Determinants of Bone Mineral Density in Middle Aged Men: A Population-Based Study

Osteoporosis is a growing health problem not only in women but also in men. To assess determinants of bone mineral density (BMD) at the spine and proximal femur, a randomly selected sample of 140 Finnish men aged 54–63 years was measured using fan beam dual-energy X-ray absorptiometry. Isometric muscle strength was measured using a computerized measurement system and cardiorespiratory fitness was assessed with maximal oxygen uptake (VO₂max) using breath-by-breath respiratory gas analyses during an incremental bicycle ergometer exercise. Intakes of calcium and energy were estimated using 4-day food records. Smoking habits and alcohol consumption were assessed from an interview and a 4 week diary, respectively. Isometric muscle strength of triceps and biceps brachii, extensors and flexors of thigh and rectus abdominis correlated significantly with BMD (r= 0.18–0.35, p= 0.02–0.000). Calcium intake correlated positively with femoral (r= 0.19–0.28, p= 0.03–0.003), but not with lumbar BMD. In addition, calcium intake adjusted for dietary energy content (mg/MJ) correlated with femoral BMD (r= 0.25–0.36, p= 0.03–0.000). Smoking had no effect on BMD, whereas alcohol intake correlated positively with BMD at L2–L4 (r = 0.19, p= 0.031). In the multiple linear regression analysis adjusted calcium intake predicted BMD in every site measured, while strength of abdominal muscles predicted BMD at Ward’s triangle and femoral neck. Body weight was a predictor of trochanteric BMD. Body height was the best predictor of lumbar and femoral neck area. We conclude that low dietary calcium intake, weak muscle strength and low body weight are risk factors for low BMD in men. Received: 30 August 1999 / Accepted: 29 December 1999     

Bone Density in an Immigrant Population from Southeast Asia

The epidemiology of bone loss in populations of Asian heritage is still poorly known. This study compared the skeletal status of a convenience sample of 396 Southeast Asian immigrants (172 Vietnamese, 171 Cambodians and 53 Laotians) residing in Rochester, Minnesota in 1997 with 684 white subjects previously recruited from an age-stratified random sample of community residents. Areal bone mineral density (BMD, g/cm²) and volumetric bone mineral apparent density (BMAD, g/cm³) were determined for lumbar spine and proximal femur using the Hologic QDR 2000 instrument for the white population and the QDR 4500 for Southeast Asian subjects; the machines were cross-calibrated from data on 20 volunteers. Lumbar spine BMD was 7% higher in white than Southeast Asian women ( p < 0.001), and similar results were observed for the femoral neck; lumbar spine BMD was 12% higher in white than nonwhite men ( p < 0.001). Race-specific discrepancies were reduced by calculating BMAD: for premenopausal women, lumbar spine and femoral neck differences between whites and Southeast Asians were eliminated; for postmenopausal women the lumbar spine differences persisted ( p < 0.0001), while femoral neck BMAD was actually higher for Southeast Asians. There were no race-specific differences in femoral neck BMAD among men of any age ( p= 0.312), but lumbar spine BMAD was less for younger ( p= 0.042) but not older ( p= 0.693) Southeast Asian men. There were differences among the Southeast Asian subgroups, but no clear pattern emerged. Predictors of lumbar spine BMAD in Southeast Asian women were age ( p < 0.001), weight ( p= 0.015) and gravidity ( p= 0.037). Even after adjusting for bone size using BMAD, 32% and 9% of Southeast Asian women and men, respectively, would be considered to have osteoporosis at the femoral neck and 25% and 4%, respectively, at the lumbar spine. These findings indicate a need for culturally sensitive educational interventions for Southeast Asians and for physicians to pursue diagnosis and treatment to prevent osteoporosis-related disabilities in this population. Received: 12 October 2000 / Accepted: 15 February 2001     

Vitamin D and Bone Mineral Density in Ambulatory Women Living in Buenos Aires, Argentina

The aim of this study was to determine possible associations between bone mineral density (BMD), 25-hydroxyvitamin D (25(OH)D) and intact parathyroid hormone (PTH). In a retrospective study we examined the case notes of free-living postmenopausal women living in our city (34° S). We also report a low prevalence of vitamin D deficiency (25(OH)D <25 nmol/l, 5.6%) and of secondary hyperparathyroidism (intact PTH >65 pg/ml, 7.5%). Age was correlated with BMD at the lumbar spine (r=−0.25, p = 0.00038) and femoral neck (r=−0.252, p = 0.0003). Body mass index (BMI) was correlated with BMD at the femoral neck (r= 0.177, p = 0.021) but not at the lumbar spine. 25(OH)D was positively correlated with BMD at the femoral neck (r = 0.149, p=0.036) but not at the lumbar spine. PTH was positively correlated with age (r= 0.279, p = 0.012) and negatively correlated with 25(OH)D (r=−0.322, p = 0.0036). PTH was also negatively correlated with BMD at the lumbar spine (r=−0.258, p=0.02) and the femoral neck (r=−0.282, p = 0.011). Forward stepwise multiple regression showed that BMI, age and 25(OH)D made significant contributions to BMD at the femoral neck. PTH also showed a significant contribution to BMD at both sites. In conclusion, weak correlations found between PTH and 25(OH)D and BMD suggest these biochemical variables, among other factors, contribute to lumbar spine and femoral neck BMD. Received: 19 February 2000 / Accepted: 20 June 2000     

