Mary E. Melton

Precision and Discriminatory Ability of Calcaneal Bone Assessment Technologies

To determine if measuring skeletal status at the calcaneus is a potentially valuable technique for diagnosing osteoporosis, we examined five calcaneal assessment techniques in 53 young normal women and 108 postmenopausal women with osteoporosis and compared these measurements to dual‐energy X‐ray absorptiometry (DEXA) at the calcaneus, hip, and spine. The five instruments, including single‐energy X‐ray absorptiometry (SEXA) and four quantitative ultrasound (QUS) instruments, were evaluated for precision, ability to discriminate osteoporotic from young normal subjects, and correlation to the other instruments. The coefficient of variation (%CV) for instrument, positioning, interobserver, and short‐term precision of the five calcaneal instruments ranged from 1.34–7.76%, 1.63–7.00%, 1.84–9.44%, and 1.99–7.04%, respectively. The %CVs for positioning, interobserver, and short‐term precision were similar for calcaneal DEXA, calcaneal SEXA, and stiffness (as measured by Achilles). The %CVs for instrument precision were similar between calcaneal DEXA and SEXA. The ability of the five calcaneal instruments to discriminate osteoporotic from young normal subjects was similar based on the analysis of area under the receiver operating characteristic curves (range 0.88–0.93) and equivalent to DEXA of the calcaneus and hip (0.88–0.93). The correlations between the measurements of five calcaneal instruments were strong (0.80 ≤ r ≤ 0.91, p < 0.001). These data suggest that although the precision is variable, the calcaneal QUS and SEXA instruments can discriminate between osteoporotic patients and young normal controls and appear to be a useful technique for assessment of osteoporosis.

Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: a randomized, controlled clinical trial

Alendronate and estrogen are effective therapies for postmenopausal osteoporosis, but their efficacy and safety as combined therapy are unknown. The objective of this study was to evaluate the addition of alendronate to ongoing hormone replacement therapy (HRT) in the treatment of postmenopausal women with osteoporosis. A total of 428 postmenopausal women with osteoporosis, who had been receiving HRT for at least 1 yr, were randomized to receive either alendronate (10 mg/day) or placebo. HRT was continued in both groups. Changes in bone mineral density (BMD) and biochemical markers of bone turnover were assessed. Compared with HRT alone, at 12 months, alendronate plus HRT produced significantly greater increases in BMD of the lumbar spine (3.6% vs. 1.0%, P < 0.001) and hip trochanter (2.7% vs. 0.5%, P < 0.001); however, the between-group difference in BMD at the femoral neck was not significant (1.7% vs. 0.8%, P = 0.072). Biochemical markers of bone turnover (serum bone-specific alkaline phosphatase and urine N-telopeptide) decreased significantly at 6 and 12 months with alendronate plus HRT, and they remained within premenopausal levels. Addition of alendronate to ongoing HRT was generally well tolerated, with no significant between-group differences in upper gastrointestinal adverse events or fractures. This study demonstrated that, in postmenopausal women with low bone density despite ongoing treatment with estrogen, alendronate added to HRT significantly increased bone mass at both spine and hip trochanter and was generally well tolerated.

Performance of Risk Indices for Identifying Low Bone Density in Postmenopausal Women

OBJECTIVE To examine the ability of 4 published osteoporosis risk indices to identify women with low bone density. SUBJECTS AND METHODS Subjects included postmenopausal women 45 years and older consecutively recruited from US clinics, women from general practice centers in The Netherlands (age range, 50-80 years), women in the Rotterdam Study (The Netherlands) 55 years and older, and women aged 55 to 81 years old screened for a clinical trial of alendronate. Bone mineral density (BMD) was measured at the femoral neck or lumbar spine; T scores represent the number of SDs below the mean for young healthy women. One risk index was calculated from age and weight; the other risk indices included up to 4 additional variables obtained by questionnaire. We calculated the sensitivity and specificity for identifying women with BMD T scores of -2.5 or less or -2.0 or less in the US clinic sample and created 3 risk categories, using each of the 4 indices. RESULTS Data were available for 1102 women from the US clinic sample, 3374 women in the Rotterdam Study, 23,833 women screened for a clinical trial of alendronate, and 4204 women from general practice centers in The Netherlands. Specificity for identifying BMD T scores of -2.5 or less ranged from 37% to 58% (depending on risk index) when sensitivity was approximately 90%. The prevalence of osteoporosis (defined as T scores < or = -2.5) differed widely across the 3 risk categories, ranging from 2% to 4% for the low-risk category to 47% to 61% for the high-risk category in the US clinic sample. For spine BMD in the US clinic sample, the prevalence of T scores of -2.5 or less ranged from 7% (low risk) to 38% (high risk). The large differences in prevalence across risk categories were consistent across the other 3 samples of postmenopausal women in the United States and The Netherlands for all 4 risk indices. CONCLUSIONS We recommend measuring BMD in women who are classified as having an increased risk of osteoporosis by using any of these risk indices because all 4 indices appear to predict low bone mass equally well. The Osteoporosis Self-assessment Tool index is easiest to calculate and therefore may be most useful in clinical practice.

