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Background The extent of coronary disease affects clinical outcomes and may predict the effectiveness of coronary revascularization with either coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI). The SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score quantifies the extent of coronary disease. Objectives This study sought to determine whether SYNTAX scores predicted outcomes and the effectiveness of coronary revascularization compared with medical therapy in the BARI-2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. Methods Baseline SYNTAX scores were retrospectively calculated for BARI-2D patients without prior revascularization (N = 1,550) by angiographic laboratory investigators masked to patient characteristics and outcomes. The primary outcome was major cardiovascular events (a composite of death, myocardial infarction, and stroke) over 5 years. Results A mid/high SYNTAX score (≥23) was associated with a higher risk of major cardiovascular events (hazard ratio: 1.36, confidence interval: 1.07 to 1.75, p = 0.01). Patients in the CABG stratum had significantly higher SYNTAX scores: 36% had mid/high SYNTAX scores compared with 13% in the PCI stratum (p Conclusions Among patients with diabetes and stable ischemic heart disease, higher SYNTAX scores predict higher rates of major cardiovascular events and were associated with more favorable outcomes of revascularization compared with medical therapy among patients suitable for CABG. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes; NCT00006305)

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

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.

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.

Bone mineral density (BMD) of the phalanges of the hand was measured by the technique of radiographic absorptiometry (RA) in 199 older postmenopausal women previously determined to have normal BMD by dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT). The average age of the women was 66.8 +/- 4.9 years, and they were 19.9 +/- 6.7 years postmenopause. In the 54 black women, phalangeal BMD was 11.7% greater than in the 145 white women, a difference comparable to that found using DXA at the radial midshaft, the lumbar spine, and femoral neck. A correlation matrix comparing BMD measured by RA to BMD measured by DXA and QCT indicates that, in general, RA was related to the various DXA and QCT measurement sites as well as these sites were related to each other. When results for RA, DXA, and QCT obtained in our cohort of older women were compared to available reference data for peak adult bone mass, the average difference (SD units) from peak value was greatest for RA (-1.77 radius, -1.24 spine, -2.13 femoral neck, -2.34 QCT spine, and -2.71 phalanges). We conclude that RA is an acceptable measure of phalangeal BMD and that the data in our cohort can serve as reference data for older white and black women aged 55-75 years. Once the ability of RA to predict future fracture occurrence has been demonstrated, it could be rapidly deployed as a low-cost, widely available bone mass measurement technique.

The sustained effects of biochemical screening to increase both apparent incidence and age at diagnosis indicate that, without screening, most patients with primary hyperparathyroidism would would never be diagnosed. This suggests that asymptomatic patients discovered as a result of screening have a nonprogressive form of the disease, with adverse health effects that are few or nontraditional, for which treatment policies validated only in symptomatic patients may be inappropriate. Accordingly, in 1975 we formulated criteria for withholding surgical treatment from such patients. Of 174 who were eligible for study over a 10 year period, clinical, biochemical, and densitometric assessment was repeated after at least 1 year (mean 52 months) in 106 patients who did not differ in any initial characteristic from 68 patients in whom follow-up was inadequate. There was no change in symptoms, no disease complications, and no change in any index of hormone secretion or disease severity. In 30 patients, individual regression slopes against time were not significant for any serum measurement. In these patients the disease appeared to have stopped progressing by the time the diagnosis was made, most likely because of cessation of tumor growth. There was a significant deficit in appendicular cortical bone at the time of diagnosis but no further acceleration of bone loss thereafter. In an earlier study, surgical cure was followed by a modest increase in forearm bone density for the first 6 months, but even after 3 years only about 20% of the deficit was corrected. The deficit in bone density is smaller in the spine than in the forearm and is not accompanied by any increase in vertebral fracture risk.(ABSTRACT TRUNCATED AT 250 WORDS)

It has been suggested recently that, although fluoride therapy may decrease the occurrence of vertebral fractures, it could increase the risk of hip fractures. To evaluate this possibility, we combined retrospective data from five medical centers that have had a large experience with this therapeutic regimen. In 416 osteoporotic patients who were followed for more than 1,000 patient-years of fluoride treatment, there were 17 nontraumatic hip fractures. This incidence of 1.6% per year is similar to the incidence, 1.9% per year, for 120 of the patients in this series who had been followed prospectively for 3 years prior to initiation of fluoride therapy. The expected incidence for women of the same age in the general community is 0.5% per year. Thus, untreated osteoporotic women are at increased risk for hip fracture, but treatment with fluoride seems neither to decrease nor to increase the incidence of hip fracture substantially.

