Charles W. Slemenda

Age and bone mass as predictors of fracture in a prospective study.

To study the effect of bone mass on the risk of fracture, we followed 521 Caucasian women over an average of 6.5 yr and took repeated bone mass measurements at the radius. We observed 138 nonspinal fractures in 3,388 person-yr. The person-years of follow-up and the incident fractures were cross-classified by age and bone mass. The incidence of fracture was then fitted to a log-linear model in age and bone mass. It was found that incidence of fracture increased with both increasing age and decreasing radius bone mass. When subsets of fractures were examined it was found that age was a stronger predictor of hip fractures, whereas midshaft radius bone mass was a stronger predictor of fractures at the distal forearm. We concluded that bone mass is a useful predictor of fractures but that other age-related factors associated with fractures need to be identified.

Quadriceps Weakness and Osteoarthritis of the Knee

Osteoarthritis of the knee is the most common cause of chronic disability among older persons in the United States [1]. In persons with symptomatic osteoarthritis of the knee, quadriceps muscle weakness is common and is widely believed to result from disuse atrophy secondary to joint pain. Although exercises to strengthen the quadriceps may relieve joint pain in persons with osteoarthritis of the knee [2-6], the role of periarticular muscle weakness in the pathogenesis of joint pain and disability in these persons is poorly understood. The basis for the beneficial effect of strengthening exercises is unclear, and the duration of the improvement has not been studied. Furthermore, the possibility that muscle weakness is an etiologic factor underlying the pathologic changes of osteoarthritis has seldom been considered. Elucidation of the role of muscle weakness in osteoarthritis is particularly important given our growing understanding of safe and effective methods for increasing strength in elderly persons [7, 8]. A substantial proportion of persons who have radiographic evidence of osteoarthritis of the knee have no joint pain [9]. Because asymptomatic persons with radiographic changes seldom seek medical attention for osteoarthritis, muscle weakness has not been studied previously in this group. Thus, it is not known whether quadriceps weakness precedes or follows joint pain or (if it follows joint pain) whether it is mediated by disuse atrophy or by physiologic mechanisms that may inhibit muscle contraction [10]. To address this issue, we studied the relation among lower-extremity muscle strength, lower-extremity lean tissue mass, and osteoarthritis of the knee in men and women 65 years of age and older. Methods Study Group To obtain a sample of elderly persons living in the community, we conducted brief telephone interviews with residents of households in central Indiana. Potential participants were selected through modified random-digit dialing to increase the sampled proportion of persons 65 years of age and older. Persons were eligible if they met the minimal criteria for participation: They were willing and able to provide informed consent and to undergo the necessary strength assessments and other evaluations. Persons were excluded if they had had amputations of both lower extremities, had undergone total knee arthroplasty, or had recently had a cerebrovascular accident or myocardial infarction. A total of 462 persons (approximately 55% of all who were eligible) agreed to participate and completed the following evaluations. Evaluations Radiography of the Knee Standing anteroposterior and lateral radiographs of both knees of each study participant were obtained, and the severity of osteoarthritis in the tibiofemoral compartment was graded by a musculoskeletal radiologist according to the criteria of Kellgren and Lawrence. Similar criteria, based on the presence of osteophytes and joint space narrowing, were used for the patellofemoral compartment [11]. The radiologist was blinded to the clinical status and characteristics of all patients. A participant had to have a Kellgren and Lawrence grade of 2 or more in either knee to be classified as having osteoarthritis. Knee Pain and Function The Western Ontario and McMaster Universities Arthritis Index was used to evaluate knee pain and function [12]. This index assesses the severity of knee pain during 5 activities or situations (walking on a flat surface, going up or down stairs, at night while in bed, sitting or lying, and standing upright) and the severity of impairment of lower-extremity function during 17 activities. Pain and functional impairment were assessed in each knee separately. Responses to each question about the severity of knee pain and level of impairment were recorded on a categorical scale as none, mild, moderate, severe, or extreme. Each category was assigned a corresponding numeric score from 1 to 5 (5 = extreme). Hence, the range on the pain scale was 5 to 25 and the range on the physical impairment scale was 17 to 85 (85 = greatest functional limitation). For the purposes of analysis, participants who rated the severity of their knee pain as moderate or greater (3) with any of the 5 activities on more than half of the days in the month preceding the evaluation were considered to have knee pain. Thus, pain in the more distant past that had resolved was not included. Participants were also questioned about current and previous regular (5 