Radiological criteria for atypical features of femur fractures: what we can learn when applied in a clinical study setting.

The paper focuses on the identification of atypical fractures (AFFs). This paper examines the concordance between objective classification and expert subjective review. We believe the paper adds critical information about how to apply the American Society of Bone and Mineral Research (ASBMR) criteria to diagnose AFFs and is of high interest to the field. INTRODUCTION: Assess American Society of Bone and Mineral Research (ASBMR) criteria for identifying atypical femoral fractures (AFFs). METHODS: Two orthopedic surgeons independently evaluated radiographs of 372 fractures, applying ASBMR criteria. We assessed ease of applying ASBMR criteria and whether criteria-based assessment matched qualitative expert assessment. RESULTS: There was up to 27% uncertainty about how to classify specific features. 84% of films were classified similarly for the presence of AFF according to ASBMR criteria; agreement increased to 94% after consensus meeting. Of 37 fractures categorized as AFFs based on ASBMR criteria, 23 (62.2%) were considered AFFs according to expert assessment (not relying on criteria). Only one (0.5%) femoral shaft fracture that did not meet ASBMR criteria was considered an AFF per expert assessment. The number of major ASBMR features present (four vs five) and whether there was periosteal or endosteal thickening ("beaking" or "flaring") played major roles in the discrepancies between ASBMR criteria-based and expert-based determinations. CONCLUSIONS: ASBMR AFF criteria were useful for reviewers but several features were difficult to interpret. Expert assessments did not agree with the ASBMR classification in almost one-third of cases, but rarely identified an AFF when a femoral shaft fracture did not meet ASBMR AFF criteria. Experts identified lateral cortical transverse fracture line and associated new-bone formation along with no or minimal comminution as crucial features necessary for the definition of atypical femoral fractures.

Multiple vertebral fractures following osteoporosis treatment discontinuation: a case-report after long-term Odanacatib.

INTRODUCTION: Case reports of women sustaining multiple vertebral fractures (VF) soon afterdenosumab discontinuation are accumulating. METHODS: We report a woman with five new vertebral fractures in ~8 months following discontinuation of long-term odanacatib (ODN), an experimental cathepsin K inhibitor. RESULTS: DXA examination demonstrated an ~12% decline in bone mineral density (BMD) and ~9% decline in trabecular bone score (TBS) since ODN discontinuation. Laboratory evaluation did not reveal a secondary cause of bone loss. CONCLUSIONS: This case mimics observations following denosumab discontinuation, but, to our knowledge, is the first reported with ODN and the first documenting substantial decline in TBS. While not directly clinically relevant as ODN is no longer being developed, this case raises the possibility that a syndrome of multiple vertebral fractures could follow discontinuation of various potent osteoporosis therapies that produce major BMD increases but do not have persisting bone effects (i.e., all non-bisphosphonates). Use of antiresorptive therapies to prevent rapid bone loss following discontinuation of potent bone active agents seems appropriate. Identification of those patients who could be at risk for the multiple VF syndrome is needed.

Disparities in osteoporosis treatments.

UNLABELLED: Osteoporosis treatment rates within 2 years following an index event (fragility fracture, osteoporotic bone mineral density (BMD) T-score, or osteoporosis ICD-9 codes) were determined from 2005 to 2011. Most patients were not treated. Fracture patients had the lowest treatment rate. Low treatment rates also occurred in patients that were male, black, or had non-commercial insurance. INTRODUCTION: Clinical recognition of osteoporosis (osteoporotic BMD, assignment of an ICD-9 code, or the occurrence of fragility fractures) provides opportunities to treat patients at risk for future fracture. METHODS: A cohort of 36,965 patients was identified from 2005 to 2011 in the Indiana Health Information Exchange, with index events after age 50 of either non-traumatic fractures, an osteoporosis ICD-9 code, or a BMD T-score ≤ -2.5. Patients with osteoporosis treatment in the preceding year were excluded. Medication records during the ensuing 2 years were extracted to identify osteoporosis treatments, demographics, comorbidities, and co-medications. Predictors of treatment were evaluated in a multivariable logistic regression model. RESULTS: The cohort was 78 % female, 11 % black, 91 % urban-dwelling, and 53 % commercially insured. The index events were as follows: osteoporosis diagnosis (47 % of patients), fragility fracture (44 %), and osteoporotic T-scores (9 %). Within 2 years after the index event, 23.3 % received osteoporosis medications (of which, 82.2 % were oral bisphosphonates). Treatment rates were higher after osteoporosis diagnosis codes (29.3 %) or osteoporotic T-score (53.9 %) than after fracture index events (10.5 %) (p < 0.001). Age had an inverted U-shaped effect for women with highest odds around 60-65 years. Women (OR 1.86) and non-black patients (OR 1.52) were more likely to be treated (p < 0.001). Patients with public (versus commercial) insurance (OR 0.86, p < 0.001) or chronic comorbidities (ORs about 0.7-0.9, p < 0.001) were less likely to be treated. CONCLUSION: Most osteoporosis treatment candidates remained untreated. Men, black patients, and patients with fracture or chronic comorbidities were less likely to receive treatment, representing disparity in the recognition and treatment of osteoporosis.

