Shreyasee Amin

Osteoporosis in Men

With the aging of the population, there is a growing recognition that osteoporosis and fractures in men are a significant public health problem, and both hip and vertebral fractures are associated with increased morbidity and mortality in men. Osteoporosis in men is a heterogeneous clinical entity: whereas most men experience bone loss with aging, some men develop osteoporosis at a relatively young age, often for unexplained reasons (idiopathic osteoporosis). Declining sex steroid levels and other hormonal changes likely contribute to age-related bone loss, as do impairments in osteoblast number and/or activity. Secondary causes of osteoporosis also play a significant role in pathogenesis. Although there is ongoing controversy regarding whether osteoporosis in men should be diagnosed based on female- or male-specific reference ranges (because some evidence indicates that the risk of fracture is similar in women and men for a given level of bone mineral density), a diagnosis of osteoporosis in men is generally made based on male-specific reference ranges. Treatment consists both of nonpharmacological (lifestyle factors, calcium and vitamin D supplementation) and pharmacological (most commonly bisphosphonates or PTH) approaches, with efficacy similar to that seen in women. Increasing awareness of osteoporosis in men among physicians and the lay public is critical for the prevention of fractures in our aging male population.

A Population-Based Assessment of Rates of Bone Loss at Multiple Skeletal Sites : Evidence for Substantial Trabecular Bone Loss in Young Adult Women and Men

Using QCT, we made a longitudinal, population‐based assessment of rates of bone loss over life at the distal radius, distal tibia, and lumbar spine. Cortical bone loss began in perimenopause in women and later in life in men. In contrast, trabecular bone loss began in young adulthood in both sexes.

Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study

Osteoporosis is not a problem confined to women; it has important medical and socioeconomic consequences for men as well (1-3). With advancing age, men lose bone mineral density (4, 5), which leads to increased risk for fracture after minimal trauma (6). It is estimated that 13% of white men older than 50 years of age will experience a fracture during their lifetime (7). Approximately 30% of all hip fractures occur in men (8), and the morbidity and mortality after such fractures are much greater in men than in women (9-11). As the aging population grows worldwide, a better understanding of risk factors that contribute to low bone mineral density in elderly men will be needed. The effect of sex hormones on bone mineral density in elderly men is of particular interest because it could have diagnostic and therapeutic implications, as it does in women (12, 13). Both androgens and estrogens have been shown to be important for bone health in young men, but their role in elderly men is not as clear (14, 15). Testosterone, the predominant circulating androgen in men, is produced mainly by Leydig cells of the testes and is regulated by luteinizing hormone (16, 17). Hypogonadism in men, whether caused by primary or secondary failure of Leydig cell function, results in low testosterone levels. Young adult men who are hypogonadal because of medical conditions or castration have low bone mineral density (18-20); testosterone replacement improves bone mineral density in these men (19, 21). Given the association between hypogonadism and bone mineral density in young men and the decrease in serum testosterone levels with increasing age (22, 23), it has been assumed that hypogonadism related to aging explains low bone mineral density in elderly men. However, evidence to support this association remains weak. Results of studies that include men of a wide age range or hypogonadal men with an identifiable medical cause (such as orchiectomy or pituitary tumors) are not generalizable to elderly men from the general population. Among studies specifically of elderly men from the general population, several failed to show an association between testosterone levels and bone mineral density (24-28). It could be that an association with bone mineral density exists only below the normal reference range for testosterone (29) and that continuous measurement of testosterone levels, as was done in most studies, missed this relation. Previous studies may have also been limited by the fact that single measurements of sex hormones obtained at the same time as bone mineral density measurement may not adequately reflect the influence of these hormones on bone metabolism. Recent evidence suggests that estrogens may also be important for bone health in young and older men (14, 27, 28, 30-36). However, the magnitude of effect of estrogen levels on bone mineral density in elderly men is not known, nor is the relative effect of testosterone and estrogens clearly defined. Only a small fraction of estradiol, the major circulating form of estrogen, is produced directly by the testes; the main source is peripheral conversion of testosterone and adrenal sex steroids by the aromatase enzyme (17, 37). Thus, some or all of the effect of low testosterone on bone mineral density in elderly men could be explained by low estradiol levels. We examined the association of testosterone and estradiol status with bone mineral density among men from the Framingham Study, a population-based cohort with a large number of elderly men who had repeated measurement of sex hormones before bone mineral density assessment. We explored the association of a threshold effect of low testosterone level on bone mineral density in these men by considering different definitions of hypogonadism based on sex hormone measures. Methods The Framingham Study began in 1948 in Framingham, Massachusetts, with the initial goal of evaluating risk factors for heart disease in a population-based cohort (38). As part of this ongoing study, participants have received comprehensive medical examinations every 2 years. The Framingham Osteoporosis Study, designed to study risk factors for osteoporosis, started in 19881989 as a component of the 20th biennial examination and involved surviving members of the cohort, most of whom were white (39). We studied the 448 men of the cohort who had bone mineral density measurements in 19881989 and sex hormones measurements during previous biennial examinations. Assessment of Sex Hormones Total testosterone, total estradiol, and luteinizing hormone were measured in all male participants at four consecutive biennial examinations from 1981 to 1989. Serum samples were measured by using radioimmunoassay for total testosterone (Diagnostic Products Corp., Los Angeles, California; interassay coefficient of variation, 11%; reference range for young adult men, 10 to 35 nmol/L [3 to 10 ng/mL]), total estradiol (Diagnostic Products Corp.; lower limit of assay detection, 2 pg/mL; interassay coefficient of variation, 4%; reference range for young adult men, 7 to 184 pmol/L [2 to 50 pg/mL]), and luteinizing hormone (Serono Laboratories, Randolph, Massachusetts, in 1981 to 1983, then Diagnostic Products Corp. for the three biennial examinations from 1983 to 1989; intraclass correlation, 0.92; interassay coefficient of variation, 6%; reference range for young adult men, 3 to 13 IU/L). Data were originally collected in traditional units, and cutoff values were defined on the basis of these units. Conversions to SI units were performed in accordance with the publication policy of Annals of Internal Medicine. Assessment of Bone Mineral Density In 19881989, bone mineral density was measured at the proximal femur (femoral neck, Ward triangle, and trochanter) and lumbar spine by using dual-photon absorptiometry (LUNAR DP3, Lunar Corp., Madison, Wisconsin) and at the radial shaft (measured at the junction of the proximal two thirds and the distal one third of the radius) by using single-photon absorptiometry (LUNAR SP2, Lunar Corp.) (39). If participants had a history of fracture or hip joint replacement, the contralateral side was scanned. Because the lumbar spine was assessed during a callback examination, the number of participants for whom this measurement was available is smaller than that for the proximal femur or radial shaft. All bone mineral density scans were reviewed to ensure that correct placement and analysis were performed according to the manufacturers recommendations. Scans for which placement was incorrect, those that did not include the complete anatomic region of interest, and those found to include metal or other attenuating material were considered technically inadequate and were deleted. The coefficients of variation in normal persons for bone mineral density at the proximal femur were 2.6% for the femoral neck, 4.1% for Ward triangle, and 2.8% for the trochanter; the coefficients of variation were 2.2% and 2.0% for the lumbar spine and radial shaft, respectively. Assessment of Other Covariates Factors previously shown to be associated with bone mineral density in men were also assessed (15, 39-46). These variables were age, body mass index, serum 25-hydroxyvitamin D level, calcium intake, physical activity, cigarette smoking, alcohol intake, thiazide diuretic use, and glucocorticoid use. Age, body mass index, serum 25-hydroxyvitamin D, calcium intake, and physical activity were determined in 19881989 at the time of the bone mineral density assessment. Serum 25-hydroxyvitamin D was measured by using a competitive binding-protein assay (47) (interassay coefficient of variation, 10%) and was categorized as low (<50 nmol/L), medium (50 to 75 nmol/L), or high (>75 nmol/L). Information on dietary calcium intake, including supplements, was collected by using the Willett 126-item food frequency questionnaire (48, 49) and was categorized as low (<500 mg/d), moderate (500 to 1000 mg/d), or high (>1000 mg/d). Physical activity was assessed by using the Framingham Physical Activity Index, a weighted 24-hour score of typical daily activity based on hours spent performing heavy, moderate, light, or sedentary activity (50, 51). Information on smoking and alcohol intake was available from previous biennial examinations. Participants were characterized as current smokers if they smoked cigarettes during 1981 to 1989, former smokers if they reported smoking before 1981 but not between 1981 and 1989, and never-smokers if they reported no cigarette use since inception of the study in 1948. Alcohol intake was defined according to the average ounces of alcohol consumed per week between 1981 and 1989. Information on thiazide diuretic use among participants was available from three consecutive examinations from 1983 to 1989, and information on glucocorticoid use was available from all four examinations from 1981 to 1989. Statistical Analysis To examine the association between sex hormone status and bone mineral density, we averaged hormone values for each participant if measurements were available from at least three of four examinations from 1981 to 1989. We excluded one participant whose serum estradiol value was considered unreliable. All analyses were performed by using SAS software, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Gonadal Status and Bone Mineral Density Hypogonadism in men is the loss of testicular function, which includes primary and secondary failure of the Leydig cell function in the testes, leading to a deficiency in serum testosterone levels. Studying hypogonadal elderly men from the general population is difficult, however, because there are no standard definitions of hypogonadism, and symptoms and signs are not well correlated with hormonal status (52, 53). Therefore, to examine whether hypogonadism was associated with low bone mineral density in our population-based sample of elderly men, we created a definition based on the mean total testosterone o