Household Tobacco Smoke Exposure is Negatively Associated with Premenopausal Bone Mass

Subjects exposed to environmental tobacco smoke have been found to be at increased risk for several health problems. Whether exposure to passive tobacco smoke is associated with reduced bone mineral density (BMD) is unknown. In order to examine this, we measured BMD in 154 healthy premenopausal women (age range 40–45 years). BMD of the total hip, femoral neck, lumbar spine and total body was measured by dual-energy X-ray absorptiometry (DXA). Data were collected on exposure to household tobacco smoke from age 10 years to the present as well as on other lifestyle factors related to bone mass. We found that 67.5% of the subjects had a history of household tobacco smoke exposure. Subjects exposed to household tobacco smoke had a mean adjusted BMD that was significantly lower at the total hip (p= 0.021) and femoral neck (p= 0.018) compared with subjects who were not exposed. In addition, duration of household tobacco smoke exposure was negatively associated with BMD at the total hip (p = 0.010), femoral neck (p= 0.004), lumbar spine (p = 0.037) and total body (p = 0.031). Subjects exposed to household tobacco smoke for 15 years or more had mean adjusted BMD that was 4% lower at the total body, and more than 8% lower at the total hip, femoral neck and lumbar spine, compared with subjects who were not exposed. In conclusion, household tobacco smoke exposure during adolescence and young adulthood was found to be negatively associated with BMD at the total hip and femoral neck, and duration of exposure was negatively associated with BMD at the total hip, femoral neck, lumbar spine and total body in premenopausal women. Received: 17 December 2001 / Accepted: 16 February 2002     

Osteocalcin Gene Polymorphism is Related to Bone Density in Healthy Adolescent Females

Recently a polymorphism was found in the human osteocalcin gene, and its association with bone mass was investigated in healthy postmenopausal Japanese women. The osteocalcin gene allelic variant HH was found to be overrepresented in women with osteopenia. The purpose of this study was to investigate whether the previously demonstrated polymorphism of the osteocalcin gene was related to bone mineral density (BMD; g/cm²) or osteopenia in a group of 97 healthy Caucasian adolescent females (aged 16.9 ± 1.2 years, mean ± SD). BMD of the left humerus, right femoral neck, lumbar spine and total body was measured using dual-energy X-ray absorptiometry. The relation between the allelic variants and bone density was analyzed as presence or absence of the H allele. Presence of the H allele was found to be related to a lower BMD of the humerus (0.97 vs 1.02, p = 0.03). There was also a strong tendency towards significance at the femoral neck (p = 0.06) and total body (p = 0.11). Using a multiple linear regression and including physical activity, weight, height and years since menarche, presence of the H allele was found to be an independent predictor of humerus BMD (β=−0.21, p<0.05) and femoral neck BMD (β=−0.23, p<0.01). Using logistic regression, presence of the H allele was also independently associated with a 4.5 times increased risk of osteopenia (p = 0.03) in the whole group. Osteopenia was defined as at least 1 SD lower bone density than the mean for the whole group of at least one of the BMD sites measured. We have demonstrated that the osteocalcin HindIII genotype is independently related to bone density in healthy adolescent females. The present study also suggests that presence of the H allele is predictive of osteopenia at an early age. Received: 31 January 2000 / Accepted: 25 April 2000     

Estimation of Bone Mineral Density by Digital X-ray Radiogrammetry: Theoretical Background and Clinical Testing

