Showing papers by "Cyrus Cooper published in 2005"
TL;DR: The findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.
903 citations
TL;DR: Osteoporosis is widely viewed as a major public health concern, but the exact magnitude of the problem is uncertain and likely to depend on how the condition is defined, and the design and implementation of control programs directed at this major health problem must be given.
Abstract: Osteoporosis is widely viewed as a major public health concern, but the exact magnitude of the problem is uncertain and likely to depend on how the condition is defined. Noninvasive bone mineral measurements can be used to define a state of heightened fracture risk (osteopenia), or the ultimate clinical manifestation of fracture can be assessed (established osteoporosis). If bone mineral measurements more than 2 standard deviations below the mean of young normal women represent osteopenia, then 45% of white women aged 50 years and over have the condition at one or more sites in the hip, spine, or forearm on the basis of population-based data from Rochester, Minnesota. A smaller proportion is affected at each specific skeletal site: 32% have bone mineral values this low in the lumbar spine, 29% in either of two regions in the proximal femur, and 26% in the midradius. Although this overall estimate is substantial, some other serious chronic diseases are almost as common. More importantly, low bone mass is associated with adverse health outcomes, especially fractures. The lifetime risk of any fracture of the hip, spine, or distal forearm is almost 40% in white women and 13% in white men from age 50 years onward. If the enormous costs associated with these fractures are to be reduced, increased attention must be given to the design and implementation of control programs directed at this major health problem.
841 citations
Journal Article•
TL;DR: In this article, a retrospective cohort study was conducted in a general medical practice setting in the United Kingdom (using data from the General Practice Research Database [GPRD]). For each oral corticosteroid user aged 18 years or older, a control patient was selected randomly, who was matched by age, sex, and medical practice.
Abstract: Treatment with oral corticosteroids is known to decrease bone density but there are few data on the attendant risk of fracture and on the reversibility of this risk after cessation of therapy. A retrospective cohort study was conducted in a general medical practice setting in the United Kingdom (using data from the General Practice Research Database [GPRD]). For each oral corticosteroid user aged 18 years or older, a control patient was selected randomly, who was matched by age, sex, and medical practice. The study comprised 244,235 oral corticosteroid users and 244,235 controls. The average age was 57.1 years in the oral corticosteroid cohort and 56.9 years in the control cohort. In both cohorts 58.6% were female. The most frequent indication for treatment was respiratory disease (40%). The relative rate of nonvertebral fracture during oral corticosteroid treatment was 1.33 (95% confidence interval [CI], 1.29–1.38), that of hip fracture 1.61 (1.47–1.76), that of forearm fracture 1.09 (1.01–1.17), and that of vertebral fracture 2.60 (2.31–2.92). A dose dependence of fracture risk was observed. With a standardized daily dose of less than 2.5 mg prednisolone, hip fracture risk was 0.99 (0.82–1.20) relative to control, rising to 1.77 (1.55–2.02) at daily doses of 2.5–7.5 mg, and 2.27 (1.94–2.66) at doses of 7.5 mg or greater. For vertebral fracture, the relative rates were 1.55 (1.20–2.01), 2.59 (2.16–3.10), and 5.18 (4.25–6.31), respectively. All fracture risks declined toward baseline rapidly after cessation of oral corticosteroid treatment. These results quantify the increased fracture risk during oral corticosteroid therapy, with greater effects on the hip and spine than forearm. They also suggest a rapid offset of this increased fracture risk on cessation of therapy, which has implications for the use of preventative agents against bone loss in patients at highest risk.
502 citations
TL;DR: Whether there is a relationship among glucose tolerance, muscle strength, and physical function in men and women with and without type 2 diabetes is determined.
Abstract: There is growing recognition that the complications associated with type 2 diabetes may translate into functional impairment in older people (1). This may reflect a link between the metabolic and mechanical functions of muscle. However, the possibility that the link between glucose tolerance and physical function extends to people without diabetes has not been previously considered. The objective of this study was to determine whether there is a relationship among glucose tolerance, muscle strength, and physical function in men and women with and without type 2 diabetes.
A cross-sectional survey within a cohort study design was used. Information was obtained on self-reported diabetes status cross-checked with medication data, glucose, and insulin levels 2 h after an oral glucose tolerance test (for participants without a previous diagnosis of diabetes) (2), grip strength using a Jamar dynamometer (3), and physical function using the physical function component of the Medical Outcomes Study 36-item short form questionnaire. This is a measure of subjective health status widely validated in both men and women (4,5).
The population-based study sample consisted of 1,391 men and women aged between 60 and 70 years and living in the …
352 citations
TL;DR: Once‐monthly (50/50, 100, and 150 mg) and daily (2.5 mg; 3‐year vertebral fracture risk reduction: 52%) oral ibandronate regimens were compared in 1609 women with postmenopausal osteoporosis.
