Assessing the Effects of Teriparatide Treatment on Bone Mineral Density, Bone Microarchitecture, and Bone Strength.

BACKGROUND: To gain insight into how teriparatide affects various bone health parameters, we assessed the effects of teriparatide treatment with use of standard DXA (dual x-ray absorptiometry) technology and two newer technologies, high-resolution MRI (magnetic resonance imaging) and finite element analysis of quantitative CT (computed tomography) scans. METHODS: In this phase-4, open-label study, postmenopausal women with severe osteoporosis received 20 µg/day of teriparatide. Assessments included (1) changes in areal BMD (bone mineral density) (in g/cm2) at the radius, spine, and hip on DXA, (2) changes in volumetric BMD (in mg/cm3) at the spine and hip on quantitative CT scans, (3) changes in bone microarchitecture at the radius on high-resolution MRI, (4) estimated changes in spine and hip strength according to finite element analysis of quantitative CT scans, (5) changes in bone turnover markers in serum, and (6) safety. RESULTS: Thirty-five subjects were enrolled; thirty completed eighteen months and twenty-five completed an optional six-month extension. No significant changes were observed for the primary outcome, high-resolution MRI at the distal aspect of the radius. At month eighteen, the least-squares mean percentage change from baseline in total volumetric BMD at the spine was 10.05% (95% confidence interval [CI], 6.83% to 13.26%; p < 0.001), and estimated spine strength increased 17.43% (95% CI, 12.09% to 22.76%; p < 0.001). Total volumetric BMD at the hip increased 2.22% (95% CI, 0.37% to 4.06%; p = 0.021), and estimated hip strength increased 2.54% (95% CI, 0.06% to 5.01%; p = 0.045). Areal BMD increased at the lumbar spine and femoral neck, was unchanged for the total hip and at the distalmost aspect of the radius, and decreased at a point one-third of the distance between the wrist and elbow. Bone turnover markers increased at months three, six, and twenty-four (all p < 0.05). No unexpected adverse events were observed. CONCLUSIONS: High-resolution MRI failed to identify changes in bone microarchitecture at the distal aspect of the radius, a non-weight-bearing site that may not be suitable for assessing effects of an osteoanabolic agent. Teriparatide increased areal BMD at the spine and femoral neck and volumetric BMD at the spine and hip. Estimated vertebral and femoral strength also increased. These findings and increases in bone turnover markers through month twenty-four are consistent with the known osteoanabolic effect of teriparatide. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Reduced bone mineral density is not associated with significantly reduced bone quality in men and women practicing long-term calorie restriction with adequate nutrition.

Calorie restriction (CR) reduces bone quantity but not bone quality in rodents. Nothing is known regarding the long-term effects of CR with adequate intake of vitamin and minerals on bone quantity and quality in middle-aged lean individuals. In this study, we evaluated body composition, bone mineral density (BMD), and serum markers of bone turnover and inflammation in 32 volunteers who had been eating a CR diet (approximately 35% less calories than controls) for an average of 6.8 ± 5.2 years (mean age 52.7 ± 10.3 years) and 32 age- and sex-matched sedentary controls eating Western diets (WD). In a subgroup of 10 CR and 10 WD volunteers, we also measured trabecular bone (TB) microarchitecture of the distal radius using high-resolution magnetic resonance imaging. We found that the CR volunteers had significantly lower body mass index than the WD volunteers (18.9 ± 1.2 vs. 26.5 ± 2.2 kg m(-2) ; P = 0.0001). BMD of the lumbar spine (0.870 ± 0.11 vs. 1.138 ± 0.12 g cm(-2) , P = 0.0001) and hip (0.806 ± 0.12 vs. 1.047 ± 0.12 g cm(-2) , P = 0.0001) was also lower in the CR than in the WD group. Serum C-terminal telopeptide and bone-specific alkaline phosphatase concentration were similar between groups, while serum C-reactive protein (0.19 ± 0.26 vs. 1.46 ± 1.56 mg L(-1) , P = 0.0001) was lower in the CR group. Trabecular bone microarchitecture parameters such as the erosion index (0.916 ± 0.087 vs. 0.877 ± 0.088; P = 0.739) and surface-to-curve ratio (10.3 ± 1.4 vs. 12.1 ± 2.1, P = 0.440) were not significantly different between groups. These findings suggest that markedly reduced BMD is not associated with significantly reduced bone quality in middle-aged men and women practicing long-term calorie restriction with adequate nutrition.

