clodronate (CLOD) 1,600 mg/day orally, or oral ibandronate (IBAN) 50 mg/day orally. The primary endpoint was disease-free survival (DFS). On-treatment data collection forms specifically queried whether a fracture had occurred during the reporting period, the site of the fracture, and whether or not it was associated with trauma. Results: A total of 6,097 patients were randomized to S0307, with a median age of 53 years. Rates for overall fractures at 7.7 years were higher for CLOD (9.3%) compared to IBAN (7.4%) and ZA (7.1%) (p=0.02), with differences being mostly in the spine. Traumatic fracture differences were not significant (CLOD 2.0%, ZA 1.9%, IBAN 1.7%; p=0.83). Fragility fracture rates were 5.2% with ZA, 7.2% with CLOD, and 5.6% with IBAN. Ankle fractures were the most common fracture site at 2.8% overall. Leg fractures, including femur fractures, were relatively low with a rate of 1.5% overall and not different between agents. AFF were not specifically queried/determined. Conclusion: In S0307, BPs were used in higher doses than is recommended for treatment of postmenopausal osteoporosis. There is limited data comparing the long-term effects across BP drugs used at these higher doses on the skeleton. In S0307, an overall fracture rate of 8% was seen in early stage breast cancer patients despite receiving BPs along with conventional systemic therapy. Fracture rates were slightly higher for CLOD than ZA and IBAN for fragility and overall fractures, but similar for traumatic fractures. This may reflect the potency of CLOD or the dosing schedule. Rates of femur fractures were relatively low in all arms without evidence of excess femur fractures. Funding: NIH/NCI CA180888, CA180819, CA180820, CA180821, CA180868, CA180863, CA196175; BCRF, Komen, Berlex (Bayer), Roche/Genentech, Novartis. Citation Format: Rachel L (MD) Yung, Jieling Miao, Alexander HG Paterson, Mark Clemons, Elizabeth C Dees, James N Ingle, Carla I Falkson, William Barlow, Gabriel N Hortobagyi, Julie R Gralow. Fractures in women with breast cancer receiving high-dose bisphosphonates to prevent breast cancer metastases as part of the SWOG S0307 trial (ClinicalTrials.gov Identifier: NCT00127205) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-18-02.

Diabetes and fractures: new evidence of atypical femoral fractures?

Patients with diabetes have an increased risk of femoral fractures, but little is known about the risk of atypical femoral fractures (AFFs). The aim of this study was to identify the risk of subtrochanteric and femoral shaft (ST/FS) fractures and estimate the risk of AFFs in patients with type 1 (T1D) and type 2 diabetes (T2D). From the nationwide Danish National Patient Register, we identified patients with T1D (n = 19,896), T2D (n = 312,188), and sex- and aged-matched controls without diabetes (n = 996,252) from the general population and all ST/FS fractures (n = 7509). Data were analyzed using a Cox proportional-hazards model and the incidence rate and rate ratio of ST/FS fractures were estimated. The incidence rate of ST/FS fractures in T1D was 52.14 events per 100,000 person years and 73.21 per 100,000 person years in T2D. T1D was associated with an increased risk of ST/FS (HR 2.07 (95% CI 1.68-2.56)), whereas T2D was not (HR 0.99 (95% CI 0.94-1.10)). Previous ST/FS fractures were associated with an increased risk of subsequent ST/FS fractures (HR 6.95 (95% CI 6.00-8.05)) and the use of bisphosphonates with an increased risk of ST/FS fractures (HR 1.72 (95% CI 1.54-1.91)). Patients with T1D have a higher risk of ST/FS fractures compared with sex- and age-matched controls. Since a proportion of ST/FS fractures are classified as AFFs, this could point towards the fact that AFFs also are increased in patients with T1D, but not T2D.

Detection and management of atypical femur fractures.

This article summarizes the risk factors for atypical femur fractures (AFF), discusses current and emerging imaging modalities for early identification of AFF, and offers recommendations for prevention and management of AFFs based on the current concepts. Antiresorptive therapies are widely recommended for prevention and treatment of osteoporosis. Despite their well established effectiveness to reduce fracture risk, emerging concerns related to potential adverse effects have led to a substantial decline in the use of bisphosphonates. Although, the pathogenesis of AFF has not yet been elucidated, the bulk of evidence supports that the well known therapeutic benefits of bisphosphonate far outweigh the relatively low risk of AFFs. Recommendations for early identification of patients at risk for AFF using radiographic imaging have been established. Consensus on the management of AFF and osteoporosis in patients with AFF needs to be formulated. AFF is a rare event associated with long-term bisphosphonate therapy, which represents an apparent paradox in the management of osteoporosis. Improved understanding of pathogenetic mechanisms will be helpful in further refining of screening guidelines and standardization of management and treatment strategies.