Relation of age, gender, and bone mass to circulating sclerostin levels in women and men.

Sclerostin is a potent inhibitor of Wnt signaling and bone formation. However, there is currently no information on the relation of circulating sclerostin levels to age, gender, or bone mass in humans. Thus we measured serum sclerostin levels in a population‐based sample of 362 women [123 premenopausal, 152 postmenopausal not on estrogen treatment (ET), and 87 postmenopausal on ET] and 318 men, aged 21 to 97 years. Sclerostin levels (mean ± SEM) were significantly higher in men than women (33.3 ± 1.0 pmol/L versus 23.7 ± 0.6 pmol/L, p < .001). In pre‐ and postmenopausal women not on ET combined (n = 275) as well as in men, sclerostin levels were positively associated with age (r = 0.52 and r = 0.64, respectively, p < .001 for both). Over life, serum sclerostin levels increased by 2.4‐ and 4.6‐fold in the women and men, respectively. Moreover, for a given total‐body bone mineral content, elderly subjects (age ≥ 60 years) had higher serum sclerostin levels than younger subjects (ages 20 to 39 years). Our data thus demonstrate that (1) men have higher serum sclerostin levels than women, (2) serum sclerostin levels increase markedly with age, and (3) compared with younger subjects, elderly individuals have higher serum sclerostin levels for a given amount of bone mass. Further studies are needed to define the cause of the age‐related increase in serum sclerostin levels in humans as well as the potential role of this increase in mediating the known age‐related impairment in bone formation.

In vivo assessment of bone quality in postmenopausal women with type 2 diabetes

Although patients with type 2 diabetes (T2D) are at significant risk for well‐recognized diabetic complications, including macrovascular disease, retinopathy, nephropathy, and neuropathy, it is also clear that T2D patients are at increased risk for fragility fractures. Furthermore, fragility fractures in patients with T2D occur at higher bone mineral density (BMD) values compared to nondiabetic controls, suggesting abnormalities in bone material strength (BMS) and/or bone microarchitecture (bone “quality”). Thus, we performed in vivo microindentation testing of the tibia to directly measure BMS in 60 postmenopausal women (age range, 50–80 years) including 30 patients diagnosed with T2D for >10 years and 30 age‐matched, nondiabetic controls. Regional BMD was measured by dual‐energy X‐ray absorptiometry (DXA); cortical and trabecular bone microarchitecture was assessed from high‐resolution peripheral quantitative computed tomography (HRpQCT) images of the distal radius and tibia. Compared to controls, T2D patients had significantly lower BMS: unadjusted (−11.7%; p < 0.001); following adjustment for body mass index (BMI) (−10.5%; p < 0.001); and following additional adjustment for age, hypertension, nephropathy, neuropathy, retinopathy, and vascular disease (−9.2%; p = 0.022). By contrast, after adjustment for confounding by BMI, T2D patients had bone microarchitecture and BMD that were not significantly different than controls; however, radial cortical porosity tended to be higher in the T2D patients. In addition, patients with T2D had significantly reduced serum markers of bone turnover (all p < 0.001) compared to controls. Of note, in patients with T2D, the average glycated hemoglobin level over the previous 10 years was negatively correlated with BMS (r = −0.41; p = 0.026). In conclusion, these findings represent the first demonstration of compromised BMS in patients with T2D. Furthermore, our results confirm previous studies demonstrating low bone turnover in patients with T2D and highlight the potential detrimental effects of prolonged hyperglycemia on bone quality. Thus, the skeleton needs to be recognized as another important target tissue subject to diabetic complications.

