Susan L. Greenspan

Effect of Recombinant Human Parathyroid Hormone (1-84) on Vertebral Fracture and Bone Mineral Density in Postmenopausal Women with Osteoporosis: A Randomized Trial

Context Researchers have not previously reported the efficacy and safety of parathyroid hormone (1-84) (PTH) for the primary prevention of osteoporotic fractures. Contributions Among 2532 postmenopausal women with osteoporosis randomly assigned to receive PTH or placebo, PTH decreased new vertebral fractures. The magnitude of the effect depended on assumptions about fractures in the one third of patients who withdrew from the trial prematurely. Adverse effects included hypercalciuria, hypercalcemia, and nausea. Caution Endogenous PTH and vitamin D levels could affect patients response to the drug but were not assessed in the study. Implications Parathyroid hormone (1-84) effectively prevented new vertebral fractures but also increased hypercalciuria, hypercalcemia, and nausea. The Editors Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing patients to an increased risk for fracture (1). Optimal treatment for osteoporosis should improve the amount, density, and quality of bone, thereby reducing skeletal fragility and fractures. Antiresorptive agents, such as bisphosphonates, are commonly used for treating postmenopausal osteoporosis. Although these agents preserve bone architecture, they do not stimulate new bone formation or improve bone architecture. Anabolic or bone-forming agents are an alternative approach to the treatment of osteoporosis. Researchers have shown that parathyroid hormone (PTH) and certain peptide fragments of PTH increase bone mass and improve bone quality (2, 3). Teriparatide, a fragment of human PTH composed of its N-terminal 34 amino acids, has been approved for the treatment of postmenopausal women with osteoporosis who are at high risk for bone fracture. However, researchers have studied this agent only in women with prevalent vertebral fractures (4), and data demonstrating prevention of the first vertebral fracture are lacking. We conducted the Treatment of Osteoporosis with Parathyroid Hormone (TOP) Study to examine the efficacy and safety of PTH (1-84) versus placebo for treating postmenopausal women with osteoporosis. We designed the study to examine the change in incidence of all vertebral fractures between the treatment groups. We also designed the study to examine the efficacy of this new bone-forming agent in preventing a first vertebral fracture in women without a vertebral fracture. Methods Study Participants We included postmenopausal women 45 to 54 years of age if bone mineral density (BMD) was 3.0 SDs or more (T-score 3.0) below the mean peak bone mass of young adult women at the lumbar spine, femoral neck, or total hip with no prevalent vertebral fracture or if BMD T-score was2.5 and they had 1 to 4 vertebral fractures before enrollment. We included postmenopausal women 55 years of age or older if BMD T-score was2.5 and they had no vertebral fractures or if BMD T-score was2.0 and they had 1 to 4 vertebral fractures. We excluded women if baseline serum calcium level was greater than 2.66 mmol/L (>10.7 mg/dL) or if urinary calciumcreatinine ratio was 1.0 or more. We included women with mild hypercalcemia (serum calcium, 2.55 to 2.66 mmol/L [10.2 to 10.7 mg/dL]) and mild hypercalciuria (24-hour urine calcium7.6 mmol [302 mg]) at baseline. We did not measure baseline levels of serum PTH and vitamin D. We excluded women if they had taken bisphosphonates for a total of more than 12 months or for more than 90 days in the 12 months before enrollment. We allowed previous estrogen therapy if it had been discontinued for at least 4 weeks before the screening visit. We excluded women who had received PTH (or a peptide fragment or analogue), PTH-related protein, fluoride, or strontium and those who had a history of metabolic bone disease (other than osteoporosis), nephrolithiasis, or clinically significant hepatic or renal disorders. We also excluded women who were taking medications known to affect bone mineral metabolism. The ethics review committee for each center approved the study. All women provided written informed consent. An independent data and safety monitoring board reviewed the progress and safety of the study. Study Design We conducted a randomized, double-blind, placebo-controlled, parallel-group study in 168 centers in 9 countries. We randomly assigned the study drug to blocks of 4 patients by using a computer-generated algorithm and shipped it in blocks of 4 to each study site. Women at each site were sequentially assigned the uniquely numbered, randomly assigned study drug treatment kits by telephone. Women were stabilized for at least 2 weeks with supplemental calcium, 700 mg/d citrate salt, and vitamin D3, 400 U/d, and then received 100 g of recombinant human PTH or placebo daily by subcutaneous injection for 18 months with continued calcium and vitamin D3 supplementation. Patients were instructed to administer the injection in the morning in the thigh