Romosozumab in patients who experienced an on-study fracture: post hoc analyses of the FRAME and ARCH phase 3 trials.

Post hoc analysis of FRAME and ARCH revealed that on-study nonvertebral and vertebral fractures by Month 12 were less common in women initially treated with romosozumab versus placebo or alendronate. Recurrent fracture risk was also lower in romosozumab­treated patients, and there were no fracture­related complications. Results support continuing romosozumab treatment post­fracture. PURPOSE: Post hoc analysis evaluating efficacy and safety of romosozumab, administered in the immediate post­fracture period, in the FRAME and ARCH phase 3 trials. METHODS: In FRAME (NCT01575834) and ARCH (NCT01631214), postmenopausal women with osteoporosis were randomized 1:1 to romosozumab 210 mg monthly or comparator (FRAME, placebo; ARCH, alendronate 70 mg weekly) for 12 months, followed by antiresorptive therapy (FRAME, denosumab; ARCH, alendronate). In patients who experienced on-study nonvertebral or new/worsening vertebral fracture by Month 12, we report the following: fracture and treatment­emergent adverse event (TEAE) incidence through 36 months, bone mineral density changes (BMD), and romosozumab timing. Due to the sample sizes employed, meaningful statistical comparisons between treatments were not possible. RESULTS: Incidence of on-study nonvertebral and vertebral fractures by Month 12 was numerically lower in romosozumab- versus comparator-treated patients (FRAME, 1.6% and 0.5% versus 2.1% and 1.6%; ARCH, 3.4% and 3.3% versus 4.6% and 4.9%, respectively). In those who experienced on-study nonvertebral fracture by Month 12, recurrent nonvertebral and subsequent vertebral fracture incidences were numerically lower in patients initially treated with romosozumab versus comparator (FRAME, 3.6% [2/56] and 1.8% [1/56] versus 9.2% [7/76] and 3.9% [3/76]; ARCH, 10.0% [7/70] and 5.7% [4/70] versus 12.6% [12/95] and 8.4% [8/95], respectively). Among those with on-study vertebral fracture by Month 12, recurrent vertebral and subsequent nonvertebral fracture incidences were numerically lower with romosozumab versus comparator (FRAME, 0.0% [0/17] and 0.0% [0/17] versus 11.9% [7/59] and 8.5% [5/59]; ARCH, 9.0% [6/67] and 7.5% [5/67] versus 15.0% [15/100] and 16.0% [16/100], respectively). In patients with fracture by Month 12, no fracture­related complications were reported in romosozumab-treated patients. BMD gains were numerically greater with romosozumab than comparators. CONCLUSION: Data suggest support for the efficacy and safety of continuing romosozumab treatment following fracture. TRIAL REGISTRATIONS: NCT01575834; NCT01631214.

Selective replication and vertical transmission of Ebola virus in experimentally infected Angolan free-tailed bats.

The natural reservoir of Ebola virus (EBOV), agent of a zoonosis burdening several African countries, remains unidentified, albeit evidence points towards bats. In contrast, the ecology of the related Marburg virus is much better understood; with experimental infections of bats being instrumental for understanding reservoir-pathogen interactions. Experiments have focused on elucidating reservoir competence, infection kinetics and specifically horizontal transmission, although, vertical transmission plays a key role in many viral enzootic cycles. Herein, we investigate the permissiveness of Angolan free-tailed bats (AFBs), known to harbour Bombali virus, to other filoviruses: Ebola, Marburg, Taï Forest and Reston viruses. We demonstrate that only the bats inoculated with EBOV show high and disseminated viral replication and infectious virus shedding, without clinical disease, while the other filoviruses fail to establish productive infections. Notably, we evidence placental-specific tissue tropism and a unique ability of EBOV to traverse the placenta, infect and persist in foetal tissues of AFBs, which results in distinct genetic signatures of adaptive evolution. These findings not only demonstrate plausible routes of horizontal and vertical transmission in these bats, which are expectant of reservoir hosts, but may also reveal an ancillary transmission mechanism, potentially required for the maintenance of EBOV in small reservoir populations.