Abstract: Once-monthly (50/50, 100, and 150 mg) and daily (2.5 mg; 3-year vertebral fracture risk reduction: 52%) oral ibandronate regimens were compared in 1609 women with postmenopausal osteoporosis. At least equivalent efficacy and similar safety and tolerability were shown after 1 year. Introduction: Suboptimal adherence to daily and weekly oral bisphosphonates can potentially compromise therapeutic outcomes in postmenopausal osteoporosis. Although yet to be prospectively shown in osteoporosis, evidence from randomized clinical trials in several other chronic conditions shows that reducing dosing frequency enhances therapeutic adherence. Ibandronate is a new and potent bisphosphonate with antifracture efficacy proven for daily administration and also intermittent administration with a dose-free interval of >2 months. This report presents comparative data on the efficacy and safety of monthly and daily oral ibandronate regimens. Materials and Methods: MOBILE is a 2-year, randomized, double-blind, phase III, noninferiority trial. A total of 1609 women with postmenopausal osteoporosis were assigned to one of four oral ibandronate regimens: 2.5 mg daily, 50 mg/50 mg monthly (single doses, consecutive days), 100 mg monthly, or 150 mg monthly. Results: After 1 year, lumbar spine BMD increased by 3.9%, 4.3%, 4.1%, and 4.9% in the 2.5, 50 /50, 100, and 150 mg arms, respectively. All monthly regimens were proven noninferior, and the 150 mg regimen superior, to the daily regimen. All monthly regimens produced similar hip BMD gains, which were larger than those with the daily regimen. All regimens similarly decreased serum levels of C-telopeptide, a biochemical marker of bone resorption. Compared with the daily regimen, a significantly larger proportion of women receiving the 100 and 150 mg monthly regimens achieved predefined threshold levels for percent change from baseline in lumbar spine (6%) or total hip BMD (3%). All regimens were similarly well tolerated. Conclusions: Monthly ibandronate is at least as effective and well tolerated as the currently approved daily ibandronate regimen in postmenopausal osteoporosis.
325 citations
TL;DR: A cohort study was needed which linked information about the early environment of individuals born at least 60 years earlier to their health outcomes in later life and discovered a large set of records maintained in Hertfordshire during the early 20th century.
Abstract: How did the study come about? Ecological studies conducted in the 1980s demonstrated a close geographic correlation between death rates from coronary heart disease during the years 1968–78 in different parts of England and Wales and the infant mortality rate in these areas 60 years earlier.1 These studies suggested that adverse environmental influences acting in utero and during infancy might increase the risk of cardiovascular disease in later life. However, this hypothesis required investigation using more robust epidemiological techniques. To yield results within a relatively short space of time, a cohort study was needed which linked information about the early environment of individuals born at least 60 years earlier to their health outcomes in later life. As part of a nationwide search of archives, staff working at the MRC Environmental Epidemiology Unit (MRC EEU), University of Southampton, discovered a large set of records maintained in Hertfordshire during the early 20th century.
246 citations
TL;DR: The results quantify the increased fracture risk during oral corticosteroid therapy, with greater effects on the hip and spine than forearm, which has implications for the use of preventative agents against bone loss in patients at highest risk.
Abstract: Treatment with oral corticosteroids is known to decrease bone density but there are few data on the attendant risk of fracture and on the reversibility of this risk after cessation of therapy. A retrospective cohort study was conducted in a general medical practice setting in the United Kingdom (using data from the General Practice Research Database [GPRD]). For each oral corticosteroid user aged 18 years or older, a control patient was selected randomly, who was matched by age, sex, and medical practice. The study comprised 244,235 oral corticosteroid users and 244,235 controls. The average age was 57.1 years in the oral corticosteroid cohort and 56.9 years in the control cohort. In both cohorts 58.6% were female. The most frequent indication for treatment was respiratory disease (40%). The relative rate of nonvertebral fracture during oral corticosteroid treatment was 1.33 (95% confidence interval [CI], 1.29–1.38), that of hip fracture 1.61 (1.47–1.76), that of forearm fracture 1.09 (1.01–1.17), and that of vertebral fracture 2.60 (2.31–2.92). A dose dependence of fracture risk was observed. With a standardized daily dose of less than 2.5 mg prednisolone, hip fracture risk was 0.99 (0.82–1.20) relative to control, rising to 1.77 (1.55–2.02) at daily doses of 2.5–7.5 mg, and 2.27 (1.94–2.66) at doses of 7.5 mg or greater. For vertebral fracture, the relative rates were 1.55 (1.20–2.01), 2.59 (2.16–3.10), and 5.18 (4.25–6.31), respectively. All fracture risks declined toward baseline rapidly after cessation of oral corticosteroid treatment. These results quantify the increased fracture risk during oral corticosteroid therapy, with greater effects on the hip and spine than forearm. They also suggest a rapid offset of this increased fracture risk on cessation of therapy, which has implications for the use of preventative agents against bone loss in patients at highest risk. (J Bone Miner Res 2000;15:993–1000)
231 citations
TL;DR: In this pragmatic study, ESIs offered transient benefit in symptoms at 3 weeks in patients with sciatica, but no sustained benefits in terms of pain, function or need for surgery.
Abstract: Objective. To determine the effectiveness and predictors of response to lumbar epidural corticosteroid injections (ESI) in patients with sciatica. We performed a 12-month, multicentre, double-blind, randomized, placebo-controlled, parallel-group trial in four secondary pain-care clinics in the Wessex Region. Methods. Two hundred and twenty-eight patients with a clinical diagnosis of unilateral sciatica of 1–18 months’ duration were randomized to either three lumbar ESIs of triamcinolone acetonide or interligamentous saline injections at intervals of 3 weeks. The main outcome measure was the Oswestry low back pain disability questionnaire (ODQ). Results. At 3 weeks, the ESI group demonstrated a transient benefit over the placebo group (patients achieving a 75% improvement in ODQ, 12.5 vs 3.7%; number needed to treat, 11.4). No benefit was demonstrated from 6 to 52 weeks. ESIs did not improve physical function, hasten return to work or reduce the need for surgery. There was no benefit of repeated ESIs over single injection. No clinical predictors of response were found. At the end of the study the majority of patients still had significant pain and disability regardless of intervention. Conclusions. In this pragmatic study, ESIs offered transient benefit in symptoms at 3 weeks in patients with sciatica, but no sustained benefits in terms of pain, function or need for surgery. Sciatica is a chronic condition requiring a multidisciplinary approach. To fully investigate the value of ESIs, they need to be evaluated as part of a multidisciplinary approach.