or abdomen by using an injector pen. Study Conduct and Outcome Measures The primary end point was the occurrence of new or worsened vertebral fractures (in all women and in women with and without a prevalent fracture) identified by radiography at baseline, month 18, or the final study visit. Radiologists assessed vertebral fractures in a blinded manner at a central reading organization by using a semiquantitative 4-point grading scale (5). An incident vertebral fracture (new or worsened) was identified by a change in grade of 1 or more from baseline. Secondary outcomes included changes in BMD at lumbar spine, hip, whole body, and forearm (distal one-third radius) that we measured by using dual-energy x-ray absorptiometry with Hologic (Hologic Inc., Bedford, Massachusetts) or Lunar (GE Medical Systems, Madison, Wisconsin) densitometers (reported as percentage change from baseline to standardize instrumental differences in determining absolute BMD) and stadiometric measurements of height. We measured whole body and forearm BMD only in a subset of approximately 300 women from selected sites with appropriate software. We reported nonvertebral clinical fractures and bone loss (>7% at lumbar spine or >9% at total hip or femoral neck) as adverse events. We did not distinguish between traumatic and fragility nonvertebral fractures. We used quantitative computed tomography (6, 7) to evaluate the effects of PTH treatment at month 18 on volumetric cortical and trabecular BMD at lumbar vertebra (L3) and the hip in 122 consenting women from a single center at which the technique was available. We assessed bone turnover markers (serum bone-specific alkaline phosphatase and urinary N-telopeptides of type I collagen) in the first 600 randomly assigned women in the study. We measured bone-specific alkaline phosphatase by using the Tandem R-Ostase immunoradiometric assay (interassay coefficient of variation, 8%) (Hybritech, San Diego, California). We measured N-telopeptides of type I collagen by using Osteomark enzyme-linked immunoabsorbent assay kits (interassay coefficient of variation, 4.0%) (Wampole Laboratories, Princeton, New Jersey) normalized to urine creatinine concentrations. We made safety assessments at months 1, 3, 6, 9, 12, 15, and 18 that included physical examinations, vital signs, electrocardiography (months 1, 12, and 18), adverse-event monitoring and central clinical laboratory assessments consisting of chemistry (including serum total calcium and creatinine), hematology, and urinalysis (including 24-hour urine collections and fasting, morning urinary calciumcreatinine ratios). Adverse events were reported spontaneously by patients, captured in a patients diary, or reported by a patient in response to an open-ended question from clinical study personnel. We used a central laboratory normal range for serum total calcium level of 2.15 to 2.55 mmol/L (8.6 to 10.2 mg/dL). We performed an analysis for antibodies to PTH with a validated electrochemiluminescent immunoassay by using biotinylated recombinant human PTH (range, 26.3 to 2632.5 pmol/L; intra-assay coefficient of variation, 8% to 16%) (Igen International, Inc., Gaithersburg, Maryland). We obtained iliac crest bone biopsy specimens at month 12 or 18 from a subset of 40 consenting women after tetracycline double-labeling (8) that we examined for abnormal bone structure. We anticipated that women might need to discontinue calcium supplementation and reduce the dosing frequency of the study drug to prevent excessive increases in serum calcium level, urinary calcium level, or both. We conservatively predefined hypercalcemia as a single, unconfirmed, predose serum total calcium value greater than 2.66 mmol/L (>10.7 mg/dL) and hypercalciuria as a 24-hour urinary calcium value of 7.6 mmol or more (302 mg) (increased to >9.0 mmol [>360 mg] during the study) or a fasting urinary calciumcreatinine ratio of 1.0 or more. If a woman developed hypercalcemia or hypercalciuria, we discontinued the daily calcium supplementation; if either condition continued, we reduced the dosing frequency of the study drug. Statistical Analysis We estimated the sample size for our study by assuming that 67% of the patients would not have a prevalent fracture; that the 18-month vertebral fracture incidence for patients with and without a prevalent fracture who received placebo would be 10% and 2.5%, respectively; and that 20% of the patients in each group would discontinue the study early without a new or worsened fracture. We expected a sample of 2600 patients (1300 per treatment group) to provide at least 90% power to detect a significant 60% or greater reduction in vertebral fracture incidence in the PTH treatment group compared with the placebo group (2-sided level of 0.05). We analyzed data by using SAS software, version 8.0 (SAS Institute, Inc., Cary, North Carolina). We used descriptive statistics to summarize demographic and other baseline variables. We assessed comparability of the treatment groups at baseline by using t-tests for continuous varia

Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis

Dosing convenience is a key element in the effective management of any chronic disease, and is particularly important in the long-term management of osteoporosis. Less frequent dosing with any medication may enhance compliance, thereby maximizing the effectiveness of therapy. Animal data support the rationale that once-weekly dosing with alendronate 70 mg (7 times the daily oral treatment dose) could provide similar efficacy to daily dosing with alendronate 10 mg due to its long duration of effect in bone. In addition, dog studies suggest that the potential for esophageal irritation, observed with daily oral bisphosphonates, may be substantially reduced with once-weekly dosing. This dosing regimen would provide patients with increased convenience and would be likely to enhance patient compliance. We compared the efficacy and safety of treatment with oral once-weekly alendronate 70 mg (N=519), twice-weekly alendronate 35 mg (N=369), and daily alendronate 10 mg (N=370) in a one-year, double- blind, multicenter study of postmenopausal women (ages 42 to 95) with osteoporosis (bone mineral density [BMD] of either lumbar spine or femoral neck at least 2.5 SDs below peak premenopausal mean, or prior vertebral or hip fracture). The primary efficacy endpoint was the comparability of increases in lumbar spine BMD, using strict pre-defined equivalence criteria. Secondary endpoints included changes in BMD at the hip and total body and rate of bone turnover, as assessed by biochemical markers. Both of the new regimens fully satisfied the equivalence criteria relative to daily therapy. Mean increases in lumbar spine BMD at 12 months were: 5.1% (95% CI 4.8, 5.4) in the 70 mg once-weekly group, 5.2% (4.9, 5.6) in the 35 mg twice-weekly group, and 5.4% (5.0, 5.8) in the 10 mg daily treatment group. Increases in BMD at the total hip, femoral neck, trochanter, and total body were similar for the three dosing regimens. All three treatment groups similarly reduced biochemical markers of bone resorption (urinary N-telopeptides of type I collagen) and bone formation (serum bone-specific alkaline phosphatase) into the middle of the premenopausal reference range. All treatment regimens were well tolerated with a similar incidence of upper GI adverse experiences. There were fewer serious upper GI adverse experiences and a trend toward a lower incidence of esophageal events in the once-weekly dosing group compared to the daily dosing group. These data are consistent with preclinical animal models, and suggest that once-weekly dosing has the potential for improved upper GI tolerability. Clinical fractures, captured as adverse experiences, were similar among the groups. We conclude that the alendronate 70 mg once-weekly dosing regimen will provide patients with a more convenient, therapeutically equivalent alternative to daily dosing, and may enhance compliance and long-term persistence with therapy.

Fall Direction, Bone Mineral Density, and Function: Risk Factors for Hip Fracture in Frail Nursing Home Elderly