times per week) or occasional use of over-the-counter and prescription analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) in the past year. Lower-Extremity Muscle Strength The strength of each leg was evaluated by using an isokinetic dynamometer (KIN-COM 500H, Chattecx Corp., Hixson, Tennessee). Peak torque was recorded in both the concentric (contractions during muscle shortening) and eccentric (contractions during muscle lengthening) modes. Participants were allowed several submaximal or maximal practice efforts to familiarize themselves with the operation of the dynamometer. Once formal testing began, the best of three maximal efforts was recorded for flexion and extension at both 60 degrees per second and 120 degrees per second. Aborted efforts were repeated in order to obtain the best possible representation of strength for each participant. Concentric and eccentric testing yielded similar results, but because of greater variability in eccentric testing, only the concentric test results are shown. Lower-Extremity Lean Tissue Mass Total-body dual-energy x-ray absorptiometry was done in all participants by using a Lunar-DPX-L instrument (Lunar Corp., Madison, Wisconsin). Results were analyzed for total and regional body composition, including body fat, mineral, and lean components (lean components were components other than fat or mineral). The right and left lower extremities were analyzed separately. The lower extremity was defined as all tissue below a diagonal line drawn outward and upward from the groin area through the femoral neck. Statistical Analysis Participants were divided into four groups on the basis of presence or absence of radiographic evidence of osteoarthritis of the knee and presence or absence of knee pain, as defined above. Men and women were compared by using the t-test. Comparisons of Arthritis Index pain and functional impairment scores were done by using nonparametric approaches. For analyses of continuous data involving more than two groups of participants (for example, osteoarthritis with or without knee pain), analysis of variance was used to determine whether an overall difference was present. The Fisher protected least-significant-difference procedure was used for pairwise comparisons. Comparisons within participants (for example, comparison of the two legs in a person with unilateral osteoarthritis of the knee) were done by using paired t-tests. Regression models were constructed with the generalized estimating equations approach of Zeger and Liang [13]. This approach inflates the standard errors to adjust for correlations in both independent variables (such as strength) and dependent variables (such as radiographic grade) within participants. Statistically significant differences (P < 0.05) in the above analyses are specifically noted below. Results The characteristics of the 462 men and women in the cohort are shown in Table 1. As expected, men were taller, were heavier, and had greater lower-extremity strength and lean tissue mass in the lower extremities compared with women (P < 0.001 for all comparisons). Table 1. Age, Height, Weight, and Lower-Extremity Strength and Lean Tissue Mass* One hundred forty-five participants (31%; 33% of the women and 30% of the men) had radiographic evidence of osteoarthritis involving the tibiofemoral compartment, the patellofemoral compartment, or both. In 62 participants (43%), the radiographic changes were unilateral. Table 2 shows the association between osteoarthritis and obesity [14-16]. Women in the cohort who had osteoarthritis were approximately 15% heavier than women with normal radiographs and no knee pain. Men with osteoarthritis were also slightly heavier than men without osteoarthritis. Table 2. Body Weight and Summed Arthritis Index Scores for Recent Pain and Function in the Left Knee in Participants with and without Radiographic Evidence of Osteoarthritis* Among those with radiographic evidence of tibiofemoral osteoarthritis, women were slightly more likely than men to report knee pain (P = 0.10; Table 3). Table 3. Radiography and Recent Pain in the Left Knee Table 2 also shows the mean summed and the distribution of scores for left knee pain and functional impairment (data for the right knee were similar). Among men and women with radiographic evidence of osteoarthritis who reported having knee pain, the mean summed pain score for the knee with osteoarthritis was approximately 12 (median score, 2 of 5). In comparison, the mean pain score of participants who reported knee pain but did not have radiographic evidence of osteoarthritis in the painful knee was approximately 10 (median score, 2 of 5)-only slightly lower than the mean pain score of participants with radiographic changes. Consistent with their relatively low pain scores, these community-dwelling participants with osteoarthritis reported moderately low use of NSAIDs (Table 4). Table 4. Participants Reporting Regular Current or Previous Use of Analgesics and Nonsteroidal Anti-inflammatory Drugs Related to the Presence of Radiographic Evidence of Osteoarthritis of the Knee and Recent Knee Pain* Arthritis Index scores for functional impairment paralleled those for pain (Table 2). Participants with osteoarthritis had the greatest functional impairment (P < 0.001 for the comparison with patients who did not have pain or radiographic evidence of osteoarthritis). Functional impairment in participants who had pain but no radiographic evidence of osteoarthrit

