Cross-Sectional Versus Longitudinal Evaluation of Bone Loss in Men and Women

We evaluated age- and sex-specific differences in bone density at a variety of skeletal sites in a population-based sample of 348 men (age 22–90 years) and 351 women (age 21–93 years) by dual-energy X-ray absorptiometry. Several patterns of age-related bone loss were observed, but adjustments for height (or, where possible, calculation of bone mineral apparent density) dampened the apparent rate of bone loss from most skeletal sites as judged from cross-sectional measurements at baseline. Cross-sectional data also overestimated the rate of bone loss observed longitudinally over 4 years at many sites, particularly the hip and spine; conversely, in some forearm regions, cross-sectional rates of loss underestimated the bone loss seen prospectively. Longitudinal rates of bone loss were generally greater among individuals age 70 years or older compared with younger men and women, but some of the latter effect was due to a greater proportion of younger women on hormone replacement therapy, whose rate of bone loss was generally less. These observations highlight the limitations of cross-sectional data for defining the patterns of bone loss over life at different skeletal sites. Received: 6 January 1999 / Accepted: 10 January 2000     

Changes in Bone Mineral Density with Age in Men and Women: A Longitudinal Study

We performed a prospective study to evaluate the normal changes in bone mineral density (BMD) in the forearm, hip, spine and total body, and to study the agreement between changes in BMD estimated from cross-sectional data and the actual longitudinal changes. Six hundred and twenty subjects (398 women, 222 men; age 20–89 years) without diseases or medication known to affect bone metabolism undertook baseline evaluations, and 525 (336 women, 189 men) completed the study. BMD was measured twice 2 years apart by dual-energy X-ray absorptiometry. From cross-sectional evaluations the only premenopausal bone loss (<0.003 g/cm²/year) was found in the hip. In women after menopause and in men an age-related bone loss (0.002–0.006 g/cm²/year) was found at all sites. The data from the longitudinal evaluation showed a small bone loss in women before menopause at the hip and lumbar spine (<0.4%/year (<0.004 g/cm²/year)); this bone loss nearly tripled in the early postmenopausal years (<10 years since menopause), and thereafter decreased to the premenopausal rate for the hip, and to zero for the lumbar spine. The most pronounced bone loss after menopause occurred in the forearm (1.2 %/year (0.006 g/cm²/year)), and it remained constant throughout life. In men there was a small longitudinal bone loss in the hip throughout life, and a small bone loss in the distal forearm after the age of 50 years. In all groups, except for the early postmenopausal women, we found a small increase in total body BMD with age. When comparing the changes in BMD estimated from cross-sectional data with the longitudinal changes, only the hip and forearm generally displayed agreement, whereas the changes in the total body and spine generally were incongruous. In conclusion, the hip and forearm appear to be the sites with the best agreement between the cross-sectional estimated and the longitudinal age-related changes in BMD. Received: 22 August 2000 / Accepted: 22 June 2001     

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     

Osteoprotegerin and its Ligand: A New Paradigm for Regulation of Osteoclastogenesis and Bone Resorption

In just 3 years, striking new advances have been made in understanding the molecular mechanisms that govern the crosstalk between osteoblasts/stromal cells and hematopoietic osteoclast precursor cells that leads to osteoclastogenesis. Led first by the discovery of osteoprotegerin (OPG), a naturally occurring protein with potent osteoclastogenesis inhibitory activity, rapid progress was made to the isolation of RANKL, a transmembrane ligand expressed on osteoblasts/stromal cells that binds to RANK, a transmembrane receptor on hematopoietic osteoclast precursor cells. The interaction of RANK and RANKL initiates a signaling and gene expression cascade that results in differentiation and maturation of osteoclast precursor cells to active osteoclasts capable of resorbing bone. OPG acts as a decoy receptor, binding to RANKL and blocking its interaction with RANK, inhibiting osteoclast development. Many of the calciotropic hormones and cytokines, including 1,25(OH)₂D₃, PTH, PGE₂ and IL-11, appear to act through a dual capacity to inhibit production of OPG and stimulate production of RANKL. Estrogen, on the other hand, appears to inhibit production of RANKL and RANKL-stimulated osteoclastogenesis. Recently, the results of the first clinical trial with OPG supported its potential as a therapeutic agent for diseases such as osteoporosis. The new understanding provided by the RANK/RANKL/OPG paradigm for both differentiation of osteoclasts and their activation has had tremendous impact on the field and opened new avenues for development of possible treatments of diseases characterized by excessive bone resorption.     

