Evaluating Pneumonitis Incidence in Patients with Non-small Cell Lung Cancer Treated with Immunotherapy and/or Chemotherapy Using Real-world and Clinical Trial Data.

Pneumonitis is a potentially life-threatening complication of anticancer therapy, and future treatment decisions may be informed by characterizing patients receiving therapies in the real-world setting. In this study, the incidence of treatment-associated pneumonitis (TAP) was compared among patients with advanced non-small cell lung cancer receiving immune checkpoint inhibitors (ICI) or chemotherapies in either of two settings: randomized clinical trials (RCT) or real world data (RWD)-based clinical practice. Pneumonitis cases were identified using International Classification of Diseases codes (for RWD), or the Medical Dictionary for Regulatory Activities preferred terms (for RCTs). TAP was defined as pneumonitis diagnosed during treatment or within 30 days of the last treatment administration. Overall TAP rates in the RWD cohort were lower [ICI: 1.9%; 95% confidence interval (CI), 1.2-3.2; chemotherapy: 0.8%; 95% CI, 0.4-1.6] than overall rates in the RCT cohort (ICI: 5.6%; 95% CI, 5.0-6.2; chemotherapy: 1.2%; 95% CI, 0.9-1.5). Overall RWD TAP rates were similar to grade 3+ RCT TAP rates (ICI: 2.0%; 95% CI, 1.6-2.3; chemotherapy: 0.6%; 95% CI, 0.4-0.9). In both cohorts, higher TAP incidence was observed among patients with a past medical history of pneumonitis than those without, regardless of treatment group. On the basis of this sizable study leveraging RWD, TAP incidence was low in the RWD cohort, likely in part due to methodology used for RWD focusing on clinically significant cases. Past medical history of pneumonitis was associated with TAP in both cohorts. Significance: Pneumonitis is a potentially life-threatening complication of anticancer treatment. As treatment options expand, management decisions become increasingly complex, and there is a greater need to understand the safety profiles of the treatment options in the real-world setting. Real-world data serve as an additional source of valuable information to complement clinical trial data and inform understanding of toxicity in patients with non-small cell lung cancer receiving ICIs or chemotherapies.

Epidemiology of interstitial lung disease in patients with metastatic breast cancer at baseline and after treatment with HER2-directed therapy: a real-world data analysis.

PURPOSE: Using real-world data, interstitial lung disease (ILD) prevalence before and after HER2-directed therapy was estimated. Potential ILD risk factors in patients receiving HER2-directed therapy for metastatic breast cancer (mBC) were evaluated. METHODS: Adults with HER2-directed therapy for mBC initiated between September 25, 1998, and February 22, 2020 were, included. ILD was defined broadly as one or more of 64 lung conditions. Patients were followed until incident ILD, death, last contact, or study end. RESULTS: In total, 533 patients were identified with median age at mBC of 57, 51% had de novo mBC, 43% were ever smokers, 30% had lung metastases, 9% had thoracic radiation, 6% had chronic obstructive pulmonary disease, and 16% had prevalent ILD. ILD cumulative incidence at one year was 9% (95% CI 6%, 12%), with a median follow-up of 23 months. Smoking (HR 2.2, 95% CI 1.1, 4.8) and Black/African-American race (HR 3.4, 95% CI 1.6, 7.5) were significantly associated with ILD; HRs for preexisting lung conditions (HR 1.8, 95% CI 0.9, 3.8) and thoracic radiation (HR 2.3, 95% CI 0.8, 7.1) were not statistically significant. Prevalent ILD was associated with 13-fold greater occurrence of incident ILD. 85% of patients with prevalent or incident ILD were symptomatic. CONCLUSIONS: This real-world population of patients with mBC had a high prevalence of ILD prior to HER2-directed therapy, reflecting the multifactorial causation of interstitial lung changes. The cumulative incidence of ILD in patients receiving HER2-directed therapy for mBC augments prior reports. Symptomatic presentation suggests an opportunity for early intervention.

Rapid real-world data analysis of patients with cancer, with and without COVID-19, across distinct health systems.