The Role of Lower-Limb Geometry in the Pathophysiology of Atypical Femoral Fracture.

The etiology of atypical femoral fracture (AFF) is likely multifactorial. In this review, we examined the recent literature investigating the role of lower-limb geometry in the pathophysiology of AFF. Increased femoral bowing was associated with prevalent AFF and a greater likelihood of a diaphyseal versus a subtrochanteric AFF location. Femoral neck geometry or hip alignment may also be related to AFF, but findings remain equivocal. Differences in femoral geometry may, in part, be responsible for the high rate of AFF in Asian compared with Caucasian populations. Finally, simulation studies suggest that lower-limb geometry influences AFF risk via its effects on mechanical strain of the lateral femoral cortex. Femoral geometry, and bowing in particular, is related to prevalent AFF, but more prospective investigation is needed to determine whether measurements of geometry can be used for clinical risk stratification.

High bisphosphonate treatment rates and the prevalence of atypical femoral fractures in patients with systematic lupus erythematosus: a single-center retrospective study performed in Japan

Treatment of systemic lupus erythematosus (SLE) often continues with moderate-to-low doses of glucocorticoids for the long term. Bisphosphonates aid in the prevention and management of glucocorticoid-induced osteoporosis (GIOP). However, long-term use of bisphosphonates increases the relative risk of atypical femoral fracture (AFF) and the incidence is typically 16 or 113 per 100,000 person-years in patients treated with bisphosphonates for 5 or 10years, respectively. Here, we explored bisphosphonate prescription rate and prevalence of AFF in patients with SLE. In total, 270 patients with SLE were enrolled. The Japanese Society for Bone and Mineral Research Guideline 2014 for GIOP management and treatment was used. We also explored AFF history through medical records. Most (n = 251) patients were recommended to treat by the GIOP guideline (scores ≥ 3); bisphosphonates, denosumab, teriparatide, or active vitamin D was prescribed for 85.7%. Bisphosphonates were currently used by 66.1% of the patients, and 65% had used them for ≥ 5years. Of all patients, 76.7% had a history of bisphosphonate use, 5 of 270 (1.9%) had histories of AFF. Four of five patients with AFF had taken bisphosphonates for ≥ 3.5years, in addition to moderate doses (≥ 10mg/day) of glucocorticoids. For the SLE patients with a history of bisphosphonate use, the incidence of AFF was calculated to be 278 per 100,000 person-years. Our single-center study found that bisphosphonates were commonly used long term by Japanese patients with SLE. As AFF is not rare, AFF should be cared in patients with SLE.

Functional Characterization of a GGPPS Variant Identified in Atypical Femoral Fracture Patients and Delineation of the Role of GGPPS in Bone-Relevant Cell Types.

Atypical femoral fractures (AFFs) are a rare but potentially devastating event, often but not always linked to bisphosphonate (BP) therapy. The pathogenic mechanisms underlying AFFs remain obscure, and there are no tests available that might assist in identifying those at high risk of AFF. We previously used exome sequencing to explore the genetic background of three sisters with AFFs and three additional unrelated AFF cases, all previously treated with BPs. We detected 37 rare mutations (in 34 genes) shared by the three sisters. Notably, we found a p.Asp188Tyr mutation in the enzyme geranylgeranyl pyrophosphate synthase, a component of the mevalonate pathway, which is critical to osteoclast function and is inhibited by N-BPs. In addition, the CYP1A1 gene, responsible for the hydroxylation of 17β-estradiol, estrone, and vitamin D, was also mutated in all three sisters and one unrelated patient. Here we present a detailed list of the variants found and report functional analyses of the GGPS1 p.Asp188Tyr mutation, which showed a severe reduction in enzyme activity together with oligomerization defects. Unlike BP treatment, this genetic mutation will affect all cells in the carriers. RNAi knockdown of GGPS1 in osteoblasts produced a strong mineralization reduction and a reduced expression of osteocalcin, osterix, and RANKL, whereas in osteoclasts, it led to a lower resorption activity. Taken together, the impact of the mutated GGPPS and the relevance of the downstream effects in bone cells make it a strong candidate for AFF susceptibility. We speculate that other genes such as CYP1A1 might be involved in AFF pathogenesis, which remains to be functionally proved. The identification of the genetic background for AFFs provides new insights for future development of novel risk assessment tools. © 2018 American Society for Bone and Mineral Research.

