Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Secondary fracture prevention in primary care: a narrative review.

The global burden of osteoporosis continues to rise with an ageing population. Untreated osteoporotic fractures not only heighten the risk of subsequent fractures but are associated with excess mortality. Although primary care guidelines consistently stress the importance of secondary fracture prevention, fewer than 20% of patients are appropriately treated for osteoporosis following an initial osteoporotic fracture. This worldwide phenomenon is known as the osteoporosis care gap. This literature review examines the barriers to secondary fracture prevention in primary care and evaluates the effectiveness of targeted primary care interventions. Common themes emerged from the majority of qualitative studies, including a need for improved communication between the hospital team and primary care, better defined responsibilities and osteoporosis-directed education for the primary care physicians. Quantitative studies demonstrated that most targeted, intensive interventions aimed at educating patients and their primary care physician about osteoporosis treatment significantly increased rates of investigation and treatment. Greater uptake of models of secondary fracture prevention in primary care is urgently needed to address the osteoporosis care gap.

Expanding access to fracture liaison services in Australia for people with minimal trauma fractures: a system dynamics modelling study.

OBJECTIVES: To project how many minimal trauma fractures could be averted in Australia by expanding the number and changing the operational characteristics of fracture liaison services (FLS). STUDY DESIGN: System dynamics modelling. SETTING, PARTICIPANTS: People aged 50 years or more who present to hospitals with minimal trauma fractures, Australia, 2020-31. MAIN OUTCOME MEASURES: Numbers of all minimal trauma fractures and of hip fractures averted by increasing the FLS number (from 29 to 58 or 100), patient screening rate (from 30% to 60%), and capacity for accepting new patients (from 40 to 80 per service per month), and reducing the proportion of eligible patients who do not attend FLS (from 30% to 15%); cost per fracture averted. RESULTS: Our model projected a total of 2 441 320 minimal trauma fractures (258 680 hip fractures; 2 182 640 non-hip fractures) in people aged 50 years or older during 2020-31, including 1 211 646 second or later fractures. Increasing the FLS number to 100 averted a projected 5405 fractures (0.22%; $39 510 per fracture averted); doubling FLS capacity averted a projected 3674 fractures (0.15%; $35 835 per fracture averted). Our model projected that neither doubling the screening rate nor reducing by half the proportion of eligible patients who did not attend FLS alone would reduce the number of fractures. Increasing the FLS number to 100, the screening rate to 60%, and capacity to 80 new patients per service per month would together avert a projected 13 672 fractures (0.56%) at a cost of $42 828 per fracture averted. CONCLUSION: Our modelling indicates that increasing the number of hospital-based FLS and changing key operational characteristics would achieve only moderate reductions in the number of minimal trauma fractures among people aged 50 years or more, and the cost would be relatively high. Alternatives to specialist-led, hospital-based FLS should be explored.

The glucocorticoid receptor in skeletal health and disease: insights from targeted knockout mice.

Glucocorticoids are steroid hormones, secreted by the adrenals to regulate a range of metabolic, immunologic, and homeostatic functions. Due to their potent anti-inflammatory effects, synthetic glucocorticoids are widely used to treat inflammatory disorders. However, their use especially at high doses and over the long-term is associated with several unwanted side effects that compromises their intended use (e.g. glucocorticoid-induced osteoporosis and/or diabetes, myopathy, and skin atrophy). Both endogenous and synthetic glucocorticoids exert their effects through the glucocorticoid receptor, a transcription factor present in nearly all nucleated cells. Glucocorticoid receptor knockout mouse models have proved to be valuable tools in understanding how glucocorticoids contribute to skeletal health and disease. These models, described in this review, have helped to establish that the effects of glucocorticoids on the skeleton are multifaceted, cell specific and concentration dependent. Intriguingly, while endogenous glucocorticoids are essential for bone formation, high-dose exogenous glucocorticoids may induce bone loss. Additionally, the actions of endogenous glucocorticoids vary greatly depending on the disease microenvironment. For example, endogenous glucocorticoids have predominately beneficial anti-inflammatory effects in rheumatoid arthritis, but detrimental actions in osteoarthritis by driving cartilage loss and abnormal bone formation. Studies in tissue-specific knockout models provide important insights that will aid the development of new glucocorticoid therapeutics that can specifically target certain cell types to minimise unwanted effects from current glucocorticoid therapy.