Alendronate and atrial fibrillation: a meta-analysis of randomized placebo-controlled clinical trials.

UNLABELLED: In this meta-analysis of all Merck-conducted, placebo-controlled clinical trials of alendronate, the occurrence of AF was uncommon, with most studies reporting two or fewer events. Across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or non-serious AF was observed. INTRODUCTION: To explore the incidence of atrial fibrillation (AF) and other cardiovascular endpoints in clinical trials of alendronate. METHODS: All double-blind, placebo-controlled studies of alendronate 5, 10, or 20 mg daily, 35 mg once-weekly, 35 mg twice-weekly, and 70 mg once-weekly of at least 3 months duration conducted by Merck were included in this meta-analysis. The primary method of analysis was exact Poisson regression. Estimated relative risk (RR) of alendronate versus placebo and the associated 95% confidence interval was derived from a model that included number of episodes with factors for treatment group and study and an offset parameter for number of person-years on study. RESULTS: Of 41 studies considered, 32 met all criteria for inclusion in the analysis (participants-9,518 alendronate, 7,773 placebo). Estimated RR for all AF events was 1.16 (95% CI = 0.87, 1.55; p = 0.33). Most trials had two or fewer AF events. The RR of AF classified as a serious adverse event was 1.25 (95% CI = 0.82, 1.93; p = 0.33), but became 0.97 (95% CI = 0.51, 1.85) when the clinical fracture cohort of the Fracture Intervention Trial was excluded, indicating that results were driven by events in that study. Estimated RRs for other cardiovascular endpoints were less than 1. CONCLUSIONS: The incidence of atrial fibrillation was low in Merck clinical trials of alendronate and was not significantly increased in any single trial nor in the meta-analysis. Based on this analysis, alendronate use does not appear to be associated with an increased risk of atrial fibrillation.

Short-term in vivo precision of BMD and parameters of trabecular architecture at the distal forearm and tibia.

UNLABELLED: In vivo hr-pQCT precision was determined in 42 postmenopausal women using double baseline measurements from a multicenter trial of odanacatib. Errors, e.g., at the radius below 1.3% for BMD and below 6.3% for trabecular structure, were comparable to single-center results. Motion artifacts remain a challenge, particularly at the forearm. INTRODUCTION: The short-term in vivo precision of BMD, trabecular bone structure, cortical thickness and porosity of the forearm and tibia was measured by hr-pQCT. Also the effect of image quality on precision was evaluated. METHODS: In 42 postmenopausal women (age 64.4 ± 6.8 years) out of 214 subjects enrolled in a multi center advanced imaging phase III study of odanacatib (DXA spine or hip T-scores between -1.5 and -3.5), double baseline hr-pQCT (XtremeCT) measurements with repositioning were performed. The standard ultradistal location and a second, more proximally located VOI were measured at the radius and tibia to better assess cortical thickness and porosity. Image analysis and quality grading (grades: perfect, slight artifacts, pronounced artifacts, unacceptable) were performed centrally. RESULTS: At the radius RMS%CV values varied from 0.7% to 1.3% for BMD and BV/TV and from 5.6% to 6.3% for Tb.Sp, Tb.Th, Tb.N, and cortical porosity. Numerically at the tibia, precision errors were approx. 0.5% lower for BMD and 1% to 2% lower for structural parameters although most differences were insignificant. In the radius but not in the tibia, precision errors for cortical thickness were smaller at the distal compared to the ultradistal location (1% versus 2%). CONCLUSIONS: BMD precision errors were lower than those for trabecular architecture and cortical porosity. Motion artifacts remain a challenge, particularly at the forearm. Quality grading remains subjective, and more objective evaluation methods are needed. Precision in the context of a multicenter clinical trial, with centralized training and scan analysis, was comparable to single-center results previously reported.

DXA-based hip structural analysis of once-weekly bisphosphonate-treated postmenopausal women with low bone mass.

