Opinder Sahota

Alendronate and Estrogen–Progestin in the Long-Term Prevention of Bone Loss: Four-Year Results from the Early Postmenopausal Intervention Cohort Study: A Randomized, Controlled Trial

Osteoporosis is a serious disease that develops slowly over many years and results in fractures and associated health care costs (1-3). Available treatments increase bone mineral density and reduce the risk for fractures but do not fully restore bone mass or microarchitecture (4). Alendronate, a bisphosphonate that inhibits bone resorption but not bone mineralization (5), prevents bone loss, increases bone mineral density (6-10), and reduces the incidence of fractures at the spine and hip by 30% to 50% in postmenopausal women with osteoporosis (7, 11, 12). Because alendronate prevents bone loss, it can be used as an alternative to estrogenprogestin in the prevention of postmenopausal osteoporosis (13, 14). The optimal length and regimen of alendronate treatment, however, have not yet been determined. Long-term treatment is probably needed to substantially affect bone mass and achieve lasting prevention of bone loss. However, clinical trials must be done to address the continuing efficacy and safety of agents used for prevention of osteoporosis, including alendronate. We compared the effects of 4 years of alendronate treatment or placebo on bone mass and bone turnover. We also evaluated the residual effects of alendronate after treatment was discontinued. A small comparison group of participants who received estrogenprogestin was included. Results of the first 2 years of the study were published elsewhere (13). Methods The Early Postmenopausal Intervention Cohort Study is a clinical trial of oral alendronate in 1609 postmenopausal women who were randomly assigned in a double-blind manner to receive alendronate, placebo, or open-label estrogenprogestin (13). Four study centers (two in the United States [Portland, Oregon, and Honolulu, Hawaii] and two in Europe [Nottingham, England, United Kingdom, and Copenhagen, Denmark]) are involved in this trial. Women in the alendronate groups received alendronate during the first 2 years of the study. Treatment was then continued without change or was discontinued and replaced with placebo for the last 2 years of the study (Table 1). All women treated with estrogenprogestin followed the same regimen for 4 years. The randomization schedule for the duration of the study was predetermined at baseline. The study was approved by the local ethics committees and institutional review boards. Table 1. Demographic Characteristics of the Study Sample at Year 2 and Distribution of Study Groups at Different Time Points Participants We selected healthy women 45 to 59 years of age who were at least 6 months past menopause at study entry. Bone mineral density at the spine at baseline was 0.8 g/cm2 or greater in approximately 90% of participants (13). Treatment Treatment was distributed across two strata. In stratum 1, women were assigned to receive 5 mg of oral alendronate per day, 2.5 mg of oral alendronate per day, placebo (Merck Research Laboratories, Rahway, New Jersey), or open-label estrogenprogestin. Dosages of alendronate were selected on the basis of results from previous dose-finding studies (10, 14). Prevention of bone loss or a slight increase in bone mineral density was the desired outcome. Participants in whom estrogenprogestin was contraindicated or unacceptable were enrolled in stratum 2, which did not include an estrogenprogestin group. In the United States, estrogenprogestin was given in a continuous combined regimen of conjugated equine estrogens, 0.625 mg/d (Premarin, Wyeth-Ayerst, Philadelphia, Pennsylvania), plus medroxyprogesterone acetate, 5 mg/d (Provera, Upjohn, Kalamazoo, Michigan). In Europe, estrogenprogestin was given in a cyclic combined regimen of micronized 17-estradiol, 2 mg/d, for 22 days; norethisterone acetate, 1 mg/d, on days 13 to 22; and estradiol, 1 mg/d, on days 23 to 28 (Trisequens, Novo Nordisk, Lyngby, Denmark). Dietary calcium intake was estimated at baseline and at annual visits (13). All women whose calcium intake was lower than that dictated by the local standard of care were advised to increase their intake by changing their diet or by taking supplements. Measurements of Bone Mineral Density and Biochemical Markers of Bone Turnover Bone mineral density was measured at baseline and annually thereafter (QDR-2000, Hologic, Waltham, Massachusetts) (13). Fasting blood and urine samples (second morning void) were collected every 6 months. Bone resorption and formation were estimated by using urine N-telopeptide cross-links of type I collagen (Osteomark, Ostex, Seattle, Washington) corrected for creatinine excretion and serum osteocalcin (Human Osteocalcin Kit, Nichols Institute, San Juan Capistrano, California), respectively. In addition, the serum level of bone-specific alkaline phosphatase (Ostase, Hybritech, San Diego, California) was measured at baseline and at months 12, 24, and 36 in a random sample of 550 women. Assessment of Treatment