Empirically derived dietary patterns are associated with major adverse cardiovascular events, all-cause mortality, and congestive cardiac failure in older men: The Concord Health and Ageing in Men Project.

BACKGROUND: Diet is associated with major adverse cardiovascular events (MACE). OBJECTIVE: We evaluated the associations between empirically derived dietary patterns and MACE. DESIGN: Prospective cohort study. SETTING: The Concord Health and Ageing in Men Project, Sydney, Australia. PARTICIPANTS: 539 community-dwelling older Australian men aged 75 years and older. METHODS: Men underwent dietary assessment using a validated dietitian-administered diet history questionnaire. Cox regression analyses were conducted between MACE and the three dietary patterns identified from factor analysis. Five-point MACE comprised of all-cause mortality, myocardial infarction (MI), congestive cardiac failure (CCF), coronary revascularisation, and/or ischaemic stroke. Four-point MACE included the four endpoints of MI, CCF, coronary revascularisation, and/or ischaemic stroke, and excluded all-cause mortality. RESULTS: At a median of 5.3 (IQR 4.6-6.3) years of follow-up, the incidences were: five-point MACE 31.2% (n = 168); four-point MACE excluding all-cause mortality 17.8% (n = 96); all-cause mortality 20.1% (n = 111); CCF 11.3% (n = 61); MI 3.7% (n = 20); stroke 3.2% (n = 17); and coronary revascularisation 3.1% (n = 15). In fully adjusted analyses, compared to the bottom tertile, the middle tertile of 'vegetables-legumes-seafood' dietary pattern was associated with reduced five-point MACE (HR 0.67 [95% CI: 0.45, 0.99, P = .047]), and CCF (HR 0.31 [95% CI: 0.15, 0.65, P = .002]), whilst the middle tertile of 'wholegrains-milk-other fruits' dietary pattern was associated with increased five-point MACE (HR 1.78 [95% CI: 1.17, 2.70, P = .007]), four-point MACE (HR 1.92 [95% CI: 1.12, 3.30, P = .018]), and CCF (HR 2.33 [95% CI: 1.17, 4.65, P = .016]). For the 'discretionary-starchy vegetables-processed meats' dietary pattern, a higher score was associated with increased five-point MACE (HR 1.33 [95% CI: 1.09, 1.62, P = .004]), and all-cause mortality (HR 1.63 [95% CI: 1.26, 2.12, P < .001]), and compared to the bottom tertile, the top tertile was associated with increased all-cause mortality (HR 2.26 [95% CI: 1.27, 4.00, P = .005]). CONCLUSION: Older men may benefit from consuming a 'vegetables-legumes-seafood' dietary pattern rather than 'discretionary-starchy vegetables-processed meats' and 'wholegrains-milk-other fruits' dietary patterns for the prevention of MACE.

Cross-sectional and longitudinal associations between empirically derived dietary patterns and frailty among older men: The Concord Health and Ageing in Men Project.