Digitized morphometry of vertebral bodies on lateral spine films is used to identify and quantify vertebral deformities or fractures. One problem associated with this method is the phenomenon of "disappearing fractures," which results from the apparent increase in vertebral body heights of previously deformed vertebrae on subsequent radiographs. These have been considered biologically implausible and therefore a result of measurement error. Measurement error is unlikely to be unidirectional, so that a proportion of fractures identified by morphometry is also the result of measurement error. Since some vertebral deformities are real events, some disappearances of deformities detected by morphometry may be real events. In this report, we examine the data from our clinical trial of sodium fluoride in spinal osteoporosis to assess critically the plausibility of two hypotheses: (1) The "rebound" phenomenon results from measurement error. If this is the case, then some fractures of the same magnitude as the rebound must also represent measurement error. (2) Some deformed vertebrae in fact rebound toward their original shape and size, displaying an elastic response to deformation. If this occurs, then some vertebral deformities are transient events, not true fractures. We conclude that the variability inherent in morphometric data obtained from serial spine x-rays results in both disappearing fractures and a high false positive fracture rate. The use of more stringent criteria for defining significant deformities, or true fractures, will minimize these problems. We cannot exclude the second hypothesis, that some vertebral deformities may be transient events, but this needs further study.

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.

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.

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.

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. (Endocr Pract. 2006; 12:436-445)

American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice are systematically developed statements to assist health-care professionals in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances. AACE Guidelines

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 ifor =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, p0.0001). 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.

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 of2% 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 lost2% 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 lost2% 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 lost2% 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.

Background.Research has shown less aggressive treatment and poorer control of cardiovascular disease (CVD) risk factors in women than men.Methods.We analyzed sex differences in pharmacotherapy strategies and attainment of goals for hemoglobin A1c (HbA1c), blood pressure (BP), and low density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes and established coronary artery disease enrolled into the BARI 2D trial.Results.Similar numbers of drugs were prescribed in both women and men. Women were less frequent on metformin or sulfonylurea and more likely to take insulin and to be on higher doses of hydroxymethylglutaryl-CoA reductase inhibitors (statins) than men. After adjusting for baseline differences and treatment prescribed, women were less likely to achieve goals for HbA1c (OR = 0.71, 95% CI 0.57, 0.88) and LDL-C (OR = 0.64, 95% CI 0.53, 0.78). More antihypertensives were prescribed to women, and yet BP ≤ 130/80 mmHg did not differ by sex.Conclusions.Women entering the BARI 2D trial were as aggressively treated with drugs as men. Despite equivalent treatment, women less frequently met targets for HbA1c and LDL-C. Our findings suggest that there may be sex differences in response to drug therapies used to treat diabetes, hypertension, and hyperlipidemia.