Safety Participants were clinically evaluated every 3 months (13). All unfavorable and unintended clinical events, including fractures and abnormal laboratory values, were considered to be adverse events and were evaluated for severity, duration, and probable causal relation to study drug and outcome. Statistical Analysis Bone mineral density was analyzed by using an intention-to-treat approach in the 1404 participants who received the same treatment for 4 years and had a baseline measurement and at least one follow-up measurement and in participants who switched from alendronate to placebo and had at least one measurement during years 3 and 4. No data from years 1 and 2 were included in later analyses of participants whose treatment did not remain constant during the study. Treatment effects were evaluated by using analysis of variance that included treatment, study center, stratum, and treatment-by-center interaction terms as factors. Interaction terms that were nonsignificant (P>0.10) or nonqualitative were removed from the model. Between-treatment comparisons of least-squares means (adjusted for stratum and study center) were performed by using analysis of variance. Within-group changes were evaluated by using the pairwise t-test to examine whether the mean percentage changes differed significantly from 0. In the groups that received alendronate for 4 years, the progressiveness of the response with an increasing dose of alendronate was assessed by using the stepwise Tukey trend test, adjusted for multiplicity. In addition, subgroup analyses were performed according to years since menopause (<3 years, 3 to 9 years, and 10 years) and baseline bone mineral density at the spine (in all women and in women with osteopenia). All statistical tests were two-sided. All between-group comparisons of placebo or alendronate and estrogenprogestin were performed within stratum 1. estrogenprogestin regimens differed in U.S. and European centers; therefore, estrogenprogestin and alendronate were compared separately in each group by location of study center (United States or Europe). For graphical presentation, data from the groups receiving 4 years of alendronate or 2 years of alendronate followed by 2 years of placebo were pooled by dose during the first 2 years of the study because they were similar with respect to effect of treatment on bone mineral density and biochemical markers until that time. In the groups that received alendronate followed by placebo, a stepwise multiple regression analysis was used to compare cumulative bone loss in years 3 and 4 (after withdrawal of alendronate) with bone loss in years 1 and 2 in the group that continuously received placebo. Treatment, study center, stratum, bone mineral density at year 2, age, years since menopause, and body mass index were covariates of interest, and the least significant difference interval method was used to compare rates of cumulative bone loss. Role of the Funding Source Employees of Merck & Co., Inc., participated in the study as co-investigators. After designing the study with the input of the other study investigators, these employees implemented the protocol and coordinated data collection and statistical analyses. They also contributed to the writing of this paper, but data interpretation and decisions about the content of the paper and submission for publication resided with the entire group of investigators. Results All study groups had similar demographic characteristics at baseline; however, women in the estrogenprogestin group had experienced menopause more recently (Table 1). By the end of year 4, the relative proportion across treatment groups of women who had continued to participate in the study was similar to that at baseline (Table 1). Eighty-five percent of participants were white, 10% were Oriental (persons of Chinese, Japanese, and Korean descent), 1.4% were Asian (persons of Indian and Philippine descent), and less than 1% were from other ethnic groups. Bone Mineral Density Groups That Received the Same Treatment for 4 Years In the placebo group, bone mineral density decreased at all skeletal sites (Figure 1, Table 2). Bone loss usually decreased as years since menopause increased. In contrast, 4 years of treatment with 5 mg of alendronate per day increased bone mineral density at the spine, hip, and total body and attenuated bone loss at the forearm (Figure 1, Table 2). Five mg of alendronate per day had a more pronounced effect on bone mineral density than did 2.5 mg of alendronate per day (P<0.01). In both alendronate groups, bone mineral density at the spine, hip, and total body increased or remained unchanged during years 3 and 4 compared with year 2. Figure 1. Mean percentage change (SE) from baseline in bone mineral density at the lumbar spine, total hip, total body, and one-third distal forearm. Table 2. Mean Percentage Change in Bone Mineral Density at Subregions of the Hip Compared with 4 years of treatment with 5 mg of alendronate per day, treatment with estrogen-medroxyprogesterone acetate resulted in greater increases in