Baseline measurement of bone mass predicts fracture in white women.

STUDY OBJECTIVE To determine if a single bone mass measurement of the radius is predictive of future fractures at any site. DESIGN Observational study of a cohort of free-living subjects and a cohort of retirement-home residents with an average follow-up of 6.7 years and 5.5 years, respectively (range, 1 to 15 years for both cohorts). SETTING General community and a retirement home. SUBJECTS Volunteer sample of white women (386 free-living and 135 living in a retirement home) who were free of disease and were not receiving medication known to affect bone metabolism. In terms of physical condition subjects ranged from the totally independent to the wheelchair-bound. MEASUREMENTS AND MAIN RESULTS A radial bone mass measurement was done at the initial visit. Subsequent non-spine fractures were reported by the subjects at follow-up visits, which were less than a year apart in most cases, and verified with medical records. Cox regression was used to model time to first fracture as a function of age and bone mass. These analyses showed that for every 0.1 g/cm decrement in bone mass, the relative risk of fracture was 2.2 (CI, 1.7 to 2.8) for the free-living and 1.5 (CI, 1.2 to 1.9) for the retirement-home residents. Baseline age did not predict the risk of fracture in either cohort, and controlling for baseline age did not reduce the relative-risk estimates of bone mass. Similar analyses also showed that bone mass was a statistically significant predictor for first hip fractures (n = 30) among the nursing-home residents (relative risk, 1.9; CI, 1.4 to 2.7) and first forearm fractures (n = 10) among the free living (relative risk, 3.6; CI, 1.9 to 6.8). For both cohorts, the 8-year probability of any nonspine fracture was about 80% for subjects with initial bone mass less than 0.6 g/cm and was less than 10% for subjects with initial bone mass greater than 0.8 g/cm. Similarly, those in the retirement home with bone mass below 0.6 g/cm had a 6-year probability of hip fracture of 43%, compared with a 17% risk for those with greater bone mass. CONCLUSION A single bone mass measurement of the radius is predictive of future nonspine fractures at all sites, and at both the forearm and the hip. Baseline age was not a significant predictor of fracture within either cohort. Relative-risk estimates were not dissimilar across fracture sites.

Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens.

The purpose of this study was to determine whether bone density in older men was associated with serum sex steroids or sex hormone binding globulin (SHBG). Bone density and sex steroids were measured in men over age 65 at 6-mo intervals for an average of 2.1 yr. Bone density was significantly positively associated with greater serum E2 concentrations (+0.21 < r < +0.35; 0.01 < P < 0.05) at all skeletal sites. There were weak negative correlations between serum testosterone and bone density (-0.20 < r < -0.28; 0.03 < P < 0.10) at the spine and hip. SHBG was negatively associated only with bone density in the greater trochanter (r = -0.26, P < 0.05). Greater body weight was associated with lower serum testosterone and SHBG, and greater E2. Because of these associations, regression models which adjusted for age, body weight, and serum sex steroids were constructed; these accounted for 10-30% of the variability in bone density, and showed consistent, significant positive associations between bone density and serum E2 concentrations in men, even after adjustments for weight and SHBG. These data suggest that estrogens may play an important role in the development or maintenance of the male skeleton, much as is the case for the female skeleton. These data also indicate that, within the normal range, lower serum testosterone concentrations are not associated with low bone density in men.