BACKGROUND: The understanding of the impact of COVID-19 in patients with cancer is evolving, with need for rapid analysis. AIMS: This study aims to compare the clinical and demographic characteristics of patients with cancer (with and without COVID-19) and characterize the clinical outcomes of patients with COVID-19 and cancer. METHODS AND RESULTS: Real-world data (RWD) from two health systems were used to identify 146 702 adults diagnosed with cancer between 2015 and 2020; 1267 COVID-19 cases were identified between February 1 and July 30, 2020. Demographic, clinical, and socioeconomic characteristics were extracted. Incidence of all-cause mortality, hospitalizations, and invasive respiratory support was assessed between February 1 and August 14, 2020. Among patients with cancer, patients with COVID-19 were more likely to be Non-Hispanic black (NHB), have active cancer, have comorbidities, and/or live in zip codes with median household income <$30 000. Patients with COVID-19 living in lower-income areas and NHB patients were at greatest risk for hospitalization from pneumonia, fluid and electrolyte disorders, cough, respiratory failure, and acute renal failure and were more likely to receive hydroxychloroquine. All-cause mortality, hospital admission, and invasive respiratory support were more frequent among patients with cancer and COVID-19. Male sex, increasing age, living in zip codes with median household income <$30 000, history of pulmonary circulation disorders, and recent treatment with immune checkpoint inhibitors or chemotherapy were associated with greater odds of all-cause mortality in multivariable logistic regression models. CONCLUSION: RWD can be rapidly leveraged to understand urgent healthcare challenges. Patients with cancer are more vulnerable to COVID-19 effects, especially in the setting of active cancer and comorbidities, with additional risk observed in NHB patients and those living in zip codes with median household income <$30 000.

Implementation of Smart Pump Technology With Home Infusion Providers: An Assessment of Clinician Workflow and Patient Satisfaction.

While hospitals have adopted smart pump technology (SPT) featuring drug libraries and medication safety software, most home infusion providers (HIPs) continue to use traditional infusion pumps that don't offer drug libraries or medication safety software. As infusion delivery is moving from the hospital to the home, the purpose of this study was to determine whether SPT was a feasible alternative at both a hospital-based and a rural HIP. HIP personnel were trained on an ambulatory infusion pump. Patients requiring home infusion used the pump and recorded daily pump interactions for 5 to 7 days. After the creation of a drug library, clinicians felt comfortable programming pumps after 7 uses. Patients reported 100% overall satisfaction, and the majority of alarms were resolved without contacting the HIP. Ambulatory SPT can be implemented successfully by HIPs and can be used effectively by patients.

Art and Challenges of Precision Medicine: Interpreting and Integrating Genomic Data Into Clinical Practice.

Precision medicine is at the forefront of innovation in cancer care. With the development of technologies to rapidly sequence DNA from tumors, cell-free DNA, proteins, and even metabolites coupled with the rapid decline in the cost of genomic sequencing, there has been an exponential increase in the amount of data generated for each patient diagnosed with cancer. The ability to harness this explosion of data will be critical to improving treatments for patients. Precision medicine lends itself to big data or "informatics" approaches and is focused on storing, accessing, sharing, and studying these data while taking necessary precautions to protect patients' privacy. Major cancer care stakeholders have developed a variety of systems to incorporate precision medicine technologies into patient care as soon as possible and also to provide the ability to store and analyze the omics and clinical data aggregately in the future. Scaling these precision medicine programs within the confines of health care system silos is challenging, and research consortiums are being formed to overcome these limitations. Incorporating and interpreting the results of precision medicine sequencing is complex and rapidly changing, necessitating reliance on a group of experts. This is often performed at molecular tumor boards at large academic and research institutions with available in-house expertise, but alternative models clinical decision support software or of virtual tumor boards potentially expand these advances to almost any patient, regardless of site of care. The promises of precision medicine will be more quickly realized by expanding collaborations to rapidly process and interpret the growing volumes of omics data.

Human Gut Microbiota and Gastrointestinal Cancer.

Human gut microbiota play an essential role in both healthy and diseased states of humans. In the past decade, the interactions between microorganisms and tumors have attracted much attention in the efforts to understand various features of the complex microbial communities, as well as the possible mechanisms through which the microbiota are involved in cancer prevention, carcinogenesis, and anti-cancer therapy. A large number of studies have indicated that microbial dysbiosis contributes to cancer susceptibility via multiple pathways. Further studies have suggested that the microbiota and their associated metabolites are not only closely related to carcinogenesis by inducing inflammation and immune dysregulation, which lead to genetic instability, but also interfere with the pharmacodynamics of anticancer agents. In this article, we mainly reviewed the influence of gut microbiota on cancers in the gastrointestinal (GI) tract (including esophageal, gastric, colorectal, liver, and pancreatic cancers) and the regulation of microbiota by diet, prebiotics, probiotics, synbiotics, antibiotics, or the Traditional Chinese Medicine. We also proposed some new strategies in the prevention and treatment of GI cancers that could be explored in the future. We hope that this review could provide a comprehensive overview of the studies on the interactions between the gut microbiota and GI cancers, which are likely to yield translational opportunities to reduce cancer morbidity and mortality by improving prevention, diagnosis, and treatment.

