Joan McGowan

Bisphosphonate-Associated Osteonecrosis of the Jaw: Report of a Task Force of the American Society for Bone and Mineral Research

ONJ has been increasingly suspected to be a potential complication of bisphosphonate therapy in recent years. Thus, the ASBMR leadership appointed a multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder. This report summarizes the findings and recommendations of the task force.

Statin Use, Clinical Fracture, and Bone Density in Postmenopausal Women: Results from the Women's Health Initiative Observational Study

Context Some observational studies have shown fewer fractures in patients receiving statins, but other studies have shown no effect. The studies have been small and had limited ability to adjust for potential confounders. Contribution In this subanalysis of the Womens Health Initiative, postmenopausal women had similar rates of hip, lower arm or wrist, and other fractures whether or not they used statins. The authors adjusted for many potential confounders, and the estimates of fracture rates were very precise. Implications Statins do not seem to prevent fractures in postmenopausal women. The Editors The long-term efficacy and safety of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been established in large multicenter trials of cholesterol-lowering for preventing coronary events in both sexes (1-4). Recent laboratory studies have shown that statins stimulate bone formation in cultured osteoblasts, neonatal murine calvaria, and the cortical bone of mice (5). Statins administered orally increased the trabecular bone volume of female rats by 90%. These findings raise the possibility that statin treatment might prevent both coronary and fracture events, two major causes of morbidity in older women, later in life. Early epidemiologic studies examining the association of statin use with risk for hip fracture produced encouraging results (6-9). These studies were limited, however, by either small numbers of fractures (6) or lack of data on important potential confounders (7-9). More recent studies had mixed results (10-12), with some showing no association (11, 12). Few studies have examined associations with both fracture rates and bone density in the same study group. Therefore, we examined the association of statin use with levels of bone density and rates of hip, lower arm or wrist, and other clinical fractures in the Womens Health Initiative (WHI) Observational Study cohort of postmenopausal women. Methods Study Group The study group for this paper is the WHI Observational Study, a prospective cohort study that enrolled 93 716 women ages 50 to 79 years from 1994 to 1998 at 40 clinical centers throughout the United States. Study methods have been described in detail elsewhere (13). Briefly, women were eligible if they were postmenopausal, were unlikely to relocate or die within 3 years, were not enrolled in the WHI Clinical Trial, and were not participating in any other clinical trial. At baseline, women completed screening and enrollment questionnaires by interview and self-report, physical examination, and blood specimen collection. Human subjects review committees at each participating institution reviewed and approved the study. Follow-up and Outcome Ascertainment Women are sent questionnaires annually to report any hospitalization and a wide variety of outcomes, including clinical fractures of any type. Follow-up time ranged from 2 to 6 years per participant as of February 2001 (median duration, 3.9 years). At that time, 2.8% of participants (n = 2632) had withdrawn or were lost to follow-up [2.7% of statin users and 2.8% of nonusers]. Hip fractures are confirmed by central review of radiology reports. Other fractures are counted on the basis of self-report. Nonetheless, in the WHI Clinical Trial, in which all fractures are adjudicated, 81% of self-reported nonhip clinical fractures are confirmed by physician review of medical records, suggesting that the self-report of such fractures is reasonably accurate. For this report, we classified fractures into three mutually exclusive categories: 1) hip fractures, 2) lower arm or wrist fractures, and 3) other clinical fractures. Clinically recognized vertebral fractures were classified as other clinical fractures. Bone mineral density at the total hip, posterioranterior spine, and total body was measured at baseline in three clinical centers among 6442 women (97% of participants enrolled in Pittsburgh, Pennsylvania; Birmingham, Alabama; and Phoenix and Tucson, Arizona) with dual-energy x-ray absorptiometry using a Hologic QDR densitometer (Hologic, Inc., Waltham, Massachusetts). Standard protocols for positioning and analysis were used by technicians who were trained and certified by the University of California, San Francisco, Bone Density Coordinating Center, San Francisco, California. The ongoing quality assurance program includes monitoring spine and hip phantom scans; reviewing a random sample of all scans and flagging scans with specific problems; hardware or software change control, including in vitro and in vivo cross-calibration; and scanning calibration phantoms across instruments and clinical sites. Statin Exposure and Potential Confounders Participants