Inoculation route-dependent Lassa virus dissemination and shedding dynamics in the natural reservoir - Mastomys natalensis.

Lassa virus (LASV), a Risk Group-4 zoonotic haemorrhagic fever virus, affects sub-Saharan African countries. Lassa fever, caused by LASV, results in thousands of annual deaths. Although decades have elapsed since the identification of the Natal multimammate mouse (Mastomys natalensis) as a natural reservoir of LASV, little effort has been made to characterize LASV infection in its reservoir. The natural route of infection and transmission of LASV within M. natalensis remains unknown, and the clinical impact of LASV in M. natalensis is mostly undescribed. Herein, using an outbred colony of M. natalensis, we investigate the replication and dissemination dynamics of LASV in this reservoir following various inoculation routes. Inoculation with LASV, regardless of route, resulted in a systemic infection and accumulation of abundant LASV-RNA in many tissues. LASV infection in the Natal multimammate mice was subclinical, however, clinical chemistry values were transiently altered and immune infiltrates were observed histologically in lungs, spleens and livers, indicating a minor disease with coordinated immune responses are elicited, controlling infection. Intranasal infection resulted in unique virus tissue dissemination dynamics and heightened LASV shedding, compared to subcutaneous inoculation. Our study provides important insights into LASV infection in its natural reservoir using a contemporary infection system, demonstrating that specific inoculation routes result in disparate dissemination outcomes, suggesting intranasal inoculation is important in the maintenance of LASV in the natural reservoir, and emphasizes that selection of the appropriate inoculation route is necessary to examine aspects of viral replication, transmission and responses to zoonotic viruses in their natural reservoirs.

How can the orthopedic surgeon ensure optimal vitamin D status in patients operated for an osteoporotic fracture?

In this narrative review, the role of vitamin D deficiency in the pathophysiology, healing of fragility fractures, and rehabilitation is discussed. Vitamin D status can be assessed by measuring serum 25(OH)-vitamin D level with standardized assays. There is a high prevalence of vitamin D insufficiency (25(OH)D < 50 nmol/l (i.e., 20 ng/mL)) or deficiency (25(OH)D < 25 nmol/l (i.e., 10 ng/mL)) in patients with fragility fractures and especially in those with a hip fracture. The evidence on the effects of vitamin D deficiency and/or vitamin D supplementation on fracture healing and material osseointegration is still limited. However, it appears that vitamin D have a rather positive influence on these processes. The fracture liaison service (FLS) model can help to inform orthopedic surgeons, all caregivers, and fractured patients about the importance of optimal vitamin D status in the management of patients with fragility fractures. Therefore, vitamin D status should be included in Capture the Fracture® program as an outcome of FLS in addition to dual-energy X-ray absorptiometry (DXA) and specific antiosteoporosis medication. Vitamin D plays a significant role in the pathophysiology and healing of fragility fractures and in rehabilitation after fracture. Correction of vitamin D deficiency should be one of the main outcomes in fracture liaison services.

Alternative and complementary therapies in osteoarthritis and cartilage repair.

