People living with HIV and fracture risk.

PLHIV have an increased risk of osteoporosis and fractures when compared with people of the same age and sex. In this review, we address the epidemiology and the pathophysiology of bone disease and fractures in PLHIV. The assessment of fracture risk and fracture prevention in these subjects is also discussed. The spectrum of HIV-associated disease has changed dramatically since the introduction of potent antiretroviral drugs. Today, the survival of people living with HIV (PLHIV) is close to that of the general population. However, the longer life-span in PLHIV is accompanied by an increased prevalence of chronic diseases. Detrimental effects on bone health are well recognised, with an increased risk of osteoporosis and fractures, including vertebral fractures, compared to the general population. The causes of bone disease in PLHIV are not fully understood, but include HIV-specific risk factors such as use of antiretrovirals and the presence of chronic inflammation, as well as traditional risk factors for fracture. Current guidelines recommend the use of FRAX to assess fracture probability in PLHIV age ≥ 40 years and measurement of bone mineral density in those at increased fracture risk. Vitamin D deficiency, if present, should be treated. Bisphosphonates have been shown to increase bone density in PLHIV although fracture outcomes are not available.

Cost-effective but clinically inappropriate: new NICE intervention thresholds in osteoporosis (Technology Appraisal 464).

PURPOSE: To comment on the latest technology appraisal of the National Institute for Clinical Excellence (NICE) in osteoporosis. METHODS: Review of NICE Technology Appraisal (TA464) on bisphosphonate use in osteoporosis. RESULTS: The NICE appraisal on bisphosphonate use in osteoporosis indicates that treatment with oral bisphosphonates may be instituted at a FRAX 10-year probability of major osteoporotic fracture above 1%. Implementation would mean that all women aged 50 years or older are deemed eligible for treatment, a position that would increase the burden of rare long-term side effects across the population. CONCLUSION: Cost-effectiveness thresholds for low-cost interventions should not be used to set intervention thresholds but rather to validate the implementation of clinically driven intervention thresholds.

Type 2 diabetes mellitus and bone.

Type 2 diabetes (T2DM) is a rapidly growing public health problem. It is associated with an increased risk of fracture, particularly of the hip, despite normal or high bone mineral density. Longer duration of disease and poor glycaemic control are both associated with higher fracture risk. The factors underlying increased fracture risk have not been clearly established, but increased falls risk, obesity, sarcopenia and co-morbidities are likely to contribute. The basis for reduced bone strength despite higher bone mineral density remains to be fully elucidated. Bone turnover is reduced in individuals with T2DM, with evidence of impaired bone formation. Most studies indicate normal or superior trabecular bone structure although reduced lumbar spine trabecular bone score (TBS) has been reported. Deficits in cortical bone structure have been demonstrated in some, but not all, studies whilst reduced bone material strength index (BMSi), as assessed by microindentation, has been a consistent finding. Accumulation of advanced glycation end products in bone may also contribute to reduced bone strength. The use of FRAX in individuals with T2DM underestimates fracture probability. Clinical management should focus on falls prevention strategies, avoidance of known risk factors, maintenance of good glycaemic control and bone protective intervention in individuals at high risk of fracture. Dietary and surgical strategies to reduce weight have beneficial effects on diabetes but may have adverse effects on skeletal health. Future research priorities include better definition of the mechanisms underlying increased fracture risk in T2DM and optimal strategies for identifying and treating those at high risk.

Self-perception of fracture risk: what can it tell us?