were asked to bring all current prescription medications to their first screening interview. Clinic interviewers entered each medication name directly from the containers into the WHI database, which assigned drug codes using Medispan software (First DataBank, Inc., San Bruno, California). Women reported duration of use for each current medication. Information on dose was not recorded. Current medication use was ascertained by using identical methods at the year 3 clinic visit. Current statin medication use was defined as use of any HMG-CoA reductase inhibitor. Duration of use was examined in three categories (<1 year, 1 to 3 years, or >3 years). Statin medications were further categorized into three groups according to their demonstrated potency for lipid-lowering on the basis of a dose-efficacy trial (14): low potency (fluvastatin and lovastatin), medium potency (pravastatin), and high potency (atorvastatin, simvastatin). Other lipid-lowering medications were fibrate, colestipol, probucol, cholestyramine, niacin, or nicotinic acid. All covariates were ascertained at baseline. Current use of thiazide diuretics, alendronate, corticosteroid, and sedative or hypnotic medications was recorded by using the same procedures described. Current and previous use of hormone replacement therapy was ascertained by interview using a detailed questionnaire that measured type, route of administration, number of pills per day or week, and duration for each hormonal preparation ever taken. For the purposes of this report, hormone replacement therapy was defined as current use of any estrogen with or without progestin. Dietary supplements, including calcium preparations, taken at least twice weekly for the past 2 weeks were also entered into the database. Dietary intake of calcium was measured by using a semi-quantitative food-frequency questionnaire (15). Total calcium intake was defined as the sum of calcium from diet and supplements. Baseline questionnaires ascertained information on race or ethnicity, history of fracture or coronary heart disease (history of myocardial infarction or angina), current and past smoking, coffee consumption (cups per day), and time spent walking outside the home for more than 10 minutes without stopping (minutes per week). Alcohol consumption was estimated from the food-frequency questionnaire. Physical function was measured by using the 10-item Medical Outcomes Study scale (16). Weight was measured to the nearest 0.1 kg on a balance-beam scale with the participant dressed in indoor clothing without shoes. Height was measured to the nearest 0.1 cm by using a wall-mounted stadiometer. Body mass index was calculated as weight in kg/height in m2. Statistical Analysis The characteristics of women taking a statin medication at baseline were compared with those of women not taking statin medication by using chi-square tests to determine the statistical significance of the differences. Age-adjusted incidence rates of hip, lower arm or wrist, and other clinical fractures per 1000 person-years were calculated according to duration of statin use by the direct method, using the age distribution of the full cohort as the standard population. Women contributed follow-up time until the occurrence of fracture, death, or the end of follow-up, whichever came first. The a priori analysis plan specified selected stratified analyses to determine whether associations between statin use and fracture were apparent in key subgroups of women. For these analyses, women were stratified according to age group (50 to 64 years versus 65 years), current hormone replacement therapy use, body mass index (<25 kg/m2 versus 25 kg/m2, the standard threshold for overweight) (17), history of fracture, and history of coronary disease. Hazard ratios adjusted for age and corresponding 95% CIs were calculated by using Cox proportional-hazards survival models for each fracture category using PHREG in SAS software, version 8.2 (SAS Institute, Inc., Cary, North Carolina). To control for potential confounding factors, hazard ratios and corresponding 95% CIs for categories of duration and potency of statin use were calculated by using multivariate Cox proportional-hazards survival models, using the forced entry approach for variable selection. The multivariate models adjusted for age; race or ethnicity; body mass index; previous fracture; previous coronary disease; current and past hormone replacement therapy use; thiazide, alendronate, corticosteroid, or psychoactive drug use; calcium intake; walking; current and past smoking; coffee intake; and physical function. The multivariate models included individual clinical center as a stratification (or blocking) variable to allow the underlying hazard to be estimated separately for each clinical center. Interaction by clinical center was evaluated by comparing log likelihood statistics (chi-squares) for a model with interaction terms for each clinical center and a reduced model without these terms. Tests for the proportional hazards assumption were conducted by examining plots of the baseline hazard by statin duration categories and by testing interaction terms of statin use by time. Multivariate models were based on 81 896 individuals after exclusion