Tibial Plateau Fractures: A New Rank Ordering Method For Determining To What Degree Injury Severity Or Quality Of Reduction Correlate With Clinical Outcome.

BACKGROUND: Injury severity may be the most important factor in determining outcome after articular fractures, but there is a surprising paucity of clinical evidence to support this assertion. The purpose of this study was to utilize a new method for rank ordering a group of patient radiographs to assess the effect of injury severity and quality of reduction on patient outcomes after tibial plateau fractures. METHODS: Tibial plateau fractures in 64 patients were treated operatively or non-operatively based on physician preference from standard of care techniques. Fracture severity and reduction quality were stratified from radiographs by four expert clinicians using an iTunes-based rank ordering methodology. The images were distributed electronically, and the ranks were performed on local computers at three different institutions. Clinical outcomes were measured with the SF-12 health questionnaire and the Knee injury and Osteoarthritis Outcome Score (KOOS). RESULTS: There was excellent or very good agreement between raters for injury severity ranking (correlation 0.77-0.91) and quality of reduction (correlation 0.66-0.82). There was no correlation between the injury severity nor quality of reduction and general or joint-specific clinical outcomes. CONCLUSIONS: Expert orthopaedic traumatologists strongly agree on how to rank order tibial plateau fractures based both on injury severity and quality of reduction. The novel electronic interface utilized allows an ever-expanding series of cases to be ranked quickly, conveniently, and across multiple centers. This interface holds great promise for establishing prospective, continuously expanding rank orders of various fracture types, which may have great value for clinical research, education about fracture severity, and for prognosis and treatment decisions. In the present study, neither injury severity nor quality of reduction correlated with the clinical outcomes. Other patient- and injury-related factors may be more important in determining clinical outcome of tibial plateau fractures than the appearances of the radiographs at the time of injury or after reduction. Level of Evidence: level III evidence.

Goal-Directed Treatment for Osteoporosis: A Progress Report From the ASBMR-NOF Working Group on Goal-Directed Treatment for Osteoporosis.

The American Society for Bone and Mineral Research and the United States National Osteoporosis Foundation (NOF) formed a working group to develop principles of goal-directed treatment and identify gaps that need to be filled to implement this approach. With goal-directed treatment, a treatment goal would first be established and choice of treatment determined by the probability of achieving that goal. Goals of treatment would be freedom from fracture, a T-score > -2.5, which is above the NOF threshold for initiating treatment, or achievement of an estimated risk level below the threshold for initiating treatment. Progress toward reaching the patient's goal would be periodically and systematically assessed by estimating the patient's compliance with treatment, reviewing fracture history, repeating vertebral imaging when indicated, and repeating measurement of bone mineral density (BMD). Using these data, a decision would be made to stop, continue, or change therapy. Some of these approaches can now be applied to clinical practice. However, the application of goal-directed treatment cannot be fully achieved until medications are available that provide greater increases in BMD and greater reduction in fracture risk than those that are currently approved; only then can patients with very high fracture risk and very low BMD achieve such goals. Furthermore, assessing future fracture risk in patients on treatment requires a new assessment tool that accurately captures the change in fracture risk associated with treatment and should also be sensitive to the importance of recent fractures as predictors of imminent fracture risk. Lastly, evidence is needed to confirm that selecting and switching treatments to achieve goals reduces fracture risk more effectively than current standard care. © 2016 American Society for Bone and Mineral Research.

Bearing-Foreign Material Deposition on Retrieved Co-Cr Femoral Heads: Composition and Morphology.