Postmenopausal hormone therapy: an Endocrine Society scientific statement.

OBJECTIVE: Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement. EVIDENCE: Each expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence. CONSENSUS PROCESS: A consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors. CONCLUSIONS: The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

Contribution of bone and mineral abnormalities to cardiovascular disease in patients with chronic kidney disease.

1,25-Dihydroxyvitamin D(3) levels begin to drop early in the course of kidney disease, leading to elevated parathyroid hormone levels and disrupted mineral metabolism. Impaired mineral metabolism seems to be associated not only with bone disease but also with vascular calcification. Animal models have identified molecular mechanisms by which high mineral levels and other uremic substances induce vascular smooth muscle cells to undergo phenotypic changes that initiate the calcification process. Moreover, several epidemiologic and clinical studies showed strong associations between bone loss, arterial calcification, and cardiovascular disease in populations with and without kidney disease. This review discusses evidence that two early complications of chronic kidney disease--vitamin D deficiency and secondary hyperparathyroidism--contribute to bone and cardiovascular disease. New treatment strategies aimed at the prevention of bone loss and parathyroid hyperplasia, such as vitamin D receptor ligand therapy, calcimimetic agents, and noncalcifying phosphate binders, are being investigated for their impact on improving overall outcome in dialysis patients.

Is BMD testing appropriate for all menopausal women?

The United States Preventive Services Task Force has provided an evidence-based guideline indicating that bone mineral density (BMD) testing is appropriate for all women aged 65 or older. This does not preclude BMD testing in younger postmenopausal women but places the onus on the treating physician to justify the procedure to the patient and often the patient's insurance carrier. There are very few circumstances in which BMD testing is appropriate for healthy premenopausal women, but BMD testing in younger postmenopausal women is often appropriate: when there is a family history of osteoporosis with fracture, a personal history of fracture as an adult, and a medical, surgical or therapeutic history that might be associated with accelerated bone loss or increased risk of fracture. Medical conditions include intestinal diseases associated with malabsorption, such as non-tropical sprue, or primary hyperparathyroidism. Women who have neurologic conditions that increase the risk of falling should also be tested. There are data to suggest that patients with hemoglobinopathy are at increased risk for osteoporosis. Surgical conditions include the increasingly performed surgery for obesity and other surgery resulting in bowel resection (e.g., for inflammatory bowel disease). The major medication-related concern is corticosteroid therapy, but chronic or over-treatment with thyroxine, and chronic heparin therapy, should also be considered risk factors for osteoporosis. When performing a BMD test for the first time, it is essential to remember that 50% of women at menopause will have a negative T-score, but this does not imply that the patient has indeed lost any bone from her peak bone mass.

Activity of estradiol and selective estrogen receptor modulators in the mouse N20.1 oligodendrocyte/astrocytes cell line.