223 citations
TL;DR: Critical in the development of this field will be an understanding of the phenotype, plasticity, and potentiality of these cells and the tempering of patients’ expectations driven by commercial and media hype to match current laboratory and clinical observations.
Abstract: The tremendous capacity of bone to regenerate is indicative of the presence of stem cells with the capability, by definition, to self-renew as well as to give rise to daughter cells. These primitive progenitors, termed mesenchymal stem cells or bone marrow stromal stem cells, exist postnatally, and are multipotent with the ability to generate cartilage, bone, muscle, tendon, ligament, and fat. Given the demographic challenge of an ageing population, the development of strategies to exploit the potential of stem cells to augment bone formation to replace or restore the function of traumatized, diseased, or degenerated bone is a major clinical and socioeconomic need. Owing to the developmental plasticity of mesenchymal stem cells, there is great interest in their application to replace damaged tissues. Combined with modern advances in gene therapy and tissue engineering, they have the potential to improve the quality of life for many. Critical in the development of this field will be an understanding of the phenotype, plasticity, and potentiality of these cells and the tempering of patients' expectations driven by commercial and media hype to match current laboratory and clinical observations.
197 citations
TL;DR: Evidence is accumulating that factors such as prolonged abnormal posture and repetition contribute to conditions such as pain in the neck and upper limb and Psychosocial factors may also play a part.
Abstract: Pain in the neck and upper limb is common and contributes considerably to absence from work due to sickness. Evidence suggest that prolonged abnormal posture and repetition contribute to such conditions. Psychosocial risk factors may also play a part in the aetiology of upper limb disorders.
172 citations
TL;DR: Weight at each of these three points in the life course is important in the determination of adult bone mass, with greater contributions of earlier growth to bone size and mineral content than to bone mineral density.
Abstract: Several studies have shown relationships between growth in early life and adult bone mass; in this article, we evaluate the relative contributions of pre- and postnatal factors to bone mass in the seventh decade. A total of 498 eight men and 468 women who were born in Hertfordshire during the period 1931–1939 and still living there were recruited. Detailed birth records were available. Participants attended a clinic where they completed a detailed health questionnaire, before performance of anthropometric measurements and bone densitometry of the proximal femur and lumbar spine (Hologic QDR 4500). Birth weight was associated with bone mineral content in both men (proximal femur: r = 0.16, p = 0.0003; lumbar spine: r = 0.10, p = 0.03) and women (proximal femur: r = 0.16, p = 0.0008; lumbar spine: r = 0.11, p = 0.03); relationships with bone mineral density were weaker and were significant at the proximal femur in men only (p = 0.03). Relationships between weight at 1 y and bone mineral content were even stronger (proximal femur: men r = 0.22, p < 0.0001; women r = 0.14, p = 0.002). In men, 18% of the variance in proximal femoral bone area was explained by a model that included birth weight, weight at 1 y, and adult weight, with the relative contributions attributed to each being 2.8, 6.8, and 8.2%, respectively. In women, similar modeling produced figures of 6.7, 4.2, and 3.9% (overall variance of 15% in proximal femoral bone area). Hence, weight at each of these three points in the life course is important in the determination of adult bone mass, with greater contributions of earlier growth to bone size and mineral content than to bone mineral density.
TL;DR: This risk score helps to predict an individual's risk of fracture during GC use, and decisions about bone protection treatment could be based on long-term risks of fracture.
Abstract: BACKGROUND: Previous analyses of risk factors for glucocorticoid (GC)-induced osteoporosis have focused on the estimation of relative rather than absolute fracture probability. AIM: To estimate risk scores for the individual probability of fracture in GC users. DESIGN: Retrospective data analysis. METHODS: We evaluated all patients aged 40 years or older with a prescription for oral GCs in the General Practice Research Database (GPRD), which comprises the computerized medical records of around 7 million UK subjects. Individual risk factors for osteoporotic fractures were identified, and combined in a predictive model for 10-year absolute fracture risk. RESULTS: Of 191 752 oral GC users aged > or =40 years, 7412 experienced an osteoporotic fracture. Several characteristics independently contributed to the fracture risk score (GC therapy, age, gender, fall history, fracture history, body mass index, smoking, previous diagnoses, use of medication, recent hospitalization and indication for GC treatment). Scores of 30, 40 and 50 corresponded to absolute 5-year fracture risks of 6.2%, 15.3% and 35.2%, respectively. A woman aged 65 years with RA, low BMI, and a previous history of fracture and falls, who used 15 mg GC daily (total risk score 54) would have a 5-year fracture risk of 47% (a man with similar history, 30.1%). Short-term use of high-dose GC therapy (> or =30 mg) was associated with only a small increased risk of osteoporotic fracture (RR 1.21, 95%CI 1.04-1.42) in patients with a history of GC use. DISCUSSION: This risk score helps to predict an individual's risk of fracture during GC use. Decisions about bone protection treatment could be based on long-term risks of fracture.
TL;DR: This study provides evidence for gender-specific, site-specific and age-specific QTL, which regulate BMD in humans, and illustrates the importance of conducting subgroup analysis to detect these loci.