A new automated radiogrammetric method to estimate bone mineral density (BMD) from a single radiograph of the hand and forearm is described. Five regions of interest in radius, ulna and the three middle metacarpal bones are identified and approximately 1800 geometrical measurements from these bones are used to obtain a BMD estimate of the distal forearm, referred to as BMD_DXR (from digital X-ray radiogrammetry, DXR). The measured dimensions for each bone are the cortical thickness and the outer width, in combination with an estimate of the cortical porosity. The short-term in vivo precision of BMD_DXR was observed to be 0.60% in a clinical study of 24 women and the in vitro variation over 12 different radiological clinics was found to be 1% of the young normal BMD_DXR level. In a cohort of 416 women BMD_DXR was found to be closely correlated with BMD at the distal forearm measured by dual-energy X-ray absoptiometry (r= 0.86, p<0.0001) and also with BMD at the spine, total hip and femoral neck (r= 0.62, 0.69 and 0.73, respectively, p<0.0001 for all). The annual decline was estimated from the cohort to be 1.05% in the age group 55–65 years. Relative to this age-related loss, the reported short-term precision allows for monitoring intervals of 1.0 years and 1.6 years in order to detect expected age-related changes with a confidence of 80% and 95%, respectively. It is concluded that the DXR method offers a BMD estimate with a good correlation with distal forearm BMD, a low variation between geographical sites and a precision that potentially allows for relatively short observation intervals. Received: 8 November 2000 / Accepted: 14 June 2001     

Vitamin D Receptor Gene Polymorphisms, Bone Mass, Bone Loss and Prevalence of Vertebral Fracture: Differences in Postmenopausal Women and Men

Bone mineral density (BMD), the major determinant of fracture risk, is under strong genetic control. Although polymorphisms of the vitamin D receptor (VDR) gene have been suggested to account for some of the genetic variation in bone mass, the influence of VDR genotypes on osteoporosis remains controversial. Previous published studies have focused mainly on women, but the pattern of response in men has not been determined. Using the BsmI restriction enzyme, we studied the influence of the different VDR genotypes on bone mass, bone loss and the prevalence of vertebral fractures in a population-based sample of both sexes (n = 326). BMD was measured at the lumbar spine and femoral neck, with a 4-year interval, using dual-energy X-ray absorptiometry. Vertebral fractures were assessed by two lateral radiographs at the beginning and end of the study. The prevalence of the three possible VDR genotypes was similar to those in other Caucasian populations and no differences were found between men and women. Women with the favorable bb genotype showed significantly higher BMD values at the lumbar spine and femoral neck, and a positive rate of BMD change at the femoral neck compared with women with the BB and Bb genotypes. Moreover, women with the bb genotype showed a trend toward a lower prevalence and incidence of vertebral fractures (p= 0.07). We have not found any differences between VDR genotypes in men. In conclusion, VDR gene polymorphisms are related to bone mass and bone loss in women; also a trend in the prevalence of vertebral fractures was observed in postmenopausal women but not in men. Received: 8 June 1998 / Accepted: 7 December 1998     

Determinants of Bone Loss in Elderly Men and Women: A Prospective Population-Based Study

While several studies have described the rate and pattern of involutional bone loss in women, far less information is available for men. Furthermore, the roles of lifestyle and body build in determining bone loss rate in both sexes have been largely extrapolated from cross-sectional studies. We addressed this issue in a population-based longitudinal study which sought to ascertain rates of bone loss at the femoral neck and lumbar spine in a cohort of men and women aged 60–75 years at baseline, and to relate this loss to anthropometric and lifestyle variables. We additionally investigated the capacity of biochemical markers of bone turnover to predict bone loss rates in these subjects. Women lost bone at all sites; this ranged from 0.20%/year at the lumbar spine to 1.43%/year at the femoral trochanteric region. By contrast, men lost only 0.20%/year at the trochanteric region, and gained at the lumbar spine (0.33%/year) and at Ward’s triangle (0.27%/year) over the 4-year period. Anthropometric measurements were associated with bone loss in both sexes; lower baseline body mass index (BMI) and a greater rate of loss of adiposity over the follow-up period were both associated with greater bone loss at all proximal femoral sites. These attained statistical significance after Bonferroni correction at the total proximal femur among both men (r= 0.29), p<0.01) and women (r= 0.31, p<0.05). Lifestyle factors associated with lower rates of bone loss (after adjustment for BMI) included alcohol consumption at the femoral neck among women (p= 0.007) and physical activity at the lumbar spine among men (p = 0.05). Serum parathyroid hormone, 25-hydroxyvitamin D and biochemical markers of bone turnover did not predict bone loss after adjustment for adiposity. Received: 8 December 1998 / Accepted: 8 April 1999     