Osteoarthritis (OA) is the most common joint condition and, with a burgeoning ageing population, is due to increase in prevalence. Beyond conventional medical and surgical interventions, there are an increasing number of 'alternative' therapies. These alternative therapies may have a limited evidence base and, for this reason, are often only afforded brief reference (or completely excluded) from current OA guidelines. Thus, the aim of this review was to synthesize the current evidence regarding autologous chondrocyte implantation (ACI), mesenchymal stem cell (MSC) therapy, platelet-rich plasma (PRP), vitamin D and other alternative therapies. The majority of studies were in knee OA or chondral defects. Matrix-assisted ACI has demonstrated exceedingly limited, symptomatic improvements in the treatment of cartilage defects of the knee and is not supported for the treatment of knee OA. There is some evidence to suggest symptomatic improvement with MSC injection in knee OA, with the suggestion of minimal structural improvement demonstrated on MRI and there are positive signals that PRP may also lead to symptomatic improvement, though variation in preparation makes inter-study comparison difficult. There is variability in findings with vitamin D supplementation in OA, and the only recommendation which can be made, at this time, is for replacement when vitamin D is deplete. Other alternative therapies reviewed have some evidence (though from small, poor-quality studies) to support improvement in symptoms and again there is often a wide variation in dosage and regimens. For all these therapeutic modalities, although controlled studies have been undertaken to evaluate effectiveness in OA, these have often been of small size, limited statistical power, uncertain blindness and using various methodologies. These deficiencies must leave the question as to whether they have been validated as effective therapies in OA (or chondral defects). The conclusions of this review are that all alternative interventions definitely require clinical trials with robust methodology, to assess their efficacy and safety in the treatment of OA beyond contextual and placebo effects.

Systems leadership doctor of nursing practice: global relevance.

AIM: This article considers the systems leadership doctor of nursing practice degree as an option to increase nursing leadership roles and heighten presence at policy tables globally, particularly in low- and middle-income countries. Recent global reports emphasize core competencies needed for nursing leadership, particularly systems leadership and health policy, to successfully move the global health agenda forward. Using the Yale University School of Nursing programme as an exemplar, this paper is focused on the elements directly linked to leadership competencies and relevance of a systems leadership doctor of nursing practice programme globally. BACKGROUND/INTRODUCTION: The dramatic growth and wide variability of doctor of nursing practice programmes offered in all 50 US States have generated questions and debate. According to the American Association of Colleges of Nursing as of May 2018, there are 121 schools that reported having a leadership focus in postmaster's doctor of nursing practice degree offering. Yet there has not been the same enthusiasm for development and implementation for a practice doctorate in nursing across the globe. SOURCES OF EVIDENCE: A narrative literature review was conducted aimed at addressing the relevance of a practice doctorate globally. This analysis of the literature included a search of peer-reviewed and grey literature. Nursing school websites were visited, and opinions of nurse leaders and students were sought. In addition, global reports that supported nursing leadership and their role in policy development were reviewed. DISCUSSION/CONCLUSION: Globally, nurses have a critical role in leading health systems. Developing a cadre of nurse leaders educated at the doctoral level who can communicate with policymakers and develop strategies to meet health systems' goals is necessary. IMPLICATIONS FOR NURSING, HEALTH AND EDUCATION POLICY: In recent global health reports and campaigns, strengthening nursing leadership and presence at policymaking tables are recurring themes. Offering a systems leadership doctor of nursing practice degree is one viable option to increase doctorally prepared nurse leaders for nursing policy and practice engagement. This calls for work with country and regional governments, regulatory bodies and nursing associations to empower nursing to contribute fully.

Identification and management of patients at increased risk of osteoporotic fracture: outcomes of an ESCEO expert consensus meeting.

Osteoporosis represents a significant and increasing healthcare burden in Europe, but most patients at increased risk of fracture do not receive medication, resulting in a large treatment gap. Identification of patients who are at particularly high risk will help clinicians target appropriate treatment more precisely and cost-effectively, and should be the focus of future research. INTRODUCTION: The purpose of the study was to review data on the identification and treatment of patients with osteoporosis at increased risk of fracture. METHODS: A working group convened by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis met to review current data on the epidemiology and burden of osteoporosis and the patterns of medical management throughout Europe. RESULTS: In Europe in 2010, the cost of managing osteoporosis was estimated at €37 billion and notably the costs of treatment and long-term care of patients with fractures were considerably higher than the costs for pharmacological prevention. Despite the availability of effective treatments, the uptake of osteoporosis therapy is low and declining, in particular for secondary fracture prevention where the risk of a subsequent fracture following a first fracture is high. Consequently, there is a significant treatment gap between those who would benefit from treatment and those who receive it, which urgently needs to be addressed so that the burden of disease can be reduced. CONCLUSIONS: Implementation of global fracture prevention strategies is a critical need. Future research should focus on identifying specific risk factors for imminent fractures, periods of high fracture risk, patients who are at increased risk of fracture and therapies that are most suited to such high-risk patients and optimal implementation strategies in primary, secondary and tertiary care.