Abstract: Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mass and an increased risk of fracture. Bone mineral density (BMD) is a highly heritable trait and a key determinant of osteoporotic fracture risk, but the genes responsible are incompletely defined. Here, we identified quantitative trait loci (QTL) for regulation of BMD by a genome wide scan involving 3691 individuals from 715 families, who were selected because of reduced BMD values at the lumbar spine (LS-BMD) or femoral neck (FN-BMD) in probands. Linkage analysis was conducted in the study group as a whole with correction for age, gender, weight and height. Further analyses were conducted for men and women separately to identify gender-specific QTL and for those under and over the age of 50 years to distinguish QTL for peak bone mass from those that influence bone mass in older people. No regions of suggestive or significant linkage were identified when data from all subjects were analyzed together. On subgroup analysis, however, we identified a significant QTL for FN-BMD on chromosome 10q21 (LOD score +4.42; men 50 years) and 20q13 (LOD score +3.20; women < or =50 years). We identified five other QTL for BMD with LOD scores of greater than +2.20 on chromosomes 3q25, 4q25, 7p14, 16p13 and 16q23. This study provides evidence for gender-specific, site-specific and age-specific QTL, which regulate BMD in humans, and illustrates the importance of conducting subgroup analysis to detect these loci.
TL;DR: Patients with severe obstructive airway disease are at risk of fracture, and adequate adjustment for disease severity is essential when the association between the use of inhaled corticosteroids and risk of osteoporotic fracture is studied in observational research.
Abstract: The use of inhaled corticosteroids has been associated with a dose-related increased risk of fracture. This may be related to systemic absorption. However, several studies have found that patients with more severe reductions in pulmonary function had reduced bone mineral density, independent of inhaled corticosteroids. The objective of this study was to evaluate the relationship between disease severity and fracture risk. A large case-control study (108,754 cases) was conducted using data from the UK General Practice Research Database. It was found that higher doses of inhaled corticosteroids were associated with greater risks of fracture. The crude odds ratio of fracture among patients exposed to >1,600 microg beclomethasone equivalents per day was 1.95 (95% confidence interval (CI) 1.68-2.27). When adjustments were made for disease severity and use of bronchodilators, the initial dose-response relationship between inhaled corticosteroids and fracture risk disappeared (adjusted odds ratio of 1.19 (95% CI 1.01-1.41)). In conclusion, patients with severe obstructive airway disease are at risk of fracture. However, adequate adjustment for disease severity is essential when the association between the use of inhaled corticosteroids and risk of osteoporotic fracture is studied in observational research.
TL;DR: Evidence for fetal programming of body composition and musculoskeletal development comes from epidemiological studies, investigation of the role of early undernutrition and preliminary findings on underlying mechanisms.
TL;DR: A one-standard-deviation increase in birth weight reduced all-cause mortality risk by age 75 years by 0.86% for both men and women.
Abstract: Low birth weight, a marker of adverse intrauterine circumstances, is known to be associated with a range of disease outcomes in later life, including coronary heart disease, hypertension, type 2 diabetes, and osteoporosis. However, it may also decrease the risk of other common conditions, most notably neoplastic disease. The authors describe the associations between birth weight, infant weight gain, and a range of mortality outcomes in the Hertfordshire Cohort. This study included 37,615 men and women born in Hertfordshire, United Kingdom, in 1911-1939; 7,916 had died by the end of 1999. For men, lower birth weight was associated with increased risk of mortality from circulatory disease (hazard ratio per standard deviation decrease in birth weight = 1.08, 95% confidence interval: 1.04, 1.11) and from accidental falls but with decreased risk of mortality from cancer (hazard ratio per standard deviation decrease in birth weight = 0.94, 95% confidence interval: 0.90, 0.98). For women, lower birth weight was associated with a significantly (p < 0.05) increased risk of mortality from circulatory and musculoskeletal disease, pneumonia, injury, and diabetes. Overall, a one-standard-deviation increase in birth weight reduced all-cause mortality risk by age 75 years by 0.86% for both men and women.
TL;DR: The observation that constituents of maternal diet are related to DXA measures at age 9 is consistent with the hypothesis that the trajectory of bone development in childhood is programmed by early life factors.
Abstract: Evidence that birth weight is related to bone mass in later life suggests that the intrauterine environment programs the trajectory of subsequent bone development. To explore this hypothesis, we examined whether maternal diet in pregnancy, as assessed by the maternal food frequency questionnaire (FFQ) completed at 32 weeks gestation, is related to bone mass of the child, as measured by total body DXA carried out at age 9 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). Diet records were linked to DXA scan results for the total body and spine sub-region and pooled between pre- and early pubertal boys and girls ( n =4,451). Regression analysis was carried out between DXA values and dietary factors following adjustment for social and other confounding factors. Maternal magnesium intake was related to total body BMC (β=4.9, 7.4–23.1; g) and BMD (β=4.9, 2.5–7.3; g/cm2 ×103) (standardized regression coefficient with 95% confidence limits; P <0.001). An equivalent relationship was no longer observed after adjusting for the height of the child, to which magnesium intake was also related (β=0.48, 0.20–0.77; cm; P =0.001). Maternal intake of potassium was related to spinal BMC (β=1.8, 0.8–2.9; g) and BMD (β=10.5, 4.9–16.0; g/cm2 ×103) ( P =0.001), which was no longer observed after adjusting for the weight of the child, to which potassium intake was also related (β=0.52, 0.16–0.88, P =0.005; kg). A significant association was also observed between maternal dietary folate intake and spinal BMC adjusted for bone area using a linear regression model (β=0.55, 0.16–0.94; g; P =0.006), which persisted after adjusting for height and weight. Our observation that constituents of maternal diet are related to DXA measures at age 9 is consistent with the hypothesis that the trajectory of bone development in childhood is programmed by early life factors.