In these clinical practice guidelines, specific recommendations are made for determining the most effective methods of diagnosing and treating hypogonadism in adult male patients. The target populations for these guidelines include the following: (1) men with primary testicular failure requiring testosterone replacement (hypergonadotropic hypogonadism); (2) male patients with gonadotropin deficiency or dysfunction who may have received testosterone replacement therapy or treatment for infertility (hypogonadotropic hypogonadism); and (3) aging men with symptoms relating to testosterone deficiency who could benefit from testosterone replacement therapy. Initial hormonal evaluation generally consists of a testosterone determination, in conjunction with a free testosterone or sex hormone-binding globulin level, inpatients with clear symptoms and signs but normal-range total testosterone, follicle-stimulating hormone, luteinizing hormone, and prolactin levels. Other possible tests include semen analysis, pituitary imaging studies, genetic studies, bone densitometry, testicular ultrasonography,testicular biopsy, and specialized hormonal dynamic testing. Therapeutic options generally consist of testosterone replacement by injections, patches, or topically applied gel in hypergonadotropic patients and in hypogonadotropic patients not interested in fertility. In hypogonadotropic patients interested in fertility, gonadal stimulation option scan be considered, including human chorionic gonadotropin stimulation therapy with or without human menopausal gonadotropin (or follicle-stimulating hormone) or gonadotropin-releasing hormone pump therapy. These therapies may be combined with assisted reproductive technologies such as in vitro fertilization with intracytoplasmic sperm injection, which may allow pregnancy to occur with very low numbers of sperm.

Background: Pyridinoline (PYD) and deoxypyridinoline (DPD) are two of the most extensively characterized biochemical bone markers, but the interpretation of results is hampered by biologic and other preanalytical variability. We reviewed factors contributing to preanalytical variation of pyridinium cross-links in urine.Methods: We searched four databases for English-language reports on PYD and/or DPD in urine. Searches were restricted to humans, except for studies of stability, when the search was expanded to other species. The 599 identified articles were supplemented with references from those articles and with articles known to the authors.Results: The mean reported within-day variability was 71% for PYD (range, 57–78%) and 67% for DPD (range, 53–75%). The mean interday variability was 16% for both DPD and PYD (range for PYD, 12–21%; range for DPD, 5–24%). The mean intersubject variabilities across studies were 26% for PYD (range, 12–63%) and 34% for DPD (range, 8–98%) for healthy premenopausal women and 36% (range, 22–61%) and 40%, (range, 27–54%) for postmenopausal women, respectively. Specimen instability and errors in creatinine measurements were additional sources of variability.Conclusions: Intra- and intersubject variability can be reduced by collecting specimens at a specific time of the day and by maintaining similar patient status at each specimen collection regarding factors such as medications and dietary supplements.

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.

Bone densitometry, regardless of the specific technique, is not perfectly reproducible even when consistently performed in exact accordance with the manufacturer's recommendations. Precision must be quantified at each densitometry facility in precision studies of the various skeletal sites used for monitoring. The precision, as the root-mean-square standard deviation or root-mean-square coefficient of variation, is then used to determine the change in bone density that constitutes the least significant change and the minimum interval between follow-up measurements. Until precision studies are performed, the least significant change cannot be determined for any level of statistical confidence, making the interpretation of serial studies impossible.

In 1994, the WHO published a detailed report that was developed over a number of years by an international group of experts in osteoporosis [1]. This work formalized the current prefracture diagnos...

The treatment of patients with asymptomatic primary hyperparathyroidism remains controversial despite a National Institutes of Health consensus statement. This statement also recommended a randomized clinical trial because none exists to address this issue.Informed consent was obtained from 53 asymptomatic patients with confirmed asymptomatic primary hyperparathyroidism who participated in this randomized trial of parathyroidectomy versus observation. Patients completed the SF-36 Health Survey, an instrument that measures wellness, every 6 months for 2 years. Average annual changes were compared.Fifty-three patients (42 female, 11 male) with asymptomatic, mild (serum calcium level, 10.1-11.5 mg/dL) asymptomatic primary hyperparathyroidism who agreed to participate were randomized into either a surgical group or an observation group. The mean calcium level was 10.31 mg/dL. The only demographic difference between groups was age, with the operative group being older (66.7 vs 62.6 years; P.03). The scores on 2 of the 9 domains of the SF-36 were significantly different (P.007 and.012, respectively); both favored the operative group.Improved function is seen after parathyroidectomy when compared with patients who did not undergo operation. This study supports surgical management of mild primary hyperparathyroidism at the time of diagnosis because many patients have reversible nonclassic symptoms of the disease.

