AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS - 2016--EXECUTIVE SUMMARY.

ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists AFF = atypical femur fracture ASBMR = American Society for Bone and Mineral Research BEL = best evidence level BMD = bone mineral density BTM = bone turnover marker CBC = complete blood count CI = confidence interval DXA = dual-energy X-ray absorptiometry EL = evidence level FDA = U.S. Food and Drug Administration FLEX = Fracture Intervention Trial (FIT) Long-term Extension FRAX(®) = Fracture Risk Assessment Tool GFR = glomerular filtration rate GI = gastrointestinal HORIZON = Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly IOF = International Osteoporosis Foundation ISCD = International Society for Clinical Densitometry IU = international units IV = intravenous LSC = least significant change NBHA = National Bone Health Alliance NOF = National Osteoporosis Foundation 25(OH)D = 25-hydroxy vitamin D ONJ = osteonecrosis of the jaw PINP = serum carboxy-terminal propeptide of type I collagen PTH = parathyroid hormone R = recommendation RANK = receptor activator of nuclear factor kappa-B RANKL = receptor activator of nuclear factor kappa-B ligand RCT = randomized controlled trial RR = relative risk S-CTX = serum C-terminal telopeptide SQ = subcutaneous VFA = vertebral fracture assessment WHO = World Health Organization.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS - 2016.

ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists AFF = atypical femur fracture ASBMR = American Society for Bone and Mineral Research BEL = best evidence level BMD = bone mineral density BTM = bone turnover marker CBC = complete blood count CI = confidence interval DXA = dual-energy X-ray absorptiometry EL = evidence level FDA = U.S. Food and Drug Administration FLEX = Fracture Intervention Trial (FIT) Long-term Extension FRAX® = Fracture Risk Assessment Tool GFR = glomerular filtration rate GI = gastrointestinal HORIZON = Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly IOF = International Osteoporosis Foundation ISCD = International Society for Clinical Densitometry IU = international units IV = intravenous LSC = least significant change NBHA = National Bone Health Alliance NOF = National Osteoporosis Foundation 25(OH)D = 25-hydroxy vitamin D ONJ = osteonecrosis of the jaw PINP = serum carboxy-terminal propeptide of type I collagen PTH = parathyroid hormone R = recommendation RANK = receptor activator of nuclear factor kappa-B RANKL = receptor activator of nuclear factor kappa-B ligand RCT = randomized controlled trial RR = relative risk S-CTX = serum C-terminal telopeptide SQ = subcutaneous VFA = vertebral fracture assessment WHO = World Health Organization.

Poststroke fractures in a bi-ethnic community.

BACKGROUND: Mexican Americans have increased risks of stroke and lower fractures compared with non-Hispanic whites, but little is known about poststroke fracture risk in Mexican Americans. The objective of this study was to describe poststroke fracture risk in a bi-ethnic population and to compare risk by ethnicity. METHODS: In the Brain Attack Surveillance in Corpus Christi Project, strokes were identified through hospital surveillance (2000-2004) and validated by neurologists (n = 2389). Inpatient claims for fractures were ascertained (2000-2004) and cross-referenced with strokes. Survival free from fracture (any and hip) poststroke was estimated and compared by ethnicity. Cox regression was used to test the association of ethnicity and fracture risk adjusted for confounders. Interaction terms for ethnicity and age were considered. RESULTS: The mean age was 71 years (SD, 13 yrs); 54% were Mexican American and 52% were women. The mean follow-up was 4 years. There were 105 fractures (33% of the hips). Survival free of any fracture and of hip fracture did not differ by ethnicity. Increasing age, female gender, intracerebral hemorrhage, and greater stroke severity were associated with risk of any fracture, but ethnicity was not. Ethnicity was associated with risk of hip fracture, but this association was modified by age (P = .02), where Mexican Americans were protected from hip fractures at younger but not older ages. CONCLUSIONS: Stroke patients were at high risk for fractures, with a 10% risk at 5 years. Mexican Americans were protected from hip fractures at younger but not older ages. Both elderly Mexican Americans and non-Hispanic whites should be targeted for poststroke fracture prevention.

Soy isoflavones in the management of postmenopausal osteoporosis.

This is a review article designed to address the effects of soy isoflavones on bone metabolism in postmenopausal women and their place in the prevention and treatment of postmenopausal osteoporosis. Soy isoflavones are natural products that could be used as an alternative to menopausal hormone therapy because they are structurally and functionally related to 17beta-estradiol. In vitro and animal studies have shown that they act in multiple ways to exert their bone-supporting effects. They act on both osteoblasts and osteoclasts through genomic and nongenomic pathways. Epidemiological studies and clinical trials suggest that soy isoflavones have beneficial effects on bone mineral density, bone turnover markers, and bone mechanical strength in postmenopausal women. However, there are conflicting results related to differences in study design, estrogen status of the body, metabolism of isoflavones among individuals, and other dietary factors. The long-term safety of soy isoflavone supplements remains to be demonstrated.

Risk of fractures after stroke.