GRAND-4: the German retrospective analysis of long-term persistence in women with osteoporosis treated with bisphosphonates or denosumab.

UNLABELLED: This retrospective database study assessed 2-year persistence with bisphosphonates or denosumab in a large German cohort of women with a first-time prescription for osteoporosis treatment. Compared with intravenous or oral bisphosphonates, 2-year persistence was 1.5-2 times higher and risk of discontinuation was significantly lower (P < 0.0001) with denosumab. INTRODUCTION: Persistence with osteoporosis therapies is critical for fracture risk reduction. Detailed data on long-term persistence (≥2 years) with bisphosphonates and denosumab are sparse. METHODS: From the German IMS® database, we included women aged 40 years or older with a first-time prescription for bisphosphonates or denosumab between July 2010 and August 2014; patients were followed up until December 2014. The main outcome was treatment discontinuation, with a 60-day permissible gap between filled prescriptions. Two-year persistence was estimated using Kaplan-Meier survival curves, with treatment discontinuation as the failure event. Denosumab was compared with intravenous (i.v.) and oral bisphosphonates separately. Cox proportional hazard ratios (HRs) for the 2-year risk of discontinuation were calculated, with adjustment for age, physician specialty, health insurance status, and previous medication use. RESULTS: Two-year persistence with denosumab was significantly higher than with i.v. or oral bisphosphonates (39.8 % [n = 21,154] vs 20.9 % [i.v. ibandronate; n = 20,472] and 24.8 % [i.v. zoledronic acid; n = 3966] and 16.7-17.5 % [oral bisphosphonates; n = 114,401]; all P < 0.001). Patients receiving i.v. ibandronate, i.v. zoledronic acid, or oral bisphosphonates had a significantly increased risk of treatment discontinuation than did those receiving denosumab (HR = 1.65, 1.28, and 1.96-2.02, respectively; all P < 0.0001). CONCLUSIONS: Two-year persistence with denosumab was 1.5-2 times higher than with i.v. or oral bisphosphonates, and risk of discontinuation was significantly lower with denosumab than with bisphosphonates. A more detailed understanding of factors affecting medication-taking behavior may improve persistence and thereby reduce rates of fracture.

[Supportive drugs for improved implant healing]. / Medikamentöse Verbesserung der Implantateinheilung.

BACKGROUND: Improvement of implant healing in orthopedic and trauma surgery serves to improve the life expectancy of the implant. Good primary stability by clamping is a prerequisite for secondary stability and for the actual integration and healing of the implant. RESULTS: Possible causes of implant loosening are abrasive particles, which arrive at non-integrated implants at the unsealed prosthesis-bone interface and provoke a macrophage-mediated foreign body reaction, resulting in periprosthetic osteolysis. Numerous animal studies have already described the use of bisphosphonates to inhibit osteolysis induced by abrasion and secondary instability. In patients with total knee arthroplasty, a decrease in prosthetic migration under the influence of bisphosphonates could be shown. The stimulation of bone formation around the implants and the resulting implant healing was demonstrated both in animal experiments for bone morphogenetic proteins (BMP) and in case reports for intermittent parathyroid hormone administration. CONCLUSION: By using supportive drugs, it is possible to achieve an improvement in the osseointegration of implants; thus, more rapid secondary stability and load-bearing are expected.

The prevalence of vitamin D deficiency in patients with vertebral fragility fractures.