In this study, we report that self-perception of fracture risk captures some aspect of fracture risk not currently measured using conventional fracture prediction tools and is associated with improved medication uptake. It suggests that adequate appreciation of fracture risk may be beneficial and lead to greater healthcare engagement and treatment. INTRODUCTION: This study aimed to assess how well self-perception of fracture risk, and fracture risk as estimated by the fracture prediction tool FRAX, related to fracture incidence and uptake and persistence of anti-osteoporosis medication among women participating in the Global Longitudinal study of Osteoporosis in Women (GLOW). METHODS: GLOW is an international cohort study involving 723 physician practices across 10 countries in Europe, North America and Australia. Aged ≥ 55 years, 60,393 women completed baseline questionnaires detailing medical history, including co-morbidities, fractures and self-perceived fracture risk (SPR). Annual follow-up included self-reported incident fractures and anti-osteoporosis medication (AOM) use. We calculated FRAX risk without bone mineral density measurement. RESULTS: Of the 39,241 women with at least 1 year of follow-up data, 2132 (5.4%) sustained an incident major osteoporotic fracture over 5 years of follow-up. Within each SPR category, risk of fracture increased as the FRAX categorisation of risk increased. In GLOW, only 11% of women with a lower baseline SPR were taking AOM at baseline, compared with 46% of women with a higher SPR. AOM use tended to increase in the years after a reported fracture. However, women with a lower SPR who were fractured still reported lower AOM rates than women with or without a fracture but had a higher SPR. CONCLUSIONS: These results suggest that SPR captures some aspect of fracture risk not currently measured using conventional fracture prediction tools and is also associated with improved medication uptake.

UK clinical guideline for the prevention and treatment of osteoporosis.

INTRODUCTION: In 2008, the UK National Osteoporosis Guideline Group (NOGG) produced a guideline on the prevention and treatment of osteoporosis, with an update in 2013. This paper presents a major update of the guideline, the scope of which is to review the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women and men age 50 years or over. METHODS: Where available, systematic reviews, meta-analyses and randomised controlled trials were used to provide the evidence base. Conclusions and recommendations were systematically graded according to the strength of the available evidence. RESULTS: Review of the evidence and recommendations are provided for the diagnosis of osteoporosis, fracture-risk assessment, lifestyle measures and pharmacological interventions, duration and monitoring of bisphosphonate therapy, glucocorticoid-induced osteoporosis, osteoporosis in men, postfracture care and intervention thresholds. CONCLUSION: The guideline, which has received accreditation from the National Institute of Health and Care Excellence (NICE), provides a comprehensive overview of the assessment and management of osteoporosis for all healthcare professionals who are involved in its management.

Access to fracture risk assessment by FRAX and linked National Osteoporosis Guideline Group (NOGG) guidance in the UK-an analysis of anonymous website activity.

In the UK, fracture risk guidance is provided by the National Osteoporosis Guideline Group (NOGG). NOGG usage showed widespread access through direct web-based linkage to FRAX. The facilitated interaction between fracture risk assessment and clinical guidelines could usefully be adopted in other countries. INTRODUCTION: In the UK, guidance on assessment of osteoporosis and fracture risk is provided by the National Osteoporosis Guideline Group ( www.shef.ac.uk/NOGG ). We wished to determine access to this guidance by exploring website activity. METHODS: We undertook an analysis of FRAX and NOGG website usage for the year between 1st July 2013 and 30th June 2014 using Google Analytics software. RESULTS: During this period, there was a total of 1,774,812 sessions (a user interaction with the website) on the FRAX website with 348,964 of these from UK-based users; 253,530 sessions were recorded on the NOGG website. Of the latter, two-thirds were returning visitors, with the vast majority (208,766; 82 %) arising from sites within the UK. The remainder of sessions were from other countries demonstrating that some users of FRAX in other countries make use of the NOGG guidance. Of the UK-sourced sessions, the majority was from England, but the session rate (adjusted for population) was the highest for Scotland. Almost all (95.7 %) of the UK sessions arose from calculations being passed through from the FRAX tool ( www.shef.ac.uk/FRAX ) to the NOGG website, comprising FRAX calculations in patients without a bone mineral density (BMD) measurement (74.5 %) or FRAX calculations with a BMD result (21.2 %). National Health Service (NHS) sites were identified as the major source of visits to the NOGG website, comprising 79.9 % of the identifiable visiting locations, but this is an underestimate as many sites from within the NHS are not classified as such. CONCLUSION: The study shows that the facilitated interaction between web-based fracture risk assessment and clinical guidelines is widely used in the UK. The approach could usefully be adopted in other countries for which a FRAX model is available.