A Prospective Study of Bone Loss in Menopausal Australian-Born Women

Two hundred and twenty-four women (74 pre-, 90 peri-, 60 post-menopausal), aged 46–59 years, from a population-based cohort participated in a longitudinal study of bone mineral density (BMD). BMD was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and femoral neck and the time between bone scans was on average 25 (range 14–41) months. The aim of the study was to assess changes in BMD in relation to changes in normal menopausal status. During the study period women who were between 3 and 12 months past their last menstrual period (n= 22, late perimenopausal) at the time of the second bone scan had a mean (SE) annual change in BMD of 70.9% (0.4%) at the lumbar spine and 70.7% (0.6%) at the femoral neck (both p50.05 compared with women who remained premenopausal). In the women who became postmenopausal (n= 42) the mean annual changes in BMD were 72.5% (0.2%) at the lumbar spine and 71.7% (0.2%) at the femoral neck (both p50.0005), and in the women who remained postmenopausal (n= 60) they were 70.7% (0.2%) per year and 70.5% (0.3%) per year respectively (both p50.05), compared with women who remained premenopausal. In the 1–3 years after the final menstrual period (FMP) there was greater bone loss from the lumbar spine than the femoral neck (p50.05). In women who were menstruating at the time of the second bone scan and whose FMP could be dated prospectively (n= 35), higher baseline oestradiol levels were associated with less lumbar spine bone loss (p50.005). In the women who remained postmenopausal there was an association between baseline body mass index (BMI) and percentage change per year in femoral neck BMD (p50.05), such that women with higher BMI had less bone loss. In conclusion, during the time of transition from peri- to post-menopause, women had accelerated BMD loss at both the hip and spine. Received: 23 June 1997 / Accepted: 5 November 1997     

Bone Mineral Density and Metabolism in Familial Dysautonomia

Familial dysautonomia (FD) patients suffer from multiple fractures and have reduced bone pain, which defers the diagnosis. The pathogenesis of bone fragility in FD is unknown. This study aimed to characterize bone mineral metabolism and density in FD. Seventy-nine FD patients aged 8 months to 48 years (mean age 13.9 ± 10.4 years, median 12.3) were studied. Clinical data included weight, height, bone age, weekly physical activity and history of fractures. Bone mineral density (BMD) of the lumbar spine (n= 43), femoral neck (n= 26), total hip (n= 22) and whole body (n= 15) were determined by dual-energy X-ray absorptiometry. Serum 25-hydroxyvitamin D₃, osteocalcin, bone alkaline phosphatase (B-ALP), parathyroid hormone and urinary N-telopeptide cross-linked type 1 collagen (NTx) were determined in 68 patients and age- and sex-matched controls. Forty-two of 79 patients (53%) sustained 75 fractures. Twenty-four of 43 patients had a spine Z-score <–2.0, and 13 of 26 had a femoral neck Z-score <–2.0. Mean femoral neck BMD Z-score was lower in patients with fractures compared with those without (–2.5 ± 0.9 vs –1.5 ± 1.0, p= 0.01). Mean body mass index (BMI) was 16 kg/m² in prepubertal patients and 18.4 kg/m² in postpubertal patients. Bone age was significantly lower than chronological age (75.5 vs 99.3 months in prepubertal patients, p<0.001; 151 vs 174 in post-pubertal patients, p<0.05). NTx and osteocalcin levels were higher in FD patients compared with controls (400 ± 338 vs 303 ± 308, BCE/mM creatinine p<0.02; 90 ± 59.5 vs 61.8 ± 36.9 ng/ml, p<0.001, respectively). B-ALP was lower in FD patients compared with controls (44.66 ± 21.8 vs 55.36 ± 36.6 ng/ml, p<0.04). Mean spine Z-score was significantly lower in physically inactive compared with active patients (–3.00 ± 1.70 vs –1.77 ± 1.3, respectively, p= 0.05). We conclude that fractures in FD patients are associated with reduced BMD. FD patients have increased NTx and osteocalcin. Contributing factors include reduced BMI, failure to thrive and reduced physical activity. Preventive therapy and early diagnosis are essential. Received: 21 May 2001 / Accepted: 27 November 2001     

Changes in Bone Density in Patients with Ankylosing Spondylitis: A Two-Year Follow-Up Study

The objectives of the study were to determine the 2 year rate of bone changes in patients with ankylosing spondylitis (AS) and, whether bone loss is related to physical impairment, systemic inflammation, and therapy. Consecutive outpatients fulfilling the modified New York criteria for AS were included. Baseline assessment included age, disease duration, treatment, clinical, radiologic and laboratory data. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were determined every 6 months. Persistent systemic inflammation was defined as mean ESR ≥ 28 mm/h or mean CRP ≥ 15 mg/l. Bone mineral density (BMD) at the lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry, at baseline and year 2. Statistical analysis compared the baseline and 24 month follow-up BMD data, and determined whether baseline data, and persistent systemic inflammation during the 2 years, were related to the 24 month percentage changes in BMD. Fifty-four patients (35 men, 19 women; mean age 37.3 ± 11.3 years, mean disease duration 12.4 ± 8.6 years) were included. After 2 years, BMD did not change at the lumbar spine (+0.75%± 3.5, p= 0.23), and decreased at the femoral neck (–1.6%± 4, p= 0.006). The 24 month percentage change in femoral neck BMD was related to persistent systemic inflammation, defined using ESR (mean percentage change –4.1%± 5.7 and –1.2%± 3.9 in patients with and without persistent inflammation; respectively; p= 0.007). These results suggest that persistent inflammation might be an etiologic factor of bone loss in AS. Received: 15 November 2000 / Accepted: 15 February 2001     

