Richard D. Wasnich

PREVENTION OF BONE LOSS WITH ALENDRONATE IN POSTMENOPAUSAL WOMEN UNDER 60 YEARS OF AGE

Background Estrogen-replacement therapy prevents osteoporosis in postmenopausal women by inhibiting bone resorption, but the balance between its long-term risks and benefits remains unclear. Whether other antiresorptive therapies can prevent osteoporosis in these women is also not clear. Methods We studied the effect of 2.5 mg or 5 mg of alendronate per day or placebo on bone mineral density in 1174 postmenopausal women under 60 years of age. An additional 435 women who were prepared to receive a combination of estrogen and progestin were randomly assigned to one of the above treatments or open-label estrogen–progestin. The main outcome measure was the change in bone mineral density of the lumbar spine, hip, distal forearm, and total body measured annually for two years by dual-energy x-ray absorptiometry. Results The women who received placebo lost bone mineral density at all measured sites, whereas the women treated with 5 mg of alendronate daily had a mean (±SE) increase in bone mineral density of 3.5±...

Predicting vertebral fracture incidence from prevalent fractures and bone density among non-black, osteoporotic women.

We evaluated the ability of bone density and vertebral fractures at baseline to predict vertebral fracture incidence in a cohort of postmenopausal women with osteoporosis. The study population was 380 postmenopausal women (mean age 65 years) treated for osteoporosis in a randomized, placebo-controlled, clinical trial of the bisphosphonate etidronate at seven geographic centers in the United States. Baseline measurements of bone mineral density were obtained in 1986 by quantitative computed tomography at the spine and dual-photon absorptiometry at the lumbar spine and hip. Vertebral fractures were documented on serial spine radiographs. Proportional hazards models were used to evaluate the ability to predict the risk of subsequent fractures during an average of 2.9 years of follow-up. Presence of one or two fractures increased the rate of new vertebral fractures 7.4-fold (95% confidence interval = 1.0 to 55.9). Additional fractures at baseline further increased the fracture rate. A decrease of 2 standard deviations in spinal bone density by absorptiometry was associated with a 5.8-fold increase in fracture rate (95% confidence interval = 2.9 to 11.6). The lowest and highest quintiles of bone density had absolute fracture rates of 120 and 6 cases per 1000 patient-years, respectively. In general, the simultaneous use of two predictors (bone density and prevalent fractures or two bone density measurements) improved fracture prediction, compared with the use of a single predictor. We conclude that both bone density and prevalent vertebral fractures are strong, complementary predictors of vertebral fracture risk. The results suggest that physicians can use bone density and prevalent vertebral fractures, individually or in combination, as risk factors to identify patients at greatest risk of new fractures.

Low body mass index is an important risk factor for low bone mass and increased bone loss in early postmenopausal women

Thinness (low percentage of body fat, low body mass index [BMI], or low body weight) was evaluated as a risk factor for low bone mineral density (BMD) or increased bone loss in a randomized trial of alendronate for prevention of osteoporosis in recently postmenopausal women with normal bone mass (n = 1609). The 2‐year data from the placebo group were used (n = 417). Percentage of body fat, BMI, and body weight were correlated with baseline BMD (r = −0.13 to −0.43, p < 0.01) and 2‐year bone loss (r = −0.14 to −0.19, p < 0.01). Women in the lowest tertiles of percentage of body fat or BMI had up to 12% lower BMD at baseline and a more than 2‐fold higher 2‐year bone loss as compared with women in the highest tertiles (p ≤ 0.004). Women with a lower percentage of body fat or BMI had higher baseline levels of urine N‐telopeptide cross‐links (r = −0.24 to −0.31, p < 0.0001) and serum osteocalcin (r = −0.12 to −0.15, p < 0.01). To determine if the magnitude of treatment effect of alendronate was dependent on these risk factors, the group treated with 5 mg of alendronate was included (n = 403). There were no associations between fat mass parameters and response to alendronate treatment, which indicated that risk of low bone mass and increased bone loss caused by thinness could be compensated by alendronate treatment. In conclusion, thinness is an important risk factor for low bone mass and increased bone loss in postmenopausal women. Because the response to alendronate treatment is independent of fat mass parameters, prevention of postmenopausal osteoporosis can be equally achieved in thinner and heavier women.