The new definition of osteoporosis moves this disorder from a disease of fractures to a disease of fracture risks. Like blood lipids and blood pressure, bone mineral density is now viewed as a predictor of possible problems. Through careful history taking and physical examination, primary care physicians can identify patients in whom intervention is likely to prevent the anguish of broken bones and lost mobility. In this article, Drs Goddard and Kleerekoper discuss the new diagnostic criteria and what they mean for your patients. Language: en

Lower cost, portable, peripheral bone mass measurement devices are being increasingly utilized for widespread bone mass testing. These devices are being placed in traditional medical settings as well as nontraditional settings, such as pharmacies and grocery stores. Increased bone mass testing is appropriate at menopause in women who are undecided whether to begin systemic estrogen replacement. Women may decide to begin estrogen replacement if they are aware they have low bone mass and understand that bone mass will predictably decline after the menopause (1). With the approval of alendronate and raloxifene for the prevention of osteoporosis, even women who cannot or will not utilize estrogen replacement may be offered preventive interventions if they are identified as having low bone mass. More accessible bone mass measurements and more approved pharmacologic interventions will shift the focus of osteoporosis management to strategies that emphasize the reduction of lifetime fracture risk as well as current fracture risk. It will also be an impetus to focus on earlier identification and intervention (2-4).

There are several million breast cancer survivors worldwide. In the United States, 180,000 women were diagnosed with breast cancer in 1997, and approximately 97,000 of these women have an extremely low chance of suffering a recurrence of their cancer. With an average age at diagnosis of 60 years and a 25-year expected duration of survival, the current number of breast cancer survivors in the United States may approach 2.5 million women. Since breast cancer is now being detected at an earlier stage than previously and since adjuvant chemotherapy may cause ovarian failure, an increasing number of women are becoming postmenopausal at a younger age after breast cancer treatment. This conference was convened in September 1997 to consider how menopausal breast cancer survivors should be treated at the present time and what future studies are needed to develop improved therapeutic strategies. A total of 59 breast cancer experts and patient advocates participated. The proceedings of the conference will be published in six installments in successive issues of oncology. The first part, published last month, defined the problem and explored its magnitude and ramifications for patient management. This second part focuses on the benefits and risks of hormone replacement therapy (HRT) in patients with breast cancer. [ONCOLOGY 13(2):245-267, 1999]

The objective of this study was to determine retrospectively the prevalence of osteoporosis in a referral population and to compare the effectiveness of measuring multiple skeletal sites for identifying osteoporosis. Although osteoporosis is considered to be a major public health problem in the United States, and there are reliable methods for diagnosis based on bone densitometry, fewer than 25% of cases are currently identified. There is no consensus about which skeletal site(s) should be measured for optimal results. In this study, bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) at the radius (proximal site), lumbar spine, femoral neck, and total proximal femur regions in 537 consecutive white females age 50 and older referred by community physicians for bone densitometry. The prevalence of osteopenia and osteoporosis (based on the World Health Organization definitions) was determined, as well as the incidence of misclassification of patients based on different skeletal sites. Overall, 53.3% had osteoporosis, an additional 37.7% had osteopenia, and only 8.7% had normal BMD at all measurement sites. The prevalence was similar at all measurement sites and the incidence of misclassification was low. Given the magnitude of undetected osteoporosis and the efficacy of bone densitometry at any skeletal site, these data have important implications for the optimal deployment of bone density measurement facilities.