Vitamin D insufficiency increases bone turnover markers and enhances bone loss at the hip in patients with established vertebral osteoporosis

The aim of this study was to determine whether the presence of vitamin D insufficiency increases bone turnover and enhances bone loss by examining the relationship between bone turnover markers and Bone mineral density (BMD) in vitamin D insufficient and vitamin D sufficient patients, with established vertebral osteoporosis.

Community falls prevention for people who call an emergency ambulance after a fall: randomised controlled trial

Objective To evaluate whether a service to prevent falls in the community would help reduce the rate of falls in older people who call an emergency ambulance when they fall but are not taken to hospital. Design Randomised controlled trial. Setting Community covered by four primary care trusts, England. Participants 204 adults aged more than 60 living at home or in residential care who had fallen and called an emergency ambulance but were not taken to hospital. Interventions Referral to community fall prevention services or standard medical and social care. Main outcome measures The primary outcome was the rate of falls over 12 months, ascertained from monthly diaries. Secondary outcomes were scores on the Barthel index, Nottingham extended activities of daily living scale, and falls efficacy scale at baseline and by postal questionnaire at 12 months. Analysis was by intention to treat. Results 102 people were allocated to each group. 99 (97%) participants in the intervention group received the intervention. Falls diaries were analysed for 88.6 person years in the intervention group and 84.5 person years in the control group. The incidence rates of falls per year were 3.46 in the intervention group and 7.68 in the control group (incidence rate ratio 0.45, 95% confidence interval 0.35 to 0.58, P<0.001). The intervention group achieved higher scores on the Barthel index and Nottingham extended activities of daily living and lower scores on the falls efficacy scale (all P<0.05) at the 12 month follow-up. The number of times an emergency ambulance was called because of a fall was significantly different during follow-up (incidence rate ratio 0.60, 95% confidence interval 0.40 to 0.92, P=0.018). Conclusion A service to prevent falls in the community reduced the fall rate and improved clinical outcome in the high risk group of older people who call an emergency ambulance after a fall but are not taken to hospital. Trial registration Current Controlled Trials ISRCTN67535605.

Nottingham Hip Fracture Score as a predictor of one year mortality in patients undergoing surgical repair of fractured neck of femur

BACKGROUND Surgical repair of hip fractures is associated with high postoperative mortality. The identification of high-risk patients might be of value in aiding clinical management decisions and resource allocation. The Nottingham Hip Fracture Score (NHFS) is a scoring system validated for the prediction of 30 day mortality after hip fracture surgery. It is made up of seven independent predictors of mortality that have been incorporated into a risk score: age (66-85 and ≥86 yr); sex (male); number of co-morbidities (≥2), admission mini-mental test score (≤6 out of 10), admission haemoglobin concentration (≤10 g dl(-1)), living in an institution; and the presence of malignancy. We investigated whether the NHFS was a predictor of 1 yr mortality in patients undergoing surgical repair of fractured neck of femur. METHODS NHFS was retrospectively calculated for 6202 patients who had undergone hip fracture surgery between 1999 and 2009. One year and 30 day postoperative mortality data were collected both from hospital statistics and the Office of National Statistics. RESULTS Overall mortality was 8.3% at 30 days and 29.3% at 1 yr. An NHFS of ≤4 was considered low risk and a score of ≥5 high risk. Survival was greater in the low-risk group at 30 days [96.5% vs 86.3% (P<0.001)] and at 1 yr [84.1% vs 54.5% (P<0.001)]. CONCLUSIONS NHFS can be used to stratify the risk of 1 yr mortality after hip fracture surgery.