Comparison of Bone and Total Alkaline Phosphatase and Bone Mineral Density in Postmenopausal Osteoporotic Women Treated with Alendronate

Alendronate therapy in osteoporotic women decreases bone turnover and increases bone mineral density (BMD). Optimal patient management should include verification that each patient is responding to therapy. Markers of bone turnover and BMD have both been proposed for this purpose. We have investigated changes resulting from alendronate therapy with an enzyme immunoassay for bone alkaline phosphatase (BAP) and compared it with total alkaline phosphatase (TAP) and BMD of the lumbar spine, hip, and total body. Subjects were drawn from a multicenter randomized, placebo-controlled trial of alendronate in postmenopausal women with osteoporosis. BAP and TAP levels were measured at baseline and following 3, 6 and 12 months of therapy with either placebo (n= 180) or alendronate 10 mg/day (n= 134). All subjects also received 500 mg/day supplemental calcium. BMD was measured at baseline and following 3, 6, 12, 18, 24 and 36 months of therapy. To compare BAP, TAP and BMD at each site for identifying women that experienced a skeletal effect of alendronate, we calculated least significant change (LSC) values from the long-term intraindividual variability in each placebo-treated woman. Median levels of BAP decreased by 34%, 44% and 43% at 3, 6 and 12 months, respectively, in alendronate-treated women (p<0.0001 compared with baseline and with placebo). These changes were significantly greater (p<0.0001) than changes observed for TAP. Following 6 months of alendronate therapy, 90% of the women had experienced a decrease in BAP exceeding the LSC compared with only 71% for TAP. The greatest number of women similarly identified with BMD at any site (i.e. a gain in BMD exceeding the LSC) was 81% for spinal BMD at 36 months. All other sites were less than 70% at 36 months. Short-term changes in BAP and TAP were modestly associated with subsequent changes in BMD at all sites (Spearman’s rho −0.22 to −0.52, p<0.05). Compared with TAP and BMD, BAP testing rapidly and sensitively identified skeletal effects of alendronate thus enabling appropriate drug monitoring of osteoporotic women. Though BAP and TAP changes were modestly predictive of BMD changes, the value of the bone marker tests is their ability to detect rapidly a skeletal effect of therapy. Received: 19 May 2000 / Accepted: 31 October 2000     

Effects of Body Size and Skeletal Site on the Estimated Prevalence of Osteoporosis in Women and Men

There is growing awareness that therapeutic decision-making may be confounded by discrepancies in the prevalence of osteoporosis by World Health Organization criteria when bone density is measured at different skeletal sites. To explore this issue, we measured bone density at a variety of skeletal sites in a population-based sample of 348 men (age 22–90 years) and 351 women (age 21–93 years). Men had greater areal bone mineral density (BMD, g/cm²) than women at almost every subregion on total body, anteroposterior (AP) and lateral lumbar spine, proximal femur and forearm scans by dual-energy X-ray absorptiometry. However, adjustment for height or, where possible, calculation of bone mineral apparent density (BMAD, g/cm³) reduced or eliminated these differences. In addition, three different patterns of change in bone density over life were observed at the various skeletal sites as judged from cross-sectional data: no apparent age-related bone loss (e.g., AP spine BMD in men); linear bone loss over life in both sexes beginning in young adulthood (e.g., femoral neck BMD); and bone loss beginning around the time of menopause or a comparable age in men (e.g., midradius BMD). The various adjustments for bone size and the different patterns of age-related change in bone density had profound effects on the estimated prevalence of osteoporosis by World Health Organization criteria, which ranged from 2% to 45% among postmenopausal women and from 0 to 36% among men 50 years of age and older depending upon the skeletal parameter that was assessed. These observations emphasize the difficulties involved in attempts to standardize BMD scores and definitions of osteoporosis for clinical use. Received: 3 February 2000 / Accepted: 2 June 2000     