The Changing Role of Patient Education in Osteoporosis.

The Changing Role of Patient Education in Osteoporosis.

Economic Analysis of Bisphosphonate Use after Distal Radius Fracture for Prevention of Hip Fracture.

Osteoporosis is a common condition among the elderly population, and is associated with an increased risk of fracture. One of the most common fragility fractures involve the distal radius, and are associated with risk of subsequent fragility fracture. Early treatment with bisphosphonates has been suggested to decrease the population hip fracture burden. However, there have been no prior economic evaluations of the routine treatment of distal radius fracture patients with bisphosphonates, or the implications on hip fracture rate reduction. Age specific distal radius fracture incidence, age specific hip fracture rates after distal radius fracture with and without risendronate treatment, cost of risendronate treatment, risk of atypical femur fracture with bisphosphonate treatment, and cost of hip fracture treatment were obtained from the literature. A unique stochastic Markov chain decision tree model was constructed from derived estimates. The results were evaluated with comparative statistics, and a one-way threshold analysis performed to identify the break-even cost of bisphosphonate treatment. Routine treatment of the current population of all women over the age of 65 suffering a distal radius fracture with bisphosphonates would avoid 94,888 lifetime hip fractures at the cost of 19,464 atypical femur fractures and $19,502,834,240, or on average $2,186,617,527 annually, which translates to costs of $205,534 per hip fracture avoided. The breakeven price point of annual bisphosphonate therapy after distal radius fracture for prevention of hip fractures would be approximately $70 for therapy annually. Routine treatment of all women over 65 suffering distal radius fracture with bisphosphonates would result in a significant reduction in the overall hip fracture burden, however at a substantial cost of over a $2 billion dollars annually. To optimize efficiency of treatment either patients may be selectively treated, or the cost of annual bisphosphonate treatment should be reduced to cost-effective margins.

Predisposing factors associated with atypical femur fracture among postmenopausal Korean women receiving bisphosphonate therapy: 8years' experience in a single center.

The purpose of the present study is to determine whether rheumatoid arthritis (RA) and other clinical factors are associated with an increased risk of bisphosphonate (BP)-related atypical femur fracture (AFF). A retrospective nested case-control study of patients who had taken BPs for at least 1year was conducted. Patients with AFF were identified by reviewing surgical and radiographic records. Three controls with no history of AFFs were randomly selected and age- and sex-matched to each patient with AFFs. Cox proportional hazard models were used to analyze the independent contribution of risk factors to BP-related AFF. Among the 35,104 patients prescribed BPs for at least 1year, 43 females (mean age, 68years) suffered AFFs (0.12%). Patients with AFFs were exposed to BPs for a mean of 7.3years. Patients with AFFs were exposed to BPs for longer than those without AFFs and continued treatment without a drug holiday. More patients with AFF than controls had taken glucocorticoids and disease-modifying anti-rheumatic drugs. Multivariate Cox regression analyses estimated that long-term use of glucocorticoids, prolonged exposure to BP without cessation, and every 1kg/m2 increase in the body mass index (BMI) increased the hazard ratio for AFFs by 3.0, 5.2, and 1.2, respectively. Prolonged and continuous use of BPs, long-term use of glucocorticoids, and a higher BMI increase the risk of AFFs. Switching long-term BP and glucocorticoid users to other bone-protective agents should be considered.

Identifying Incomplete Atypical Femoral Fractures With Single-Energy Absorptiometry: Declining Prevalence.