A Comparison of the Longitudinal Changes in Quantitative Ultrasound with Dual-Energy X-ray Absorptiometry: The Four-Year Effects of Hormone Replacement Therapy

Abstract: Quantitative ultrasound (QUS) has been proposed as a tool which can measure both the quantitative and qualitative aspects of bone tissue and can predict the future risk of osteoporotic fractures. However, the usefulness of QUS in long-term monitoring has yet to be defined. We studied a group of early postmenopausal women over a 4-year period. Thirty subjects were allocated to hormone replacement therapy and 30 selected as controls matched for age, years past the menopause (YPM) and bone mineral density (BMD) at the anteroposterior spine (AP spine). The mean age of the subjects was 52.4 years (SD 3.9 years), mean YPM 4.0 years (SD 3.2) and all subjects had a BMD T-score above −2.5 SD (number of standard units related to the young normal mean population). BMD was measured at baseline and annually by dual-energy X-ray absorptiometry (DXA) at the AP spine and total hip, and QUS carried out at the calcaneus, measuring broadband ultrasound attenuation (BUA), speed of sound (SOS) and Stiffness. Mean percentage changes from baseline were assessed at 2 and 4 years. The overall treatment effect (defined as the difference in percentage change between the two groups) was: AP spine BMD, 11.4%; total hip BMD, 7.4%; BUA, 6.4%; SOS, 1.1%; and Stiffness, 10.4% (p<0.01). To compare the long-term precision of the two techniques we calculated the Standardized Precision, which for QUS was approximately 2–3 times that of DXA, for a given rate of change. The ability of each site to monitor response to treatment was assessed by calculating the Treatment Response Index (Treatment Effect/Standardized Precision), which was: AP spine BMD, 10.4; total hip BMD, 3.9; BUA, 3.1; SOS, 0.3; and Stiffness, 4.2. This was then normalized for AP spine BMD (to compare the role of QUS against the current standard, AP Spine BMD), which was: total hip BMD, 0.38; BUA, 0.30; Stiffness, 0.40 (p<0.01); and SOS, 0.03 (NS). In summary, QUS parameters in the early menopause showed a similar rate of decline as AP spine BMD and total hip BMD measured by DXA. Hormone replacement therapy results in bone gain at the AP spine and total hip, and prevents loss in BUA and SOS measured by QUS at the calcaneus. QUS has a potential role in long-term monitoring, although presently the time period to follow individual subjects remains 2–3 times that for DXA, for a given rate of change. Anteroposterior spine remains the current optimal DXA monitoring site due to its greater rate of change and better long-term precision.

Do calcium plus vitamin D supplements increase cardiovascular risk

Insufficient evidence is available to support or refute the association

A Comparison of Calcaneal Dual-Energy X-Ray Absorptiometry and Calcaneal Ultrasound for Predicting the Diagnosis of Osteoporosis From Hip and Spine Bone Densitometry

Peripheral densitometry is increasingly being used in the management of osteoporosis, but the optimal diagnostic thresholds have not been defined. The aim of this study was to determine the optimal T-score for peripheral dual-energy X-ray absorptiometry (pDXA) of the heel using a GE Lunar PIXI and quantitative ultrasound (QUS) of the heel using a GE Lunar Achilles Plus when compared with dual-energy X-ray absorptiometry (DXA) of central sites (spine, femoral neck, or total hip). Ninety-nine women (mean age 69 +/- 8, range 33-86 yr) referred from the metabolic bone clinic were studied. The optimal T-score for pDXA from ROC analysis was -1.7 and for QUS was -2.5. The pDXA T-score that defined the same prevalence of osteoporosis at any central site was also -1.7 and for QUS was -2.4. These results are similar to the manufacturers recommendations. There is no significant difference in performance between the PIXI and QUS.