Bearing-foreign material deposition onto a femoral head can occur from contact with an acetabular shell due to dislocation, reduction, or subluxation. The purpose of this study was to comprehensively characterize deposit regions on retrieved cobalt-chrome femoral heads from metal-on-polyethylene total hip arthroplasties that had experienced such adverse events. The morphology, topography, and composition of deposition regions were characterized using macrophotography, optical profilometry, scanning electron microscopy, energy dispersive spectroscopy, and X-ray photoelectron spectroscopy. The deposit areas were relatively large, they were much rougher than the surrounding undamaged clean areas, and they displayed several distinct morphologies. Titanium alloy elements were the predominant constituents. Calcium and phosphorous were also detected within the deposit areas, in a composition that could nucleate abrasive hydroxyapatite. In addition, tungsten-rich particles, likely present as tungsten carbide, were observed on top of the titanium deposits. The increased roughness associated with these deposition features would be expected to accelerate damage and wear of the opposing liner and hence accelerate the development of osteolysis.

THA Retrievals: The Need to Mark the Anatomic Orientation of the Femoral Head.

The hypothesis of this study was that the rotational orientation of femoral head damage would greatly affect the volumetric wear rate of the opposing polyethylene (PE) liner. Damage on twenty retrieved cobalt-chromium femoral heads was simulated in a validated damage-feature-based finite element model. For each individual retrieval, the anatomic orientation of the femoral head about the femoral neck axis was systematically varied, in 30° increments. The PE wear rate differential between the maximum- versus minimum-wear orientations was often sizable, as high as 7-fold. Knowing the correct femoral head anatomic orientation is therefore important when analyzing the effects of femoral head damage on PE liner wear. Surgeons retrieving modular femoral heads should routinely mark the anatomic orientation of those components.

Novel silica surface charge density mediated control of the optical properties of embedded optically active materials and its application for fiber optic pH sensing at elevated temperatures.

Silica and silica incorporated nanocomposite materials have been extensively studied for a wide range of applications. Here we demonstrate an intriguing optical effect of silica that, depending on the solution pH, amplifies or attenuates the optical absorption of a variety of embedded optically active materials with very distinct properties, such as plasmonic Au nanoparticles, non-plasmonic Pt nanoparticles, and the organic dye rhodamine B (not a pH indicator), coated on an optical fiber. Interestingly, the observed optical response to varying pH appears to follow the surface charge density of the silica matrix for all the three different optically active materials. To the best of our knowledge, this optical effect has not been previously reported and it appears universal in that it is likely that any optically active material can be incorporated into the silica matrix to respond to solution pH or surface charge density variations. A direct application of this effect is for optical pH sensing which has very attractive features that can enable minimally invasive, remote, real time and continuous distributed pH monitoring. Particularly, as demonstrated here, using highly stable metal nanoparticles embedded in an inorganic silica matrix can significantly improve the capability of pH sensing in extremely harsh environments which is of increasing importance for applications in unconventional oil and gas resource recovery, carbon sequestration, water quality monitoring, etc. Our approach opens a pathway towards possible future development of robust optical pH sensors for the most demanding environmental conditions. The newly discovered optical effect of silica also offers the potential for control of the optical properties of optically active materials for a range of other potential applications such as electrochromic devices.

The 2014 Frank Stinchfield Award: The 'landing zone' for wear and stability in total hip arthroplasty is smaller than we thought: a computational analysis.