PURPOSE To determine the importance of fall characteristics, body habitus, function, and hip bone mineral density as independent risk factors for hip fracture in frail nursing home residents. SUBJECTS AND METHODS In this prospective, case-control study of a single, long-term care facility, we enrolled 132 ambulatory residents (95 women and 37 men) aged 65 and older, including 32 cases (fallers with hip fracture) and 100 controls (fallers with no hip fracture). Principal risk factors included fall characteristics, body habitus, measures of functional assessment, and hip bone mineral density by dual-energy X-ray absorptiometry. RESULTS In multivariate analysis, including only those with knowledge of the fall direction (n=100), those who fell and suffered a hip fracture were more likely to have fallen sideways (odds ratio 5.7, 95% confidence interval [CI] 1.7 to 18, P= 0.004) and have a low hip bone mineral density (odds ratio 1.9, 95% CI 0.97 to 3.7, P=0.06) than those who fell and did not fracture. When all participants were included (n=132) and subjects who did not know fall direction were coded as not having fallen to the side, a fall to the side (odds ratio 3.9, 95% CI 1.3 to 11, P=0.01), low hip bone density (odds ratio 1.8, 95% CI 1.03 to 3, P=0.04), and impaired mobility (odds ratios 6.4, 95% CI 1.9 to 21, P=0.002) were independently associated with hip fracture. Sixty-seven percent of subjects (87% with and 62% without hip fracture) had a total hip bone mineral density greater than 2.5 SD below adult peak bone mass and were therefore classified as having osteoporosis using World Health Organization criteria. CONCLUSIONS Among frail elderly nursing home fallers, the preponderance of whom are osteoporotic, a fall to the side, a low hip bone density, and impairment in mobility are all important and independent risk factors for hip fracture. These data suggest that, among the frailest elderly, measures to reduce the severity of a sideways fall and improve mobility touch on new domains of risk, independent of bone mineral density, that need to be targeted for hip fracture prevention in this high-risk group.

Obesity is not protective against fracture in postmenopausal women: GLOW

OBJECTIVE To investigate the prevalence and incidence of clinical fractures in obese, postmenopausal women enrolled in the Global Longitudinal study of Osteoporosis in Women (GLOW). METHODS This was a multinational, prospective, observational, population-based study carried out by 723 physician practices at 17 sites in 10 countries. A total of 60,393 women aged ≥ 55 years were included. Data were collected using self-administered questionnaires that covered domains that included patient characteristics, fracture history, risk factors for fracture, and anti-osteoporosis medications. RESULTS Body mass index (BMI) and fracture history were available at baseline and at 1 and 2 years in 44,534 women, 23.4% of whom were obese (BMI ≥ 30 kg/m(2)). Fracture prevalence in obese women at baseline was 222 per 1000 and incidence at 2 years was 61.7 per 1000, similar to rates in nonobese women (227 and 66.0 per 1000, respectively). Fractures in obese women accounted for 23% and 22% of all previous and incident fractures, respectively. The risk of incident ankle and upper leg fractures was significantly higher in obese than in nonobese women, while the risk of wrist fracture was significantly lower. Obese women with fracture were more likely to have experienced early menopause and to report 2 or more falls in the past year. Self-reported asthma, emphysema, and type 1 diabetes were all significantly more common in obese than nonobese women with incident fracture. At 2 years, 27% of obese women with incident fracture were receiving bone protective therapy, compared with 41% of nonobese and 57% of underweight women. CONCLUSIONS Our results demonstrate that obesity is not protective against fracture in postmenopausal women and is associated with increased risk of ankle and upper leg fractures.

Osteoporosis in men with hyperprolactinemic hypogonadism.

To ascertain the effects of chronic hyperprolactinemia and testosterone deficiency on skeletal integrity in men, we measured forearm bone density and hormone concentrations in 18 men aged 30 to 79 who had prolactin-secreting pituitary tumors. We also measured vertebral bone density in 12 of the men. Patients with hyperprolactinemia had significant decreases in both forearm (p less than 0.001) and vertebral bone density (p = 0.003) compared with age-matched controls. Cortical osteopenia was significantly related to the duration of hyperprolactinemia (p less than 0.01) but not to the absolute levels of prolactin or androgens. Seven patients had longitudinal follow-up measurements of forearm bone density. Normalization of serum levels of prolactin or testosterone was associated with an increase in forearm bone density (p less than 0.05). These data show that chronic hyperprolactinemia and testosterone deficiency in men have deleterious and previously unrecognized extragonadal effects that may be alleviated after normalization of hormone concentrations.

Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: a randomized clinical trial.