Alendronate Improves Bone Mineral Density in Elderly Women with Osteoporosis Residing in Long-Term Care Facilities: A Randomized, Double-Blind, Placebo-Controlled Trial

Context Although the prevalence of osteoporosis increases with advancing age, most therapeutic studies have focused on younger postmenopausal women. It is not known whether treatment is effective in elderly women. Contribution The efficacy and tolerability of alendronate in elderly female residents of long-term care facilities were tested in a 2-year randomized, double-blind, placebo-controlled study. Alendronate significantly increased bone mineral density and decreased bone turnover when compared with placebo in this elderly population. Side effects did not differ between treatment groups. Implications Elderly women with osteoporosis may benefit from alendronate therapy. The effect of this therapy on incidence of fractures or the optimum length of therapy cannot be determined from this study. The Editors Osteoporosis increases in prevalence with age and is very common in elderly women. The estimated prevalence of osteoporosis in community-dwelling elderly women aged 70 to 79 years is 55%; this rate increases to 73% among those older than 80 years of age (1). The prevalence in elderly female residents of long-term care facilities is even higher. One study (2) reported an 85% prevalence of osteoporosis at nursing home admission. A large survey of nursing home residents found a prevalence of 63.5% for women aged 65 to 74 years and 85.8% for women older than 85 years of age (3). Because most osteoporosis studies have focused on younger postmenopausal women and few studies have evaluated residents of long-term care facilities, we examined the efficacy and tolerability of alendronate for treating osteoporosis in elderly female residents of long-term care facilities. Methods This randomized, double-blind, placebo-controlled, 2-year study was conducted at 25 U.S. centers. Each center recruited ambulatory female residents 65 years of age or older who lived in local long-term care facilities, including skilled-care nursing homes and assisted-living centers, but not facilities that housed independent, community-dwelling elderly persons. Participants were required to have a bone mineral density (BMD) lower than a T-score of 2.0 at the posterioranterior lumbar spine or total hip. Women were excluded for the following: disorders of bone mineralization, 25-hydroxycholecalciferol level less than 25 nmol/L, untreated hyperthyroidism, recent major upper gastrointestinal mucosal erosive disease, or use of bone-active agents. The ethics committee for each site approved the study, and all patients gave informed consent. A total of 832 women consented to participate; the 327 women who met the inclusion and exclusion criteria were enrolled. Patients were randomly assigned (using a computer-generated allocation schedule) to receive alendronate, 10 mg/d (Fosamax, Merck & Co., Inc., Whitehouse Station, New Jersey), or matching placebo for 24 months. Patients also received vitamin D, 400 IU/d. Calcium carbonate (OsCal 500, SmithKlineBeecham Consumer Healthcare, Pittsburgh, Pennsylvania) was given to patients whose daily dietary calcium intake was less than 1500 mg. Bone mineral density of the hip and spine was measured by using dual-energy x-ray absorptiometry (Hologic, Waltham, Massachusetts) and was analyzed by a central quality assurance center (MDM, Waltham, Massachusetts). A central laboratory (Pacific Biometrics, Seattle, Washington) analyzed biochemical markers of bone formation (serum bone-specific alkaline phosphatase, measured by using Tandem-R Ostase kit, Hybritech, Inc., San Diego, California) and bone resorption (urinary N-telopeptide of type I collagen adjusted for urinary creatinine, measured by using Osteomark enzyme-linked immunoassay, Ostex International, Inc., Seattle, Washington). We also collected routine laboratory measures for safety (chemistry, hematology, and urinalysis) and information on the occurrence of clinical adverse experiences and clinical fractures. We used SAS software, version 6.12, for statistical analyses (SAS Institute, Inc., Cary, North Carolina). Baseline demographic characteristics of the two treatment groups were compared by using t-tests (for continuous data) and Fisher exact tests (for categorical data). Analysis of variance was used to compare BMD and biomarker end points between groups. Paired t-tests were used to compare outcomes against baseline values within treatment groups. An intention-to-treat approach was followed in the analyses of BMD end points (for missing data, the last postrandomization observation was carried forward to subsequent time points) and safety data. A per protocol approach was used for analysis of biomarkers. Sensitivity analyses were done separately for BMD and biomarker end points by using mixed models that accounted for the correlation between all available measurements of BMD (up to 12 for each participant) and biomarkers (up to 8 for each participant). Data points were