Racial differences in hip axis lengths might explain racial differences in rates of hip fracture

Compared with white women, Asian women have about a 40%–50% and blacks a 50%–60% lower risk of hip fracture, but the reason for this racial difference is not known. Women with a shorter hip axis have a lower risk of hip fracture. To test the hypothesis that a shorter hip axis length could account for the lower risk of hip fracture among Asian and black women, we measured hip axis length in 135 Caucasian, 74 Asian and 50 black women. The mean hip axis lengths of Asian and black women were significantly shorter (1.2 and 0.7 standard deviations, respectively) than that of the whites (p<0.0001). We estimate that, compared with white women, Asians would have a 47% lower risk (95% confidence interval: 32%–63%) and blacks would have a 32% (15%–45%) lower risk of hip fracture because of their shorter hip axis. We conclude that a shorter hip axis length might be a major factor accounting for Asian womens lower risk of hip fracture and might contribute to the lower risk in black women.

A critical review of bone mass and the risk of fractures in osteoporosis.

SummaryThe usefulness of various bone mineral measurement techniques is a subject of current controversy. In order to explore whether disparate conclusions may have arisen from differences in analytic methodology, data from published reports of bone mass and nonviolent fractures have been reanalyzed in terms of fracture risk. In the large majority of studies, reduced bone mass was associated with an increased risk of fractures. However, the magnitude of the relationship varied much more among cross-sectional studies than among prospective studies, suggesting that bias related to subject selection and/or postfracture bone loss may have strongly influenced the cross-sectional findings. We conclude that more emphasis should be given to the results of prospective studies, and that more attention should be paid to subject selection in all investigations. Analyzing and presenting results in terms of fracture risk would probably reduce the level of confusion in the field and provide more clinically relevant information. These issues are also applicable to studies of potential fracture risk factors other than bone mass, such as bone structure and bone quality.

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

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

Spine fracture risk is predicted by non-spine fractures.

A prospective cohort study of 1098 postmenopausal Japanese-American women evaluated the relationship between baseline non-spine fractures and new (incident) spine fractures. At the baseline examination in 1981, prevalent non-spine fractures were ascertained by interview, and prevalent spine fractures by radiograph. Bone mass measurements of the distal radius, proximal radius, calcaneus (1981), the lumbar spine (1984) were obtained and repeated at 1- to 2-year intervals. Women with existing non-spine fractures have a threefold greater risk of subsequent spine fractures, independent of bone mass, and independent of the known association between prevalent spine fractures and subsequent spine fractures. Women with both a prevalent non-spine fracture and low bone mass (50th percentile or lower) have an eightfold greater risk of new spine fractures compared with women above the 50th percentile of bone mass and no prevalent fractures. In addition to low bone mass, both prevalent spine fractures and prevalent non-spine fractures are strong risk factors for subsequent spine fracture. These data suggest that not all osteoporotic risk factors are expressed via bone mass, and that other, unmeasured risk factors, such as bone quality defects, may explain these results. In clinical terms, women with both prevalent fractures and low bone mass should be recognized as being at extremely high risk, and treatment potency should be commensurate with this level of risk.

What Are the Criteria by Which a Densitometric Diagnosis of Osteoporosis Can Be Made in Males and Non-Caucasians?