OBJECTIVE: The mechanism through which estrogen exerts its neuroprotective and anti-neurodegenerative effects in the central nervous system is poorly understood. Human glial cells are implicated in the pathogenesis of Alzheimer's disease and have both alpha and beta estrogen receptors (ER). We developed a glial cell model for ER function using the N20.1 mouse oligodendroglial cell line to evaluate the response of ERalpha and ERbeta to estradiol (E2), a raloxifene analog LY117018 (LY) and 4-hydroxytamoxifen (4OHT). DESIGN: We tested the ability of exogenous ER to activate transcription in response to ligands (100 nM) using the glial cell line N20.1 in a transient cotransfection assay with an ERalpha or ERbeta expression vector, an ERE-driven reporter and a Renilla luciferase transfection control. RESULTS: Endogenous ER was not detected in the N20.1 cells by Western immunoblotting. E2 stimulated both ERalpha and ERbeta on both ERE- and AP-1 driven promoters. The transcription stimulation by E2 in the ERalpha and ERbeta through the AP-1driven promoter, though significant, was not of the same magnitude as the stimulation of the ERalpha through the ERE-driven promoter. 4OHT and LY did not show significant transcriptional activation of either the ERalpha or ERbeta, through either the ERE or AP-1 driven promoters. LY, at a 10-fold higher concentration than E2, showed a difference in its antagonist activity on the ERbeta through the AP-1 pathway when compared with the ERE- driven promoter, demonstrating not only promoter specificity, but also receptor specificity. CONCLUSIONS: This is the first description of the activity of 4OHT and LY on estrogen receptors in glia.

Usefulness of bone mineral density to predict significant coronary artery disease.

Low bone mineral density (BMD) and coronary artery disease (CAD) share common risk factors. To investigate whether low BMD (osteoporosis and/or osteopenia) independently predicts CAD compared with traditional cardiovascular risk factors, a retrospective analysis was performed in consecutive ambulatory patients (n = 209, 89% women) who underwent dual-energy x-ray absorptiometry and coronary angiography within the same 12-month period. Angiograms were classified as showing significant CAD if > or =50% luminal narrowing in a major coronary artery was noted. Clinical variables associated with CAD (age, hypertension, diabetes, high fasting glucose level, smoking, family history of CAD, and dyslipidemia) were examined. Dual-energy x-ray absorptiometric scans were classified based on World Health Organization criteria: normal (T score >-1.0 SD), osteopenia (T score -1.0 to -2.5 SD), and osteoporosis (T score <-2.5 SD). Univariate and multivariate analyses were employed to determine whether low BMD independently predicts CAD. Univariate predictors of CAD were hypertension, smoking, diabetes, high fasting glucose level, dyslipidemia, family history of CAD, and low BMD. Multivariate predictors were hypertension, family history of CAD, fasting glucose level, and osteoporosis. Odds ratio for the prediction of angiographically documented CAD was highest for osteoporosis (odds ratio 5.6, 95% confidence interval 2.6 to 12.0, p <0.0001). In conclusion, low BMD appears to independently predict significant CAD in women, with a higher odds ratio than traditional risk factors. Our study is the first to report osteoporosis as a predictor of angiographically proved CAD in a population predominantly of women.

Prevention of postmenopausal bone loss and treatment of osteoporosis.

Osteoporosis is now recognized as an increasingly prevalent disorder throughout the world. Fragility fractures and their subsequent short- and long-term complications are the adverse outcomes of this disease that is essentially silent until fractures occur. Given that the presence of one fragility fracture is an important predictor of the risk of subsequent fractures, prevention of the first fracture is critical whenever possible. Two key elements in fracture prevention that are discussed in this article are the attainment of optimal peak bone mass and the prevention of bone loss at menopause, with the major focus on the prevention of postmenopausal bone loss.

Bone response to treatment with lower doses of conjugated estrogens with and without medroxyprogesterone acetate in early postmenopausal women.