Although the antiresorptive agent alendronate has been shown to increase bone mineral density (BMD) at the hip and spine and decrease the incidence of osteoporotic fractures in older women, few data are available regarding early prediction of long‐term response to therapy, particularly with regard to increases in hip BMD. Examining short‐term changes in biochemical markers incorporates physiologic response with therapeutic compliance and should provide useful prognostic information for patients. The objective of this study was to examine whether early changes in biochemical markers of bone turnover predict long‐term changes in hip BMD in elderly women. The study was a double‐blind, placebo‐controlled, randomized clinical trial which took place in a community‐based academic hospital. One hundred and twenty community‐dwelling, ambulatory women 65 years of age and older participated in the study. Intervention consisted of alendronate versus placebo for 2.5 years. All patients received appropriate calcium and vitamin D supplementation. The principal outcome measures included BMD of the hip (total hip, femoral neck, trochanter, and intertrochanter), spine (posteroanterior [PA] and lateral), total body, and radius. Biochemical markers of bone resorption included urinary N‐telopeptide cross‐linked collagen type I and free deoxypyridinoline; markers of bone formation included serum osteocalcin and bone‐specific alkaline phosphatase. Long‐term alendronate therapy was associated with increased BMD at the total hip (4.0%), femoral neck (3.1%), trochanter (5.5%), intertrochanter (3.8%), PA spine (7.8%), lateral spine (10.6%), total body (2.2%), and one‐third distal radius (1.3%) in elderly women (all p < 0.01). In the placebo group, bone density increased 1.9–2.1% at the spine (p < 0.05) and remained stable at all other sites. At 6 months, there were significant decreases in all markers of bone turnover (–10% to –53%, p < 0.01) in women on alendronate. The changes in urinary cross‐linked collagen at 6 months correlated with long‐term bone density changes at the hip (r = –0.35, p < 0.01), trochanter (r = –0.36, p < 0.01), PA spine (r = –0.41, p < 0.01), and total body (r = –0.34, p < 0.05). At 6 months, patients with the greatest drop in urinary cross‐linked collagen (65% or more) demonstrated the greatest gains in total hip, trochanteric, and vertebral bone density (all p < 0.05). A 30% decrease in urinary cross‐linked collagen at 6 months predicted a bone density increase of 2.8–4.1% for the hip regions and 5.8–6.9% for the spine views at the 2.5‐year time point (p < 0.05). There were no substantive associations between changes in biochemical markers and bone density in the placebo group. Alendronate therapy was associated with significant long‐term gains in BMD at all clinically relevant sites, including the hip, in elderly women. Moreover, these improvements were associated with early decreases in biochemical markers of bone turnover. Early dynamic decreases in urinary cross‐linked collagen can be used to monitor and predict long‐term response to bisphosphonate therapy in elderly women. Future studies are needed to determine if early assessment improves long‐term patient compliance or uncovers poor compliance, thereby aiding the physician in maximizing the benefits of therapy.

The Effect of Thyroid Hormone on Skeletal Integrity

Women with a history of hyperthyroidism or thyroid-stimulating hormone suppression by thyroid hormone should have skeletal status assessed by bone mineral densitometry, preferably at a site contain...

Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy.

Abstract: Serum CrossLaps is a new assay for measuring carboxy-terminal collagen crosslinks (CTX) in serum. This measurement is reported to be more specific to bone resorption than other measurements. However, the utility of this and other markers in monitoring patients on antiresorptive therapy depends on how often changes anticipated with therapy exceed changes attributable to random variability. In a study where subjects received either placebo or pamidronate, we calculated the minimum significant change (MSC), that is, the change that was sufficiently large that it was unlikely to be due to spontaneous variability. We also examined the changes in markers of bone turnover in subjects treated with pamidronate (APD) (30 mg I.V. in 500 ml D5W over 4 hours) to see how often observed changes in turnover after treatment exceeded the MSC. The MSC for serum CTX was 30.2%, and was significantly (P < 0.05) lower than the MSC for urinary NTX (54.0%), and not significantly different from the MSC of urinary DPD (20.6%). Ninety percent of subjects treated with APD had a decline in serum CTX that exceeded the MSC, compared with 74% for bone-specific alkaline phophatase (BSAP), 57% for urinary N-telopeptide cross-links (NTX), and 48% for free deoxypyridinoline. Changes in serum CTX correlated reasonably well with changes in spine BMD after 2 years (r = 0.47), but this correlation did not quite reach statistical significance because of the small number of subjects. In conclusion, the serum CTX assay shows greater utility for assessing efficacy of antiresorptive treatment than some previously described markers.