Bone Structure at the Distal Radius During Adolescent Growth

The incidence of distal forearm fractures peaks during the adolescent growth spurt, but the structural basis for this is unclear. Thus, we studied healthy 6‐ to 21‐yr‐old girls (n = 66) and boys (n = 61) using high‐resolution pQCT (voxel size, 82 μm) at the distal radius. Subjects were classified into five groups by bone‐age: group I (prepuberty, 6–8 yr), group II (early puberty, 9–11 yr), group III (midpuberty, 12–14 yr), group IV (late puberty, 15–17 yr), and group V (postpuberty, 18–21 yr). Compared with group I, trabecular parameters (bone volume fraction, trabecular number, and thickness) did not change in girls but increased in boys from late puberty onward. Cortical thickness and density decreased from pre‐ to midpuberty in girls but were unchanged in boys, before rising to higher levels at the end of puberty in both sexes. Total bone strength, assessed using microfinite element models, increased linearly across bone age groups in both sexes, with boys showing greater bone strength than girls after midpuberty. The proportion of load borne by cortical bone, and the ratio of cortical to trabecular bone volume, decreased transiently during mid‐ to late puberty in both sexes, with apparent cortical porosity peaking during this time. This mirrors the incidence of distal forearm fractures in prior studies. We conclude that regional deficits in cortical bone may underlie the adolescent peak in forearm fractures. Whether these deficits are more severe in children who sustain forearm fractures or persist into later life warrants further study.

Quadriceps strength and the risk of cartilage loss and symptom progression in knee osteoarthritis

OBJECTIVE To determine the effect of quadriceps strength in individuals with knee osteoarthritis (OA) on loss of cartilage at the tibiofemoral and patellofemoral joints (assessed by magnetic resonance imaging [MRI]) and on knee pain and function. METHODS We studied 265 subjects (154 men and 111 women, mean+/-SD age 67+/-9 years) who met the American College of Rheumatology criteria for symptomatic knee OA and who were participating in a prospective, 30-month natural history study of knee OA. Quadriceps strength was measured at baseline, isokinetically, during concentric knee extension. MRI of the knee at baseline and at 15 and 30 months was used to assess cartilage loss at the tibiofemoral and patellofemoral joints, with medial and lateral compartments assessed separately. At baseline and at followup visits, knee pain was assessed using a visual analog scale, and physical function was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index. RESULTS There was no association between quadriceps strength and cartilage loss at the tibiofemoral joint. Results were similar in malaligned knees. However, greater quadriceps strength was protective against cartilage loss at the lateral compartment of the patellofemoral joint (for highest versus lowest tertile of strength, odds ratio 0.4 [95% confidence interval 0.2, 0.9]). Those with greater quadriceps strength had less knee pain and better physical function over followup (P<0.001). CONCLUSION Greater quadriceps strength had no influence on cartilage loss at the tibiofemoral joint, including in malaligned knees. We report for the first time that greater quadriceps strength protected against cartilage loss at the lateral compartment of the patellofemoral joint, a finding that requires confirmation. Subjects with greater quadriceps strength also had less knee pain and better physical function over followup.

