History of etidronate.

Etidronate is a non-nitrogen-containing bisphosphonate. Because it binds with calcium and inhibits crystal formation and dissolution, it was considered by Procter & Gamble as an additive to toothpaste (to prevent build-up of tartar) and detergent (to bind calcium and increase sudsing in "hard" water). The first clinical use (1968) was for fibrodysplasia ossificans progressiva. The first approved clinical use (1977) was for treatment of Paget's disease of bone. Other approved indications are hypercalcemia of malignancy and heterotopic ossification, with a host of off-label uses (including fibrous dysplasia, periodontal disease, multiple myeloma, neuropathic arthropathy, pulmonary microlithiasis, diabetic retinopathy, bone metastases, melorheostosis, urinary stone disease, periodontal disease, etc.). Unique among bisphosphonates, etidronate (oral therapy) results in hyperphosphatemia, increased tubular reabsorption of phosphorus and increased levels of 1,25-dihydroxyvitamin D. The dose that reduces bone resorption is close to the dose that impairs mineralization; prolonged high-dose use can result in osteomalacia and bone fractures. Intermittent cyclic etidronate for osteoporosis resulted in favorable changes in bone density and histomorphometry (no mineralization defect) as well as a decrease in vertebral fracture rates in postmenopausal women with osteoporosis. Later studies showed similar effects in men with osteoporosis and patients with glucocorticoid-induced osteoporosis. Although its use for osteoporosis has given way to newer bisphosphonates and other agents, because of its unique properties, it remains the bisphosphonate of choice for treatment of heterotopic ossification.

Insights into the epidemiology of postmenopausal osteoporosis: the Women's Health Initiative.

Osteoporosis and its associated increased risk for fragility fracture is one of the most disabling consequences of aging in women. To successfully reduce the public health burden of this pervasive disease, it is necessary to develop strategies that permit the earlier identification of women at risk for fracture and ensure that preventive interventions to reduce the risk for fracture are both safe and effective. The Women's Health Initiative offers the unprecedented opportunity to systematically address both of these issues. Eleven clinically available risk factors (age, race/ethnicity, self-reported health, weight, height, physical activity, parental hip fracture, fracture history after age 54, current smoking, corticosteroid use, and history of treated diabetes), have been identified to predict 5-year hip fracture risk in white women. Two of these factors (age and fracture history) also predict risk for total fractures in women irrespective of race-ethnicity. Biomarkers including low vitamin D or bioavailable testosterone and/or high cystatin C, pro-inflammatory cytokines, osteoprotegerin and sex hormone-binding globulin also predict risk for hip fracture independent of clinical risk factors. Two cornerstones of therapy for postmenopausal osteoporosis-postmenopausal hormone therapy and calcium plus vitamin D supplementation- were rigorously studied. Estrogen with or without a progestin was effective at preventing bone loss and reducing risk for hip, clinical vertebral and total fractures but the balance of risks and benefits failed to show an overall benefit of taking estrogen-alone or estrogen plus progestin as a preventive strategy for skeletal health. Calcium plus vitamin D supplementation also demonstrated a small but significant favorable effect on hip bone density but in contrast, the modest effect did not translate into a significant reduction in the risk of fractures in intent-to-treat analyses. Data such as these have helped to lay a foundation for the more effective management of postmenopausal osteoporosis.

Significance of preradiographic magnetic resonance imaging lesions in persons at increased risk of knee osteoarthritis.

