Michael C. Nevitt

Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures

BACKGROUND Previous studies have shown that alendronate can increase bone mineral density (BMD) and prevent radiographically defined (morphometric) vertebral fractures. The Fracture Intervention Trial aimed to investigate the effect of alendronate on the risk of morphometric as well as clinically evident fractures in postmenopausal women with low bone mass. METHODS Women aged 55-81 with low femoral-neck BMD were enrolled in two study groups based on presence or absence of an existing vertebral fracture. Results for women with at least one vertebral fracture at baseline are reported here. 2027 women were randomly assigned placebo (1005) or alendronate (1022) and followed up for 36 months. The dose of alendronate (initially 5 mg daily) was increased (to 10 mg daily) at 24 months, with maintenance of the double blind. Lateral spine radiography was done at baseline and at 24 and 36 months. New vertebral fractures, the primary endpoint, were defined by morphometry as a decrease of 20% (and at least 4 mm) in at least one vertebral height between the baseline and latest follow-up radiograph. Non-spine clinical fractures were confirmed by radiographic reports. New symptomatic vertebral fractures were based on self-report and confirmed by radiography. FINDINGS Follow-up radiographs were obtained for 1946 women (98% of surviving participants). 78 (8.0%) of women in the alendronate group had one or more new morphometric vertebral fractures compared with 145 (15.0%) in the placebo group (relative risk 0.53 [95% Cl 0.41-0.68]). For clinically apparent vertebral fractures, the corresponding numbers were 23 (2.3%) alendronate and 50 (5.0%) placebo (relative hazard 0.45 [0.27-0.72]). The risk of any clinical fracture, the main secondary endpoint, was lower in the alendronate than in the placebo group (139 [13.6%] vs 183 [18.2%]; relative hazard 0.72 [0.58-0.90]). The relative hazards for hip fracture and wrist fracture for alendronate versus placebo were 0.49 (0.23-0.99) and 0.52 (0.31-0.87). There was no significant difference between the groups in numbers of adverse experiences, including upper-gastrointestinal disorders. INTERPRETATION We conclude that among women with low bone mass and existing vertebral fractures, alendronate is well tolerated and substantially reduces the frequency of morphometric and clinical vertebral fractures, as well as other clinical fractures.

Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.

BACKGROUND Many risk factors for hip fractures have been suggested but have not been evaluated in a comprehensive prospective study. METHODS We assessed potential risk factors, including bone mass, in 9516 white women 65 years of age or older who had had no previous hip fracture. We then followed these women at 4-month intervals for an average of 4.1 years to determine the frequency of hip fracture. All reports of hip fractures were validated by review of x-ray films. RESULTS During the follow-up period, 192 women had first hip fractures not due to motor vehicle accidents. In multivariable age-adjusted analyses, a maternal history of hip fracture doubled the risk of hip fracture (relative risk, 2.0; 95 percent confidence interval, 1.4 to 2.9), and the increase in risk remained significant after adjustment for bone density. Women who had gained weight since the age of 25 had a lower risk. The risk was higher among women who had previous fractures of any type after the age of 50, were tall at the age of 25, rated their own health as fair or poor, had previous hyperthyroidism, had been treated with long-acting benzodiazepines or anticonvulsant drugs, ingested greater amounts of caffeine, or spent four hours a day or less on their feet. Examination findings associated with an increased risk included the inability to rise from a chair without using ones arms, poor depth perception, poor contrast sensitivity, and tachycardia at rest. Low calcaneal bone density was also an independent risk factor. The incidence of hip fracture ranged from 1.1 (95 percent confidence interval, 0.5 to 1.6) per 1,000 woman-years among women with no more than two risk factors and normal calcaneal bone density for their age to 27 (95 percent confidence interval, 20 to 34) per 1,000 woman-years among those with five or more risk factors and bone density in the lowest third for their age. CONCLUSIONS Women with multiple risk factors and low bone density have an especially high risk of hip fracture. Maintaining body weight, walking for exercise, avoiding long-acting benzodiazepines, minimizing caffeine intake, and treating impaired visual function are among the steps that may decrease the risk.