Significant Differential Effects of Alendronate, Estrogen, or Combination Therapy on the Rate of Bone Loss after Discontinuation of Treatment of Postmenopausal Osteoporosis: A Randomized, Double-Blind, Placebo-Controlled Trial

Context Alendronate and conjugated estrogen therapy both increase bone mineral density in postmenopausal women, but is the rate of bone loss greater when alendronate or estrogen therapy is discontinued? Contribution The discontinuation phase of this double-blind, placebo-controlled trial showed loss of spine and trochanter bone mass in postmenopausal women 1 year after withdrawal of estrogen and no such loss after withdrawal of either alendronate or combination therapy with alendronate and estrogen therapy. Cautions The study was not large or long enough to show whether discontinuation of estrogen therapy is associated with more fractures than discontinuation of either alendronate or combination therapy. The Editors Several antiresorptive agents have been shown to increase bone mass and reduce osteoporotic fractures (1-3). Because greater improvements in bone mass in women using therapy are associated with greater reductions in fracture (4, 5), investigators have begun to examine combinations of antiresorptive therapies to achieve more substantial gains in bone mass. Lindsay and colleagues demonstrated that addition of alendronate to hormone replacement therapy in postmenopausal women resulted in greater increases in bone mass than did maintenance of estrogen therapy alone (6). We previously showed that administration of alendronate and estrogen for 2 years in postmenopausal women with low bone mass resulted in statistically significantly greater increases in bone mass at the lumbar spine and femoral neck than those seen in women taking either agent alone (7). Furthermore, combination therapy was safe and resulted in normal findings on histologic examination of bone. In clinical practice, a key concern is the potential for accelerated bone loss when antiresorptive therapy is discontinued. Approximately one third of women discontinue hormone replacement therapy within 1 year of initiation (8). Older studies have demonstrated significant losses in bone mass after discontinuation of hormone replacement therapy (9-11). In contrast, when therapy with oral alendronate, 10 mg/d, is discontinued after osteoporosis treatment, bone mass at the hip and spine are maintained for 1 year (12). However, no head-to-head comparison of hormone replacement therapy and alendronate or the combination of antiresorptive therapy after discontinuation has been done. In addition, future losses in bone mass when patients discontinue therapy must be considered in management of osteoporosis in postmenopausal women. We therefore sought to examine the rate of bone loss after discontinuation of 2 years of alendronate therapy, hormone replacement therapy, or combination therapy. A subset of participants continued to take combination therapy for a third year to determine whether prolonged therapy remained beneficial. Methods Study Participants Four hundred twenty-five postmenopausal women 42 to 82 years of age who had low bone mass were enrolled in a 2-year randomized, double-blind, placebo-controlled clinical trial conducted at 18 centers in the United States (7). Participants were recruited from clinics, private practices, newspaper advertisements, and targeted mailings. All participants who completed the initial study were asked to enroll in the 1-year extension. Participants were told that if they were taking active treatment, they might be randomly allocated to receive placebo or treatment for the third year and that if they were taking placebo, they would continue to do so. Entry criteria for the initial study are described elsewhere (7). All women had had hysterectomy and had a bone mineral density at the lumbar spine that was less than or equal to a T score of 2.0 SDs below the peak bone mass in young adults. Data on presence or absence of ovaries were not collected. Exclusion criteria were metabolic bone disease, a low serum 25-hydroxyvitamin D level, use of medications known to affect bone turnover, renal insufficiency, severe cardiac disease, and recent major upper gastrointestinal disease. The institutional review board at each clinical site approved the extension protocol. After signing the extension consent form and undergoing baseline evaluation for the extension, participants were allocated to blinded treatment on the basis of their original treatment in the first 2 years of the study. The randomization process was centrally determined by a statistician; as in the initial study, treatment allocation was concealed. Design As described for the initial study at each center, patients were randomly allocated to one of four treatment groups: placebo (n = 50); alendronate, 10 mg/d (n = 92); conjugated estrogen, 0.625 mg/d (n = 143); or alendronate, 10 mg/d, plus conjugated estrogen, 0.625 mg/d (n = 140) (Figure 1). The conjugated estrogen used was Premarin (Wyeth-Ayerst, Philadelphia, Pennsylvania). All women received calcium carbonate to provide 