Osteoporotic fractures are not rare in men or non-Caucasian women. However, for these groups, there is no consensus densitometric definition of osteoporosis. As is the case in Caucasian women, low bone mineral density (BMD) is associated with increased fracture risk among men and non-Caucasian women; thus, a densitometric definition of osteoporosis seems feasible. Reaching agreement on criteria for diagnosing osteoporosis in men and non-Caucasians was among the goals of the International Society for Clinical Densitometry Position Development Conference held in July 2001. To this end, the conference recommendation for males is that osteoporosis be defined as a BMD T-score of -2.5 or below the young normal mean for men. Since the relationship between BMD and fracture risk may differ between men and women, it is recommended that T scores in men continue to be derived using a male normative database. Similarly, for non-Caucasians, the recommendation is to diagnose osteoporosis at or below a T-score of -2.5. However, given the difficulty in defining race or ethnic groups, a dearth of data, and their conflicting nature correlating BMD with fracture risk in different ethnicities, it is recommended that a uniform normative database (not adjusted for race) be utilized in the United States for T-score derivation in non-Caucasians. Note that these are current clinical recommendations, which may change as additional data accumulate. Furthermore, there was agreement that the following individuals should have their bone density measured: anyone (male or female, regardless of race) with prior fragility fractures or with conditions widely recognized to increase the risk of bone loss and fracture (such as hypogonadism, corticosteroid treatment, hyperparathyroidism, alcohol abuse, anticonvulsant use, and prior gastrectomy); women on long-term hormone replacement therapy; and in the absence of these conditions, women age 65 and older (regardless of race) and men age 70 and older.

Body Size Accounts for Most Differences in Bone Density Between Asian and Caucasian Women

Abstract. We compared bone mineral density (BMD) of the whole body (and subregions: arm, leg, and pelvis), hip, spine, lateral spine, wrist, and forearm among Caucasian and Asian women at four geographic centers (Honolulu, HI; Nottingham, UK; Portland, OR; Copenhagen, Denmark). Data were derived from the baseline examination of 1367 Caucasian and 162 Asian women enrolled in the 1609-subject Early Postmenopausal Interventional Cohort (EPIC) study. After adjusting for age, study site, years postmenopause, and years of estrogen use, BMD was approximately 4–6% lower (P < 0.05) among Asian women at most skeletal sites, but there was no significant difference for wrist or forearm BMD. Adding height, lean body mass, fat mass, and/or quadriceps muscle strength to the regression models reduced the racial differences at most skeletal sites; after these additional adjustments, Asian women had significantly lower BMD only for the lateral spine (−4.4%; P < 0.005), arm (−2.20%; P < 0.05) and leg (−1.65%; P < 0.05), whereas the wrist was significantly greater (4.64%; P < 0.005) for Asian women. Further research is needed to determine why racial differences in BMD persist at certain skeletal sites, but not others, after adjusting for body size.

Users of low-dose glucocorticoids have increased bone loss rates: A longitudinal study

Although high doses of glucocorticoids are believed to cause bone loss, the effects of low glucocorticoid doses are still controversial. Our study examined the effects of low-dose glucocorticoids on the rate of bone loss at three appendicular bone sites. The study population was a cohort of elderly Japanese-Americans, 1094 women and 1378 men. The women were all postmenopausal. At the baseline examination the mean age of the women was 64 years (range 45–81), and the mean age of the men was 68 years (range 61–82). Glucocorticoid users (19 women and 21 men) had used oral systemic or inhaled glucocorticoids on a regular schedule for more than 1 month (mean use was 2.1 years for the women and 1.9 years for the men). The most common dose was equivalent to 5 mg/day of prednisone; fewer than 15% of users had taken doses equivalent to 10 mg/day or more. Changes in bone mass at the calcaneus, distal radius, and proximal radius were documented using bone densitometry at 1 to 2-year intervals over an 8-year period. The initial bone mass of the glucocorticoid users and controls was similar at the baseline examination. The subsequent loss rates among females during glucocorticoid use, however, were approximately double that of the controls. Among males, bone loss rates during glucocorticoid use were 2–3 times that of controls for the calcaneus and radius sites. The differences between glucocorticoid users and controls persisted after adjusting for confounding variables such as age and use of thiazides and estrogens. We conclude that users of low-dose glucocorticoids have increased rates of bone loss at appendicular sites among both elderly women and men.