BACKGROUND: Positioning of total hip bearings involves tradeoffs, because cup orientations most favorable in terms of stability are not necessarily ideal in terms of reduction of contact stress and wear potential. Previous studies and models have not addressed these potentially competing considerations for optimal total hip arthroplasty (THA) function. QUESTIONS/PURPOSES: We therefore asked if component positioning in total hips could be addressed in terms of balancing bearing surface wear and stability. Specifically, we sought to identify acetabular component inclination and anteversion orientation, which simultaneously resulted in minimal wear while maximizing construct stability, for several permutations of femoral head diameter and femoral stem anteversion. METHODS: A validated metal-on-metal THA finite element (FE) model was used in this investigation. Five dislocation-prone motions as well as gait were considered as were permutations of femoral anteversion (0°-30°), femoral head diameter (32-48 mm), cup inclination (25°-75°), and cup anteversion (0°-50°), resulting in 4320 distinct FE simulations. A novel metric was developed to identify a range of favorable cup orientations (so-called "landing zone") by considering both surface wear and component stability. RESULTS: When considering both wear and stability with equal weight, ideal cup position was more restrictive than the historically defined safe zone and was substantially more sensitive to cup anteversion than to inclination. Ideal acetabular positioning varied with both femoral head diameter and femoral version. In general, ideal cup inclination decreased with increased head diameter (approximately 0.5° per millimeter increase in head diameter). Additionally, ideal inclination increased with increased values of femoral anteversion (approximately 0.3° per degree increase in stem anteversion). Conversely, ideal cup anteversion increased with increased femoral head diameter (0.3° per millimeter increase) and decreased with increased femoral stem anteversion (approximately 0.3° per degree increase). Regressions demonstrated strong correlations between optimal cup inclination versus head diameter (Pearson's r=-0.88), between optimal cup inclination versus femoral anteversion (r=0.96), between optimal cup anteversion versus head diameter (r=0.99), and between optimal cup anteversion and femoral anteversion (r=-0.98). For a 36-mm cup with a 20° anteverted stem, the ideal cup orientation was 46°±12° inclination and 15°±4° anteversion. CONCLUSIONS: The range of cup orientations that maximized stability and minimized wear (so-called "landing zone") was substantially smaller than historical guidelines and specifically did not increase with increased head size, challenging the presumption that larger heads are more forgiving. In particular, when the cup is oriented to improve not only stability, but also wear in the model, there was little or no added stability achieved by the use of larger femoral heads. Additionally, ideal cup positioning was more sensitive to cup anteversion than to inclination. CLINICAL RELEVANCE: Positioning THA bearings involves tradeoffs regarding stability and long-term bearing wear. Cup positions most favorable to minimization of wear such as low inclination and elevated anteversion were detrimental in terms of construct stability. Orientations were identified that best balanced the competing considerations of wear and stability.

Impingement and dislocation in total hip arthroplasty: mechanisms and consequences.

In contemporary total hip arthroplasty, instability has been a complication in approximately 2% to 5% of primary surgeries and 5% to 10% of revisions. Due to the reduction in the incidence of wear-induced osteolysis that has been achieved over the last decade, instability now stands as the single most common reason for revision surgery. Moreover, even without frank dislocation, impingement and subluxation are implicated in a set of new concerns arising with advanced bearings, associated with the relatively unforgiving nature of many of those designs. Against that backdrop, the biomechanical factors responsible for impingement, subluxation, and dislocation remain under-investigated relative to their burden of morbidity. This manuscript outlines a 15-year program of laboratory and clinical research undertaken to improve the scientific basis for understanding total hip impingement and dislocation. The broad theme has been to systematically evaluate the role of surgical factors, implant design factors, and patient factors in predisposing total hip constructs to impinge, sublux, and/or dislocate. Because this class of adverse biomechanical events had not lent itself well to study with existing approaches, it was necessary to develop (and validate) a series of new research methodologies, relying heavily on advanced finite element formulations. Specific areas of focus have included identifying the biomechanical challenges posed by dislocation-prone patient activities, quantifying design parameter effects and component surgical positioning effects for conventional metal-on-polyethylene implant constructs, and the impingement/dislocation behavior of non-conventional constructs, quantifying the stabilizing role of the hip capsule (and of surgical repairs of capsule defects), and systematically studying impingement and edge loading of hard-on-hard bearings, fracture of ceramic liners, confounding effects of patient obesity, and subluxation-mediated worsening of third body particle challenge.

Distinctive damage patterns on THA metal bearing surfaces: case studies.

Retrieval analysis of total joint arthroplasty components has primarily focused on assessing wear or other damage to polyethylene components. As damage to the opposing bearing surface can accelerate polyethylene wear and damage, and especially with the use of hard-on-hard articulations, retrieval analysis benefits from incorporating evaluation of hard bearing surfaces as well. The purpose of this study is to report six case studies of metal bearing surfaces with distinctive damage patterns, to interpret them in the context of adverse events plausibly responsible for their creation, and to suggest their likely clinical or scientific significance. The specific damage patterns reported here are 1) extensive scraping, 2) circumferential discoloration, 3) a long chain of periodic micro-indentations, 4) pitting with deposits, 5) scratches with small-radius directional changes, and 6) indentation with scraping.

Modeling polyethylene wear acceleration due to femoral head dislocation damage.