Background:Atypical femur fractures (AFFs) are associated with long-term bisphosphonate (BP) therapy. Early identification of AFF prior to their completion provides an opportunity to intervene, potentially reducing morbidity associated with these fractures. Single-energy X-ray absorptiometry (SE) is an imaging method recently shown to detect incomplete AFF (iAFF) prior to fracture completion.Methods:Between May 2013 and September 2014, we assessed 173 patients who had been prescribed BP therapy for >5 years for iAFF using SE at their presentation for routine bone mineral density testing. We compared these findings with those of our previously published prospective study (n = 257) in which the femur was imaged for iAFF using dual-energy X-ray absorptiometry. In addition, we estimated the yearly prevalence of complete AFF among patients with subtrochanteric fracture at our institution from 2006 to 2014, and we evaluated prescribing trends for BP in Ireland from 2009 to 2014.Results:No patients had iAFF using SE femur compared with a prevalence of 2.7% in the earlier study. Between 2006 and 2014, we observed a rise and decline in AFFs at our hospital and a similar national trend in BP prescribing.Conclusions:AFFs appear to be decreasing. New customized scan modes of dual-energy X-ray absorptiometry systems, which visualize the entire femur at high image quality and take measurements, have the potential to identify iAFF prior to fracture completion and to ascertain those at highest risk of AFF.

Bisphosphonates and atypical femoral fractures.

Bisphosphonates are used widely for the treatment of osteoporosis and prevention of fractures. Although generally well tolerated and effective, bisphosphonates (and denosumab, a newer antiresorptive agent) have been associated with unusual fractures of the femoral shaft. New information about the incidence, pathophysiology, and management of atypical femoral fractures (AFFs) are reviewed. Histomorphometric studies have shown variable amounts of bone turnover suppression, but new studies suggest that healing near bone cracks may not occur in patients with AFF. Some studies suggest that hip and femur geometry make certain people more at risk for AFF. In some but not all studies, the risk of AFF appears to be related to duration of treatment. Thus, the benefit/risk ratio needs to be reassessed as bisphosphonate therapy is prolonged. If we can better understand the pathogenesis of AFF, it may be possible to identify those patients at highest risk. In the meantime, clinicians must periodically assess risk for osteoporotic fracture versus risk for AFF in managing patients with osteoporosis.

Study Explores Potential Trends in Bisphosphonate Use and Atypical Femoral Fracture Risk

Ms. Hoffmeister is a freelance medical writer in Camp Hill, Pennsylvania. To earn CME credit, you must read the CME articles and complete the quiz and evaluation assessment survey on the enclosed form, answering at least 70% of the quiz questions correctly. This continuing medical enduring material activity expires August 30, 2017.The author and all staff in a position to control the content of this CME activity have disclosed that they and their spouses/life partners (if any) have no financial relationships with, or financial interests in, any commercial companies pertaining to this educational activity.Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.Lippincott Continuing Medical Education Institute, Inc., designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only credit commensurate with the extent of their participation in the activity.Lippincott's Bone and Joint Newsletter is an independent publication solely owned and published by Lippincott Williams & Wilkins and has no affiliation with the Journal of Bone & Joint Surgery.

Hypophosphatasia and the risk of atypical femur fractures: a case-control study.

BackgroundCase reports have linked adult hypophosphatasia as a possible cause of atypical femur fractures (AFF) associated with bisphosphonate use. Adult hypophosphatasia is an asymptomatic genetic condition which results in low alkaline phosphatase and elevated pyridoxal phosphate. We conducted a case–control study to assess the role of hypophosphatasia and atypical femur fracture.MethodsWe recruited 13 control patients who took long term bisphosphonates without complication and 10 patients who sustained atypical femur fractures (mean bisphosphonate use, 9 years both cohorts). Patients underwent clinical exam and measurement of alkaline phosphatase and pyridoxal phosphate (PLP) levels. In addition, DNA was extracted and the ALPL gene was sequenced in both cohorts.ResultsLow alkaline phosphatase levels (<55 U/L) were seen in 5/10 AFF patients and 5/13 control patients. Two control patients demonstrated low alkaline phosphatase levels and elevated PLP. The alkaline phosphatase (ALPL) gene exons and intron splice sites were sequenced in the atypical femur fracture and control cohorts and no coding mutations were identified in any subjects. Atypical femur fracture patients demonstrated more varus hip alignment (p < 0.048) with no significant difference in mechanical axis.ConclusionsWe found no evidence of hypophosphatasia as a risk factor for atypical femur fractures. Laboratory findings of mildly low alkaline phosphatase activity were equally common in atypical and control cohorts and may be due to long term bisphosphonate use.Trial registrationClinicaltrials.gov number NCT01360099. Prospectively registered May 20, 2011. First patient enrolled June 14, 2011.

Atypical femur fractures in patients receiving bisphosphonate therapy: etiology and management.