Hormonal and Anthropometric Predictors of Bone Mass in Healthy Elderly Men: Major Effect of Sex Hormone Binding Globulin, Parathyroid Hormone and Body Weight

Osteoporosis in men is a significant health problem, and factors associated with bone mass are being investigated. Although osteoporosis is a typical feature of hypogonadism, the influence of testosterone levels and other hormonal factors on bone mass of eugonadal males is unknown. Our aim was to identify several anthropometric and hormonal predictors that could be responsible for the variability in bone mineral density (BMD) in healthy men. One hundred elderly men (age 68 ± 7 years) were investigated in this cross-sectional study. BMD was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and femoral sites (femoral neck, Ward’s triangle, trochanter, intertrochanter and total femur). Anthropometric measures were obtained including: weight, height, body mass index (BMI), waist–hip ratio and testicular volume. Hormonal data measures were total, free and bioavailable testosterone, dihidrotestosterone, estradiol, sex hormone binding globulin (SHBG), insulin-like growth factor I (IGF-I), intact parathyroid hormone (iPTH) and 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃). One subject was excluded because primary hypogonadism was found. SHBG levels were increased in 53.5% of men, and 8% showed a mild increase in iPTH levels. Twenty-eight subjects had densitometric criteria of osteoporosis (T-score ≤−2.5). All BMD sites were positively correlated with body weight (r= 0.29–0.48, p<0.001) and BMI (r= 0.24–0.47, p<0.001). A negative correlation between SHBG levels and intertrochanter (IT) and total femur (TL) BMD was found (r=−0.24 and r=−0.22, p<0.05). After adjusting for age and BMI, SHBG and IGF-I levels were negatively correlated (r=−0.33, p<0.001). In multiple linear regression analysis independent predictors of bone mass were body weight, SHBG and iPTH levels. The best predictive model accounted for 24–40% of the observed variability of BMD. However, most of the BMD variability was explained by body weight. In conclusion, in our study body weight, SHBG and iPTH levels were predictors of BMD in healthy elderly men. Received: 9 June 2000 / Accepted: 27 September 2000     

Effects of Gender and Age on the Association of Apolipoprotein E ε4 with Bone Mineral Density,Bone Turnover and the Risk of Fractures in Older People*

The aim of this study was to examine whether the presence of apolipoprotein E ε4 (ApoE ε4) is associated with a lower bone mineral density (BMD), lower quantitative ultrasound (QUS) measurements, higher bone turnover and fracture risk, and whether these relations are modified by gender and age. A total of 1406 elderly men and women (≥65 years) of the Longitudinal Aging Study Amsterdam (LASA) participated in this study. In all participants, QUS measurements were assessed, as well as serum osteocalcin (OC) and urine deoxypyridinolin (DPD/Cr urine). Follow-up of fractures was done each three months. In a subsample (n = 604), total body bone mineral content (BMC) and BMD of the hip and lumbar spine were measured. In addition, prevalent vertebral deformities were identified on radiographs. In women, the presence of ApoE ε4 was associated with significantly lower femoral neck BMD (g/cm²; mean ± SEM; ε4+, 0.64 ± 0.01 vs. ε4−, 0.67 ± 0.01; p= 0.04), lower trochanter BMD (g/cm²; mean ± SEM; ε4+, 0.58 ± 0.01 vs. ε4–, 0.61 ± 0.01; p= 0.01) and lower total body BMC (g; mean ± SEM; ε4+, 1787 ± 40.0 vs. ε4–, 1863 ± 23.8; p= 0.04). Women with ApoE ε4 also had a higher risk of severe vertebral deformities (OR=2.78; 95%CI: 1.21–6.34). In men, the associations between ApoE status and both hip BMD and QUS depended on age. Only among the younger men (65–69 years) was the presence of ApoE ε4 associated with lower BMD values. Bone markers and fractures were not associated with ApoE ε4 in either women, or men. In conclusion, this large community-based study confirms the importance of ApoE ε4 as a possible genetic risk factor related to BMD and vertebral deformities and demonstrates that its effect is gender related, and depends on age in men only. Received: 6 July 2001 / Accepted: 2 April 2002     

Association of VDR and Estrogen Receptor Genotypes with Bone Mass in Postmenopausal Caucasian Women: Different Conclusions with Different Analyses and the Implications