The women's health initiative calcium–vitamin D trial: overview and baseline characteristics of participants

Osteoporosis is a major public health issue leading to significant morbidity, loss of independence and excess loss of life. It has been estimated that 13 to 17 million postmenopausal women have low bone mass or osteoporosis (1, 2). This is associated with almost 1.5 million fractures annually, including 300,000 hip fractures (2, 3). A review of the evidence by Cumming in 1990 (4) and subsequently published randomized clinical trials have shown that calcium and/or vitamin D supplements may play a role in the prevention and treatment of osteoporosis by slowing the rates of bone loss in postmenopausal and elderly women (5–9). However, there are a limited number of calcium and/or vitamin D trials (10–13) and observational studies [review of evidence by Cumming and Nevitt (14) and Kanis (15)], to support a role for calcium and vitamin D supplementation in the reduction of hip and other fractures. It has also been suggested that calcium and vitamin D supplementation may play a role in the reduction of colorectal cancer incidence (16–21). To address these major health concerns of postmenopausal women, the Calcium-Vitamin D (CaD) trial of the Women’s Health Initiative (WHI) was designed to test the primary hypothesis that women who are randomized to receive calcium and vitamin D supplementation will have a lower risk of hip fracture and secondarily, a lower risk of all fractures and colorectal cancer than women receiving corresponding placebo. The objective of this paper is to

Arthritis Increases the Risk for Fractures---Results from the Women’s Health Initiative

Objective. To examine the relationship between arthritis and fracture. Methods. Women were classified into 3 self-reported groups at baseline: no arthritis (n = 83,295), osteoarthritis (OA; n = 63,402), and rheumatoid arthritis (RA; n = 960). Incident fractures were self-reported throughout followup. Age-adjusted fracture rates by arthritis category were generated, and the Cox proportional hazards model was used to test the association between arthritis and fracture. Results. After an average of 7.80 years, 24,137 total fractures were reported including 2559 self-reported clinical spinal fractures and 1698 adjudicated hip fractures. For each fracture type, age-adjusted fracture rates were highest in the RA group and lowest in the nonarthritic group. After adjustment for several covariates, report of arthritis was associated with increased risk for spine, hip, and any clinical fractures. Compared to the nonarthritis group, the risk of sustaining any clinical fracture in the OA group was HR 1.09 (95% CI 1.05, 1.13; p < 0.001) and HR 1.49 (95% CI 1.26, 1.75; p < 0.001) in the RA group. The risk of sustaining a hip fracture was not statistically increased in the OA group (HR 1.11; 95% CI 0.98, 1.25; p = 0.122) compared to the nonarthritis group; however, the risk of hip fracture increased significantly (HR 3.03; 95% CI 2.03, 4.51; p < 0.001) in the RA group compared to the nonarthritis group. Conclusion. The increase in fracture risk confirms the importance of fracture prevention in patients with RA and OA.

Randomized Trial of Once-Weekly Parathyroid Hormone (1-84) on Bone Mineral Density and Remodeling

CONTEXT Daily PTH administration increases bone mineral density (BMD) and reduces fracture risk. However, cost and compliance significantly limit clinical use. OBJECTIVE Our objective was to determine whether less frequent PTH administration increases lumbar spine BMD. PARTICIPANTS, DESIGN, AND SETTING Fifty postmenopausal women ages 45-70 yr with femoral neck BMD T-score between -1.0 and -2.0 participated in a double-blind, randomized, placebo-controlled trial at St. Joseph Hospital, Bangor, ME. INTERVENTION Subjects received sc injections of daily PTH(1-84) (100 mug) or placebo for 1 month, followed by weekly injections (PTH or placebo) for 11 months. OUTCOMES Change in lumbar spine dual-energy x-ray absorptiometry areal BMD (primary) was assessed. Secondary outcomes included volumetric BMD at spine and hip by quantitative computed tomography, trabecular bone microarchitecture by magnetic resonance imaging of distal radius, and biochemical bone turnover markers. RESULTS At 12 months, lumbar spine areal BMD increased 2.1% in PTH-treated women compared with placebo (P = 0.03). Vertebral trabecular volumetric BMD increased 3.8% in PTH-treated women compared with placebo group (P = 0.08). PTH-treated women also had higher distal radial trabecular bone volume, number, and thickness compared with placebo-treated women (P < 0.04). After 1 month of daily PTH, N-terminal propeptide of type I collagen (P1NP) was markedly increased compared with placebo (P < 0 .0001), and a difference persisted, although lessened, throughout the study. Bone resorption indices were unchanged in PTH-treated women and were reduced in the placebo group. CONCLUSION Once-weekly PTH after 1 month of daily treatment increases spine BMD, radial trabecular bone, and bone formation markers in postmenopausal women. These results suggest that less frequent alternatives to daily PTH dosing for 2 yr could be effective. Additional studies are required to define the optimal frequency of PTH administration.