Endogenous sex hormones and cardiovascular disease incidence in men

Context Studies of the role of endogenous sex hormones in cardiovascular disease (CVD) in men have been inconclusive. Contribution A total of 2084 men from 2 Framingham Heart Study cohorts had levels of total serum estrogen, testosterone, and dehydroepiandrosterone sulfate (DHEA-S) measured in 1981 to 1985 for the original cohort and in 1987 to 1991 for the offspring cohort. Testosterone and DHEA-S levels were not associated with CVD risk. Estrogen levels were inversely related: Risk for CVD in the highest quartile was 0.68 (95% CI, 0.50 to 0.92) times that in the lowest level. Cautions Investigators studied only white men and did not study free unbound hormone levels. Implications Endogenous estrogen may be vasculoprotective in men, which is in contrast to the effects of exogenous estrogen. The Editors Male sex is an independent risk factor for cardiovascular disease (CVD) (1). Scientists have postulated that the 5- to 10-year lag period in CVD incidence in women (compared with men) may be related to differences in endogenous sex hormones (27). Indeed, substantial evidence suggests that sex hormones (testosterone, estrogen, and dehydroepiandrosterone sulfate [DHEA-S]) influence traditional and newer CVD risk factors (27). Interest in the role of sex hormones in the pathogenesis of CVD has been rekindled by the observation that men with genetic defects of estrogen synthesis (8) or action (9) develop premature atherosclerosis. In addition, genetic variation in estrogen receptor- has been associated with prevalent CVD (10, 11), and androgen and estrogen receptor expression in coronary arteries has been reported to influence coronary atherosclerosis in men (12). In contrast to the aforementioned data, prospective studies relating circulating sex hormone levels to incident CVD in men have been inconclusive. For example, low serum testosterone levels have been associated with greater progression of subclinical atherosclerosis in 2 previous investigations (13, 14), but other studies have reported no association of testosterone levels with CVD events (1521). On a parallel note, low DHEA-S levels have been linked to greater CVD risk in some studies (18, 2224) but not in other studies (13, 20, 2529). Investigations relating serum estradiol levels to CVD risk in men have generally found no statistically significant association (1520). Some previous investigations were limited by modest sample sizes (14, 17, 18, 22, 25, 26); an insufficient number of CVD events (1518, 22, 23, 26); and, in some instances, a retrospective study design (1721, 25, 26). In addition, some reports (15, 22, 24) focused on CVD death (they did not evaluate nonfatal CVD events). Thus, a large prospective community-based study relating sex hormones to CVD risk with adequate power to detect modest potential associations is needed. Accordingly, we evaluated the associations of serum levels of sex hormones that were measured at a routine baseline examination with CVD incidence in a prospectively assembled cohort of participants. Methods Study Sample The Framingham Heart Study, a prospective study of the risk factors for the development of heart disease and stroke, began in 1948 with the recruitment of 5209 men and women between 30 and 60 years of age who resided in Framingham, Massachusetts (30). The Framingham Offspring Study began in 1971 with the recruitment of 5124 participants who were the children of the original cohort and the spouses of the children (31). Participants in the original cohort are examined every 2 years, while offspring cohort members are assessed every 4 years. At each Framingham Heart Study examination, attendees undergo a physical examination and laboratory assessment of risk factors (31). We evaluated 2789 men who attended the 17th biennial examination (19811983) of the original cohort or the fourth quadrennial examination (19871991) of the offspring cohort. We measured serum total testosterone and estradiol levels at these examinations, and we measured DHEA-S levels at the 18th examination (19831985) for the original cohort and at the fourth examination for the offspring cohort. We excluded 705 men because of prevalent CVD (n= 541) and nonavailable testosterone data (n= 164). After exclusions, 2084 men (74.7%; 525 original cohort participants) without previous CVD were eligible. Data on serum estradiol levels and serum DHEA-S levels were available in 2047 men and 1928 participants, respectively. All participants gave written informed consent, and the institutional review board at the Boston Medical Center approved the study protocol. Biochemical Assessment of Sex Hormones As described previously (32), we measured total testosterone, total estradiol, and DHEA-S levels from serum samples by using radioimmunoassays (Diagnostic Products Corp., Los Angeles, California) for total testosterone (interassay coefficient of variation, 11%), total estradiol (interassay coefficient of variation, 4%), and DHEA-S (interassay coefficient of variation, 11%). We also measured serum luteinizing hormone levels at the baseline examinations (interassay coefficient of variation, 6%). Cardiovascular Outcomes All participants were under continuous