OBJECTIVE: Little is known about early knee osteoarthritis (OA). The significance of lesions on magnetic resonance imaging (MRI) in older persons without radiographic OA is unclear. Our objectives were to determine the extent of tissue pathology by MRI and evaluate its significance by testing the following hypotheses: cartilage damage, bone marrow lesions, and meniscal damage are associated with prevalent frequent knee symptoms and incident persistent symptoms; bone marrow lesions and meniscal damage are associated with incident tibiofemoral (TF) cartilage damage; and bone marrow lesions are associated with incident patellofemoral (PF) cartilage damage. METHODS: In a cohort study of 849 Osteoarthritis Initiative (OAI) participants who had a bilateral Kellgren/Lawrence (K/L) score of 0, we assessed cartilage damage, bone marrow lesions, and meniscal damage using the MRI OA Knee Score, as well as prevalent frequent knee symptoms, incident persistent symptoms, and incident cartilage damage. Multiple logistic regression (one knee per person) was used to evaluate associations between MRI lesions and each of these outcomes. RESULTS: Of the participants evaluated, 76% had cartilage damage, 61% had bone marrow lesions, 21% had meniscal tears, and 14% had meniscal extrusion. Cartilage damage (any; TF and PF), bone marrow lesions (any; TF and PF), meniscal extrusion, and body mass index (BMI) were associated with prevalent frequent symptoms. Cartilage damage (isolated PF; TF and PF), bone marrow lesions (any; isolated PF; TF and PF), meniscal tears, and BMI were associated with incident persistent symptoms. Hand OA, but no individual lesion type, was associated with incident TF cartilage damage, and bone marrow lesions (any; any PF) with incident PF damage. Having more lesion types was associated with a greater risk of outcomes. CONCLUSION: MRI-detected lesions are not incidental and may represent early disease in persons at increased risk of knee OA.

Relation of physical activity time to incident disability in community dwelling adults with or at risk of knee arthritis: prospective cohort study.

OBJECTIVE: To investigate whether objectively measured time spent in light intensity physical activity is related to incident disability and to disability progression. DESIGN: Prospective multisite cohort study from September 2008 to December 2012. SETTING: Baltimore, Maryland; Columbus, Ohio; Pittsburgh, Pennsylvania; and Pawtucket, Rhode Island, USA. PARTICIPANTS: Disability onset cohort of 1680 community dwelling adults aged 49 years or older with knee osteoarthritis or risk factors for knee osteoarthritis; the disability progression cohort included 1814 adults. MAIN OUTCOME MEASURES: Physical activity was measured by accelerometer monitoring. Disability was ascertained from limitations in instrumental and basic activities of daily living at baseline and two years. The primary outcome was incident disability. The secondary outcome was progression of disability defined by a more severe level (no limitations, limitations to instrumental activities only, 1-2 basic activities, or ≥3 basic activities) at two years compared with baseline. RESULTS: Greater time spent in light intensity activities had a significant inverse association with incident disability. Less incident disability and less disability progression were each significantly related to increasing quartile categories of daily time spent in light intensity physical activities (hazard ratios for disability onset 1.00, 0.62, 0.47, and 0.58, P for trend=0.007; hazard ratios for progression 1.00, 0.59, 0.50, and 0.53, P for trend=0.003) with control for socioeconomic factors (age, sex, race/ethnicity, education, income) and health factors (comorbidities, depressive symptoms, obesity, smoking, lower extremity pain and function, and knee assessments: osteoarthritis severity, pain, symptoms, prior injury). This finding was independent of time spent in moderate-vigorous activities. CONCLUSION: These prospective data showed an association between greater daily time spent in light intensity physical activities and reduced risk of onset and progression of disability in adults with osteoarthritis of the knee or risk factors for knee osteoarthritis. An increase in daily physical activity time may reduce the risk of disability, even if the intensity of that additional activity is not increased.

Prestroke factors associated with poststroke mortality and recovery in older women in the Women's Health Initiative.