Much work has been done on the association between vitamin D receptor (VDR) genotypes and bone mineral density (BMD). Despite considerable effort, the results are inconsistent. While the VDR association remains unresolved, studies have expanded to other candidate genes (i.e., estrogen receptor (ER) genotypes), also yielding inconsistent results. A few studies have suggested that interaction effects between VDR and ER genotypes significantly affect BMD. We assessed associations of BMD with VDR BsmI genotypes, and ER XbaI and PvuII polymorphisms (denoted as ERX and ERP respectively) with spine, femoral neck, distal radius BMD, and with total body bone mineral content (tbBMC) in 108 US Mid-western postmenopausal Caucasian women. We statistically controlled for confounding factors such as height, weight, etc., in the analysis. No significant association was detected for ER genotypes with spine and radius BMD, or for VDR genotypes with femoral neck and radius BMD and tbBMC. No significant interaction between VDR and ER genotypes was detected in our sample. However, the VDR genotypes are significantly (p = 0.004) associated with *5.8% spine BMD variation. Both ERX and ERP genotypes are significantly (p = 0.02) associated with *3.5% femoral neck BMD variation. ERX genotypes are significantly (p = 0.03) associated with *2.4% tbBMC variation. However, if the data were analyzed by simple ANOVA as in some previous studies, without adjusting statistically for confounding factors, all the significant results we found here would have gone undetected. Our findings suggest that: (1) VDR and ER genotypes may have different effects on BMD at different sites and on tbBMC; and (2) if significant factors influencing bone are not appropriately controlled, true significant associations can easily be missed. These findings may offer a partial explanation for some of the earlier inconsistent results of association studies on BMD with VDR and ER genotypes. Received: 4 August 1998 / Accepted: 2 November 1998     

Quantitative Ultrasound of Bone and Markers of Bone Turnover in Cushing’s Syndrome

Quantitative ultrasound (QUS) of bone is a valuable tool in the assessment of postmenopausal osteoporosis. QUS and new markers of bone turnover have been poorly assessed in Cushing’s syndrome, however. Twenty-five patients with Cushing’s syndrome (20 women, 3 men; mean age ± SEM: 38 ± 2 years) were studied and compared with 35 age- and sex-matched control patients (mean age ± SEM: 38 ± 2 years). The following variables were measured in both groups: QUS parameters at the heel (BUA; SOS; Stiffness Index, SI); bone mineral density (BMD) at both the lumbar spine (LS) and femoral neck (FN) by dual-energy X-ray absorptiometry; and serum markers of bone turnover (osteocalcin, procollagen type I N- and C-terminal propeptides (PINP and PICP), bone alkaline phosphatase (BAP), procollagen type I C-terminal telopeptide (ICTP) and urinary type I collagen C-telopepetide breakdown products (CTX)). Both BUA and SI were decreased in patients with Cushing’s syndrome (p<0.01) but not SOS (p=0.08). BMD was also strongly decreased in Cushing’s syndrome, at both the LS and FN (p<0.005). The two markers of bone turnover statistically significantly different between the two groups were osteocalcin (mean ± SEM: 3.5 ± 0.7 ng/ml (Cushing’s syndrome) vs 6.4 ± 0.5 ng/ml (controls, p<0.01)) and CTX (mean ± SEM: 148.7 ± 17.1 μg/mmol Cr (Cushing’s syndrome) vs 220.8 ± 22.9 μg/mmol Cr (controls), p<0.05). The areas under the receiver operating characteristic curve (AUC) were 0.72 (BUA), 0.73 (SI), 0.90 (BMD_LS), 0.81 (BMD_FN), 0.83 (osteocalcin) and 0.64 (CTX) respectively. AUC was significantly higher for BMD_LS than for both BUA and SI (p<0.05). Conversely AUC was not statistically significantly different for BMD_FN as compared with either BUA or SI. AUC was also higher for osteocalcin than for other markers of bone turnover. In conclusion, QUS of bone seems to be a relevant tool for assessing bone involvement in Cushing’s syndrome. QUS does have a lower sensitivity compared with DXA, however, and the relevance of QUS cannot be ascertained until some longitudinal data are forthcoming. Except for CTX, the other new markers of bone turnover assessed in this study (PINP, PICP, BAP and ICTP) do not seem of interest in Cushing’s syndrome. Received: February 2000 / Accepted: 24 August 2000     

Effects of Alendronate on Bone Density in Men with Primary and Secondary Osteoporosis