BONE DENSITY AT VARIOUS SITES FOR PREDICTION OF HIP FRACTURES

Women with low bone density in the radius or calcaneus are at increased risk of hip fracture. To see whether bone density of the hip measured by dual X-ray absorptiometry is a better predictor of hip fracture than measurements of other bones, we assessed bone density at several sites in 8134 women aged 65 years or more. 65 women had hip fractures during a mean follow-up of 1.8 years. Each SD decrease in femoral neck bone density increased the age-adjusted risk of hip fracture 2.6 times (95% CL 1.9, 3.6). Women with bone density in the lowest quartile had an 8.5-fold greater risk of hip fracture than those in the highest quartile. Bone density of the femoral neck was a better predictor than measurements of the spine (p < 0.0001), radius (p < 0.002), and moderately better than the calcaneus (p = 0.10). Low hip bone density is a stronger predictor of hip fracture than bone density at other sites. Efforts to prevent hip fractures should focus on women with low hip bone density.

Gait Speed and Survival in Older Adults

CONTEXT Survival estimates help individualize goals of care for geriatric patients, but life tables fail to account for the great variability in survival. Physical performance measures, such as gait speed, might help account for variability, allowing clinicians to make more individualized estimates. OBJECTIVE To evaluate the relationship between gait speed and survival. DESIGN, SETTING, AND PARTICIPANTS Pooled analysis of 9 cohort studies (collected between 1986 and 2000), using individual data from 34,485 community-dwelling older adults aged 65 years or older with baseline gait speed data, followed up for 6 to 21 years. Participants were a mean (SD) age of 73.5 (5.9) years; 59.6%, women; and 79.8%, white; and had a mean (SD) gait speed of 0.92 (0.27) m/s. MAIN OUTCOME MEASURES Survival rates and life expectancy. RESULTS There were 17,528 deaths; the overall 5-year survival rate was 84.8% (confidence interval [CI], 79.6%-88.8%) and 10-year survival rate was 59.7% (95% CI, 46.5%-70.6%). Gait speed was associated with survival in all studies (pooled hazard ratio per 0.1 m/s, 0.88; 95% CI, 0.87-0.90; P < .001). Survival increased across the full range of gait speeds, with significant increments per 0.1 m/s. At age 75, predicted 10-year survival across the range of gait speeds ranged from 19% to 87% in men and from 35% to 91% in women. Predicted survival based on age, sex, and gait speed was as accurate as predicted based on age, sex, use of mobility aids, and self-reported function or as age, sex, chronic conditions, smoking history, blood pressure, body mass index, and hospitalization. CONCLUSION In this pooled analysis of individual data from 9 selected cohorts, gait speed was associated with survival in older adults.

BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures.

In a large cohort of U.S. women aged 65 and older, we report the relationships of BMD measured at several sites, and subsequent fracture risk at multiple sites over >8 years of follow‐up. Although we found almost all fracture types to be related to low BMD, the overall proportion of fractures attributable to low BMD is modest.

The Association of Radiographically Detected Vertebral Fractures with Back Pain and Function: A Prospective Study