Hypovitaminosis D has been identified as a common risk factor for fragility fractures and poor fracture healing. Epidemiological data on vitamin D deficiency have been gathered in various populations, but the association between vertebral fragility fractures and hypovitaminosis D, especially in males, remains unclear. The purpose of this study was to evaluate serum levels of 25-hydroxyvitamin D (25-OH D) in patients presenting with vertebral fragility fractures and to determine whether patients with a vertebral fracture were at greater risk of hypovitaminosis D than a control population. Furthermore, we studied the seasonal variations in the serum vitamin D levels of tested patients in order to clarify the relationship between other known risk factors for osteoporosis and vitamin D levels. We measured the serum 25-OH D levels of 246 patients admitted with vertebral fractures (105 men, 141 female, mean age 69 years, sd 8.5), and in 392 orthopaedic patients with back pain and no fractures (219 men, 173 female, mean age 63 years, sd 11) to evaluate the prevalence of vitamin D insufficiency. Statistical analysis found a significant difference in vitamin D levels between patients with vertebral fragility fracture and the control group (p = 0.036). In addition, there was a significant main effect of the tested variables: obesity (p < 0.001), nicotine abuse (p = 0.002) and diabetes mellitus (p < 0.001). No statistical difference was found between vitamin D levels and gender (p = 0.34). Vitamin D insufficiency was shown to be a risk factor for vertebral fragility fractures in both men and women.

Management of pregnant women infected with Ebola virus in a treatment centre in Guinea, June 2014.

We report two cases of confirmed Ebola virus disease in pregnant women, who presented at the Médecins Sans Frontières Ebola treatment centre in Guéckédou. Despite the very high risk of death, both pregnant women survived. In both cases the critical decision was made to induce vaginal delivery. We raise a number of considerations regarding the management of Ebola virus-infected pregnant women, including the place of amniocentesis and induced delivery, and whether certain invasive medical acts are justified.

Differences in persistency with teriparatide in patients with osteoporosis according to gender and health care provider.

UNLABELLED: This analysis investigated the persistence of teriparatide for treatment of osteoporosis in 829 patients according to gender and health care provider treated with teriparatide. This study showed that female patients were less persistent than males and those patients treated in the practices of orthopedic surgeons were more treatment persistent than patients treated in general practitioner (GP) practices. INTRODUCTION: The optimal persistency of teriparatide (TPTD) is of the upmost importance to ensure fracture risk reduction and pain relief. Data reporting on gender-specific or health care provider-dependent differences on health care provider-dependent persistence is currently lacking. METHODS: We analyzed a large dataset extracted from the Disease Analyzer database (IMS Health, Germany). Out of a dataset of 15 million patients, we identified patients with osteoporosis who received first-time teriparatide prescriptions from January 2005 to December 2012. RESULTS: All 829 patients (677 females and 152 males) were included in the study. The patients were treated by 214 general practitioners (GPs) and 143 orthopedic surgeons. After 18 months of follow-up, 39.5 % of the female and 34 % of the male patients discontinued their treatment (p = 0.0308). We found a significant difference in the discontinuation rate of patients treated by orthopedic surgeons (35.0 %) compared to patients treated by GPs (44.2 %) (p = 0.0445). Additionally, at the end of the 18 months of follow up, 39.4 % of female and 47.8 % of male patients were still on treatment. We found a highly significant decreased risk for treatment discontinuation in patients with fractures prior to treatment initiation compared to those without such fractures (hazard ratio (HR) 0.77; 95 % confidence interval (CI) 0.66-0.90). There was a significantly increased risk of treatment discontinuation for female patients (HR 1.38; 95 % CI 1.10-1.74) compared to male patients. CONCLUSIONS: In conclusion, female patients presented higher discontinuation rates of TPTD compared to males. Patients treated in the practices of orthopedic surgeons were more persistent than patients treated in GP practices. TPTD persistence in patients with osteoporosis is higher than with antiresorptives but is still suboptimal and needs to be improved to ensure fracture risk reductions comparable to randomized controlled trial (RCT) results.