SUMMARY: DXA-based hip structural analysis from 947 individuals completing two large osteoporosis clinical trials was pooled and analyzed. Treatment with once-weekly (OW) ALN or OW RIS resulted in significant improvements from baseline in geometric parameters at all three HSA ROIs. Improvements were generally greater with OW ALN than OW RIS. INTRODUCTION: BMD can be altered by changes in distribution and quantity of bone and changes in mineralization. These effects cannot be distinguished with conventional measurements of BMD. Currently, tissue composition is evaluated only by invasive means. Structural geometry of the proximal femur, however, can be measured in vivo by several methods, including dual energy X-ray absorptiometry (DXA) using specialized hip structure analysis (HSA) software. METHODS: DXA-based HSA was obtained and analyzed in a subset of 947 subjects participating in the Fosamax Actonel Comparison Trials. Data were pooled to evaluate treatment effects on the structural geometry of the proximal femur by once-weekly alendronate (ALN) 70 mg and risedronate (RIS) 35 mg in postmenopausal women with low bone mass. RESULTS: Both ALN and RIS treatment over 2 years resulted in improvements in HSA-derived geometry at all three HSA regions of interest (ROI). The largest treatment effects were seen at the intertrochanteric ROI. Consistently greater treatment effects were seen with ALN compared with RIS at all three HSA-ROIs. CONCLUSIONS: HSA offers insight into the potential mechanisms of fracture risk reduction from pharmacologic intervention. In the current study, treatment with once-weekly bisphosphonates resulted in significant improvements in hip geometric parameters.

New insights into the role of vitamin D and calcium in osteoporosis management: an expert roundtable discussion.

BACKGROUND: Adequate vitamin D and calcium nutrition play a critical role in the maintenance of musculoskeletal health and are considered the first step in osteoporosis treatment. ROUNDTABLE DISCUSSION: In February 2008 Merck Sharp & Dohme sponsored a 2-day, evidence-based expert panel on the benefits of vitamin D for the patient with osteoporosis and the role of vitamin D in combination with antiresorptive therapy for the management of osteoporosis. One of the primary objectives of the meeting was to review new data on the optimal serum 25-hydroxy vitamin D [25(OH)D] levels. The symposium was attended by 29 researchers and clinicians from Europe and the Middle East. The discussion focused on optimizing vitamin D and calcium nutrition and reducing falls and fractures in osteoporotic patients. CONCLUSIONS: Current evidence and expert opinion suggests that optimal serum 25(OH)D concentrations should be at least 50 nmol/L (20 ng/mL) in all individuals. This implies a population mean close to 75 nmol/L (30 ng/mL). In order to achieve this level, vitamin D intake of at least 20 microg daily is required. There is a wider therapeutic window for vitamin D than previously believed, and doses of 800 IU per day, regardless of sun exposure, season or additional multivitamin use, appear to present little risk of toxicity. Apart from fracture and fall prevention, optimization of vitamin D status may also have additional general health benefits. Based on newly emerging data regarding calcium supplementation, and recommendations for increased vitamin D intake, the current recommendations for calcium intake in postmenopausal women may be unnecessarily high. In addition to vitamin D and calcium, treatment of patients with osteoporosis at high risk of fractures should also include pharmacologic agents with proven vertebral and non-vertebral fracture efficacy.

Parathyroid hormone-related protein as a prohormone: posttranslational processing and receptor interactions.

Since the elucidation of the structures of the three human PRHrP isoforms in 1987, information has rapidly accured which indicates that the role of PTHrP in normal physiology will prove to be crucial as well as exceedingly complex. The importance of the role of PTHrP in normal physiology is underscored by its broad tissue expression, by its intense evolutionary conservation, by its extremely early expression after fertilization of the ovum, and by the lethal consequences of PTHrP gene disruption. The complexity of the role of PTHrP in normal physiology increases almost monthly. This complexity is reflected in the broad tissue distribution of the peptide, its complex transcriptional regulation and mRNA instability motifs, and its multiple transcripts and isoforms. It is now clear that additional complexity exists at the level of posttranslational processing. Expression of the PTHrP gene leads to the tissue-specific processing and secretion of an increasingly complex family of derivative peptides, each with its own repertoire of cognate receptors, signal transduction pathways, and physiological consequences. Further elucidation of the posttranslational processing pathways and mechanisms can be anticipated in the coming years, coupled with a corresponding elucidation of multiple PTHrP receptors, their specific signal transduction pathways, and their unique physiological roles. The role of PTHrP in causing HHM is now clearly established. Work in the coming decade will focus on the normal physiological roles played by PTHrP.

Parathyroid hormone-related protein a peptide of diverse physiologic functions.

Parathyroid hormone-related protein (PTHrP) is the factor responsible for the syndrome of humoral hypercalcemia of malignancy. PTHrP is produced by a multitude o f normal as well as malignant cells, and exerts both classic parathyroid hormone (PTH)-like and PTH-unlike effects. The molecular cloning of the PTHrP gene, and the subsequent recognition of its widespread expression in normal tissues under normal physiologic conditions, has prompted intense inquiry into its biologic function. PTHrP appears to act in an autocrine or paracrine fashion in (a) normal embryogenesis and neonatal development, (b) cellular growth and differentiation, (c) reproduction and lactation, (d) epithelial calcium transport, and (e) smooth muscle relaxation. These five key emerging physiologic roles of PTHrP are the focus of this review.