surveillance for the occurrence of CVD events and death. Participants are evaluated periodically at the Framingham Heart Study and through health history updates between examinations (obtained via telephone interviews). Three experienced investigators obtained and reviewed hospitalization and physician office visit records. We defined incident CVD as coronary heart disease (recognized or unrecognized myocardial infarction, angina pectoris, coronary insufficiency, or coronary heart disease death), cerebrovascular disease (stroke or transient ischemic attack), congestive heart failure (by Framingham criteria), or peripheral vascular disease (intermittent claudication). Criteria for the diagnoses of cardiovascular events have been described elsewhere (33). We considered that an unrecognized myocardial infarction occurred if we found electrocardiographic evidence of clinically significant loss of R waves or appearance of pathologic Q waves on serial tracings in the absence of a clinically recognized event (33). We defined the follow-up period a priori as 10 years from the baseline examination (up to 1995 for the original cohort and 2002 for the offspring cohort) to permit equal durations of follow-up of original and offspring cohort participants and because sex hormone levels change considerably with age (34). The analyses that combined the original and offspring cohorts had greater statistical power and allowed us to evaluate participants over a wider age range. Statistical Analyses Serum testosterone levels were normally distributed. Serum estradiol and DHEA-S levels were skewed and were log-transformed. We examined the associations between baseline sex hormone levels and CVD incidence during follow-up (separate analyses for each hormone). We chose incident CVD as the outcome because the effects of sex hormones are not limited to a given vascular territory and this maximized our statistical power and limited multiple statistical testing (as opposed to analysis for each CVD component). We stratified all analyses by the cohort (offspring cohort vs. original cohort). We verified that the assumption of proportionality of hazards was satisfied for each hormone. We calculated age- and multivariable-adjusted 10-year incidence rates for CVD for each hormone quartile (35). We prespecified 2 types of models: Primary analyses evaluated the sex hormones as continuous variables to maximize statistical power (model A), and additional analyses compared CVD risk in hormone quartiles 2 to 4 with that in quartile 1 (referent) (model B). These models facilitated assessment of potential nonlinear relations. For each hormone, we used proportional hazards regression (36) that adjusted for 1) age alone and 2) age, smoking, systolic and diastolic blood pressure, antihypertensive medication use, ratio of total and high-density lipoprotein (HDL) cholesterol, diabetes mellitus, and body mass index (BMI). We evaluated models adjusted for age alone because some risk factors may fall along the causal pathway from estradiol to CVD. Adjustment for BMI was performed because adiposity is a strong correlate of sex hormone levels (37) and of sex hormonebinding globulin (38). Sex hormonebinding globulin strongly influences measurements of total circulating sex hormone levels and the amount of bound hormone versus free hormone. We also evaluated models without BMI as a covariate to assess whether adjustment for BMI attenuated relations of sex hormones with CVD and models that were adjusted additionally for the use of aspirin or lipid-lowering medications, alcohol consumption, and education level. We incorporated statistical interaction terms to evaluate effect modification by age, BMI, smoking status, systolic blood pressure, and total cholesterolHDL cholesterol ratio. To gain additional insights into potential nonlinearity of associations between hormone levels and CVD risk, we examined generalized additive Cox models using penalized splines (39, 40) for hormones that were statistically significantly related to CVD risk. Because potential relationships of sex hormones to CVD risk may be mediated by the development of risk factors during follow-up, we prespecified examination of time-dependent Cox models (updating established CVD risk factors [covariates in the multivariable-adjusted proportional hazards regression] every 4 years at follow-up examinations) for analyses of any sex hormone that was statistically significantly related to CVD events in the initial analyses. Additional Analyses We performed secondary analyses relating CVD risk to the estradioltestosterone ratio (37, 41). In addition, we investigated whether hypogonadism was related to CVD risk. We defined hypogonadism empirically as a serum testosterone level less than 10.4 nmol/L (<

Contribution of In Vivo Structural Measurements and Load/Strength Ratios to the Determination of Forearm Fracture Risk in Postmenopausal Women

Bone structure, strength, and load‐strength ratios contribute to forearm fracture risk independently of areal BMD.

Structural Determinants of Vertebral Fracture Risk

Vertebral fractures are more strongly associated with specific bone density, structure, and strength parameters than with areal BMD, but all of these variables are correlated.