BACKGROUND: Diet may be associated with frailty. OBJECTIVE: We aimed to evaluate the associations between empirically derived dietary patterns and frailty in older men. DESIGN: Prospective cohort study. SETTING: The Concord Health and Ageing in Men Project, Sydney, Australia. PARTICIPANTS: 785 community-dwelling older Australian men aged 75 years and older. METHODS: Men underwent dietary assessment using a validated dietitian-administered diet history questionnaire. Factor analysis identified three dietary patterns. Multinomial logistic regression was conducted between frailty and dietary patterns for cross-sectional analyses and longitudinal analyses over a 3-year follow-up. Frailty was defined by the Fried frailty phenotype. RESULTS: Of the 785 men, pre-frailty was prevalent in 47.1% (n = 370), and frailty in 8.3% (n = 65). In fully adjusted cross-sectional analyses, the top tertile and a higher 'vegetables-legumes-seafood' dietary pattern score were associated with reduced prevalence of frailty (OR 0.34 [95% CI: 0.12, 0.93, P = .036]) and OR 0.50 [95% CI: 0.30, 0.83, P = .007] respectively). The top tertile of the 'discretionary-starchy vegetables-processed meats' dietary pattern was also associated cross-sectionally with increased prevalence of pre-frailty (OR 1.75 [95% CI: 1.08, 2.83, P = .022]). Of the 296 robust men in fully adjusted longitudinal analyses, the incidence of pre-frailty was 52.4% (n = 155), and frailty was 5.4% (n = 16) over a 3-year follow-up. The middle tertile of the 'vegetables-legumes-seafood' dietary pattern had a non-significant trend towards reduced incident pre-frailty (OR 0.52 [95% CI: 0.27, 1.00, P = .050]). CONCLUSION: Consumption of a 'vegetables-legumes-seafood' dietary pattern appears to be less favoured by frail older men.

Intra-generational social mobility and mortality among older men in the Concord Health and Ageing in Men Project: A cohort study.

Objectives: We examined associations between intra-generational social mobility (reflected in life-course socioeconomic trajectories) and mortality, among older men. Methods: Data came from a prospective Australian community-based cohort of older men. Social mobility was defined by socioeconomic indicators from three points in the life-course: educational attainment (late adolescence-early adulthood), occupation (mid-life), and current sources of income (older age). We defined indicators of social mobility trajectory (6 categories; reflecting the direction of social mobility) and social mobility status (2 categories; mobile or non-mobile). We used Cox regression to examine associations with mortality, adjusting for age, country of birth, and living arrangement. Results: We followed 1568 men (mean age 76.8, SD 5.4) for a mean duration of 9.1 years, with 797 deaths recorded. Moving upward was the predominant social mobility trajectory (36.0%), followed by mixed trajectories (25.1%), downward (15.1%), stable low (12.2%), stable high (7.6%), and stable middle (4.0%). Men with downward (Hazard ratio 1.58, 95% CI 1.13 to 2.19) and stable low socioeconomic trajectories (1.77, 1.25 to 2.50) had higher mortality risks than men with stable high socioeconomic trajectories, while men with upward trajectories had similar risks to those with stable high trajectories. 76.2% of the participants were classified as having mobile status; no associations were evident between binary social mobility status and mortality. Discussions: These findings suggest cumulative and persistent exposure to disadvantaged socioeconomic conditions across the life-course, rather than social mobility, is associated with increased mortality. For each stage of the life-course, addressing socioeconomic disadvantage may reduce inequities in mortality.

Bone density and bone turnover markers in patients with epilepsy on chronic antiepileptic drug therapy

In this comparative, cross-sectional study, we evaluated 55 patients with epilepsy on chronic use of antiepileptic drugs (AED); [(38 females and 17 males, 35 ± 6 years (25 to 47)] and compared to 24 healthy subjects (17 females/7 males). Laboratorial evaluation of bone and mineral metabolism including measurements of bone specific alkaline phosphatase (BALP) and carboxyterminal telopeptide of type I collagen (CTX-I) were performed. Bone mineral density (BMD) was measured by DXA. BALP and CTX-I levels did not differ significantly between the groups. CTX-I levels were significantly higher in patients who were exposed to phenobarbital (P< 0.01) than those who were not. Patients presented BMD of both sites significantly lower than the controls (0.975 ± 0.13 vs. 1.058 ± 0.1 g/cm²; p= 0.03; 0.930 ± 0.1 vs. 0.988 ± 0.12 g/cm²; p= 0.02, respectively). Total hip BMD (0.890 ± 0.10 vs. 0.970 ± 0.08 g/cm²; p< 0.003) and femoral neck (0.830 ± 0.09 vs. 0.890 ± 0.09 g/cm²; p< 0.03) were significantly lower in patients who had been exposed to phenobarbital, in comparison to the non-phenobarbital users. In conclusion, patients on AED demonstrate reduced BMD. Among the AED, phenobarbital seems to be the main mediator of low BMD and increases in CTX-I.