HIV infection and bone disease.

The success of antiretroviral therapy in treating HIV infection has greatly prolonged life expectancy in affected individuals, transforming the disease into a chronic condition. A number of HIV-associated non-AIDS comorbidities have emerged in the ageing HIV-infected population, including osteoporosis and increased risk of fracture. The pathogenesis of fracture is multifactorial with contributions from both traditional and HIV-specific risk factors. Significant bone loss occurs on initiation of antiretroviral therapy but stabilizes on long-term therapy. Fracture risk assessment should be performed in HIV-infected individuals and bone mineral density measured when indicated. Lifestyle measures to optimize bone health should be advised and, in individuals at high risk of fracture, treatment with bisphosphonates considered.

The role of tenofovir alafenamide in future HIV management.

HIV infection has become a chronic condition rather than an acute life-threatening disease in developed countries, thanks to consistent innovation and evolution of effective interventions. This has altered HIV management and created new challenges. People living with HIV (PLWHIV) are living longer and so encounter comorbidities linked not only with their disease, but also with ageing, lifestyle and chronic exposure to antiretroviral therapy (ART). Although longevity, viral suppression and the prevention of viral transmission remain key goals, more needs to be achieved to encompass the vision of attaining an optimum level of overall health. Treatment choices and management practices should ensure patients' long-term health with minimal comorbidity. Treatments that balance optimal efficacy with the potential for improved long-term safety are needed for all patients. In this review, we consider the evolution and development of tenofovir alafenamide (TAF), a novel prodrug of tenofovir which offers high antiviral efficacy at doses over ten times lower than that of tenofovir disoproxil fumarate (TDF). Emerging clinical data suggest that elvitegravir, cobicistat, emtricitabine and TAF (E/C/F/TAF) as a single-tablet regimen offers highly effective viral suppression in treatment-naïve and treatment-experienced patients with an improved renal and bone safety profile compared with TDF, this having been demonstrated in diverse groups including patients with existing renal impairment and adolescents. The profile of TAF identifies it as an agent with a promising role within future ART regimens that aim to deliver the vision of undetectable viral load, while requiring less monitoring and having a safety profile designed to minimize comorbid risks while supporting good long-term health.

Osteonecrosis of the jaw (ONJ): diagnosis and management in 2015.

Osteonecrosis of the jaw (ONJ) has been associated with the use of aminobisphosphonates and denosumab. The vast majority (>90%) of cases occur in the oncology patient population receiving high doses of intravenous bisphosphonates or subcutaneous denosumab. The incidence of ONJ in the osteoporosis patient population is very low and is estimated at 1-90 per 100,000 patient-years of exposure. In the oncology patient population the incidence appears to be related to dose and duration of exposure, and prevalence has been estimated to be as high as 18.6%. A number of risk factors in addition to antiresorptive therapy have been identified. These include the presence of periodontal disease, oral surgical procedures with extractions or implants, radiation therapy, chemotherapy, diabetes, glucocorticoid use, and smoking. Antiangiogenic agents appear to contribute to the risk of ONJ, however, data at this time are limited and further evidence is required prior to confirming a causal relationship. ONJ may be prevented with optimization of oral hygiene, the use of oral antimicrobial mouth rinses, as well as systemic antibiotic therapy. Individuals not responding to conservative management or in the advanced stages of ONJ may be considered for surgery, as data over the past several years have demonstrated surgical success in this patient population. Case reports have indicated that teriparatide may enhance healing. A number of experimental therapies are being evaluated and include the use of bone marrow stem cell intralesional transplantation, local application of platelet-derived growth factor, hyperbaric oxygen, tissue grafting, and low-level laser therapy. This paper summarizes the current research as well as the international consensus on the diagnosis and management of ONJ.

FRAX-based assessment and intervention thresholds--an exploration of thresholds in women aged 50 years and older in the UK.