TL;DR: This article will review recent advances surrounding the epidemiology of osteoporosis, the burden of fracture in children and adults in this country and abroad, morbidity associated with such fractures, associations of disease and medication with fragility fracture, and advances in diagnostic techniques and identification of at-risk groups.
Abstract: Purpose of review: osteoporosis remains a major public health problem through its association with fragility fractures. Recent data suggest that the annual cost in Europe is 13 billion euros, mainly accounted for by hospitalisation after fracture. Understanding the epidemiology of osteoporosis is an essential step in developing strategies to reduce the burden of osteoporotic fracture in the population. Recent findings: this article will review recent advances surrounding the epidemiology of osteoporosis, the burden of fracture in children and adults in this country and abroad, morbidity associated with such fractures, associations of disease and medication with fragility fracture, and advances in diagnostic techniques and identification of at-risk groups. Summary: the papers studied highlight the wealth of high-quality research in this field, and they help in the visualisation of strategies to identify individuals at high risk of fragility fracture and to quantify fracture risk by measurement of bone density, bone quality, and risk factor algorithms
TL;DR: The optimization of maternal nutrition and intrauterine growth should also be included within preventive strategies against osteoporotic fracture, albeit for future generations.
Abstract: Osteoporosis is a major cause of morbidity and mortality through its association with age-related fractures. Although most efforts in fracture prevention have been directed at retarding the rate of age-related bone loss and reducing the frequency and the severity of trauma among elderly people, evidence is growing that peak bone mass is an important contributor to bone strength during later life. The normal patterns of skeletal growth have been well characterized in cross-sectional and longitudinal studies. It has been confirmed that boys have higher bone-mineral content, but not volumetric bone density, than girls. Furthermore, there is a disassociation between the peak velocities for height gain and bone mineral accrual in both genders. Puberty is the period during which volumetric density appears to increase in both axial and appendicular sites. Many factors influence the accumulation of bone mineral during childhood and adolescence, including heredity, gender, diet, physical activity, endocrine status, and sporadic risk factors (e.g., cigarette smoking). In addition to these modifiable factors during childhood, evidence has also accrued that fracture risk might be programmed during intrauterine life. Epidemiological studies have demonstrated a relationship between birthweight, weight in infancy, and adult bone mass. This appears to be mediated through modulation of the set-point for basal activity of endocrine systems such as the GH/IGF-1 and parathyroid hormone/vitamin D axes. Maternal vitamin D insufficiency is associated with reduced bone mineral acquisition during intrauterine and early postnatal life. Furthermore, both low birth size and poor childhood growth are directly linked to the later risk of hip fracture. The optimization of maternal nutrition and intrauterine growth should also be included within preventive strategies against osteoporotic fracture, albeit for future generations.
Journal Article•
TL;DR: In this paper, it has been shown that peak bone mass is an important contributor to bone strength during later life, and the optimal optimization of maternal nutrition and intrauterine growth should also be included within preventive strategies against osteoporotic fracture, albeit for future generations.
Abstract: Osteoporosis is a major cause of morbidity and mortality through its association with age-related fractures. Although most efforts in fracture prevention have been directed at retarding the rate of age-related bone loss and reducing the frequency and the severity of trauma among elderly people, evidence is growing that peak bone mass is an important contributor to bone strength during later life. The normal patterns of skeletal growth have been well characterized in cross-sectional and longitudinal studies. It has been confirmed that boys have higher bone-mineral content, but not volumetric bone density, than girls. Furthermore, there is a disassociation between the peak velocities for height gain and bone mineral accrual in both genders. Puberty is the period during which volumetric density appears to increase in both axial and appendicular sites. Many factors influence the accumulation of bone mineral during childhood and adolescence, including heredity, gender, diet, physical activity, endocrine status, and sporadic risk factors (e.g., cigarette smoking). In addition to these modifiable factors during childhood, evidence has also accrued that fracture risk might be programmed during intrauterine life. Epidemiological studies have demonstrated a relationship between birthweight, weight in infancy, and adult bone mass. This appears to be mediated through modulation of the set-point for basal activity of endocrine systems such as the GH/IGF-1 and parathyroid hormone/vitamin D axes. Maternal vitamin D insufficiency is associated with reduced bone mineral acquisition during intrauterine and early postnatal life. Furthermore, both low birth size and poor childhood growth are directly linked to the later risk of hip fracture. The optimization of maternal nutrition and intrauterine growth should also be included within preventive strategies against osteoporotic fracture, albeit for future generations.
TL;DR: Although many agents have been used in the treatment of osteoporosis, only in the past 10 years have large, double-blind placebo-controlled trials been published on postmenopausal women with the condition of using incident fractures as the primary endpoint.