F t p o a p ( t h r S p m i t f s h t p m d p s i m i v i m t T o t m he portal of entry of primary hyperparathyroidism into the office of the internist and endocrinologist is changing yet again. Gone are the days when paients presented with symptomatic disease: marked hyercalcemia with the protean manifestations now seen nly in patients in whom the hypercalcemia complicates malignant process; clinically overt bone disease; recurent nephrolithiasis; or abdominal pain not always exlainable by peptic ulcer disease. Probably going are the ays when primary hyperparathyroidism was diagnosed fter the serendipitous finding of hypercalcemia on an utomated biochemical profile as part of routine screenng in healthy or unhealthy patients— cost-cutting meaures in many institutions and by third-party payers have rogressively limited the spectrum of tests on these rouine profiles. The new major portal of entry is measurement, not of alcium, but of parathyroid hormone as part of the evalation of patients found to have low bone mineral denity. Purists, this author included, have looked down on his seeming abuse of the system and restricted measureent of parathyroid hormone in patients with osteopoosis/low bone mass (osteopenia) to those in whom an nitial, “appropriate” screening for potentially treatable auses of osteoporosis documented hypercalcemia. Sevral publications over the last few years have proven us urists wrong. Two, possibly three, “new” diseases have merged from the practice of routinely measuring parahyroid hormone in the evaluation of low bone mineral ensity

Bone mass is directly related to bone strength and the risk for osteoporotic fractures. Factors affecting both peak bone mass and rate of bone loss are reviewed, and their relationship to fractures is discussed.

T HIS REVIEW reflects my own clinical experience over a number of years, and it seems appropriate to describe this practice setting, at least briefly. Until recently, as a member of the Bone and Mineral Division of the Henry Ford Health System in Detroit, Michigan, I worked with a group of specialists, all but one of whom was an endocrinologist, but our clinical practice was restricted to disorders of bone and mineral metabolism: no diabetes, no thyroid, just bones. Consequently, many of our referrals were from fellow endocrinologists seeking consultation for what they regarded as out of the ordinary in our field or patients who were potential participants in clinical research trials. It was uncommon, unfortunately, for us to see patients with established osteoporosis, for example, who were “virginal” with respect to evaluation or therapy. The other source of referral to my personal practice within this group was from gynecologists whose perimenopausal patients wanted further discussion about hormone replacement therapy. More specifically, these women requested an analysis of their risk of developing osteoporosis to complete the hormone replacement “risk/benefit” equation. My admittedly extremist views on hormone replacement, that the benefits far outweigh the risks for most women, are well known in my community, and this was reflected in the referral pattern. Recently, I was fortunate to have joined the Division of Endocrinology and Metabolism at Wayne State University, still in Detroit. My metabolic bone disease clinic is conducted in the rheumatology section of the university’s major women’s hospital (Hutzel Hospital), with a significant impact on the source and type of referral. The nation’s largest obstetrics and gynecology residency program, with a long-standing active menopause program, is in the same facility. Referrals for skeletal management of perimenopausal women focuses more directly on that segment for whom hormone replacement is absolutely or relatively contraindicated. Working with rheumatologists (who as a specialty are making an increasingly aggressive attempt to move into the osteoporosis area), a major new source of referral is patients whom these rheumatologists are treating with corticosteroids. Fortunately, the outstanding group with whom I am associated recognizes this major clinical problem, and together we are moving toward a program of addressing the skeletal complications of steroids at the initiation of therapy rather than after the third or fourth osteoporotic fracture. It is worth noting that in neither facility were orthopedists or primary care providers a major source of new patient referral to a specialty bone program. From my personal experience, general endocrinologists are more likely to receive referrals from these sources, even in a major metropolitan area with acknowledged clinical expertise in bone and mineral disorders. Thus, osteoporosis has already outstripped thyroid disease and is overtaking diabetes as “bread and butter” endocrinology. This first person, biased contribution to the Journal offers some perspectives on patient evaluation and management. The current accepted definition of osteoporosis is low bone mass and microarchitectural deterioration of the skeleton, leading to an increased risk of fracture after minimal trauma (1). In practice, however, patients are seen by a clinician because of one of the following distinct clinical situations: 1) the patient concerned about her or his individual risk of developing osteoporosis; 2) the patient with diagnosed osteoporosis who has not yet sustained a fracture or in whom there is concern that a vertebral deformity seen on x-ray may have resulted from an osteoporotic fracture; and 3) the patient with established osteoporosis complicated by fractures after minimal trauma. In this review I will focus on each of these situations separately, recognizing that there will be substantial overlap in the approaches.