Serum Albumin and Bone Mineral Density in Healthy Older Men and Women: The Rancho Bernardo Study

Serum albumin has been found to be positively correlated with bone mass in small studies of ambulatory men or women with diagnosed osteoporosis. In this study the relation between serum albumin and bone mineral density (BMD) was examined in 1593 white, community-dwelling men and women aged 50–95 years. BMD was determined using single-photon absorptiometry (SPA) at the ultradistal radius and the midshaft radius, and using dual-energy X-ray absorptiometry (DXA) at the hip and spine. Albumin was measured from a fasting blood sample using the Technicon SMA 12 autoanalyzer. Mean albumin levels in both men and women decreased significantly with increasing age. All but four values were within the normal range (3.5–5.0 g/dl). BMD decreased with increasing age at all sites. In both sexes there was weak positive correlation between serum albumin and BMD in the unadjusted model (Pearson's rvalues <0.3, p values <0.005). After age adjustment, however, the relationship was no longer significant (Pearson's r values <0.05, p values >0.18). Men and women were divided into three sex-specific categories – osteoporotic, osteopenic and normal – based on World Health Organization criteria in relation to young adult means (normal, BMD > –1 SD; osteopenia, BMD between –1 SD and –2.5 SD; osteoporosis, BMD <–2.5 SD). Mean albumin values did not differ significantly across the three BMD categories in men or women. BMD levels stratified for albumin levels and calcium supplement status (a marker for osteoporosis awareness) also did not differ. Albumin levels were also not associated with a history of low-trauma fractures. In summary, there was no age-independent association between serum albumin within the normal range and low BMD or fractures in community-dwelling healthy older adults. We conclude that previously reported associations most likely reflect inadequate adjustment for the age-related decrease in albumin levels and the selection of very frail osteoporotic subjects. Received: 7 October 1997 / Revised: 21 January 1998     

Osteoprotegerin Levels in Primary Hyperparathyroidism: Effect of Parathyroidectomy and Association with Bone Metabolism

The effect of parathyroid hormone (PTH) on the production of osteoprotegerin (OPG) remains controversial. Most in vitro studies indicate that PTH decreases OPG secretion by the osteoblast, but in vivo observations are conflicting. In primary hyperparathyroidism (PHPT), hypersecretion of PTH leads to enhanced bone resorption and formation with increased risk of fracture. Patients with PHPT are cured by surgery, resulting in normalization of PTH levels and bone metabolism, but the concomitant effects on OPG production are not known. The hypothesis of the present study was that the circulating level of OPG is diminished in patients with PHPT and increases with successful parathyroidectomy. We also speculated that serum OPG may determine the magnitude of bone loss up to the time of surgery. In the present study, 20 patients (17 women and 3 men, mean age 62 y) with PHPT who were candidates for surgical cure were examined before and 12 months after surgery. Bone turnover markers decreased and BMD increased significantly after surgery. Serum OPG did not correlate with PTH before surgery (r = 0.07, P = 0.77) and was not affected by parathyroidectomy (P = 0.79). After normalization of PTH, bone formation markers showed significant (P1NP) and near-significant (osteocalcin) correlations with serum OPG. In conclusion, serum OPG is not decreased in patients with PHPT, nor is serum OPG to any demonstrable extent regulated by PTH pre- or postoperatively.     