Lower doses of conjugated estrogens (CE) alone or combined with lower doses of medroxyprogesterone acetate (MPA) increase mean bone mineral density (BMD) from baseline at the spine and hip in early postmenopausal women. However, not all women on therapy gain BMD. The incidence of continued bone loss (defined as a loss of BMD of > 2% from baseline) among women using lower doses of CE and CE/MPA is unknown. This randomized, double-blind, placebo-controlled, multicenter substudy of the Women's Health, Osteoporosis, Progestin, Estrogen (Women's HOPE) trial investigated the incidence of continued bone loss with lower-dose CE and CE/MPA. Eight hundred twenty-two healthy postmenopausal women with intact uteri received CE 0.625, CE 0.625/MPA 2.5, CE 0.45, CE 0.45/MPA 2.5, CE 0.45/MPA 1.5, CE 0.3, CE 0.3/MPA 1.5 (all doses in mg/day), or placebo for 2 years along with 600 mg/day of calcium. Changes from baseline in spine and total hip BMD were compared among treatment groups in an intent-to-treat analysis. At 12 months, < 10% of women on active treatment lost > 2% of spinal BMD (except CE 0.3/MPA 1.5 [15.6%]), compared with 41.2% of women on placebo. At 24 months, the percentages of women on active treatment who lost > 2% of spine BMD ranged from 4.5% with CE 0.45/MPA 1.5-15.6% with CE 0.3/MPA 1.5, compared with 55.2% of women taking placebo. More than 85% of women on active treatment did not experience continued BMD loss at the hip at 12 months and 24 months, in contrast to 30.6% of women on placebo at 12 months and 36.5% at 24 months. Women receiving active treatment who lost > 2% of spine or hip BMD also had a lesser reduction in biochemical markers of bone turnover. In summary, continued bone loss among early postmenopausal women treated with lower doses of CE or CE/MPA is uncommon.

Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women.

CONTEXT: Lower-than-commonly-prescribed doses of conjugated equine estrogens (CEEs) with medroxyprogesterone acetate (MPA) improve vasomotor symptoms and vaginal atrophy, provide acceptable bleeding and lipid profiles, and afford endometrial protection. This lower-dose therapy's protection against loss of bone mineral density (BMD) associated with menopause has not been thoroughly investigated. OBJECTIVE: To determine the effects of lower doses of CEEs only or CEEs-MPA on spine and hip BMD, total body bone mineral content (BMC), and biochemical markers of bone turnover in postmenopausal women. DESIGN AND SETTING: Two-year randomized, double-blind, placebo-controlled substudy of the Women's Health, Osteoporosis, Progestin, Estrogen trial, conducted at 19 US centers between August 1995 and October 2000. PARTICIPANTS: Eight hundred twenty-two healthy postmenopausal women aged 40 to 65 years who were within 4 years of their last menstrual period. INTERVENTIONS: Patients were randomly assigned to receive CEEs, 0.625; CEEs, 0.625 and MPA, 2.5; CEEs, 0.45; CEEs, 0.45 and MPA, 2.5; CEEs, 0.45 and MPA, 1.5; CEEs, 0.3; CEEs 0.3 and MPA, 1.5 (all doses in mg/d); or placebo for 2 years. All participants also received elemental calcium at 600 mg/d. MAIN OUTCOME MEASURES: Changes from baseline in spine and total hip BMD, total body BMC, and biochemical markers of bone turnover (serum osteocalcin and urinary cross-linked N-telopeptides of type I collagen), assessed at 6-month intervals and compared among treatment groups with a modified intention-to-treat approach. RESULTS: At 24 months, women assigned to all of the active treatment groups had significant gains from baseline (P<.001) in spine and hip BMD and total body BMC (except total body BMC in the group receiving CEEs, 0.3 mg/d). These changes were significantly different from those in the placebo group, in which losses of bone mass in spine and total body were evident over the course of the study (P<.001). The loss in hip BMD from baseline in the placebo group was significant at 18 (P =.02) but not at 24 months (P =.06). Osteocalcin and N-telopeptides of type I collagen were significantly reduced from baseline (P<.001) for all active treatment groups at all time points; no changes were found for the placebo group. For women treated with CEEs alone, the gains in spine BMD for the group taking CEEs, 0.625 mg/d, were significantly higher than those of the group taking CEEs, 0.3 mg/d (P =.02), but not the group treated with CEEs, 0.45 mg/d (P =.48). CONCLUSIONS: Doses of CEEs or CEEs-MPA lower than 0.625 mg/d effectively increase BMD and BMC in early postmenopausal women.