Obesity offers protection against osteoporosis in older women. The mechanisms are not well understood, but relate in part to increased aromatization of adrenal androgens to estrone in peripheral fat and muscle tissue. Two hundred and one white and 77 black women previously reported to be free of skeletal disease and to have normal bone mass had measurements of total body bone mineral (TBBM), fat mass (TBFM), and lean mass (TBLM) performed by dual energy x-ray absorptiometry. Serum estrone, androstenedione, and dihydroepiandrostenedione sulfate were measured on the same day. Body weight, body mass index, TBFM, and TBLM were all significantly higher in the black women. However, proportionately, there were no differences in body composition between the two groups. This suggests that the black women were not more obese despite their greater body mass index, and that future studies on the health impact of obesity in older black women should take this into consideration. Despite the greater TBFM and TBLM in the black women and no difference in serum androstenedione levels, the serum estrone level was not higher in the black women, and the higher bone mass in blacks was not related to serum estrone. In both ethnic groups, TBBM was significantly related to body weight (white, r = 0.80; black, r = 0.85; P0.001 for both). Both TBFM and TBLM were significantly related to TBBM in both ethnic groups. Serum estrone was significantly related to all measures of body mass in the white women, but to no measures of body mass in the black women, indicating apparent differences in the metabolism of estrone between older white and black women.

Vitamin D is a “hot topic,” with the number of citations in PubMed exceeding 2400 in 2009, a 3-fold increase in 1 year. In the US, the number of requested 25-hydroxyvitamin D (25-OHD)9 assays is increasing exponentially. Not all of the published material has validity, however. A panel of experts was invited to address a series of questions pertaining to laboratory methods and clinical applications of available assays for 25-OHD and 1,25-dihydroxyvitamin D (1,25-OHD). What should we measure: 25-OHD3, 25-OHD2, both, or 1,25-OHD? Rosemary L. Schleicher: Our interest is in providing 25-OHD data for the National Health and Nutrition Examination Survey (NHANES). Separate estimates for 25-OHD2 and 25-OHD3—together with recent food- and supplement-intake data, questionnaire data about physical activity, sun-protection behavior and skin type, and demographic information related to race/ethnicity, season, latitude, and age—provide valuable information about the sources of vitamin D for those in the noninstitutionalized civilian US population. In addition, we will be separating and quantifying the C3 epimer of 25-OHD3, which may not be as biologically active as 25-OHD3. John Eisman: 25-OHD2 and 25-OHD3 should be measured in most clinical situations, although in many countries vitamin supplements and food fortification are moving from vitamin D2 to D3. I am unaware of clinical needs requiring knowing 25-OHD2 and 25-OHD3 separately, or the C3 epimer. There are few clinical situations where knowing the 1,25-OHD concentrations are clinically critical or overly helpful. Roger Bouillon: We need to know the combined concentration of 25-OHD3 and 25-OHD2 because both products can be converted into the active hormone 1,25-OHD. In countries where vitamin D2 supplementation is not available, the measurement of 25-OHD3 alone would be sufficient, since there is very …

We report our experience with successfully recruiting 377 skeletally healthy African American and white (and other) women into a longitudinal study of bone loss. The objective of this 2-year observational study was to prospectively measure changes in bone mineral density and determinants of that change in women who were at least 10 years postmenopause. We recruited from a random sample of women who were members of our health maintenance organization, including the urban and five suburban regions of Detroit. Of those contacted by telephone, 91% completed a 15–20 survey containing demographic and eligibility variables. We recruited 1 in 17 potential subjects who were contacted by telephone. Of the eligible women, 33% participated in the study. The eligibility rate was higher among the African American than among the white women, but there was no ethnic difference in the participation rate. We also describe eligibility and participation rates with regard to demographic and sociologie variables, such...