Radiographically detected vertebral fractures (hereafter referred to as vertebral fractures) are a hallmark of postmenopausal osteoporosis and an important end point in clinical trials of osteoporosis treatment. Women with vertebral fractures have low bone mass compared with women without these fractures and, independently of bone mass, have an increased risk for additional vertebral and other fractures [1-4]. Vertebral fractures are common: Five percent of 50-year-old white women and 25% of 80-year-old women have had at least one vertebral fracture [5]. Surprisingly, however, the manner in which vertebral fractures affect health remains uncertain. Cross-sectional studies in community-derived samples of older women have demonstrated only a modest association [6-8] or no association [9-11] between prevalent vertebral fractures and back pain or disability. Cross-sectional studies do not distinguish more recent fractures from older vertebral fractures and may fail to capture transient increases in pain or disability [12], a limitation that may underestimate the clinical effect of these fractures [13]. Back pain is common among elderly women [14], and frequent causes of back pain, such as degenerative disc disease, facet joint osteoarthritis, spinal stenosis, and scoliosis, may obscure the impact of vertebral fracture. Only about one third of new vertebral fractures come to medical attention [15, 16], suggesting that most vertebral fractures are asymptomatic. However, attitudes toward back pain in older women and access to health care may also play a role in determining whether vertebral fractures come to medical attention. We examined the effect of incident vertebral fractures on back pain and back-related functional limitations in a large community-based sample of elderly women who underwent serial spinal radiography and annual assessments of back pain and disability over the same period. Methods Participants Study patients were participants in the Study of Osteoporotic Fractures, a cohort recruited from population-based listings in four U.S. metropolitan areas. Details of the design of this study are published elsewhere [17]. Lateral spine radiographs were obtained for 9677 white women between the ages of 65 and 99 years (median age, 70 years) who underwent baseline examination between 1986 and 1988. Repeated spinal radiographs suitable for morphometry were obtained for 7223 women (75% of the original cohort) at a follow-up clinic visit held an average of 3.7 years (range, 1.3 to 5.1 years) later. All participants gave informed consent. Vertebral Morphometry Lateral radiographs of the thoracic and lumbar spine were obtained in accordance with current guidelines [18]. Quantitative vertebral morphometry was performed using six-point digitization as described elsewhere [3, 19] to calculate the anterior (Ha), mid- (Hm), and posterior (Hp) height for each vertebral body from T4 to L4. A system of triage of radiographs, described elsewhere [3, 20], was used to reduce the number of radiographs requiring morphometric measurements. Briefly, trained technicians separated sets of radiographs into normal, uncertain, or probably fractured groups on the basis of a limited semiquantitative grading scheme that categorized women by the most abnormal vertebral level [20]. Uncertain grades were further categorized by the study radiologist as normal or probably fractured. Morphometry was done on the radiograph pairs that were categorized as probably fractured (42%). In a random sample of 503 women whose radiographs were triaged and then digitized, triage missed no incident fractures according to the study definition. Definition of Vertebral Fracture A vertebra was classified as having a prevalent fracture on the baseline radiograph if any of the following ratios were more than 3 SDs (>4 SDs for severe fractures) below the normal mean for that vertebral level: (Ha/Hp), (Hm/Hp), or a combination of (H/H [] 1) and (Hai/Hai 1) [3, 21]. A new (incident) fracture was identified if any of the three vertebral heights (Ha, Hm, or Hp) on follow-up radiographs decreased by 20% or more and by at least 4 mm compared with the baseline height. Incident fractures identified by morphometry were reviewed by a radiologist to exclude imaging artifacts or such conditions as osteophytosis and Scheuermann disease; 7% of vertebrae meeting the morphometric criteria for incident fracture were reclassified as not fractured. Incident Clinical Fractures We used previously described methods [22] to assess the occurrence of clinical fractures of any bone during follow-up. Women were considered to have a clinical vertebral fracture if they reported a new diagnosis of spinal fracture and a clinical radiology report confirmed that a vertebral fracture was present. Measurements of Pain, Disability, and Limited Activity We evaluated outcome measures by using a previously described questionnaire [7, 23] that asked about back pain and back-related disability in the past 12 months and the number of days of limited activity due to back pain. The questionnaire was administered at baseline and at three annual follow-up contacts held before assessment of vertebral fractures. The third follow-up contact coincided with follow-up radiography. Back pain was assessed on scales of frequency (0, never or rarely; 1, some of the time; 2, most of the time; or 3, all of the time) and severity (0, no pain; 1, mild pain; 2, moderate pain; or 3, severe pain). The two pain questions had high internal consistency (Cronbach = 0.81) and were summed for a total score that could range from 0 to 6. We defined clinically significant back pain as pain that was experienced most or all of the time or pain that was moderate or severe. Women without significant back pain at baseline were considered to have increased back pain if clinically significant pain had developed between any follow-up contacts. For women with clinically significant back pain at baseline, increased back pain was defined as an increase in total pain score of at least two points. Both types of increase had a similar association with incident fractures and thus were combined for a single outcome. Back-related disability was assessed with questions about the degree of difficulty (0, no difficulty; 1, some difficulty; 2, much difficulty; or 3, unable to perform activity) in six activities of daily living that involved the back (bending down to pick up light-weight objects, lifting a 10-pound object from the floor, reaching for objects just above the head, putting on socks or stockings, getting in and out of an automobile, and standing for 2 hours). These measures were combined in a back-related disability score ranging from 0 to 18. As reported elsewhere [7], this scale has high internal consistency (Cronbach = 0.82) and is highly correlated (Spearman r = 0.73) with a more extensive instrument used to assess disability caused by low back pain [24]. We defined clinically significant disability as much difficulty or unable in one or more of the six activities. Women without significant disability at baseline were considered to have increased disability if clinically significant disability had developed between any follow-up contacts. For women with clinically significant disability at baseline, increased disability was defined as an increase in disability score of at least three points. Both types of increase had a similar association with incident fractures and thus were combined for a single outcome. We also asked participants if they had limited their activities because of back pain since the last contact; if the answer was yes, we asked for the number of days they had stayed in bed and the number of days on which activity was limited (not including days in bed) because of back pain. Questions were adapted from previous surveys [25, 26]. For all follow-up contacts, we summed the number of days of bed rest and, in a separate measure, the number of days of limited activity; we then divided these numbers by the total years of follow-up to estimate the average number of affected days per year. Other Measurements The baseline questionnaire assessed potential confounding factors that may be associated with the risk for incident vertebral fracture and with back pain or disability, including smoking (current or past smoker); inactivity, defined as walking less than one block daily (yes or no); a previous physician diagnosis of osteoporosis or spinal fracture (yes or no); current use of estrogen (yes or no); hip pain in the past 12 months (yes or no); and height at 25 years of age. At the baseline examination, we assessed height and weight and calculated body mass index (kg/m2). We assessed grip strength by using an isometric dynamometer (Jamar Hydraulic Hand Dynamometer, JA Preston, Jackson, Mississippi) at baseline and at the follow-up examination and calculated change in grip strength between the two measurements. A random sample of 16% of baseline spine radiographs was assessed for spinal disc degeneration by using previously published methods [27]. Statistical Analysis Unless otherwise indicated, analyses were done separately in groups stratified by the presence of one or more baseline prevalent vertebral fractures. Descriptive and bivariate associations were assessed by using the t-test for continuous variables and the chi-square test for dichotomous variables. The association between incident vertebral fractures and dichotomous outcomes (increased back pain and increased back disability) was analyzed with logistic regression techniques. We analyzed the association of incident vertebral fracture with days of bed rest and days of limited activity per year by using Poisson regression. The distribution of days of bed rest (mean SD, 0.44 5.15) and limited-activity days (16.3 53.7) indicate that considerable overdispersion is present. Poisson regression allowing for this overdispersion provides a good estimation and inferential scheme [2