OBJECTIVES: To examine prestroke lifestyle factors associated with poststroke mortality and recovery in older women. DESIGN: Longitudinal prospective cohort study. SETTING: The Women's Health Initiative (WHI, clinical trials and observational study), 40 clinical centers in the United States. PARTICIPANTS: WHI participants, women aged 50 to 79, who were stroke-free at baseline (1993/98), with incident stroke before 2005. MEASUREMENTS: Participants were followed for mortality through 2010. Prestroke characteristics were from the last examination before the stroke event. Annual follow-up for clinical events ascertained hospitalization for stroke that was subsequently physician adjudicated with medical records. Multivariable regression models were used to analyze factors associated with poststroke mortality and poststroke recovery at hospital discharge (poststroke Glasgow score), adjusting for stroke type. RESULTS: Of 3,173 women with incident stroke, 1,111 (35%) died. Individuals who were overweight or obese before stroke had lower poststroke mortality than those who were normal weight (obese: hazard ratio (HR) = 0.69, 95% confidence interval (CI) = 0.53-0.88; overweight: HR = 0.72, 95% CI = 0.58-0.90); individuals who were underweight before stroke had nonsignificantly greater poststroke mortality (HR = 2.02, 95% CI = 0.98-4.16, P = .06). Other prestroke factors associated with poststroke mortality included diabetes mellitus (HR = 1.28, 95% CI = 1.01-1.64), current smoking (vs nonsmoker, HR = 2.13, 95% CI = 1.53-3.00), physical inactivity (vs >150 min of exercise per week, HR = 1.39, 95% CI = 1.09-1.78), and lowest physical function quartile (vs highest, HR = 1.54, 95% CI = 1.18-2.02). Prestroke diabetes mellitus was associated with lower odds of good recovery after stroke (odds ratio (OR) = 0.60, 95% CI = 0.44-0.82). Current hormone use before stroke was associated with greater odds of moderate than of severe disability after stroke (OR = 1.29, 95% CI = 1.00-1.66). CONCLUSION: Potentially modifiable factors before stroke, including smoking, diabetes mellitus, and being underweight, were associated with greater poststroke mortality in older women. Being overweight or obese and physical activity before stroke were associated with lower poststroke mortality in older women.

Obesity and other modifiable factors for physical inactivity measured by accelerometer in adults with knee osteoarthritis.

OBJECTIVE: To investigate the public health impact of obesity and other modifiable risk factors related to physical inactivity in adults with knee osteoarthritis (OA). METHODS: The frequency of inactivity as defined by the US Department of Health and Human Services was assessed from objective accelerometer monitoring of 1,089 participants (ages 49-84 years) with radiographic knee OA during the Osteoarthritis Initiative 48-month visit (2008-2010). The relationship between modifiable factors (weight status, dietary fat, fiber, smoking, depressive symptoms, knee function, knee pain, and knee confidence) with inactivity was assessed using odds ratios (ORs) and attributable fractions (AFs), controlling for descriptive factors (age, sex, race, education, lives alone, employment, frequent knee symptoms, and comorbidity). RESULTS: Almost half (48.9%) of participants with knee OA were inactive. Being overweight (OR 1.8, 95% confidence interval [95% CI] 1.2-2.5) or obese (OR 3.9, 95% CI 2.6-5.7), having inadequate dietary fiber intake (OR 1.6, 95% CI 1.2-2.2), severe knee dysfunction (OR 1.9, 95% CI 1.3-2.8), and severe pain (OR 1.7, 95% CI 1.1-2.5) were significantly related to inactivity, controlling for descriptive factors. Modifiable factors with significant average AFs were being overweight or obese (AF 23.8%, 95% CI 10.5-38.6%) and inadequate dietary fiber (AF 12.1%, 95% CI 0.1-24.5%), controlling for all factors. CONCLUSION: Being obese or overweight, the quality of the diet, severe pain, and severe dysfunction are significantly associated with physical inactivity in adults with knee OA. All components should be considered in designing physical activity interventions that target arthritis populations with low activity levels.

Application of machine learning methods to describe the effects of conjugated equine estrogens therapy on region-specific brain volumes.