We compared skin color, body size and bone mineral density (BMD) among three groups of postmenopausal women: 104 healthy black women, 45 healthy white women, and 52 osteoporotic white women with vertebral fractures. Skin color was measured by reflectometry, stature with a Harpenden stadiometer, weight with digital scales, and radial BMD by single photon absorptiometry. There were no significant differences in mean skin color (age-adjusted) between the healthy and osteoporotic white women, although both white groups differed from the black group. There was no significant correlation between skin color and BMD (age- and weight/height-adjusted) in any of the groups. All three groups differed significantly in age-adjusted BMD, although there was less difference between the healthy blacks and whites when covariates (body size, age) were taken into account. We further investigated body size differences by estimating stature at age 55 in all three groups based on our observations that osteoporotic women with vertebral fractures lose height at a rate that is 2.6 times faster than that of healthy aging women. Our analyses indicate that the osteoporotics were not shorter than the normals before the onset of their disease (based on estimated height), and do not have a significantly smaller body mass (weight/height and weight/height 2) than the normal white women. Additionally, the osteoporotics are above the ideal body mass index recommended by the National Institutes of Health. We conclude that fair skin is not a risk factor for osteoporosis and that large body size is not protective against the development of osteoporosis, although it may have a salutary effect on BMD in both blacks and whites.

In metabolic bone diseases other than osteoporosis (Paget disease, rickets and osteomalacia, primary and secondary hyperparathyroidism), biochemical markers of bone turnover have been important clinical tools in patient management for more than 3 decades. In these diseases, bone metabolism is often so abnormal that even crude, nonspecific markers such as total serum alkaline phosphatase and urine hydroxyproline have been sufficiently reliable to allow clinicians to make appropriate management decisions without difficulty or error. When noninvasive measurements of bone mineral density (BMD) became available, the most common metabolic bone disease, osteoporosis, began to receive attention from researchers, pharmaceutical companies, and clinical practitioners. BMD technology from the beginning had very acceptable accuracy and precision errors such that diagnosis and monitoring of disease progression or regression were straightforward (1)(2). However, there was and remains one major drawback to BMD alone in the management of osteoporosis: bone turnover is generally so slow (particularly in relation to the other metabolic bone diseases listed above) that it may take up to 2 years in most circumstances to be certain with 95% confidence that any change in BMD is more than can be accounted for by method imprecision (3)(4)(5). When studying large groups of patients in a clinical trial, this is not a practical problem because significant group changes can be detected as early as 6 months after an intervention has been started (6)(7)(8)(9). This is of limited benefit to individual patient care. To overcome this, researchers turned to biochemical markers of bone turnover as adjunctive tools in patient management. It became clear very early in this endeavor that total alkaline phosphatase and urine hydroxyproline lacked both the sensitivity and specificity to be of much value. Newer markers had to be developed, which required a …

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.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.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 EndocrinologyMetabolism; 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.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.

A 67-year-old white male presented with symptomatic hypercalcemia (15.6 mg/dl) in December 1989. He had undergone thyroidectomy for removal of a mucin-producing adenocarcinoma of the thyroid in 1967, and after eight years of follow-up during which time no other neoplasms were detected, he was reported as a unique case of this syndrome. Mild hypercalcemia (less than 11.0 mg/dl) was first noted in 1987, and this had remained stable until shortly before the acute presentation. Multiple lung nodules were observed radiographically and presumed to be granulomatous until increased size was observed shortly before presentation. Serum intact PTH was 190 pg/ml (n 10-55), but at neck exploration no parathyroid tissue was found and surgery did not resolve the hypercalcemia. Serum PTHrP was undetectable. Biopsies from all three lobes of the right lung revealed numerous nodules of metastatic adenocarcinoma with cords of tumor cells surrounded by mucin. The histology was similar to that obtained 23 years earlier. Following left upper lobe resection with removal of a 3-cm nodule, hypercalcemia resolved. The tumor stained strongly positive with a peroxidase stain for PTH using a polyclonal antibody. Northern blot hybridization of total RNA from the tumor confirmed the presence of message for PTH but not PTHrP. The original diagnosis has been revised to that of a unique case of mucin-producing parathyroid cancer with an extraordinarily long latency period before recurrence.