Age at menopause in women participating in the postmenopausal estrogen/progestins interventions (PEPI) trial: An example of bias introduced by selection criteria

Our objective is to illustrate the bias introduced in assessing factors associated with age at menopause when the population sample has been selected using restricted criteria, i.e. number of years since menopause, by using a cross-sectional analysis of baseline data from a population-based randomized clinical trial. The participants were women who participated in the Postmenopausal Estrogen/Progestins Intervention (PEPI) trial, had not had a hysterectomy, were between 45 and 64 years old, and were menopausal for at least 1 but not greater than 10 years. The outcome measures were self-reported age at menopause and factors thought to be associated with it, including smoking, alcohol use, oral contraceptive use, number of pregnancies, education, income, body mass index, waist-hip ratio, thigh girth, and systolic and diastolic blood pressures. At entry, the mean age of the 601 women was 56.2 years. Mean age at menopause was 51.0 years. Chronologic (current) age was strongly correlated with age at menopause (r = 0.74, p = 0.0001). In bivariate analyses, factors associated with younger age at menopause were ever-use of cigarettes, former oral contraceptive use, and higher thigh girth; factors associated with later age at menopause were greater number of pregnancies, higher waist-hip ratio, and higher systolic blood pressure. After stratification by 5-year age intervals, these associations were no longer statistically significant. Because of restricted sampling, an artificial association was observed between chronologic age and age at time of menopause. This artifact made it difficult to distinguish between factors associated with chronologic age and those that may be independently associated with menopause. Failure to recognize this bias could lead to erroneous conclusions.

National Institutes of Health Research Plan on Rehabilitation

One in five Americans experiences disability that affects their daily function because of impairments in mobility, cognitive function, sensory impairment, or communication impairment. The need for rehabilitation strategies to optimize function and reduce disability is a clear priority for research to address this public health challenge. The National Institutes of Health (NIH) recently published a Research Plan on Rehabilitation that provides a set of priorities to guide the field over the next 5 years. The plan was developed with input from multiple Institutes and Centers within the NIH, the National Advisory Board for Medical Rehabilitation Research, and the public. This article provides an overview of the need for this research plan, an outline of its development, and a listing of six priority areas for research. The NIH is committed to working with all stakeholder communities engaged in rehabilitation research to track progress made on these priorities and to work to advance the science of medical rehabilitation.