The pathophysiology of fluid and electrolyte balance in the older adult surgical patient

BACKGROUND & AIMS Age-related physiological changes predispose even the healthy older adult to fluid and electrolyte abnormalities which can cause morbidity and mortality. The aim of this narrative review is to highlight key aspects of age-related pathophysiological changes that affect fluid and electrolyte balance in older adults and underpin their importance in the perioperative period. METHODS The Web of Science, MEDLINE, PubMed and Google Scholar databases were searched using key terms for relevant studies published in English on fluid balance in older adults during the 15 years preceding June 2013. Randomised controlled trials and large cohort studies were sought; other studies were used when these were not available. The bibliographies of extracted papers were also searched for relevant articles. RESULTS Older adults are susceptible to dehydration and electrolyte abnormalities, with causes ranging from physical disability restricting access to fluid intake to iatrogenic causes including polypharmacy and unmonitored diuretic usage. Renal senescence, as well as physical and mental decline, increase this susceptibility. Older adults are also predisposed to water retention and related electrolyte abnormalities, exacerbated at times of physiological stress. Positive fluid balance has been shown to be an independent risk factor for morbidity and mortality in critically ill patients with acute kidney injury. CONCLUSIONS Age-related pathophysiological changes in the handling of fluid and electrolytes make older adults undergoing surgery a high-risk group and an understanding of these changes will enable better management of fluid and electrolyte therapy in the older adult.

Hydration and outcome in older patients admitted to hospital (The HOOP prospective cohort study)

Background: older adults are susceptible to dehydration due to age-related pathophysiological changes. We aimed to investigate the prevalence of hyperosmolar dehydration (HD) in hospitalised older adults, aged ≥65 years, admitted as an emergency and to assess the impact on short-term and long-term outcome. Methods: this prospective cohort study was performed on older adult participants who were admitted acutely to a large UK teaching hospital. Data collected included the Charlson comorbidity index (CCI), national early warning score (NEWS), Canadian Study of Health and Aging (CSHA) clinical frailty scale and Nutrition Risk Screening Tool (NRS) 2002. Admission bloods were used to measure serum osmolality. HD was defined as serum osmolality >300 mOsmol/kg. Participants who were still in hospital 48 h after admission were reviewed, and the same measurements were repeated. Results: a total of 200 participants were recruited at admission to hospital, 37% of whom were dehydrated. Of those dehydrated, 62% were still dehydrated when reviewed at 48 h after admission. Overall, 7% of the participants died in hospital, 79% of whom were dehydrated at admission (P = 0.001). Cox regression analysis adjusted for age, gender, CCI, NEWS, CSHA and NRS demonstrated that participants dehydrated at admission were 6 times more likely to die in hospital than those euhydrated, hazards ratio (HR) 6.04 (1.64–22.25); P = 0.007. Conclusions: HD is common in hospitalised older adults and is associated with poor outcome. Coordinated efforts are necessary to develop comprehensive hydration assessment tools to implement and monitor a real change in culture and attitude towards hydration in hospitalised older adults.

A United Kingdom perspective on the relationship between body mass index (BMI) and bone health: A cross sectional analysis of data from the Nottingham Fracture Liaison Service

OBJECTIVES This study examines the relationship between high BMI, a diagnosis of osteoporosis and low trauma fractures. METHOD This is a cross sectional analysis using data collected from the Nottingham Fracture Liaison Service. A total of 4288 participants with a low trauma fracture from 1 January 2007 to 31 August 2012 were analysed. Logistic regression adjusted for potential confounders was used investigate osteoporosis and BMI. Fracture types were compared between those who were obese and non-obese. RESULTS A total of 30% (1285) were obese. Prevalence of osteoporosis was 13.4%, 24.9%, and 40.4% in the obese, overweight and normal category respectively. Being obese has an odds ratio of 0.23 (95% CI 0.19-0.28, p<0.01) of having osteoporosis compared to a normal BMI category. When variable BMI cut offs were used (BMI 25, 30 and 35) to calculate the positive predictive value of patients not having osteoporosis, it was 80.5%, 86.3% and 88.3%. Examining fracture types, obese patients when compared with the non-obese category, were more likely to fracture their ankle (OR 1.48, p<0.01) and upper arm (OR 1.48, p<0.001), but were less likely to fracture their wrist (OR 0.65, p<0.001). In the elderly (>70years), obesity no longer influenced ankle or wrist fractures but there is an increased risk of upper arm fractures (OR 1.46, p=0.005). CONCLUSION Higher BMD in obesity is not protective against fractures as there are a significant number of fractures in this group which may be due to body habitus, mechanism of injury and the effect of adiposity on bone. A low trauma osteoporotic fracture will need to be redefined in light of these findings.