Leg Muscle Mass and Composition in Relation to Lower Extremity Performance in Men and Women Aged 70 to 79: The Health, Aging and Body Composition Study

OBJECTIVES: The loss of muscle mass with aging, or sarcopenia, is hypothesized to be associated with the deterioration of physical function. Our aim was to determine whether low leg muscle mass and greater fat infiltration in the muscle were associated with poor lower extremity performance (LEP).

Longitudinal study of muscle strength, quality, and adipose tissue infiltration

BACKGROUND Sarcopenia is thought to be accompanied by increased muscle fat infiltration. However, no longitudinal studies have examined concomitant changes in muscle mass, strength, or fat infiltration in older adults. OBJECTIVE We present longitudinal data on age-related changes in leg composition, strength, and muscle quality (MQ) in ambulatory, well-functioning men and women. We hypothesized that muscle cross-sectional area (CSA) and strength would decrease and muscular fat infiltration would increase over 5 y. DESIGN Midthigh muscle, subcutaneous fat (SF), and intermuscular fat (IMF) CSAs and isokinetic leg muscle torque (MT) and MQ (MT/quadriceps CSA) were examined over 5 y in the Health, Aging, and Body Composition study cohort (n = 1678). RESULTS Men experienced a 16.1% loss of MT, whereas women experienced a 13.4% loss. Adjusted annualized decreases in MT were 2-5 times greater than the loss of muscle CSA in those who lost weight and in those who remained weight-stable. Weight gain did not prevent the loss of MT, despite a small increase in muscle CSA. Only those who gained weight had an increase in SF (P < 0.001), whereas those who lost weight also lost SF (P < 0.001). There was an age-related increase in IMF in men and women (P < 0.001), and IMF increased in those who lost weight, gained weight, or remained weight-stable (all P < 0.001). CONCLUSIONS Loss of leg MT in older adults is greater than muscle CSA loss, which suggests a decrease in MQ. Additionally, aging is associated with an increase in IMF regardless of changes in weight or SF.

Sarcopenia: Alternative Definitions and Associations with Lower Extremity Function

Objectives: To compare two sarcopenia definitions and examine the relationship between them and lower extrem‐ity function and other health related factors using data from the baseline examination of the Health Aging and Body Composition (Health ABC) Study.

TYPE OF FALL AND RISK OF HIP AND WRIST FRACTURES: THE STUDY OF OSTEOPOROTIC FRACTURES

Objective: To determine the causes of hip or wrist fractures.