Alendronate has been reported to increase bone mineral density (BMD) and reduce fracture risk in women with osteoporosis. As there are no proven safe and effective treatments available for men with osteoporosis, we compared the effects of alendronate (10 mg/day) on BMD, measured using dual-energy X-ray absorptiometry, in a 12-month prospective, controlled, open label study involving (i) men with primary (n= 23) or secondary osteoporosis (n= 18), (ii) postmenopausal women with primary (n= 18) or secondary (n= 21) osteoporosis, and (iii) 29 male and 14 female untreated controls matched by age, height and weight. The patients had one or more vertebral fractures and ranged in age from 34.6 to 85.1 years. BMD was detectably increased relative to baseline by 6 months, and increased by comparable amounts in males and females with primary or secondary osteoporosis. At 12 months, lumbar spine BMD was 5.4%± 1.1% to 7.0%± 2.2% higher in the treated groups compared with baseline and controls (p<0.05 to 0.0001). Trochanteric BMD increased by 2.6%± 1.5% and 3.7%± 1.7% in treated men with primary and secondary osteoporosis, respectively (p = 0.06 to 0.08), and by 3.9%± 1.3% in treated women with primary osteoporosis (p<0.01) after 12 months. No significant changes were detected at the femoral neck or Ward’s triangle. BMD remained unchanged in controls. We infer that alendronate has comparable incremental effects on BMD in men and women with primary and secondary osteoporosis within 12 months of treatment. The changes are in the order of 0.5 SD – effects associated with a clinically worthwhile reduction in fracture risk. The data provide room for optimism regarding the role of alendronate in the treatment of osteoporosis in men. Randomized, double-masked and placebo-controlled trials are needed to confirm these preliminary findings and demonstrate antifracture efficacy using vertebral and nonvertebral fracture rates as the primary endpoint. Received: 23 February 1999 / Accepted: 2 June 1999     

Forearm Bone Mineral Densitometry Cannot be Used to Monitor Response to Alendronate Therapy in Postmenopausal Women

Alendronate significantly increases bone mass and reduces hip and spine fractures in postmenopausal women. To determine whether forearm densitometry could be used to monitor the efficacy of alendronate, we examined changes in bone mineral density (BMD) at the forearm (one-third distal, mid-distal, ultradistal radius) versus changes at the hip (femoral neck, total hip) and spine (posteroanterior and lateral) in a double-masked, randomized, placebo-controlled clinical trial of 120 elderly women (mean age 70 ± 4 years) treated with alendronate for 2.5 years. We found that among women in the treatment group, BMD increased by 4.0–12.2% at the hip and spine sites (all p<0.001), whereas BMD increased only nominally at the one-third distal radius (1.3%, p<0.001) and mid-radius (0.8%, p<0.05), and remained stable at the ultradistal radius. At baseline, forearm BMD correlated with that of the hip (r= 0.55–0.64, p<0.001), femoral neck (r= 0.54–0.61, p<0.001) and posteroanterior spine (r= 0.56–0.63, p<0.001). Changes in radial BMD after 1 year of therapy were not correlated with changes in hip and spine BMD after 2.5 years of therapy. In contrast, short-term changes in total hip and spine BMD were generally positively associated with long-term changes in total hip, femoral neck and spine BMD (r= 0.30–0.71, p<0.05). Furthermore, long-term BMD changes at the forearm did not correlate with long-term hip and spine BMD changes, in contrast to the moderate correlations seen between spine and hip BMD at 2.5 years (r= 0.38–0.45, p<0.01). We conclude that neither short- nor long-term changes in forearm BMD predict long-term changes in overall BMD for elderly women on alendronate therapy, suggesting that measurements of clinically relevant central sites (hip and spine) are necessary to assess therapeutic efficacy. Received: 18 February 1999 / Accepted: 20 May 1999     

In Vivo MRI Measurements of Bone Quality in the Calcaneus: A Comparison with DXA and Ultrasound

Magnetic resonance imaging (MRI) has shown promise in the assessment of bone architecture. The precision and feasibility of MRI measurements in osteoporosis in vivo have been assessed in this study. T2′ was calculated from measurements of T2 and T2* in the calcaneus of 32 postmenopausal women using a gradient-echo sequence PRIME (Partially Refocused Interleaved Multiple Echo). This sequence allows the measurement of T2 and T2* in one acquisition. In vivo measurements of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were made in the calcaneus, spine and femoral neck. The ultrasound parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were also measured in the calcaneus. These three techniques have not previously been compared in the same study population. The precision of the MRI technique was poor relative to the DXA and ultrasound techniques, with a CV of 6.9%± 4.4% for T2′ and 5.5%± 3.6% for T2*. Approximately 4% of this is due to system error as determined by phantom measurements. The postmenopausal women were classified as having low BMD if they had a lumbar spine (L2–4) BMD of less than 0.96 g/cm² (more than 2 standard deviations below normal peak bone mass). Calcaneal T2′ was significantly correlated with calcaneal BMD (r = –0.79, p <0.0001), BUA (r = –0.59, p = 0.0004) and SOS (r = –0.58, p = 0.0006). T2′ was significantly different in postmenopausal women with normal BMD and those with low BMD (p <0.01). However, the difference was of only borderline significance (p <0.06) after adjustment for age and years since menopause. Received: 8 July 1997 / Accepted: 29 April 1998     