BACKGROUND: The aim of this study was to determine the risk of fractures after stroke/transient ischemic attack (TIA) in relatively young patients. METHODS: Administrative claims data were identified for patients aged 18 years and older hospitalized for stroke/TIA from 1997 to 2005 using ICD-9 codes. Fractures after stroke/TIA were identified for the same time period. RESULTS: The median age was 56 years. Females represented 47%. There were 411 ischemic strokes, 195 TIAs and 36 intracerebral hemorrhages, as well as 46 fractures in 41 individuals. The risk of fracture after stroke/TIA was 1.2% at 30 days and 3.1% at 1 year. There was no significant difference in survival free from fracture between ischemic stroke and TIA cases (p = 0.8489). CONCLUSIONS: Patients with stroke/TIA, including men and younger patients, appear to be at risk for bone fractures.

Fat embolism syndrome.

OBJECTIVES: To assess the incidence and risk factors for fat embolism syndrome. MATERIALS AND METHODS: Data from the National Hospital Discharge Survey (NHDS) were analyzed using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. RESULTS: From 1979 through 2005 among 928,324,000 patients discharged from short-stay hospitals in the United States, 41,000 (0.004%) had fat embolism syndrome. Among 21,538,000 patients with an isolated fracture of the femur (any site), tibia, fibula, pelvis, ribs, humerus, radius, or ulna, 25,000 (0.12%) developed fat embolism syndrome. Patients with multiple fractures of the femur (excluding neck) more often had fat embolism syndrome than those with isolated fractures (1.29% versus 0.54%). The incidence of fat embolism syndrome was lower with isolated fractures of the tibia or fibula (0.30%) and even lower with isolated fractures of the neck of the femur (0.06%). The incidence of fat embolism was too low to calculate with isolated fractures of the pelvis, ribs, humerus, radius, or ulna. Nonorthopedic conditions rarely, if ever, were accompanied by fat embolism syndrome. The fat embolism syndrome was more frequent in men (relative risk 5.71). Children, aged 0 to 9 years rarely had fat embolism syndrome. The fat embolism syndrome most commonly affected patients aged 10 to 39 years. CONCLUSIONS: The incidence of the fat embolism syndrome depends on the bone involved, whether fractures are isolated or multiple, the age of the patient and the gender. It rarely occurs as a result of medical conditions.

Osteoporosis prevention and management: an evidence-based review.

Evidence-based guidelines that have been prepared by many professional organizations aimed at assisting the clinician in the initial evaluation of postmenopausal women who should be considered for bone mineral density evaluation by dual-energy x-ray absorptiometry; history, physical examination, and laboratory testing in those women being considered for pharmacologic intervention; and monitoring and management of women for whom therapy is prescribed are discussed.

Differential associations for menopause and age in measures of vitamin K, osteocalcin, and bone density: a cross-sectional exploratory study in healthy volunteers.

OBJECTIVE: To distinguish the effects of midlife aging from early postmenopause on vitamin K measures, bone formation biomarkers, and bone density. DESIGN: Cycling older volunteers (CO; 40-52 years, n = 19) were compared to cycling young (CY; 20-30 years, n = 21) and untreated, age-matched women in the early postmenopause years (EPM; 40-52 years, mean years PM = 2.8 +/- 0.5, n = 19). We assessed sex steroids, vitamin status (phylloquinone, 25-hydroxyvitamin D, retinol), osteocalcin (OC), percentage of undercarboxylated osteocalcin (%ucOC), and bone mineral density (BMD) at the spine and hip with dual-energy x-ray absorptiometry. RESULTS: CO women had similar estradiol and vitamin status as CY women, but lower OC (0.64 +/- 0.04 vs 0.97 +/- 0.08 nmol/L, P = 0.01) and BMD at the total hip (1.0038 +/- 0.032 vs 1.1126 +/- 0.030 g/cm2, P = 0.02). In the two older groups, BMD was similar at all sites, but OC was elevated in the EPM women (1.10 +/- 0.10 vs 0.64 +/- 0.04 nmol/L, EPM vs CO, P = 0.001). Although phylloquinone was highest in the EPM women, %ucOC was also higher when compared with all cycling women (21.9 +/- 1.7% vs 17.4 +/- 0.9%, n = 40; P = 0.02). CONCLUSIONS: Premenopausal women show reduced BMD despite normal estrogen profiles. %ucOC may be a specific bone marker of the early postmenopause in healthy women.

Secondary osteoporosis: a review of the recent evidence.

OBJECTIVE: To review several causes of secondary osteoporosis as well as screening recommendations for underlying disorders. METHODS: We conducted a review of the literature on many of the causes of osteoporosis that have been published during the past 15 years, focusing on those sources available from 2000 through the present. Indeed, more than two-thirds of the articles that we reviewed were printed during the past 6 years. These reports examined secondary osteoporosis in general, as well as many of the specific causes. RESULTS: Secondary osteoporosis occurs in almost two-thirds of men, more than half of premenopausal and perimenopausal women, and about one-fifth of postmenopausal women. Its causes are vast, and they include hypogonadism, medications, hyperthyroidism, vitamin D deficiency, primary hyperparathyroidism, solid organ transplantation, gastrointestinal diseases, hematologic diseases, Cushing's syndrome, and idiopathic hypercalciuria. These causes have their own pathogenesis, epidemiologic features, and effect on the skeleton. CONCLUSION: The causes of secondary osteoporosis are numerous, and an understanding of their characteristics with respect to bone density and potential fracture risk is essential in the management of osteoporosis. A heightened awareness of the possibility of their existence is necessary to provide optimal care.