Bone Mass and Structure at the Hip in Men and Women over the Age of 60 Years

Bone mass and structure at the proximal femur are important predictors of hip fracture. The aims of this study were to compare in a large sample of elderly men and women the precision of measurements of bone mass and structure at multiple sites at the proximal femur, to examine their interrelationships, to establish their relationships with age and body size, and to examine criteria for defining geometric and architectural variables in bone structure. Women (n= 336) and men (n= 141) over the age of 60 years were studied cross-sectionally. Bone mineral density (BMD) and content (BMC) at the proximal femur were measured in duplicate by dual-energy X-ray absorptiometry (DXA). Shaft and total upper femur (hip) sites in addition to femoral neck, Ward's triangle and trochanter were measured. Structural variables, measured from radiographs and from DXA images, including cortical thickness at calcar femorale, lateral cortex and mid-femur, width of the femur and medulla, Singh grade, hip and femoral axis length, femoral head and neck width and the center of mass of the femoral neck. BMD and BMC had high reproducibility and there were significant differences in reproducibility across sites. Among sites, total upper femur and shaft had the highest reproducibility. Duplicate measurements substantially improved reliability of the measurement and are recommended when the value is close to a diagnostic level or when it will be used to establish rates of change. Reproducibility of structural variables was also high except for the lateral cortex, center of mass and Singh grade. Variance due to measurement error did not change with either age or gender. Women were significantly different from men, after controlling for differences in body size, in all variables except Singh grade and medulla width. BMD and BMC were negatively related to age and positively to body size. Structural variables examined in relation to age and body size fell into two categories. The first comprised variables that were not age-related but were body-size-related, suggesting that they could be classified as geometric variables. The second comprised variables that were both body-size-related and age-related, suggesting that they could be classified as architectural variables. Using these criteria, calcar and lateral cortex were architectural variables, whereas shaft width, hip and femoral axis length, femoral head and neck width, and center of mass were geometric in both men and women. In women, shaft cortex width and medulla width were age-related, whereas in men they were not. Singh grade showed no consistent pattern with age or body size in women and men. Received: 7 January 1997 / Accepted: 7 November 1997     

Population Bone Mineral Density Measurements for Chinese Women and Men in Hong Kong

The aim of the study was to establish population ranges of bone mineral density (BMD) for Hong Kong Chinese men and women for the Hologic QDR 2000 bone densitometer, to compare these values with the manufacturer’s reference ranges, to compare these values with population ranges for women obtained for the Norland X26 bone densitometer, and to examine variations between the two densitometers. The subjects were 164 men aged 40–79 years and 436 women aged 20–89 years, who were all ethnic Chinese, recruited from volunteers, social centers for the elderly and general practice clinics. BMD in women began to decline rapidly between ages 50 and 79 years, averaging about 10% loss per decade from the young adult (20–29 years) mean. The percentage losses from young adult mean values in the spine, femroal neck, trochanter and total femur were 23%, 30%, 31% and 33%, respectively, from 20 to 79 years. In the ninth decade no further decrease in BMD occurred with the exception of a further 4% at the hip sites. In men, no decrease in spine BMD occurred between 40 and 70 years. Compared with BMD in the fourth decade, 10%, 13%, and 11% of BMD was lost at the femoral neck, trochanter and total femur, respectively, by the seventh decade. These values show differences compared with the manufacturer’s reference ranges for Caucasians and Japanese. BMD values for the spine were comparable between Hologic and Norland densitometers, but Hologic values for femoral neck and trochanteric regions were lower than the Norland values. Data provided by this study may thus be used as normative values for the Hologic QDR2000 bone densitometer, instead of values provided by the manufacturer. BMD values at the hip sites are not interchangeable between Norland and Hologic bone densitometers, and estimation of numbers of the population with osteoporosis will depend on the model of densitometer used. Received: 31 May 2000 / Accepted: 31 October 2000     

Six and Twelve Month Changes in Bone Turnover are Related to Reduction in Vertebral Fracture Risk During 3 Years of Raloxifene Treatment in Postmenopausal Osteoporosis

We studied the relationship between change in bone turnover and vertebral fracture risk during raloxifene therapy using 3-year data from the MORE trial, where 2622 of the 7705 randomized women had measurement of bone markers at baseline and after 6 and 12 months participation. Change in bone turnover was significantely related to future risk of vertebral fracture, also after adjusting for baseline vertebral fracture status and BMD. Thus, for a decrease of 9.3 mg/l in serum osteocalcin after 1 year’s raloxifene therapy, the odds ratio (OR) for a new vertebral fracture during 3 years was 0.69 (0.54–0.88), p= 0.003. Similarly, for a decrease of 5.91 mg/l in serum bone alkaline phosphatase, OR was 0.75 (0.62–0.92), p= 0.005. The change in BMD over 12 and 24 months was not related to fracture risk in any of the analyses. The strongest predictor for vertebral fracture was prevalent vertebral fracture – even during therapy. The predictive value of baseline BMD was in the same order of magnitude as bone turnover change during raloxifene treatment. In conclusion, the change in bone turnover is related to fracture risk during raloxifene therapy. In contrast the change in BMD is not related to fracture risk. The strongest predictor for vertebral fracture is prevalent vertebral fracture. Received: 2 January 2001 / Accepted: 30 May 2001     