Osteoporosis is a growing problem that is projected to affect more than 50% of American adults by 2020. Bisphosphonate therapy is currently the primary mode of treating osteoporosis in this population. While bisphosphonate therapy has been successful in increasing bone mineral density, data has shown an increased risk of atypical femur fractures with prolonged therapy. Atypical femur fractures are characterized by low-energy or atraumatic injuries that occur in the subtrochanteric region. They originate on the medial cortex, travel transversely, and typically have little or no comminution. Conservative therapy is indicated for patients with incomplete fractures without prodromal symptoms. Patients with incomplete fractures and significant prodromal symptoms or visible fracture line on radiographs, those who have failed conservative management, and those with complete fractures should be treated with intramedullary nail fixation. Evaluation should involve imaging of the contralateral femur. Teriparatide therapy may be considered for patients without contraindications. While the incidence of these fractures is low, it is likely that these rates will increase with the aging population and increased prevalence of patients being treated with bisphosphonate therapy.

The association of race/ethnicity and risk of atypical femur fracture among older women receiving oral bisphosphonate therapy

PurposeSeveral epidemiologic studies suggest that compared to white women, Asians have a greater propensity to suffer an atypical femur fracture (AFF) while taking bisphosphonate therapy. This study examines the relative risk of AFF following bisphosphonate initiation for Asian compared to white women. MethodsUsing data from a large integrated northern California healthcare delivery system, we examined diaphyseal femur fracture outcomes among women age≥50years old who initiated oral bisphosphonate therapy during 2002–2007. An AFF was defined by the 2013 American Society of Bone and Mineral Research Task Force criteria. The risk of radiographically-confirmed AFF was examined for Asian compared to white women, adjusting for differences in bisphosphonate exposure and other potential risk factors. ResultsAmong 48,390 women (65.3% white, 17.1% Asian) who newly initiated bisphosphonate therapy and were followed for a median of 7.7years, 68 women experienced an AFF. The rate of AFF was 18.7 per 100,000 person-years overall and eight-fold higher among Asian compared to white women (64.2 versus 7.6 per 100,000 person-years). Asians were also more likely to have longer bisphosphonate treatment duration compared to whites (median 3.8 versus 2.7years). The age-adjusted relative hazard for AFF was 8.5 (95% confidence interval 4.9–14.9) comparing Asian to white women, and was only modestly reduced to 6.6 (3.7–11.5) after adjusting for bisphosphonate duration and current use. ConclusionsOur study confirms marked racial disparity in AFF risk that should be further investigated, particularly the mechanisms accounting for this difference. These findings also underscore the need to further examine the association of bisphosphonate duration and AFF in women of Asian race, as well as differential risk across Asian subgroups. In the interim, counseling of Asian women about osteoporosis drug continuation should include consideration of their potentially higher AFF risk.

Epidemiology and Postoperative Outcomes of Atypical Femoral Fractures in Older Adults: A Systematic Review.

To review the literature on epidemiology and postoperative outcomes particularly surgical, functional and quality of life of atypical femoral fractures (AFFs) in the older population (aged ≥65 years) using the first and second American Society of Bone Mineral Research (ASBMR) Task Force consensus definition. Electronic search for articles on AFFs and bisphosphonates published in English was performed. Eligible studies were reviewed systematically in relation to (a) the epidemiology of AFFs in older people and (b) postoperative outcomes of AFFs. Twenty-three studies on AFFs were included: 14 on epidemiology and 11 on treatment outcomes (two articles reported on both aspects). The epidemiological studies showed that the incidence of AFFs is low (3.0-9.8 per 100,000 person-years) but relative risk increased with longer duration of bisphosphonates use, especially after more than three years. Most cases of AFFs occurred in older people aged 65 years and above. However, in six studies, the mean age of patients with bisphosphonate-related AFFs is younger than those with typical proximal femoral fractures (mean age range of 66-75 years versus 75-89 years respectively). Varying postoperative and functional outcomes have been reported but differences in study population, management approaches and endpoints may account for these variations. For incomplete AFFs, prophylactic surgical intervention is potentially beneficial. The benefits of bisphosphonates in reducing osteoporotic fractures still outweigh the risk of AFFs in view of its low absolute risk, when the ASBMR Task Force criteria for this type of fracture were applied. The risk of AFFs in different age groups is not well defined but tends to affect the younger patients more (aged <65 years) as compared to the older population (aged ≥65 years). Evidence supporting different types of treatment in AFFs such as intramedullary or extramedullary surgical devices and the use of teriparatide, a parathyroid hormone analogue, is not yet well established.