One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis

When used to treat osteoporosis, no more than 2 years of parathyroid hormone (PTH) is permitted, raising the question of whether antiresorptive therapy should be given after PTH is discontinued. This prospective, randomized, double-blind trial, the Parathyroid Hormone and Alendronate (PaTH) study, compared full-length PTH (1-84), alendronate, and the combination. The goal was to learn whether antiresorptive treatment is necessary to maintain the gain in bone mineral density (BMD) achieved after a year of PTH (1-84) treatment. The study population included 238 postmenopausal women 55 to 85 years of age who had a T score for BMD below -2.5 at the femoral neck, total hip, or spine (or a T score below -2) combined with other risk factors such as a history of fracture. Participants were randomly assigned to 1 year of PTH followed by 1 year of alendronate; PTH followed by placebo; PTH plus alendronate in the first year and alendronate in year 2; or alendronate for 2 years. Full-length PTH (1-84) was given in a dose of 100 μg daily and alendronate in an oral dose of 10 mg daily. Full compliance with treatment was 75% and 82% in the first and second years, respectively. BMD at the lumbar spine increased significantly in all treatment groups over 2 years, most markedly (12.1%) in the PTH-alendronate group and least (4.1%) in the PTH-placebo patients. The increase in BMD in the combination-alendronate and 2-year alendronate groups was significantly greater than in the PTH-placebo group but smaller than in the PTH-alendronate group. The PTH-alendronate patients had a significantly greater increase in BMD at the femoral neck and total hip over 2 years than women in the PTH-placebo group, but a significant loss at the distal radius was found in of both these groups. Women in all treatment groups-but especially the PTH-alendronate group-gained volumetric BMD in trabecular bone during the 2-year study. In the second year, women in the PTH-alendronate group gained significant BMD at the spine (4.9%) and hip (3.6%). At the same time, women in the PTH-placebo group lost significant BMD at the spine. The 21 women having clinical fractures during the 2-year study represented 8.8% of the total; there were no major differences between treatment groups. Women taking alendronate rather than placebo in year 2 were not at higher risk of adverse events. Any increase in BMD after a year of PTH treatment is rapidly lost afterward, but this is not the case if the bisphosphonate alendronate is administered for a further 12 months. There was no evidence from this study that combining PTH with alendronate is more effective than giving either agent by itself.

National Institutes of Health Research Plan on RehabilitationNIH Medical Rehabilitation Coordinating Committee

Abstract One in five Americans experiences disability that affects their daily function because of impairments in mobility, cognitive function, sensory impairment, or communication impairment. The need for rehabilitation strategies to optimize function and reduce disability is a clear priority for research to address this public health challenge. The National Institutes of Health (NIH) recently published a Research Plan on Rehabilitation that provides a set of priorities to guide the field over the next 5 years. The plan was developed with input from multiple Institutes and Centers within the NIH, the National Advisory Board for Medical Rehabilitation Research, and the public. This article provides an overview of the need for this research plan, an outline of its development, and a listing of six priority areas for research. The NIH is committed to working with all stakeholder communities engaged in rehabilitation research to track progress made on these priorities and to work to advance the science of medical rehabilitation. This article is being published almost simultaneously in the following six journals: American Journal of Occupational Therapy, American Journal of Physical Medicine and Rehabilitation, Archives of Physical Medicine and Rehabilitation, Neurorehabilitation and Neural Repair, Physical Therapy, and Rehabilitation Psychology. Citation information is as follows: NIH Medical Rehabilitation Coordinating Committee. Am J Phys Med Rehabil. 2017;97(4):404—407.

Factors Associated With New‐Onset Depression Following Ischemic Stroke: The Women's Health Initiative

Background Psychosocial characteristics have a strong effect on risk of depression, and their direct treatment with behavioral interventions reduces rates of depression. Because new‐onset poststroke depression (NPSD) is frequent, devastating, and often treatment‐resistant, novel preventive efforts are needed. As a first step toward developing behavioral interventions for NPSD, we investigated whether prestroke psychosocial factors influenced rates of NPSD in a manner similar to the general population. Methods and Results Using the Womens Health Initiative, we analyzed 1424 respondents who were stroke‐free at enrollment and had no self‐reported history of depression from enrollment to their nonfatal ischemic stroke based on initiation of treatment for depression or the Burnam screening instrument for detecting depressive disorders. NPSD was assessed using the same method during the 5‐year poststroke period. Logistic regression provided odds ratios of NPSD controlling for multiple covariates. NPSD occurred in 21.4% (305/1424) of the analytic cohort and varied by stroke severity as measured by the Glasgow scale, ranging from 16.7% of those with good recovery to 31.6% of those severely disabled. Women with total anterior circulation infarction had the highest level (31.4%) of NPSD while those with lacunar infarction had the lowest (16.1%). Prestroke psychosocial measures had different associations with NPSD depending on functional recovery of the individual. Conclusions There is a difference in the relationship of prestroke psychosocial status and risk of NPSD depending on stroke severity; thus it may be that the same preventive interventions might not work for all stroke patients. One size does not fit all.