UNLABELLED: Under current guidelines, based on prior fracture probability thresholds, inequalities in access to therapy arise especially at older ages (≥70 years) depending on the presence or absence of a prior fracture. An alternative threshold (a fixed threshold from the age of 70 years) reduces this disparity, increases treatment access and decreases the need for bone densitometry. INTRODUCTION: Several international guidelines set age-specific intervention thresholds at the 10-year probability of fracture equivalent to a woman of average BMI with a prior fracture. At older ages (≥70 years), women with prior fracture selected for treatment are at lower average absolute risk than those selected for treatment in the absence of prior fracture, prompting consideration of alternative thresholds in this age group. METHODS: Using a simulated population of 50,633 women aged 50-90 years in the UK, with a distribution of risk factors similar to that in the European FRAX derivation cohorts and a UK-matched age distribution, the current NOGG intervention and assessment thresholds were compared to one where the thresholds remained constant from 70 years upwards. RESULTS: Under current thresholds, 45.1% of women aged ≥70 years would be eligible for therapy, comprising 37.5% with prior fracture, 2.2% with high risk but no prior fracture and 5.4% selected for treatment after bone mineral density (BMD) measurement. Mean hip fracture probability was 11.3, 23.3 and 17.6%, respectively, in these groups. Under the alternative thresholds, the overall proportion of women treated increased from 45.1 to 52.9%, with 8.4% at high risk but no prior fracture and 7.0% selected for treatment after BMD measurement. In the latter group, the mean probability of hip fracture was identical to that observed in women with prior fracture (11.3%). The alternative threshold also reduced the need for BMD measurement, particularly at older ages (>80 years). CONCLUSIONS: The alternative thresholds equilibrate fracture risk, particularly hip fracture risk, in those with or without prior fracture selected for treatment and reduce BMD usage at older ages.

Epidemiological burden of postmenopausal osteoporosis in Italy from 2010 to 2020: estimations from a disease model.

The article describes the adaptation of a model to estimate the burden of postmenopausal osteoporosis in women aged 50 years and over in Italy between 2010 and 2020. For this purpose, a validated postmenopausal osteoporosis disease model developed for Sweden was adapted to Italy. For each year of the study, the 'incident cohort' (women experiencing a first osteoporotic fracture) was identified and run through a Markov model using 1-year cycles until 2020. Health states were based on the number of fractures and deaths. Fracture by site (hip, clinical vertebral, non-hip non-vertebral) was tracked for each health state. Transition probabilities reflected fracture site-specific risk of death and subsequent fractures. Model inputs specific to Italy included population size and life tables from 1970 to 2020, incidence of hip fracture and BMD by age in the general population (mean and standard deviation). The model estimated that the number of postmenopausal osteoporotic women would increase from 3.3 million to 3.7 million between 2010 and 2020 (+14.3%). Assuming unchanged incidence rates by age group over time, the model predicted the overall number of osteoporotic fractures to increase from 285.0 to 335.8 thousand fractures between 2010 and 2020 (+17.8%). The estimated expected increases in hip, vertebral and non-hip non-vertebral fractures were 22.3, 17.2 and 16.3%, respectively. Due to demographic changes, the burden of fractures is expected to increase markedly by 2020.

Disease-specific perception of fracture risk and incident fracture rates: GLOW cohort study.

UNLABELLED: Accurate patient risk perception of adverse health events promotes greater autonomy over, and motivation towards, health-related lifestyles. INTRODUCTION: We compared self-perceived fracture risk and 3-year incident fracture rates in postmenopausal women with a range of morbidities in the Global Longitudinal study of Osteoporosis in Women (GLOW). METHODS: GLOW is an international cohort study involving 723 physician practices across ten countries (Europe, North America, Australasia); 60,393 women aged ≥55 years completed baseline questionnaires detailing medical history and self-perceived fracture risk. Annual follow-up determined self-reported incident fractures. RESULTS: In total 2,945/43,832 (6.8%) sustained an incident fracture over 3 years. All morbidities were associated with increased fracture rates, particularly Parkinson's disease (hazard ratio [HR]; 95% confidence interval [CI], 3.89; 2.78-5.44), multiple sclerosis (2.70; 1.90-3.83), cerebrovascular events (2.02; 1.67-2.46), and rheumatoid arthritis (2.15; 1.53-3.04) (all p < 0.001). Most individuals perceived their fracture risk as similar to (46%) or lower than (36%) women of the same age. While increased self-perceived fracture risk was strongly associated with incident fracture rates, only 29% experiencing a fracture perceived their risk as increased. Under-appreciation of fracture risk occurred for all morbidities, including neurological disease, where women with low self-perceived fracture risk had a fracture HR 2.39 (CI 1.74-3.29) compared with women without morbidities. CONCLUSIONS: Postmenopausal women with morbidities tend to under-appreciate their risk, including in the context of neurological diseases, where fracture rates were highest in this cohort. This has important implications for health education, particularly among women with Parkinson's disease, multiple sclerosis, or cerebrovascular disease.