not carried forward in these analyses. Treatment comparisons were made by using the appropriate contrasts from the interaction term for treatment test site visit (using the MIXED procedure [4]). Employees of Merck & Co., Inc., contributed to the protocol design, recruitment of investigators, and collection and analysis of data. Merck & Co., Inc., had committed to submitting the data for publication regardless of study outcome. Results Most patients were residents of continuing-care retirement communities (68%); others resided in retirement communities (12%), congregate-care facilities (8%), and other types of facilities (12%), including skilled-care nursing homes and residential-care facilities. The characteristics of each treatment group were similar at baseline. The mean age was 78.5 years (range, 65 to 91 years). Most patients (97%) were white. The mean BMD T-scores at the hip and spine ranged from 3.5 to 2.4. Fifty-five percent of patients had a history of fracture, 19% reported a history of upper gastrointestinal disorder at baseline, and 64% used either aspirin or a nonsteroidal anti-inflammatory drug during the study. Increases in BMD at all sites were significantly greater in the alendronate group than in the placebo group at all time points measured (Figure 1). Compared with placebo, alendronate produced significantly greater increases in BMD (24-month differences: posterioranterior spine, 4.4% [95% CI, 3.3% to 5.5%]; lateral lumbar spine, 5.7% [CI, 3.9% to 7.5%]; femoral neck, 3.4% [CI, 2.3% to 4.4%]; hip trochanter, 4.7% [CI, 3.4% to 6.0%]). The largest increases from baseline with alendronate occurred at the lateral lumbar spine (7.4% [CI, 6.1% to 8.7%]; absolute change, 0.039 g/cm2 [CI, 0.032 to 0.046 g/cm2]; P < 0.001) and the posterioranterior lumbar spine (6.3% [CI, 5.5% to 7.0%]; absolute change, 0.047 g/cm2 [CI, 0.042 to 0.053 g/cm2]; P < 0.001) at 24 months. Decreases in levels of bone-specific alkaline phosphatase and urinary N-telopeptide adjusted for urinary creatinine were significantly greater in alendronate recipients than in placebo recipients at all time points measured (P < 0.001) (Figure 2). The mixed-model analyses yielded similar results. Figure 1. Changes in bone mineral density ( BMD ). circles squares P P P P P Figure 2. Changes in biochemical markers of bone turnover. N circles squares P P P P P N More patients receiving placebo experienced a fracture during the study (11% of placebo recipients vs. 8% of alendronate recipients), but this finding was not statistically significant. Hip fracture occurred in 4 patients receiving placebo and 2 patients receiving alendronate. Overall, 13 fractures were reported in 13 patients receiving alendronate and 28 fractures were reported in 18 patients receiving placebo. In each group, the percentage of patients reporting any clinical adverse experience was the same (93%). The percentage of patients reporting any upper gastrointestinal adverse event did not significantly differ between groups (33% in the alendronate group vs. 35% in the placebo group), nor did the percentage of patients reporting serious upper gastrointestinal adverse events (0.6% for alendronate vs. 1.9% for placebo). Discussion In this study, alendronate significantly improved both hip and spine BMD in elderly female residents of long-term care facilities. These improvements were associated with the expected decreases in bone resorption. In addition, alendronate was generally well tolerated in this elderly cohort. Although several studies have documented improvements in BMD among community-dwelling postmenopausal women treated with alendronate, our study is the first to examine the efficacy of 10 mg of alendronate per day in elderly residents of long-term care facilities. Bone and colleagues (5) studied community-dwelling elderly women with osteoporosis (mean age, 71 years) and found a dose-related response of BMD with use of alendronate dosages as high as 5 mg/d. The improvements in BMD in our study indicate that even in elderly women, BMD significantly increases with alendronate. Furthermore, a woman who reaches age 65 years can on average expect to live to age 84, and women who survive to age 85 can expect to live to age 92 (6). Therefore, it would be clinically relevant and appropriate to treat these patients, even though they are elderly, with a medication that reduces fracture rates in 1 to 3 years. No bone loss occurred in the placebo group. This may have been due to adequate calcium intake and the use of vitamin D. Previous studies have shown that bone loss slows with calcium supplementation (7, 8) and that hip BMD increases and fracture rate decreases with use of vitamin D and calcium supplementation in elderly female residents of long-term care facilities (9). Our study showed that while use of calcium and vitamin D alone may help slow bone loss, additional therapy is required to substantially increase BMD. Establishing safety is important when any medication is given to elderly patients in long-term care settings. Previous clinical trials with