Abstract: Although many agents have been used in the treatment of osteoporosis, only in the past 10 years have large, double-blind placebo-controlled trials been published on postmenopausal women with the condition of using incident fractures as the primary endpoint. Several agents have been proven to significantly decrease the risk of vertebral and, in some instances, long bone fractures [1]. Tables 1 and 2 show the anti-fracture efficacy of the most commonly used agents for which large fracture trials are available, i.e., the bisphosphonates alendronate and risedronate, the selective estrogen receptor modulator (SERM) raloxifene, the 1–34 fragment of recombinant human parathyroid hormone (teriparatide), and to some extent nasal calcitonin. These agents have consistently shown a substantial reduction of the risk of vertebral fracture ranging from 30–65% according to agent and patient populations. A significant reduction of the risk of nonvertebral fractures has been shown with alendronate and risedronate, ranging from 16–36% according to studies, and with teriparatide (53% reduction). Table 2 shows the effect of treatments on hip fracture risk in populations of decreasing risk from top to bottom. Indeed, hip fracture risk is highly dependent on age, and most studies performed in osteoporotic women younger than 75 years do not have the statistical power to demonstrate an effect of any agent on hip fracture incidence. A decrease in the risk of nonvertebral fractures, including hip, has been shown in the elderly, especially among institutionalized men and women treated with calcium and vitamin D supplementation [1]. That supplementation, however, cannot be considered a sufficient treatment of established osteoporosis, as it is included in the active treatment and placebo groups of most trials. Etidronate has been shown to decrease vertebral—but not nonvertebral—fracture risk, and it has been superseded by newer more potent bisphosphonates. Vitamin D metabolites and the vitamin K menatetrenone have been shown in some small studies to decrease the risk of fragility fractures, but the evidence is still limited [1]. Finally, anti-fracture efficacy has been recently shown with a new bisphosphonate, ibandronate [2] and with strontium ranelate [3], but these agents are not yet widely available. Despite these significant advances in the field of osteoporosis there is still uncertainty over the question of whom to treat. Healthcare agencies differ markedly in the indications for treatment so that authoritative guidance is needed. Following the operational definition of osteoporosis on the basis of bone mineral density measurements in 1994 [4], the International Osteoporosis Foundation (then the European Foundation for Osteoporosis) was one of the first organizations to give guidance on whom to treat [5]. The approach taken was that of a case-finding strategy, where prospective patients were identified on the basis of strong clinical risk factors for fracture. The risk factors included prolonged estrogen deficiency, exposure to gluccocorticoids and a prior fragility fracture, as well as some other risk factors associated with a marked increase in fracture risk independent of bone mineral density (BMD). It was proposed that patients with such risk factors be referred Osteoporos Int (2005) 16: 1–5 DOI 10.1007/s00198-004-1813-0
TL;DR: Urinary CTX-II and Glc-Gal-Pyd, but not systemic markers of bone turnover, are strongly associated with disease severity and the presence of OA at the tibiofemoral and patellofemoral joints in men.
Abstract: Objective: To investigate the association between biochemical markers of bone, cartilage, and synovial turnover with the presence and severity of knee osteoarthritis (OA) in men. Methods: 176 men aged 59–70 years from the MRC Hertfordshire Cohort were studied. Weightbearing anteroposterior and lateral semiflexed radiographs were taken of both knees. A lifestyle questionnaire including basic demographic details and a questionnaire detailing knee pain was completed. This random sample was stratified based on the Kellgren and Lawrence (K&L) score, and the following biochemical markers were analysed: serum osteocalcin, serum C-terminal crosslinked telopeptide of type I collagen (CTX-I), urinary C-terminal crosslinked telopeptide of type II collagen (CTX-II), and urinary glucosyl-galactosyl-pyridinoline (Glc-Gal-Pyd). Results: Age, body mass index (BMI), social class, smoking, and alcohol consumption were similar across K&L grades. Only one subject had a grade 4 K&L score, and was amalgamated with grade 3 subjects. A strong significant association was found between the presence of knee OA and urinary CTX-II and urinary Glc-Gal-Pyd (p = 0.0001 and p = 0.009), which persisted after adjustment for age and BMI. A significant positive association was also found between urinary CTX-II and urinary Glc-Gal-Pyd and the severity of K&L grade, joint space narrowing, and osteophytes scores, which persisted after adjustment for age and BMI. No associations between the presence and severity of knee OA were found for serum CTX-I or serum osteocalcin. Conclusions: Urinary CTX-II and Glc-Gal-Pyd, but not systemic markers of bone turnover, are strongly associated with disease severity and the presence of OA at the tibiofemoral and patellofemoral joints in men.
TL;DR: Evidence is provided that circulating endogenous glucocorticoids influence the rate of involutional bone loss in healthy individuals through the role of hypothalamic–pituitary–adrenal axis.
Abstract: Although excessive glucocorticoids are a well-recognized cause of osteoporosis, little is known about the role of endogenous glucocorticoids in determining skeletal mass. We have performed a detailed study of the hypothalamic–pituitary–adrenal (HPA) axis to explore the relationships between cortisol secretion and adult bone mass in 151 healthy men and 96 healthy women aged 61 to 73 years. At baseline and 4-year follow-up, bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) at the lumbar spine and proximal femur; a lifestyle questionnaire was completed; and height, weight, and waist and hip circumferences were measured. At follow-up subjects underwent a very low-dose (0.25 mg) dexamethasone suppression test, a low-dose (1 μg) short synacthen test, and a 24-hour urine collection for measurement of cortisol and its metabolites. In men, elevated peak plasma cortisol was associated with accelerated loss of mineral density in the lumbar spine (r = 0.16, P = 0.05). This relationship remained significant after adjustment for testosterone, estradiol, 25-hydroxyvitamin D, and parathyroid hormone levels (r = 0.22, P = 0.01) and after additional adjustment for age, (BM), activity, cigarette and alcohol consumption, and Kellgren/Lawrence score (r = 0.19, P = 0.03). In contrast in women, elevated peak plasma cortisol was associated with lower baseline BMD at the femoral neck (r = −0.23, P = 0.03) and greater femoral neck loss rate (r = 0.24, P = 0.02). There was no association between plasma cortisol concentrations after dexamethasone or urinary total cortisol metabolite excretion and bone density or bone loss rate at any site. These data provide evidence that circulating endogenous glucocorticoids influence the rate of involutional bone loss in healthy individuals.