Osteoporosis in the European Union: medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA).

UNLABELLED: This report describes the epidemiology, burden, and treatment of osteoporosis in the 27 countries of the European Union (EU27). INTRODUCTION: Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased risk of fragility fractures which represent the main clinical consequence of the disease. Fragility fractures are associated with substantial pain and suffering, disability and even death for affected patients and substantial costs to society. The aim of this report was to characterize the burden of osteoporosis in the EU27 in 2010 and beyond. METHODS: The literature on fracture incidence and costs of fractures in the EU27 was reviewed and incorporated into a model estimating the clinical and economic burden of osteoporotic fractures in 2010. RESULTS: Twenty-two million women and 5.5 million men were estimated to have osteoporosis; and 3.5 million new fragility fractures were sustained, comprising 610,000 hip fractures, 520,000 vertebral fractures, 560,000 forearm fractures and 1,800,000 other fractures (i.e. fractures of the pelvis, rib, humerus, tibia, fibula, clavicle, scapula, sternum and other femoral fractures). The economic burden of incident and prior fragility fractures was estimated at 37 billion. Incident fractures represented 66 % of this cost, long-term fracture care 29 % and pharmacological prevention 5 %. Previous and incident fractures also accounted for 1,180,000 quality-adjusted life years lost during 2010. The costs are expected to increase by 25 % in 2025. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are untreated and the number of patients on treatment is declining. CONCLUSIONS: In spite of the high social and economic cost of osteoporosis, a substantial treatment gap and projected increase of the economic burden driven by the aging populations, the use of pharmacological interventions to prevent fractures has decreased in recent years, suggesting that a change in healthcare policy is warranted.

Osteoporosis in the European Union: a compendium of country-specific reports.

UNLABELLED: This report describes epidemiology, burden, and treatment of osteoporosis in each of the 27 countries of the European Union (EU27). INTRODUCTION: In 2010, 22 million women and 5.5 million men were estimated to have osteoporosis in the EU; and 3.5 million new fragility fractures were sustained, comprising 620,000 hip fractures, 520,000 vertebral fractures, 560,000 forearm fractures and 1,800,000 other fractures. The economic burden of incident and prior fragility fractures was estimated at € 37 billion. Previous and incident fractures also accounted for 1,180,000 quality-adjusted life years lost during 2010. The costs are expected to increase by 25 % in 2025. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are untreated and the number of patients on treatment is declining. The aim of this report was to characterize the burden of osteoporosis in each of the EU27 countries in 2010 and beyond. METHODS: The data on fracture incidence and costs of fractures in the EU27 were taken from a concurrent publication in this journal (Osteoporosis in the European Union: Medical Management, Epidemiology and Economic Burden) and country specific information extracted. RESULTS: The clinical and economic burden of osteoporotic fractures in 2010 is given for each of the 27 countries of the EU. The costs are expected to increase on average by 25 % in 2025. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are untreated and the number of patients on treatment is declining. CONCLUSIONS: In spite of the high cost of osteoporosis, a substantial treatment gap and projected increase of the economic burden driven by aging populations, the use of pharmacological prevention of osteoporosis has decreased in recent years, suggesting that a change in healthcare policy concerning the disease is warranted.