Atypical Femoral Fracture in Rheumatoid Arthritis Patients Treated With Bisphosphonates: A Nested Case-Control Study.

To examine the clinical characteristics of atypical femoral fracture (AFF) and to determine the risk factors for and clinical outcomes of AFFs in rheumatoid arthritis (RA) patients treated with bisphosphonates (BPs). A nested case-control study was conducted using data derived from the medical records of all RA patients treated with BPs at Seoul St. Mary's Hospital, a tertiary rheumatology center, from January 1, 2008 to December 31, 2014. All of the patients with RA and had been treated with BPs for at least 1 year. Ten RA patients with AFF were identified, and each of these patients (cases) was age- and sex-matched with 4 RA patients without AFF (controls). Five hundred fifty-two RA patients had BP exposure. Of the 10 with AFF, all were female (mean ± SD age 66.3 ± 8.7 years), and 90% of cases involved fracture of the proximal femur. The mean ± SD length of BP exposure in patients with AFF was 7.4 ± 3.2 years. Compared with controls, patients with AFF had a longer exposure to BPs and more often had a femorotibial angle of <175 degrees (both P < 0.001). There were no differences in RA duration, medications taken during the previous 6 months, and bone mineral density in the femur and lumbar spine between patients with and those without AFF. Multivariate logistic analyses identified longer BP exposure (odds ratio 2.386 [95% confidence interval 1.066-5.343]) as being associated with an increased risk of AFF. RA patients who have a valgus deformity and are receiving long-term BP treatment are at higher risk of AFF compared with matched control patients with RA. These patients should be carefully followed up with hip radiography or dual x-ray absorptiometry.

Mortality After Atypical Femoral Fractures: A Cohort Study.

Although osteoporotic fracture rates can be reduced by bisphosphonates, prolonged therapy is associated with higher risk of atypical femoral fractures. Ordinary fragility fractures are linked to high mortality rates. We aimed to determine whether atypical femoral fractures also confer excess mortality. Radiographs were reviewed for all patients aged ≥55 years who had experienced a subtrochanteric or femoral shaft fracture in Sweden in 2008 to 2010. The fractures were classified as either atypical or ordinary. Data on medication use, coexisting conditions, and date of death were obtained from national registers. We estimated multivariable-adjusted relative risks of death after atypical femoral fractures compared with ordinary subtrochanteric or femoral shaft fractures and calculated age- and sex-standardized mortality ratios (SMRs) for atypical and ordinary fractures compared with the population average. During a mean of 4 years of follow-up, 39 of 172 (23%) patients with an atypical fracture had died compared with 588 of 952 (62%) with an ordinary fracture, corresponding to a relative risk of 0.51 (95% confidence interval [CI] 0.38-0.68). The lower risk was evident in both users and nonusers of bisphosphonates. No patient with atypical fracture died in the first year after fracture. Individuals with an ordinary fracture had a higher mortality risk than the general population (SMR = 1.82; 95% CI 1.69-1.99), but no excess risk was found in patients with atypical fracture (SMR = 0.92; 95% CI 0.65-1.26). We conclude that in contrast to ordinary subtrochanteric and femoral shaft fractures, atypical femoral fractures are not associated with excess mortality.

Utilization Patterns of Bone-Targeting Agents Among Patients with Multiple Myeloma: Analysis of Real-World Data

