Anthony L. Mulloy

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

Hyperthyroidism: A Secondary Cause of Isolated Systolic Hypertension

Isolated systolic hypertension is the most common form of hypertension, especially among patients 50 years or older. What is not appreciated is that there are secondary causes of isolated systolic hypertension. Hyperthyroidism increases systolic blood pressure by decreasing systemic vascular resistance, increasing heart rate, and raising cardiac output. Potential cardiovascular consequences of hyperthyroidism include atrial arrhythmias (especially atrial fibrillation), pulmonary hypertension, left ventricular hypertrophy, and heart failure. The prevalence of hypertension is greater among hyperthyroid patients than euthyroid patients. Whether there is a blunted nocturnal decline in ambulatory blood pressure among hyperthyroid patients is more controversial. Treatment is associated with a reduction in systolic blood pressure, heart rate, and cardiac output.

Follicle-stimulating hormone, interleukin-1, and bone density in adult women

Recent studies have indicated that follicle-stimulating hormone (FSH) promotes bone loss. The present study tested the hypothesis that FSH enhances the activity of bone-resorbing cytokines [interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6], either by inducing their secretion or by altering their receptor expression. Thirty-six women between the ages of 20 and 50 were assessed for bone mineral density (BMD), reproductive hormone, cytokine ligand and soluble receptor concentrations, and surface expression of cytokine receptors on monocytes. In addition, isolated mononuclear cells were incubated in vitro with exogenous FSH. Univariate regression analyses indicated that BMD was inversely related to serum FSH (r = -0.29 to -0.51, P = 0.03-0.001, depending upon the skeletal site). Physical activity and body composition were also identified as significant factors by multiple regressions. Exogenous FSH induced isolated cells to secrete IL-1beta, TNF-alpha, and IL-6 in proportion to the surface expression of FSH receptors on the monocytes. Endogenous (serum) FSH concentrations correlated with the circulating concentrations of these cytokines. None of these individual cytokines was related to BMD, but the IL-1beta to IL-1 receptor antagonist (IL-1Ra) ratio was inversely related to BMD (r = -0.53, P = 0.002) in all but the most physically active women, who had significantly lower expression of IL-1 type I receptors relative to type II (decoy receptors, P = 0.01). Physical activity also correlated positively with secretion of inhibitory soluble IL-1 receptors (r = 0.53, P = 0.003). Moreover, IL-1Ra correlated strongly with percent body fat (r = 0.66, P < 0.0001). These results indicate that BMD is related to FSH concentration, physical activity, and body composition. Although each of these factors likely has direct effects on bone, the present study suggests that each may also influence BMD by modulating the activity of the osteoresorptive cytokine IL-1beta.

Glucose-dependent insulinotropic peptide stimulates proliferation and TGF-β release from MG-63 cells

Glucose-dependent insulinotropic peptide (GIP) is known to modulate alkaline phosphatase activity and collagen type I message in osteoblastic-like cells. GIP effects on cell proliferation are not known. We report that GIP dose dependently stimulated 3H-thymidine incorporation in the osteoblastic-like cell line MG-63. Furthermore, GIP increased message and secretion of transforming growth factor beta (TGF-beta), an agent known to regulate osteoblastic proliferation and differentiation. However, when GIP was added to MG-63 cells concurrently with a TGF-beta neutralizing antibody, there was no effect on 3H-thymidine incorporation in these cells. These data demonstrate that GIP stimulates osteoblastic-like cell proliferation but that this effect is not mediated by TGF-beta.

Value of sestamibi scans in tertiary hyperparathyroidism

Objectives: To determine the value of preoperative 99mTc‐sestamibi scans and the incidence of ectopic glands in tertiary hyperparathyroidism.

Leptin regulates CD16 expression on human monocytes in a sex‐specific manner

Fat mass is linked mechanistically to the cardiovascular system through leptin, a 16 kDa protein produced primarily by adipocytes. In addition to increasing blood pressure via hypothalamic‐sympathetic pathways, leptin stimulates monocyte migration, cytokine secretion, and other functions that contribute to atherosclerotic plaque development. These functions are also characteristics of CD16‐positive monocytes that have been implicated in the clinical progression of atherosclerosis. This investigation sought to determine if leptin promoted the development of such CD16‐positive monocytes. Cells from 45 healthy men and women with age ranging from 20 to 59 years were analyzed. Circulating numbers of CD14++16++ monocytes, which are primary producers of TNFα, were positively related to plasma leptin concentrations (P < 0.0001), with a stronger correlation in men (P < 0.05 for leptin × sex interaction). In vitro, recombinant human leptin induced CD16 expression in a dose‐related manner (P = 0.02), with a stronger influence on monocytes from men (P = 0.03 for leptin × sex interaction). There were no sex‐related differences in total leptin receptor expression on any monocyte subtypes, relative expression of long versus short isoforms of the receptor, or soluble leptin receptor concentrations in the plasma. The number of circulating CD14+16++ monocytes, which preferentially migrate into nascent plaques, was positively related to systolic blood pressure (R = 0.56, P = 0.0008) and intima‐media thickness (R = 0.37, P = 0.03), and negatively related to carotid compliance (R = −0.39, P = 0.02). These observations indicate that leptin promotes the development of CD16‐positive monocyte populations in a sex‐specific manner and that these subpopulations are associated with diminished vascular function.

Use and Misuse of IOPTH Levels During Parathyroidectomy

Objective The combined use of localization and intraoperative parathyroid hormone assay (IOPTH) has facilitated the performance of targeted or minimally invasive parathyroidectomy. The precise algorithm of the use of IOPTH has been debated. We sought to clarify the optimal sequence of testing. Methods After IRB approval was obtained, demographic data and intraoperative laboratory and surgical findings from patients undergoing parathyroidectomy were prospectively gathered and analyzed. Specific attention was paid to the value of pre-excision (P-E) values and the 5-minute postoperative (5-min) levels and their impact on intraoperative decision-making. In the first 49 consecutive patients, a P-E baseline value was sought; in all cases a 5-min value was obtained when possible. Results 112 patients underwent parathyroidectomy during the study period. 30 of these were for secondary or tertiary hyperparathyroidism and were excluded. 78 (95.1%) of the patients were eucalcemic. In 4 cases (4.9%), the incorporation of the pre-excision baseline value represented a false positive, and surgery was aborted prematurely. In no case did the P-E value change what was otherwise destined to be a successful result based on pre-incision value. In 47 cases (57.3%), operative time was conserved as the procedure was correctly stopped after the 5-min level. Conclusions Pre-excision baseline levels, while logical in their original proposal, appear to play virtually no role in determining the completeness of an exploration, and may in fact be misleading. A 5-minute postoperative level adds value in over one-half of cases by allowing earlier termination of the operation.