TL;DR: Large numbers of individuals with a clinical diagnosis of RA identified from a large primary care database are not receiving DMARDs, suggesting that many individuals with RA have not been treated appropriately and this may have major long-term consequences on joint damage and general health.
Abstract: Objectives. To describe the use of disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis (RA) and changing trends in their use. Methods. We used the General Practice Research Database (GPRD) to describe DMARD use by patients with RA identified using ICD-9 codes. The GPRD is a UK national database containing records of more than 7 million individuals from 683 general practices. Subjects were studied between 1987 and 2002. The prevalence and duration of individual DMARD use and changing trends in DMARD use were investigated. Results. Thirty-four thousand three hundred and sixty-four patients with RA were identified. Only 17 115 (50%) individuals were prescribed at least one DMARD during the study period. The most commonly prescribed DMARD over the study period was sulphasalazine (46.3%) and then methotrexate (31.4%). Use of methotrexate has increased 17-fold (1.8% of all DMARD prescriptions in 1988 to 30% in 2002) whereas use of gold has fallen (13.2% to 2.3%). Analysis of DMARD persistence using Kaplan–Meier survival curves showed the methotrexate use persisted significantly longer than other DMARDs with an estimated median of 8.1 yr. Prednisolone was used in up to 50% of RA patients in any one year and has remained fairly constant throughout the study period. Conclusions. Large numbers of individuals with a clinical diagnosis of RA identified from a large primary care database are not receiving DMARDs. This work suggests that many individuals with RA have not been treated appropriately and this may have major long-term consequences on joint damage and general health.
TL;DR: It is concluded that umbilical venous leptin predicts both the size of the neonatal skeleton and its estimated volumetric mineral density.
Abstract: Evidence is accumulating that the risk of osteoporosis in later life may be determined in part by environmental influences on bone development during intrauterine and early postnatal life. A potential role for fetal leptin in mediating these effects is suggested by animal studies showing that leptin influences prenatal osteoblast growth and development, and that fetal leptin concentrations are altered by changes in maternal nutrition. In a group of term human infants we reported previously that maternal birthweight, smoking, fat mass, and exercise during late pregnancy independently predict neonatal bone mass. To investigate the potential role of leptin in mediating these effects, we now relate leptin concentrations in umbilical venous serum to neonatal bone mass and body composition in 117 infants. There were strong positive associations between umbilical venous leptin concentration and each of whole body bone mineral contents (BMC) (r = 0.42, P ≤ 0.001) and estimated volumetric bone density (r = 0.21, P = 0.02); whole body lean mass (r = 0.21, P ≤ 0.024); and whole body fat mass (r = 0.60, P < 0.001). The associations with neonatal BMC and fat mass, but not with lean mass, were independent of associations that we have reported previously between cord serum insulin-like growth factor 1 (IGF-1) concentrations and neonatal body composition. Among the maternal determinants of neonatal bone mass, cord leptin explained the relationship with maternal fat stores, but not those with the mother’s own birthweight, smoking, or physical activity. We conclude that umbilical venous leptin predicts both the size of the neonatal skeleton and its estimated volumetric mineral density. In addition, among previously documented maternal determinants of neonatal bone mass in healthy pregnancies, maternal fat stores may mediate their effect on fetal bone accrual through variation in fetal leptin concentrations.
TL;DR: It is shown that infant weight predicts femoral width and cross‐sectional moment of inertia but not femoral neck length, which supports the hypothesis that growth in early life leads to persisting differences in proximal femoral geometry.
Abstract: The relationship between early growth and adult femoral geometry has not been studied previously. In 333 adults, we were able to show that infant weight predicts femoral width and cross-sectional moment of inertia but not femoral neck length. These results support the hypothesis that growth in early life leads to persisting differences in proximal femoral geometry.
Introduction: Both femoral geometry and bone mass have been shown independently to predict both hip strength and fracture risk. Whereas growth during intrauterine and early postnatal life has been shown to influence adult bone mass, the relationship between growth in early life and adult femoral geometry has not been described previously.
Materials and Methods: We studied the relationship between growth during early life, adult hip geometry, and proximal femur bone mass in a sample of 333 men and women (60–75 years of age), for whom birth weight and weight at 1 year of age were recorded. Hip geometry was derived using Hip Structure Analysis software from proximal femur DXA scans (Hologic QDR 1000).
Results: There were significant (p < 0.002) relationships between weight at age 1 year and measures of femoral width as well as intertrochanteric (IT) cross-sectional moment of inertia (CSMI), but not with femoral neck length. The relationships with measures of femoral width but not CSMI remained after adjusting for adult body weight and were independent of proximal femoral BMC.
Conclusions: These results support the hypothesis that different patterns of growth in utero and during the first year of life lead to persisting differences in proximal femoral geometry, thereby mediating in part the effects of early growth on risk of hip fracture in adulthood.