Background: At diagnosis, 80% of patients with multiple myeloma (MM) are reported to have osteolytic lesions.MM is characterized by substantial bone destruction, resulting in increased risk of skeletal-related events (SREs), defined as pathological fracture, spinal cord compression, radiation or surgery to bone. SREs are associated with debilitating bone pain, significant morbidity, and increased mortality. SREs also have substantial economic consequences on patients and healthcare systems. Bone-targeting agents (BTAs) approved for the prevention of SREs in MM include intravenous bisphosphonates (IV BPs) zoledronic acid (ZA) and pamidronate (PA). ZA and PA may be used monthly for up to two years and longer for patients who continue to have active or relapsed disease. Given the increased risk of atypical femoral fracture and osteonecrosis of the jaw (ONJ) with cumulative dosing, and medical contraindications (e.g., renal function deterioration), there may be clinician preference to reduce or limit IV BPs. Limited information is available regarding compliance to BTAs in real-world setting in the US. The objective of this study is to examine BTA treatment patterns, including compliance and time to non-persistence among MM patients.Methods: This retrospective cohort study was conducted using the Oncology Services Comprehensive Oncology Records (OSCER) electronic medical records database, including over 750,000 patients from >200 hematology/oncology practices across the United States. The following selection criteria were used: (1) MM diagnosis (ICD-9CM: 203.0x) between 1st January 2012 and 31st December 2014; (2) ≥18 years of age at MM diagnosis; and (3) initiation of BTA therapy between 1-Jan-2012 and 31-Dec-2014. Patients with solid tumors were excluded. Compliance with BTA therapy was defined as ≥12 administrations in each year of follow-up. Non-persistence was operationalized as either a gap in therapy of ≥90 days or ≥90 days between last administration and last date of follow-up (i.e., discontinuation), or switch from initial BTA. Kaplan-Meier method was used for analysis of time to non-persistence.Results: Out of 9,617 patients diagnosed with MM, a total of 3,394 (35.3%) patients treated with ZA therapy and 341 (3.6%) treated with PA met inclusion criteria. Majority of the patients were male (ZA: 54.1%, PA: 53.1%), white (ZA: 72.2%, PA: 64.2%), and ≥65 years (ZA: 64.5%, PA: 67.7%). Average time to initiation of therapy from MM diagnosis was 3 months for both ZA and PA. Most of the patients initiated therapy within 3 months (ZA: 76.1%, PA: 75.1%) or 6 months (ZA: 86.3%, PA: 85.6%) of MM diagnosis. Overall the compliance rate was low and declined during follow-up (Table 1). The median time to non-persistence was 16.2 (15.4-17.4) months for ZA and 13.8 (11.5-15.4) months for PA (Fig. 1). Persistence rates declined over the follow-up years, ranging from 86% at 6 months to 34% at 24 months for ZA, and from 77% at 6 months to 30% at 24 months for PA (Fig. 1).Table 1Compliance with BTA therapy over follow-up yearsPatients with Minimum 12 Months of Follow-up (N=2,211)Patients with Minimum 24 Months of Follow-up (N=899)PamidronateZoledronic AcidPamidronateZoledronic AcidN1912,02095804Current Users1912,02064641Mean Administrations (Standard Deviation)7.6 (4)8.3 (3.8)7.0 (3.7)7.3 (3.9)Switch (n, %)28 (14.7)39 (1.9)3 (3.2)9 (1.1)≥12 Administrations/Year (n, %)44 (23)553 (27.4)10 (15.6)127 (19.8)Conclusions: The treatment landscape in MM has evolved in recent years with clinical trial data supporting improved survival for patients. In this dynamic landscape, it is increasingly important to understand prescribing patterns and patient compliance with BTAs. This analysis indicates there may be limited compliance to BTA therapy in the real-world setting. Potential reasons for non-compliance may include concerns of medical contraindications, patient burden associated with IV administration, or clinician preference. With emerging therapies being evaluated in MM, BTA treatment patterns warrant investigation in future studies. [Display omitted] DisclosuresQian:Amgen Inc.: Employment. Bhowmik:Amgen Inc.: Employment. Kachru:Amgen Inc.: Employment. Hernandez:Amgen Inc.: Employment. Cheng:Amgen Inc.: Employment. Liede:Amgen Inc.: Employment.

Risks and Benefits of Bisphosphonate Therapies

Bisphosphonates are the mainstay of osteoporosis treatment but also play a fundamental role in treating other bone diseases such as Osteogenesis Imperfecta, Pagets' disease, and in the prevention of adverse skeletal effects in certain cancers such as prostate cancer or multiple myeloma. In the last decades, the refinement of bisphosphonates and an increase in the number of new bisphosphonates commercialized has altered the clinical management of these diseases. Despite differences between randomized controlled trials and observational studies, overall all bisphosphonates licensed have proven to reduce the risk of fracture through the inhibition of bone resorption. Other beneficial effects include pain reduction in bone metastasis and potentially a decrease in mortality. However, the chronic nature of most of these disorders implies long-term treatments, which can be associated with long-term adverse effects. Some of the adverse effects identified include an increased risk of atypical femur fractures, osteonecrosis of the jaw, gastrointestinal side effects, or atrial fibrillation. The harm/benefit thinking and the constant update regarding these medications are vital in the day-to-day decision-making in clinical practices. The aims of this review are to compile the basic characteristics of these drugs and outline the most important benefits and side effects and provide a clinical context as well as a research agenda to fill the gaps in our knowledge.