ALENDRONATE PRODUCES GREATER EFFECTS THAN RALOXIFENE ON BONE DENSITY AND BONE TURNOVER IN POSTMENOPAUSAL WOMEN WITH LOW BONE DENSITY: RESULTS OF EFFECT (EFFICACY OF FOSAMAX VERSUS EVISTA COMPARISON TRIAL) INTERNATIONAL

Objectives.  Alendronate and raloxifene are antiresorptive agents with different mechanisms of action, each used to treat osteoporosis in postmenopausal women. This study was undertaken to compare the efficacy and tolerability of alendronate to raloxifene in postmenopausal women with low‐bone density.

Treatment with alendronate plus calcium, alendronate alone, or calcium alone for postmenopausal low bone mineral density

ABSTRACT Objective: Bisphosphonates such as alendronate are widely used for postmenopausal osteoporosis. Supplemental calcium is also generally recommended. This trial directly compares alendronate to supplemental calcium and examines the effect of calcium supplementation on alendronate treatment. Methods: This 2-year, randomized, double-blind, multicenter trial enrolled healthy, postmenopausal women with low bone mineral density (BMD). Patients with a dietary calcium intake ≥ 800 mg/day received daily vitamin D 400 IU and alendronate 10 mg/calcium-placebo, alendronate 10 mg/elemental calcium 1000 mg, or alendronate-placebo/calcium 1000 mg (2:2:1). Endpoints included BMD, bone turnover markers (BTMs), and adverse events. Results: Randomized patients (N = 701) were an average of 20.4 years postmenopausal. After 24 months, increases in lumbar spine BMD differed significantly between patients receiving calcium alone (0.8%) and either alendronate alone (5.6%) or alendronate + calcium (6.0%) ( p < 0.001). Significant differences were also seen at the trochanter and femoral neck ( p < 0.001). BTMs were significantly lower with alendronate-containing treatments than calcium alone ( p < 0.001). Addition of calcium supplementation to alendronate did not significantly increase BMD compared to alendronate alone ( p = 0.29 to 0.97), but did result in a statistically significant, though small, additional reduction in urinary NTx. Adverse events were similar among treatment groups. Limitations include no assessment of vitamin D levels and a discontinuation rate of approximately 30%, although discontinuation rates were similar among treatment groups. Conclusions: In postmenopausal women with a daily intake of ≥ 800 mg calcium and 400 IU vitamin D, 24-month treatment with alendronate 10 mg daily with or without calcium 1000 mg resulted in significantly greater increases in BMD and reduction of bone turnover than supplemental calcium alone. Addition of supplemental calcium to alendronate treatment had no effect on BMD and resulted in a small, though statistically significant, additional reduction in NTx.

Rechallenge of patients who had discontinued alendronate therapy because of upper gastrointestinal symptoms

BACKGROUND There have been reports from physicians in clinical practice that up to 30% of patients taking bisphosphonate therapy develop upper gastrointestinal (UGI) symptoms, many or most of which they assume to be related to the drug. However, in several large placebo-controlled clinical trials of bisphosphonates, the incidence of UGI symptoms has been > or =30%, even among patients receiving placebo, perhaps reflecting a high background incidence of UGI events in osteoporotic patients. OBJECTIVE To assess the relationship between alendronate treatment and UGI complaints in patients who had discontinued treatment with alendronate in clinical practice because of UGI symptoms, we compared the incidence of such events on rechallenge with alendronate or placebo. METHODS This was a multicenter, double-blind trial in which postmenopausal women with osteoporosis who had previously discontinued alendronate therapy because of a UGI adverse experience were randomized to daily treatment with either alendronate 10 mg or matching placebo (1:1 ratio) for 8 weeks. The primary end point was the cumulative incidence of discontinuations due to any UGI adverse experience. Secondary end points were the incidence of any clinical adverse experiences and the percentage change from baseline in urinary N-telopeptide adjusted for urinary creatinine at week 8. RESULTS A total of 172 women were included in the study. They were a mean of 20.9 years past menopause, ranging in age from 41 to 90 years (mean, 67.0 years); 90.7% were white. On rechallenge, 14.8% (13/88) of patients in the alendronate group and 16.7% (14/84) in the placebo group discontinued treatment because of UGI adverse experiences. CONCLUSION The results of this study suggest that many UGI adverse experiences reported during therapy with alendronate may reflect a high background incidence of UGI complaints and an increased sensitivity to detection of such complaints, rather than a causal relationship to therapy.