Scratching, scraping, and metal transfer to femoral heads commonly accompany acetabular shell contact during dislocation and closed reduction maneuvers. While head damage conceptually leads to accelerated wear, reports on this subject are mainly anecdotal, and differ widely on the potency of such effect. Towards better understanding this relationship, a physically validated finite element (FE) model was used to compute polyethylene wear acceleration propensity of specific head damage patterns on thirteen retrievals. These FE models estimated wear increases averaging half an order of magnitude when compared to simulations for undamaged heads. There was no correlation between the number of dislocations sustained and wear acceleration. These results underscore the importance of implant-gentle closed reduction, and heightened wear monitoring of successfully reduced dislocation patients.

Stability and trunnion wear potential in large-diameter metal-on-metal total hips: a finite element analysis.

BACKGROUND: Large-diameter femoral heads for metal-on-metal THA hold theoretical advantages of joint stability and low bearing surface wear. However, recent reports have indicated an unacceptably high rate of wear-associated failure with large-diameter bearings, possibly due in part to increased wear at the trunnion interface. Thus, the deleterious consequences of using large heads may outweigh their theoretical advantages. QUESTIONS/PURPOSES: We investigated (1) to what extent femoral head size influenced stability in THA for several dislocation-prone motions; and the biomechanics of wear at the trunnion interface by considering the relationship between (2) wear potential and head size and (3) wear potential and other factors, including cup orientation, type of hip motion, and assembly/impaction load. METHODS: Computational simulations were executed using a previously validated nonlinear contact finite element model. Stability was determined at 36 cup orientations for five distinct dislocation challenges. Wear at the trunnion interface was calculated for three separate cup orientations subjected to gait, stooping, and sit-to-stand motions. Seven head diameters were investigated: 32 to 56 mm, in 4-mm increments. RESULTS: Stability improved with increased diameter, although diminishing benefit was seen for sizes of greater than 40 mm. By contrast, contact stress and computed wear at the trunnion interface all increased unabatedly with increasing head size. Increased impaction forces resulted in only small decreases in trunnion wear generation. CONCLUSIONS: These data suggest that the theoretical advantages of large-diameter femoral heads have a limit. Diameters of greater than 40 mm demonstrated only modest improvement in terms of joint stability yet incurred substantial increase in wear potential at the trunnion. CLINICAL RELEVANCE: Our model has potential to help investigators and designers of hip implants to better understand the optimization of trunnion design for long-term durability.

A novel formulation for scratch-based wear modelling in total hip arthroplasty.

Damage to the femoral head in total hip arthroplasty often takes the form of discrete scratches, which can lead to dramatic wear acceleration of the polyethylene (PE) liner. Here, a novel formulation is reported for finite element (FE) analysis of wear acceleration due to scratch damage. A diffused-light photography technique was used to globally locate areas of damage, providing guidance for usage of high-magnification optical profilometry to determine individual scratch morphology. This multiscale image combination allowed comprehensive input of scratch-based damage patterns to an FE Archard wear model, to determine the wear acceleration associated with specific retrieval femoral heads. The wear algorithm imposed correspondingly elevated wear factors on areas of PE incrementally overpassed by individual scratches. Physical validation was provided by agreement with experimental data for custom-ruled scratch patterns. Illustrative wear acceleration results are presented for four retrieval femoral heads.

Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research.

Bisphosphonates (BPs) and denosumab reduce the risk of spine and nonspine fractures. Atypical femur fractures (AFFs) located in the subtrochanteric region and diaphysis of the femur have been reported in patients taking BPs and in patients on denosumab, but they also occur in patients with no exposure to these drugs. In this report, we review studies on the epidemiology, pathogenesis, and medical management of AFFs, published since 2010. This newer evidence suggests that AFFs are stress or insufficiency fractures. The original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution. The periosteal stress reaction at the fracture site was changed from a minor to a major feature. The association with specific diseases and drug exposures was removed from the minor features, because it was considered that these associations should be sought rather than be included in the case definition. Studies with radiographic review consistently report significant associations between AFFs and BP use, although the strength of associations and magnitude of effect vary. Although the relative risk of patients with AFFs taking BPs is high, the absolute risk of AFFs in patients on BPs is low, ranging from 3.2 to 50 cases per 100,000 person-years. However, long-term use may be associated with higher risk (∼100 per 100,000 person-years). BPs localize in areas that are developing stress fractures; suppression of targeted intracortical remodeling at the site of an AFF could impair the processes by which stress fractures normally heal. When BPs are stopped, risk of an AFF may decline. Lower limb geometry and Asian ethnicity may contribute to the risk of AFFs. There is inconsistent evidence that teriparatide may advance healing of AFFs.