Neste estudo comparativo, transversal, 55 pacientes com epilepsia [38 mulheres e 17 homens; 35 ± 6 anos (25 a 47anos)] foram comparados com 24 indivíduos normais (17 mulheres / 7 homens). Foi realizada uma avaliação laboratorial do metabolismo ósseo e mineral incluindo a dosagem de fosfatase alcalina específica óssea (BALP) e telopeptídeo carboxiterminal do colágeno tipo I (CTX-I). Densidade mineral óssea (DMO) da coluna lombar e do fêmur foi medida por DXA. BALP e CTX-I não foram diferentes entre os grupos. CTX-I foi significativamente mais elevado nos pacientes expostos ao fenobarbital do que os que não usaram essa medicação (p< 0,01). DMO de ambos os sítios foi menor no grupo de pacientes (0,975 ± 0,13 vs. 1,058 ± 0,1 g/cm²; p= 0,03; 0,930 ± 0,1 vs. 0,988 ± 0,12 g/cm²; p= 0,02, respectivamente). DMO do fêmur total (0,890 ± 0,10 vs. 0,970 ± 0,08 g/cm²; p< 0,003) e colo do fêmur (0,830 ± 0,09 vs. 0,890 ± 0,09 g/cm²; p< 0,03) foi significativamente menor nos pacientes que usaram fenobarbital. Em conclusão, pacientes portadores de epilepsia em uso crônico de drogas antiepilépticas (DAE) demonstraram uma redução da DMO. Entre as DAE, o fenobarbital parece ser o principal mediador da diminuição da DMO e do aumento do CTX-I.

Clinical application of biochemical markers of bone turnover / Marcadores bioquímicos da remodelação óssea

With the ageing population in most countries, disorders of bone and mineral metabolism are becoming increasingly relevant to every day clinical practice. Consequently, the interest in, and the need for effective measures to be used in the screening, diagnosis and follow-up of such pathologies have markedly grown. Together with clinical and imaging techniques, biochemical tests play an important role in the assessment and differential diagnosis of metabolic bone disease. In recent years, the isolation and characterisation of cellular and extracellular components of the skeletal matrix have resulted in the development of molecular markers that are considered to reflect either bone formation or bone resorption. These biochemical indices are non-invasive, comparatively inexpensive and, when applied and interpreted correctly, helpful tools in the diagnostic and therapeutic assessment of metabolic bone disease. This review provides an overview of the current evidence regarding the clinical use of biochemical markers of bone remodelling in bone disease, with an emphasis on osteoporosis.

Tendo em vista o crescimento da população idosa na maioria dos países, os distúrbios do metabolismo ósseo e mineral estão tornando-se cada vez mais relevantes na prática clínica diária. Conseqüentemente, o interesse e a necessidade de medidas efetivas para serem usadas no rastreamento, diagnóstico e seguimento de tais patologias vêm crescendo acentuadamente. Além da avaliação clínica e de técnicas de imagens, os marcadores bioquímicos desempenham um importante papel na avaliação e diagnóstico das doenças ósseas metabólicas. Recentemente, a melhor caracterização dos componentes intracelulares e extracelulares da matriz óssea resultou no desenvolvimento dos marcadores moleculares, os quais refletem tanto a formação como a reabsorção óssea. Estes marcadores bioquímicos não são invasivos e comparativamente são de mais baixo custo, e quando aplicados e interpretados corretamente são instrumentos úteis no diagnóstico e tratamento das doenças ósseas metabólicas. Esta revisão abordará evidências atuais, levando em consideração o uso clínico dos marcadores bioquímicos da remodelação óssea nas doenças metabólicas ósseas, com ênfase na osteoporose.