Use of conjugated equine estrogens (CEE) has been linked to smaller regional brain volumes in women aged ≥65 years; however, it is unknown whether this results in a broad-based characteristic pattern of effects. Structural magnetic resonance imaging was used to assess regional volumes of normal tissue and ischemic lesions among 513 women who had been enrolled in a randomized clinical trial of CEE therapy for an average of 6.6 years, beginning at ages 65-80 years. A multivariate pattern analysis, based on a machine learning technique that combined Random Forest and logistic regression with L(1) penalty, was applied to identify patterns among regional volumes associated with therapy and whether patterns discriminate between treatment groups. The multivariate pattern analysis detected smaller regional volumes of normal tissue within the limbic and temporal lobes among women that had been assigned to CEE therapy. Mean decrements ranged as high as 7% in the left entorhinal cortex and 5% in the left perirhinal cortex, which exceeded the effect sizes reported previously in frontal lobe and hippocampus. Overall accuracy of classification based on these patterns, however, was projected to be only 54.5%. Prescription of CEE therapy for an average of 6.6 years is associated with lower regional brain volumes, but it does not induce a characteristic spatial pattern of changes in brain volumes of sufficient magnitude to discriminate users and nonusers.

Low-fat dietary pattern and risk of cardiovascular disease: the Women's Health Initiative Randomized Controlled Dietary Modification Trial.

CONTEXT: Multiple epidemiologic studies and some trials have linked diet with cardiovascular disease (CVD) prevention, but long-term intervention data are needed. OBJECTIVE: To test the hypothesis that a dietary intervention, intended to be low in fat and high in vegetables, fruits, and grains to reduce cancer, would reduce CVD risk. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of 48,835 postmenopausal women aged 50 to 79 years, of diverse backgrounds and ethnicities, who participated in the Women's Health Initiative Dietary Modification Trial. Women were randomly assigned to an intervention (19,541 [40%]) or comparison group (29,294 [60%]) in a free-living setting. Study enrollment occurred between 1993 and 1998 in 40 US clinical centers; mean follow-up in this analysis was 8.1 years. INTERVENTION: Intensive behavior modification in group and individual sessions designed to reduce total fat intake to 20% of calories and increase intakes of vegetables/fruits to 5 servings/d and grains to at least 6 servings/d. The comparison group received diet-related education materials. MAIN OUTCOME MEASURES: Fatal and nonfatal coronary heart disease (CHD), fatal and nonfatal stroke, and CVD (composite of CHD and stroke). RESULTS: By year 6, mean fat intake decreased by 8.2% of energy intake in the intervention vs the comparison group, with small decreases in saturated (2.9%), monounsaturated (3.3%), and polyunsaturated (1.5%) fat; increases occurred in intakes of vegetables/fruits (1.1 servings/d) and grains (0.5 serving/d). Low-density lipoprotein cholesterol levels, diastolic blood pressure, and factor VIIc levels were significantly reduced by 3.55 mg/dL, 0.31 mm Hg, and 4.29%, respectively; levels of high-density lipoprotein cholesterol, triglycerides, glucose, and insulin did not significantly differ in the intervention vs comparison groups. The numbers who developed CHD, stroke, and CVD (annualized incidence rates) were 1000 (0.63%), 434 (0.28%), and 1357 (0.86%) in the intervention and 1549 (0.65%), 642 (0.27%), and 2088 (0.88%) in the comparison group. The diet had no significant effects on incidence of CHD (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.90-1.06), stroke (HR, 1.02; 95% CI, 0.90-1.15), or CVD (HR, 0.98; 95% CI, 0.92-1.05). Excluding participants with baseline CVD (3.4%), the HRs (95% CIs) for CHD and stroke were 0.94 (0.86-1.02) and 1.02 (0.90-1.17), respectively. Trends toward greater reductions in CHD risk were observed in those with lower intakes of saturated fat or trans fat or higher intakes of vegetables/fruits. CONCLUSIONS: Over a mean of 8.1 years, a dietary intervention that reduced total fat intake and increased intakes of vegetables, fruits, and grains did not significantly reduce the risk of CHD, stroke, or CVD in postmenopausal women and achieved only modest effects on CVD risk factors, suggesting that more focused diet and lifestyle interventions may be needed to improve risk factors and reduce CVD risk. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT00000611.