500 mg of elemental calcium daily. Figure 1. Design of original 2-year study and reallocation to extension phase for year 3. At the end of the second year, 244 of the 425 women (57%) continued in a 1-year extension of the study (Figure 1). Of these women, 28 who previously received placebo continued to do so. Women who were taking combination therapy were reallocated to continue taking combination therapy (n = 44) or switch to placebo (n = 41). In addition, 50 participants taking alendronate alone and 81 participants taking conjugated estrogen alone for the first 2 years were assigned to placebo for the third year. All patients and investigators remained blinded to medication allocation. Patients continued to receive calcium supplementation during the third year. Outcome Measures Women were examined at month 24 (baseline of the 1-year extension), month 30, and month 36. Bone mineral density of the lumbar spine, hip (femoral neck, trochanter, total hip), and total body were assessed by using dual-energy x-ray absorptiometry with QDR-1000W, QDR-1500, or QDR-2000 series bone densitometers (Hologic, Inc., Bedford, Massachusetts). A standard phantom was used for cross-calibration at all sites. Serum and urine samples were also obtained at months 24, 30, and 36 for assessment of biochemical markers of bone turnover, namely bone-specific alkaline phosphatase and urinary N-telopeptide cross-links of collagen type I, corrected for creatinine. Statistical Analysis We used SAS software, version 6.12, TSLevel 0060, PROCedureGLM (SAS Institute, Inc., Cary, North Carolina) to analyze the data. The primary efficacy end point was the mean difference between groups in the percentage change in bone mineral density at the lumbar spine from month 24 to month 36. Secondary efficacy end points were the mean percentage changes in bone mineral density of the hip and total body and biochemical markers of bone turnover. Overall percentage changes from month 0 to 36 in spine, hip, and total-body bone mineral density were also analyzed. The prespecified analysis was based on an intention-to-treat approach. At study design, we prespecified that all patients who had a baseline measurement and at least one measurement during treatment would be included in the analysis according to the group to which they were randomly allocated. The missing data were approximated by carrying forward the last available value on treatment forward to the missing time point. No data from the original 2-year study were carried forward to the extension period for any assessment of change. Women who violated the protocol were excluded from analysis of biochemical markers, as previously reported (7). Between-group comparisons of bone mineral density and biochemical measures were made by using analysis of variance techniques, with treatment, center, and treatment-by-center as factors. The assumption of homoscedasticity for the analysis of variance model was assessed by using the Levene test, and the normality assumption was assessed by using the ShapiroWilk test (13). If the assumptions were violated, a nonparametric method was used to corroborate the parametric results. The Fisher exact test was used to compare treatment groups for the proportion of participants who exceeded predefined limits of change in laboratory safety variables (13). Power calculations based on estimated sample sizes of 56 and 84 participants in the alendronate/placebo and estrogen/placebo treatment groups, respectively, yielded an estimate of 92% power to detect a 1.5% difference between mean percentage changes from month 24 to month 36 in bone mineral density at the lumbar spine ( = 0.05, two-tailed test). As requested by the journal editors, data on bone mineral density were also analyzed by using a mixed-model analysis, and results of this analysis are presented. An appropriate curvilinear function was fitted to the actual data, and the function was estimated by using all data available across time points for each participant. A model that regressed bone mineral density versus log (month + 1) provided the appropriate fit for the 3-year data and was used to analyze these data. The variable log (month + 1) was used because log (month) is undefined when month is 0, and log (month + 1) yields the value 0 at baseline. The fitted values from the model were used to obtain the percentage change during the period of interest. Data on bone mineral density from the mixed-model analyses are presented unless otherwise specified. Role of the Funding Source Data were collected by investigators at each study site with the support of Merck Research Laboratories, Rahway, New Jersey. Analyses were performed by statisticians at Merck & Co., Inc. Data were interpreted by the authors, who submitted the manuscript for publication. Results Patient Characteristics and Retention Baseline randomization characteristics did not differ between participants who entered the extension phase and those who did not. Baseline demographic characteristics of the 244 women who entered the extension phase were s

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.