Precision and accuracy of computed digital absorptiometry for assessment of bone density of the hand

Abstract: Widespread osteoporosis testing and diagnosis are currently limited due to the high capital cost and reduced portability of many existing bone densitometry techniques. In this study we evaluated an inexpensive, low radiation, X-ray-based technique for assessing bone density of the middle phalanx. The technique, termed computed digital absorptiometry (CDA), is similar to radiographic absorptiometry (RA), using a single-energy X-ray source, an aluminum alloy step-wedge, and a charge-coupled device (CCD) detector system to automatically compute bone mineral content (BMC, g) and bone mineral density (BMD, g/cm2) in the middle phalanx of the third finger. The potential advantage of CDA over current RA techniques is that by using a filmless detector system, no off-site processing of radiographs is required and bone density results are obtained immediately after the test. Using human cadaveric specimens we determined the accuracy and short-term precision of CDA as well as its correlation with other hand and forearm bone densitometry methods. We obtained 26 cadaveric forearms (50% female, mean age 78 years, range 52–96 years). BMC and BMD of the middle phalanx of the third finger were determined using CDA and using RA. We assessed forearm BMC and BMD using single-energy and dual-energy X-ray absorptiometry (SXA and DXA). Precision of CDA was assessed by measuring ten of the specimens five times each with repositioning between measurements. Finally, the middle phalanx was dissected and incinerated to determine ash weight. BMC estimates from CDA and from RA were strongly correlated with ash weight (r = 0.89, p < 0.001 and r = 0.93, p < 0.001, respectively). The mean coefficients of variation using CDA were 1.36% and 0.70% for phalanx BMC and BMD, respectively. BMC and BMD measured by CDA were strongly correlated with hand and forearm bone mineral measurements performed by SXA, DXA and TA (r = 0.74–0.91). These results indicate that CDA accurately and precisely predicts BMC of the middle phalanx. Thus, with further clinical verification, this technique may prove to be a useful tool for the wide-spread testing and assessment of osteoporotic fracture risk.

Upper gastrointestinal and overall tolerability of alendronate once weekly in patients with osteoporosis: results of a randomized, double-blind, placebo-controlled study

SUMMARY Objective: To compare the upper gastrointestinal (GI) and overall tolerability profiles of alendronate 70 mg once weekly with placebo. Research design and methods: This 12-week international, multi-center, randomized, double-blind, placebo-controlled trial included 449 postmenopausal women and men with osteoporosis at 44 sites in 19 countries in Europe, the Americas, Africa, and Asia-Pacific. Subjects were randomized to alendronate 70 mg once weekly or matching placebo in a 1:1 ratio. Main outcome measures: The safety and tolerability of weekly alendronate and placebo were captured as clinical and laboratory adverse events. The primary endpoint was upper GI tolerability based on the incidence of upper GI tract adverse events. Secondary endpoints included the percentage of subjects who discontinued therapy due to a drug-related upper GI adverse event. Change from baseline in bone turnover as measured by the urinary N-telopeptide-collagen crosslinks corrected for creatinine (NTx/Cr) was assessed at 12 weeks as an indicator of efficacy. Results: The percentages of subjects reporting an upper GI tract adverse event in the alendronate 70 mg once weekly group (9.8%) and the placebo group (9.4%) were similar. The risk difference between the two treatment groups (alendronate minus placebo) was 0.4% [95% confidence interval (CI), –5.1%, 5.9%]. Percentages of subjects who discontinued due to a drug-related upper GI adverse event were also similar (alendronate 2.7%; placebo 2.2%; risk difference 0.4%, 95% CI, –2.4, 3.3). The overall tolerability profile of alendronate 70 mg once weekly, as measured by the percentage of subjects reporting any adverse event, was similar to that of placebo (risk difference 2.1%, 95% CI –6.9,11.0). There was a significant 43.3% (95% CI, –47.9%, –38.3%) decrease from baseline in urinary NTx/Cr in the alendronate group compared with an 8.0% (95% CI, 1.4%, 15.0%) increase in the placebo group at Week 12 Conclusion: Alendronate 70 mg administered once weekly to women and men with osteoporosis has an upper GI and overall tolerability profile similar to that of placebo.

A comparison of the effect of alendronate and risedronate on bone mineral density in postmenopausal women with osteoporosis: 24‐month results from FACTS‐International

Objectives:  To compare alendronate 70 mg once weekly (OW) with risedronate 35 mg OW with respect to change in bone mineral density (BMD), biochemical markers and upper gastrointestinal (UGI) tolerability over 24 months.