Early identification of mild traumatic brain injury in female victims of domestic violence.

BACKGROUND: Domestic violence and traumatic brain injuries (TBIs) are major societal problems with public health implications. The inter-relationship between this specific form of violence and TBI has not been explored. However, a clinically relevant relationship is suggested by recent outcome data showing that TBI survivors who are victims of assault are more prone to a suboptimal outcome. METHODS: This observational study screened women who presented to 3 metropolitan emergency departments for health issues associated with domestic violence for a possible secondary mild TBI. RESULTS: Over a 7- to 9-month survey period, a total of 169 women with health issues directly attributable to domestic violence and who were referred to sexual assault-domestic violence health staff were identified. Thirty percent (n = 51) agreed to participate in this survey. A positive loss of consciousness on at least one occasion was reported in 30% of the respondents, and 67% of women reported residual problems that were potentially head-injury related. CONCLUSION: These data argue for greater vigilance in screening domestic violence victims for mild TBI because earlier identification and treatment of any postconcussive syndrome symptoms seems to diminish their adverse impact on outcome.

Early recognition of neuroleptic malignant syndrome during traumatic brain injury rehabilitation.

Neuroleptic malignant syndrome is a rare disorder that manifests with hyperthermia, muscle rigidity and autonomic instability. Presented is a case series of individuals with traumatic brain injury and agitation who, when treated with neuroleptics, developed neuroleptic malignant syndrome. Although the incidence of this syndrome is rare, it is associated with significant morbidity and mortality. The onset of symptoms inconsistent with the patient's current level of recovery should alert the clinician to consider other possible diagnosis and failure to distinguish the features of neuroleptic malignant syndrome from post-traumatic agitation will delay appropriate intervention for this potentially life-threatening disorder.

Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial.

CONTEXT: The Women's Health Initiative (WHI) trial of estrogen plus progestin was stopped early because of adverse effects, including an increased risk of stroke in the estrogen plus progestin group. OBJECTIVE: To assess the effect of estrogen plus progestin on ischemic and hemorrhagic stroke and in subgroups, and to determine whether the effect of estrogen plus progestin was modified by baseline levels of blood biomarkers. DESIGN: Multicenter double-blind, placebo-controlled, randomized clinical trial involving 16 608 women aged 50 through 79 years with an average follow-up of 5.6 years. Baseline levels of blood-based markers of inflammation, thrombosis, and lipid levels were measured in the first 140 centrally confirmed stroke cases and 513 controls. INTERVENTIONS: Participants received 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate (n = 8506) or placebo (n = 8102). MAIN OUTCOME MEASURES: Overall strokes and stroke subtype and severity were centrally adjudicated by stroke neurologists. RESULTS: One hundred fifty-one patients (1.8%) in the estrogen plus progestin and 107 (1.3%) in the placebo groups had strokes. Overall 79.8% of strokes were ischemic. For combined ischemic and hemorrhagic strokes, the intention-to-treat hazard ratio (HR) for estrogen plus progestin vs placebo was 1.31 (95% confidence interval [CI], 1.02-1.68); with adjustment for adherence, the HR was 1.50 (95% CI, 1.08-2.08). The HR for ischemic stroke was 1.44 (95% CI, 1.09-1.90) and for hemorrhagic stroke, 0.82 (95% CI, 0.43-1.56). Point estimates of the HRs indicate that excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin. Other risk factors for stroke, including smoking, blood pressure, diabetes, lower use of vitamin C supplements, blood-based biomarkers of inflammation, higher white blood cell count, and higher hematocrit levels did not modify the effect of estrogen plus progestin on stroke risk. CONCLUSIONS: Estrogen plus progestin increases the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to estrogen plus progestin appeared to be present in all subgroups of women examined.