SCOPE: a scorecard for osteoporosis in Europe.

SUMMARY: The scorecard summarises key indicators of the burden of osteoporosis and its management in each of the member states of the European Union. The resulting scorecard elements were then assembled on a single sheet to provide a unique overview of osteoporosis in Europe. INTRODUCTION: The scorecard for osteoporosis in Europe (SCOPE) is an independent project that seeks to raise awareness of osteoporosis care in Europe. The aim of this project was to develop a scorecard and background documents to draw attention to gaps and inequalities in the provision of primary and secondary prevention of fractures due to osteoporosis. METHODS: The SCOPE panel reviewed the information available on osteoporosis and the resulting fractures for each of the 27 countries of the European Union (EU27). The information researched covered four domains: background information (e.g. the burden of osteoporosis and fractures), policy framework, service provision and service uptake e.g. the proportion of men and women at high risk that do not receive treatment (the treatment gap). RESULTS: There was a marked difference in fracture risk among the EU27. Of concern was the marked heterogeneity in the policy framework, service provision and service uptake for osteoporotic fracture that bore little relation to the fracture burden. For example, despite the wide availability of treatments to prevent fractures, in the majority of the EU27, only a minority of patients at high risk receive treatment for osteoporosis even after their first fracture. The elements of each domain in each country were scored and coded using a traffic light system (red, orange, green) and used to synthesise a scorecard. The resulting scorecard elements were then assembled on a single sheet to provide a unique overview of osteoporosis in Europe. CONCLUSIONS: The scorecard will enable healthcare professionals and policy makers to assess their country's general approach to the disease and provide indicators to inform future provision of healthcare.

Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013.

Since the launch in 2008 by the National Osteoporosis Guideline Group (NOGG), of guidance for the diagnosis and management of osteoporosis in postmenopausal women and older men in the UK there have been significant advances in risk assessment and treatment. These have been incorporated into an updated version of the guideline, with an additional focus on the management of glucocorticoid-induced osteoporosis, the role of calcium and vitamin D therapy and the benefits and risks of long-term bisphosphonate therapy. The updated guideline is summarised below. The recommendations in the guideline are intended to aid management decisions but do not replace the need for clinical judgement in the care of individuals in clinical practice.

Non-hip, non-spine fractures drive healthcare utilization following a fracture: the Global Longitudinal Study of Osteoporosis in Women (GLOW).

UNLABELLED: We evaluated healthcare utilization associated with treating fracture types in >51,000 women aged ≥55 years. Over the course of 1 year, there were five times more non-hip, non-spine fractures than hip or spine fractures, resulting in twice as many days of hospitalization and rehabilitation/nursing home care for non-hip, non-spine fractures. INTRODUCTION: The purpose of this study is to evaluate medical healthcare utilization associated with treating several types of fractures in women ≥55 years from various geographic regions. METHODS: Information from the Global Longitudinal Study of Osteoporosis in Women (GLOW) was collected via self-administered patient questionnaires at baseline and year 1 (n = 51,491). Self-reported clinically recognized low-trauma fractures at year 1 were classified as incident spine, hip, wrist/hand, arm/shoulder, pelvis, rib, leg, and other fractures. Healthcare utilization data were self-reported and included whether the fracture was treated at a doctor's office/clinic or at a hospital. Patients were asked if they had undergone surgery or been treated at a rehabilitation center or nursing home. RESULTS: During 1-year follow-up, there were 195 spine, 134 hip, and 1,654 non-hip, non-spine fractures. Clinical vertebral fractures resulted in 617 days of hospitalization and 512 days of rehabilitation/nursing home care; hip fractures accounted for 1,306 days of hospitalization and 1,650 days of rehabilitation/nursing home care. Non-hip, non-spine fractures resulted in 3,805 days in hospital and 5,186 days of rehabilitation/nursing home care. CONCLUSIONS: While hip and vertebral fractures are well recognized for their associated increase in health resource utilization, non-hip, non-spine fractures, by virtue of their 5-fold greater number, require significantly more healthcare resources.