Journal Article•
TL;DR: Both birthweight and polymorphisms in the VDR gene were associated with the presence of lumbar spine osteophytes and a significant interaction was observed between these 2 factors in men.
Abstract: OBJECTIVE: To investigate risk factors for adult lumbar spine osteoarthritis (OA) including polymorphisms of the vitamin D receptor gene (VDR) and birthweight. METHODS: Plain radiographs of the lumbar spine were taken in 392 healthy subjects and graded for osteophytes and disc space narrowing (DSN); demographic data were collected. Details of birthweight and weight at 1 year were retrieved from historical records. VDR gene allelic variation was analyzed in 291 subjects. RESULTS: The mean age of the cohort was 65.8 years; mean weight was 68.9 kg in women and 80.1 kg and men. Osteophytes of grade >/= 2 were found in 63.5% of this cohort; DSN >/= 2 was present in 14.3% of subjects. Increasing osteophyte severity was significantly associated with age, adult weight, and manual social class; DSN was not. Presence and severity of osteophytes were associated with low birthweight and lower weight at 1 year in men, but not in women. No associations were found for DSN. The B allele of the VDR gene was associated with increasing severity of osteophyte. There was a significant interaction between birthweight and VDR gene in determining risk of osteophytosis in men (p for interaction = 0.04). The VDR-birthweight interaction pattern was similar but not statistically significant in women. CONCLUSION: Lumbar spine OA was a prevalent finding in this cohort. Both birthweight and polymorphisms in the VDR gene were associated with the presence of lumbar spine osteophytes and a significant interaction was observed between these 2 factors in men.
TL;DR: The impact of 11β‐HSD1 activity on bone in vivo is measured by examining the association of circulating cortisone with bone markers, bone mineral density (BMD) and bone loss in a cohort of women and men.
Abstract: Objective: Cortisone is an endogenous corticosteroid that has negligible intrinsic glucocorticoid activity but can be converted to the active corticosteroid cortisol by the enzyme 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1). 11?-HSD1 is expressed in osteoblasts and may play a role in determining susceptibility to glucocorticoid-induced osteoporosis. In intact osteoblasts enzyme activity, and thus cortisol generation, is dependent on substrate concentration with an almost linear increase in activity across the physiological range. We have therefore attempted to measure the impact of 11?-HSD1 activity on bone in vivo by examining the association of circulating cortisone with bone markers, bone mineral density (BMD) and bone loss in a cohort of women and men. Design and subjects: Baseline cross-sectional association study involving 135 women and 171 men aged 61–73 years from the Hertfordshire Cohort Study and a 4 year follow-up study examining changes in BMD. Measurements: Serum cortisone, cortisol and osteocalcin, and urinary type I collagen cross-linked N-telopeptide (NTX) were measured at baseline. BMD at spine and hip was measured at baseline and 4 years later. Results: In men serum cortisone levels were negatively correlated with serum osteocalcin (r = ?0·20, P = 0·01); a similar relationship was seen in women (r = ?0·16, P = 0·06). No correlation was seen between serum cortisone and urinary NTX (r = 0·03, P = 0·74 for women; r = ?0·03, P = 0·72 for men). A negative correlation was observed between serum cortisone and spine BMD in women (r = ?0·18, P = 0·04); a similar relationship was also seen in men (r =?0·14, P = 0·07). However, cortisone did not correlate with BMD at the femoral neck or total hip or changes in BMD at any site over time. In analyses adjusted for adiposity, osteoarthritis grade and a range of life-style variables, these relationships did not change substantially. All these relationships were independent of cortisol concentrations. Conclusions: The most plausible explanation for the association of circulating cortisone levels with osteocalcin is the presence of 11?-HSD1 activity within osteoblasts. The measurement of serum cortisone may independently give insights into the action of glucocorticoids on bone.
TL;DR: The AGTR1 1166 CC genotype appears to predispose to favourable anthropometric and metabolic traits, relative to cardiovascular risk.
Abstract: Background: The renin angiotensin system is important in the regulation of vascular tone and fluid and electrolyte balance. The angiotensin converting enzyme gene (ACE) genotype has been shown to affect exercise response and glucose load response dependent on birth weight. Angiotensin II type I receptor (AGTR1) A1166C has previously been associated with the development of hypertension and coronary disease, but its metabolic effects have not been investigated.
Method: AGTR1 A1166C was genotyped by allele specific PCR in 378 individuals from Hertfordshire, UK, who had been characterised for metabolic syndrome traits.
Results: Genotype counts were: AA, 183; AC, 170; CC, 25, consistent with Hardy-Weinberg equilibrium. The CC genotype was associated with significantly lower body mass index (by 1.7 units) in men (p = 0.03), and the same magnitude effect in women with significant lower weight in both genders (p = 0.01), also lower waist circumference and waist-hip ratio (p = 0.01) in men, with a trend for lower waist circumference in women also. Additionally, the CC genotype and/or C allele was associated with lower fasting glucose and insulin, and 30 and 120 min glucose in men (respectively, p = 0.08, 0.04, 0.01, 0.06). Lower means of systolic blood pressure, pulse pressure, cholesterol, and fasting triglyceride were also observed for the CC genotype in both genders though these were not statistically significant.
Conclusions: The AGTR1 1166 CC genotype appears to predispose to favourable anthropometric and metabolic traits, relative to cardiovascular risk.
TL;DR: The data suggested, but could not confirm, hepatic resistance to GH as a mechanism for this association, men with reduced BMD have low IGF-I but normal GH secretion and reserve.