The contribution of bone loss to postmenopausal osteoporosis

We have addressed the relative importance of peak bone mass and subsequent rate of loss in determining postmenopausal womens bone mass in old age, by examining longitudinal measurements of radial mid-shaft bone mass on various samples of healthy white postmenopausal women. Using both the variance estimate of age-specific rates of bone loss and the population variance in bone mass, we determined that rates of loss could contribute importantly to future bone mass. However, since we found a small negative correlation between initial bone mass and rate of loss, it was necessary to estimate the effect of bone loss as the complement of the contribution of initial bone mass. We found that the influence of bone loss (relative to initial bone mass) increases as the women age, such that by about age 70, the contribution of initial bone mass and rate of loss approached equality. However, estimated rates of bone loss were not very stable over time, so it was difficult to identify long-term ‘fast-losers’. We conclude that the rate of postmenopausal bone loss is an important contributor to osteoporosis at old age, but it is difficult to identify long-term fast-losers, thereby reducing the clinical value of assessments of rates of change in bone mass early in the postmenopause.

Influences on skeletal mineralization in children and adolescents: Evidence for varying effects of sexual maturation and physical activity

OBJECTIVE To establish rates of skeletal mineralization in children and adolescents, and to identify factors that influence these rates. DESIGN Three-year observational study. SETTING University hospital. SUBJECTS Ninety white children, aged 6 to 14 years. MEASUREMENTS Bone mineral density of the radius, spine, and hip was measured at baseline and 3 years later. Physical activity was assessed by questionnaires at 6-month intervals and dietary calcium intake by diet diary 1 day per month for 36 months. Sexual maturation (Tanner stage) was determined by an endocrinologist at 6-month intervals, as necessary to classify children as prepubertal, peripubertal, or postpubertal. RESULTS Skeletal mineralization accelerated markedly at puberty in the spine (0.077 vs 0.027 gm/cm2 per year, peripubertal vs prepubertal) and greater trochanter (0.050 vs 0.027 gm/cm2 per year), less markedly in the femoral neck (0.047 vs 0.030 gm/cm2 per year), and only slightly in the radius. Nearly one third (15 gm) of the total skeletal mineral in the lumbar spine of adult women (approximately 52 gm) was accumulated in the 3 years around the onset of puberty. Increases in height and weight were the strongest correlates of skeletal mineralization: weight changes were more strongly correlated with trabecular bone sites and changes in height with cortical bone sites. Increases in calf muscle area were strongly associated with mineralization, particularly in peripubertal children, and physical activity was associated with more rapid mineralization in prepubertal children. CONCLUSIONS Puberty has varying effects on skeletal mineralization depending on skeletal site; trabecular bone is apparently more sensitive to changing hormone concentrations. Physical activity and normal growth are also positively associated with skeletal mineralization, also depending on skeletal site and sexual maturation.

Sex steroids and bone mass. A study of changes about the time of menopause.

To examine the relationships between bone loss and sex steroids, 84 peri- and postmenopausal women were studied at 4-mo intervals for 3 yr. At each visit, measurements were made of bone mass at the midshaft and distal radius, of steroids, of gonadotropins, and of bone gla protein (BGP). Bone loss was approximately 1% per yr among late perimenopausal and postmenopausal groups, whereas the early perimenopausal group lost no bone. Mean serum estrogen and BGP concentrations predicted rates of bone loss. BGP was negatively correlated with the rate of bone loss (r = -0.45) and with mean estrogen concentrations (r = -0.40). Multivariate regressions showed estrogen concentrations to be strong independent predictors of the slope of bone mass over time. When BGP concentrations were added to the models, the significance of estrogen was reduced, suggesting that a portion of the estrogen effect was mediated through effects on rates of bone remodelling.