A Randomized Trial of Sodium Fluoride (60 mg) ± Estrogen in Postmenopausal Osteoporotic Vertebral Fractures: Increased Vertebral Fractures and Peripheral Bone Loss with Sodium Fluoride; Concurrent Estrogen Prevents Peripheral Loss, But Not Vertebral Fractures

Postmenopausal Caucasian women aged less than 80 years (n= 99) with one or more atraumatic vertebral fracture and no hip fractures, were treated by cyclical administration of enteric coated sodium fluoride (NaF) or no NaF for 27 months, with precautions to prevent excessive stimulation of bone turnover. In the first study 65 women, unexposed to estrogen (–E study), age 70.8 ± 0.8 years (mean ± SEM) were all treated with calcium (Ca) 1.0–1.2 g daily and ergocalciferol (D) 0.25 mg per 25 kg once weekly and were randomly assigned to cyclical NaF (6 months on, 3 months off, initial dose 60 mg/day; group F CaD, n= 34) or no NaF (group CaD, n= 31). In the second study 34 patients, age 65.5 ± 1.2 years, on hormone replacement therapy (E) at baseline, had this standardized, and were all treated with Ca and D and similarly randomized (FE CaD, n= 17; E CaD, n= 17) (+E study). The patients were stratified according to E status and subsequently assigned randomly to ± NaF. Seventy-five patients completed the trial. Both groups treated with NaF showed an increase in lumbar spinal density (by DXA) above baseline by 27 months: FE CaD + 16.2% and F CaD +9.3% (both p= 0.0001). In neither group CaD nor E CaD did lumbar spinal density increase. Peripheral bone loss occurred at most sites in the F CaD group at 27 months: tibia/fibula shaft –7.3% (p= 0.005); femoral shaft –7.1% (p= 0.004); distal forearm –4.0% (p = 0.004); total hip –4.1% (p = 0.003); and femoral neck –3.5% (p= 0.006). No significant loss occurred in group FE CaD. Differences between the two NaF groups were greatest at the total hip at 27 months but were not significant [p<0.05; in view of the multiple bone mineral density (BMD) sites, an alpha of 0.01 was employed to denote significance in BMD changes throughout this paper]. Using Cox’s proportional hazards model, in the –E study there were significantly more patients with first fresh vertebral fractures in those treated with NaF than in those not so treated (RR = 24.2, p= 0.008, 95% CI 2.3–255). Patients developing first fresh fractures in the first 9 months were markedly different between groups: –23% of F CaD, 0 of CaD, 29% of FE CaD and 0 of E CaD. The incidence of incomplete (stress) fractures was similar in the two NaF-treated groups. Complete nonvertebral fractures did not occur in the two +E groups; there were no differences between groups F CaD and CaD. Baseline BMD (spine and femoral neck) was related to incident vertebral fractures in the control groups (no NaF), but not in the two NaF groups. Our results and a literature review indicate that fluoride salts, if used, should be at low dosage, with pretreatment and co-treatment with a bone resorption inhibitor. Received: 22 August 2000 / Accepted: 23 July 2001     

The Association between Parathyroid Hormone, Vitamin D and Bone Mineral Density in 70-Year-Old Icelandic Women

Parathyroid hormone (PTH) may be an important determinant of cortical bone remodeling in the elderly. Vitamin D status is one of the determining factors in this relationship. The aim of this study was to quantify the relationship between serum PTH, vitamin D and bone mineral density (BMD) in elderly women in Reykjavik (64° N), where daily intake of cod liver oil is common and mean calcium intake is high. ln PTH correlated inversely with 25(OH)D (r=−0.26, p<0.01). In multivariate analysis PTH correlated inversely with whole body BMD (mostly cortical bone) (R ²= 2.2%, p = 0.04) but not with the lumbar spine BMD, reflecting more cancellous bone. No association was found between 25(OH)D levels and BMD at any site in univariate or multivariate analysis. Osteocalcin, a measure of bone turnover, was negatively associated with BMD and this association remained significant when corrected for PTH levels. In summary, in this fairly vitamin D replete population with high calcium intake, PTH was negatively associated with total body BMD. We infer that suppression of PTH may reduce cortical bone loss, but other factors are likely to contribute to age-related bone remodeling and osteoporosis. Received: 3 January 2000 / Accepted: 10 April 2000