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.

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.

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.

Prevention and treatment of postmenopausal osteoporosis.

Osteoporosis is a systemic disease characterized by low bone mass and microarchitectural deterioration of the skeleton leading to enhanced bone fragility and an increased risk of fracture. Prior to fracture, diagnosis is established by documenting low bone mass. In the first section of this article we review the clinical use of bone mass measurements and biochemical markers of bone remodeling in selecting patients most in need of preventive therapy at menopause. Women with high bone turnover lose bone at menopause more rapidly than those with normal bone turnover and are more likely to derive benefit from the several preventive therapies available. The second section addresses the available technologies used to diagnose osteoporosis and/or establish fragility fracture risk using noninvasive bone mass measurement and biochemical markers of bone remodeling separately or in combination. In the third section we review the several treatment options available for patients with osteoporosis, including alendronate (alendronic acid), risendronate (risedronic acid), calcitonin, teriparatide, and raloxifene, and the approaches to monitoring the therapeutic response. The final section deals with fall protection--an often forgotten aspect of management of the patient at risk for sustaining and osteoporotic fragility fracture.

Body composition profiles derived from dual-energy X-ray absorptiometry, total body scan, and mortality.

Little has been reported on the association of derived body composition data and cardiovascular mortality. The authors defined body composition profiles based on one- and two-variable measures from dual-energy x-ray absorptiometry (DXA) total body scans. Scan results are labeled "apple" if Z score for percent of total fat in trunk is >0 and "pear" if Z score for height-corrected limb fat is > or = 0. The fat measures were combined to define four body composition profiles: "pickle," "avocado," "mango," and "barrel." A third axis, the Z score of height-corrected limb lean tissue, is an index of skeletal muscle mass and was used to label subjects as "hard" or "soft." Subjects (n=324) who were in good health from Malmö, Sweden, underwent body composition analysis using DXA and were followed for 10 years. The distribution of body composition profiles was similar for both genders and across age groups. Among subjects aged 50-74 years at baseline (n=116), there were 21 deaths. Barrel had the highest mortality rate: 13/39 (33.3%) mortality for barrels, compared with 8/77 (10.4%) mortality for non-barrels; mortality odds ratio, 3.2; 95% confidence interval, 1.45-7.08. The increased mortality was principally attributable to cardiovascular cause-related deaths. Soft (sarcopenia) was also associated with increased mortality (25.9%; p=0.05), but not cardiovascular cause-related deaths, whereas the total mortality among apples was not significantly increased but cardiovascular cause-related deaths were predominant (75%; p=0.02). The authors propose that DXA-body composition profiles can identify increased mortality risk of magnitude similar to major cardiovascular risk factors and may prove useful in health assessment.

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.

Evaluation of trabecular microarchitecture in nonosteoporotic postmenopausal women with and without fracture.

This study compared microscopic magnetic resonance imaging (µMRI) parameters of trabecular microarchitecture between postmenopausal women with and without fracture who have normal or osteopenic bone mineral density (BMD) on dual-energy X-ray absorptiometry (DXA). It included 36 postmenopausal white women 50 years of age and older with normal or osteopenic BMD (T-scores better than -2.5 at the lumbar spine, proximal femur, and one-third radius on DXA). Eighteen women had a history of low-energy fracture, whereas 18 women had no history of fracture and served as an age, race, and ultradistal radius BMD-matched control group. A three-dimensional fast large-angle spin-echo (FLASE) sequence with 137 µm × 137 µm × 400 µm resolution was performed through the nondominant wrist of all 36 women using the same 1.5T scanner. The high-resolution images were used to measure trabecular bone volume fraction, trabecular thickness, surface-to-curve ratio, and erosion index. Wilcoxon signed-rank tests were used to compare differences in BMD and µMRI parameters between postmenopausal women with and without fracture. Post-menopausal women with fracture had significantly lower (p < 0.05) trabecular bone volume fraction and surface-to-curve ratio and significantly higher (p < 0.05) erosion index than postmenopausal women without fracture. There was no significant difference between postmenopausal women with and without fracture in trabecular thickness (p = 0.80) and BMD of the spine (p = 0.21), proximal femur (p = 0.19), one-third radius (p = 0.47), and ultradistal radius (p = 0.90). Postmenopausal women with normal or osteopenic BMD who had a history of low-energy fracture had significantly different (p < 0.05) µMRI parameters than an age, race, and ultradistal radius BMD-matched control group of postmenopausal women with no history of fracture. Our study suggests that µMRI can be used to identify individuals without a DXA-based diagnosis of osteoporosis who have impaired trabecular microarchitecture and thus a heretofore-unappreciated elevated fracture risk.