Sex steroids, bone mass, and bone loss. A prospective study of pre-, peri-, and postmenopausal women.

Although bone loss around the time of menopause is driven by estrogen deficiency, the roles of estrogens and androgens in the preservation of skeletal mass at other stages of life are less well understood. To address this issue we studied 231 women between the ages of 32 and 77 with multiple measurements of sex steroids and bone mass over a period of 2-8 yr. In all women bone mass was negatively associated with concentrations of sex-hormone binding globulin, and positively associated with weight. Bone loss occurred from all skeletal sites in peri- and postmenopausal women, but premenopausal women lost bone only from the hip (-0.3%/yr) and had positive rates of change in the radius and spine. Bone loss was significantly associated with lower androgen concentrations in premenopausal women, and with lower estrogens and androgens in peri- and postmenopausal women. Sex steroids are important for the maintenance of skeletal integrity before menopause, and for as long as 20-25 yr afterwards.

Long-Term Bone Loss in Men: Effects of Genetic and Environmental Factors

OBJECTIVE To identify environmental factors associated with bone loss in adult male twins and to determine the extent to which shared environmental characteristics affect estimates of the genetic influence on bone loss. DESIGN A 16-year cohort study. SETTING A midwestern university hospital. PARTICIPANTS One hundred and eleven male veterans of World War II or the Korean conflict, born between 1916 and 1927. All were twins, with the sample comprising 48 pairs and 15 persons whose twin brothers were deceased or seriously ill. MEASUREMENTS Bone mass and environmental characteristics (cigarette smoking, alcohol consumption, physical activity, dietary calcium intake, use of thiazide diuretics) measured at baseline and 16 years later. RESULTS Rates of radial bone loss averaged 0.45% per year. Those who both smoked and used alcohol at levels greater than the median for the population had a rate of bone loss (10% in 16 years) twice the rate of those who were below the median level for both variables (5% bone loss, P = 0.003). Rates of bone loss were correlated within twin pairs, and these correlations were diminished 25% to 35% by adjustments for environmental influences on bone loss. However, statistically significant within-pair correlations remained (r = 0.4), which did not differ between monozygotic and dizygotic twin pairs after adjustments for smoking, alcohol use, dietary calcium intake, and exercise. CONCLUSIONS Bone loss in men during mid-life is determined, at least in part, by environmental factors, including smoking, alcohol intake, and, possibly, physical activity. Rates of bone loss were similar within twin pairs, apparently because of a shared environment.

Reduced Rates of Skeletal Remodeling Are Associated with Increased Bone Mineral Density During the Development of Peak Skeletal Mass

Two related studies were conducted to assess the associations between markers of skeletal modeling and remodeling in healthy children. Members of monozygotic twin pairs, aged 6–14, enrolled in a clinical trial of calcium supplementation, were studied at the end of the period of supplementation and for 3 years thereafter. Supplemented children had significantly higher rates of gain in bone mineral density (BMD) (+3% on average) during the period of supplementation accompanied by significantly lower concentrations of serum osteocalcin (OC, −15%). During postsupplement follow‐up, both differences in BMD and OC disappeared. Black females, age matched to the baseline ages of the white children, had significantly lower serum concentrations of both OC and tartrate‐resistant acid phosphatase (TRAP) at all ages and higher BMDs. When stratified on serum TRAP concentrations, regardless of race, children with lower concentrations had significantly higher BMDs, and no racial differences were apparent. In regression models accounting for 70–80% of the variability in BMD in children, body size and TRAP, but not race, remained significantly associated with BMD. The skeletal advantages seen with calcium supplementation and black race appear to be associated with reduced rates of skeletal turnover. Given that markers of turnover during growth reflect both skeletal modeling and remodeling, and there is no apparent advantage to reduced skeletal modeling, it seems probable that reduced remodeling is the factor that accounts for the increases in bone mass.