Incidence of Distal Forearm Fracture in British Men and Women

Fracture of the distal forearm is one of the most frequent osteoporotic fractures. However, there are few data concerning its incidence in Britain. The aim of this study was to determine the incidence of distal forearm fracture in adult British men and women. Six centers took part in the study: Aberdeen, Hull, Nottingham, Portsmouth, Southampton and Truro. At each center, men and women aged 35 years and over with an incident distal forearm fracture and who resided in the catchment area of the main hospital at that center, were identified during a 12 month period. Incident fractures were identified from all possible point-of-contact sources in each locality, including accident and emergency records, fracture clinics, ward listings and plaster room registers. The population at risk was defined geographically according to postcode and the denominator obtained from 1991 census data mapped to these postcodes. During the 12 month study period, 3161 individuals with distal forearm fracture were identified. The age-adjusted incidence, age 35 years and over, was 36.8/10 000 person-years in women and 9.0/10 000 person-years in men. In women, the incidence of fracture increased progressively with age from the perimenopausal period, while in men the incidence remained low until later life. Fractures were more frequently left-sided (55.6%) and 19.4% of subjects required hospitalization. On the basis of these data we estimate that 71 000 adult men and women sustain a distal forearm fracture in Britain each year. Compared with previous British surveys the pattern of incidence with age appears to have changed in women, the reason for this is unclear. Received: August 2000 / Accepted: January 2001     

Higher Osteocalcin Levels and Cross-Links Excretion in Young Men Born with Low Birth Weight

As the result of accelerated growth, the final height of infants born with low birth weight (LBW) is near to the normal. Limited data are available about the bone density and bone turnover just after completion of skeletal development. We have investigated the bone turnover and bone density in 49 apparently healthy young LBW men (age 19–21 years; 21 born small for gestational age (SGA) and 28 appropriate for gestational age (AGA)) and in 16 age-matched controls. Bone mineral density of lumbar spine, femoral neck, and radius midshaft, the markers of calcium homeostasis, biochemical parameters of bone turnover as serum osteocalcin (OC), and urinary pyridinoline (PYD) and deoxypyridinoline (DPD) levels were measured. Bone mineral densities of LBW subjects were not altered. Serum calcium (SGA: 2.44 ± 0.15; AGA:2.41 ± 0.17, control: 2.25 ± 0.09 mmol/liter, P < 0.05), OC (SGA:23.4 ± 9.9; AGA:20.8 ± 7.6; control:13.3 ± 4.6 ng/ml, P < 0.01), total alkaline phosphatase (AP) (SGA:201 ± 61; AGA:193 ± 81, control:117 ± 34 IU/liter, P < 0.01), and urinary DPD/creat (ln.values: SGA:3.10 ± 0.48; AGA:3.17 ± 0.46; control:2.58 ± 0.57 nmol/mmol, P < 0.05) were higher, whereas fractional excretion of calcium (SGA:0.94 ± 0.470; AGA:1.03 ± 0.51, control:1.31 ± 0.75%, P < 0.05) was lower in both SGA and AGA groups. PTH and 25OHD were not different. Significant correlation was obtained between seCa, OC, AP, DPD and birth weight of the subjects, but feCa correlated inversely to the birth weight. It was concluded that the bone turnover of LBW men is accelerated, but well balanced in young adulthood. Further investigation is needed to describe the possible link between accelerated bone turnover and hormonal homeostasis of LBW subjects. Received: 30 November 1999 / Accepted: 9 September 2000 / Online publication: 22 December 2000     

Raloxifene Versus Continuous Combined Estrogen/Progestin Therapy: Densitometric and Biochemical Effects in Healthy Postmenopausal Taiwanese Women

We treated 116 healthy postmenopausal women (age 47–66 years, mean 57 years) in Taiwan with either raloxifene (RLX) 60 mg (n= 92) or 0.625 mg conjugated equine estrogen plus 5 mg medroxyprogesterone acetate (CCEP, n= 24) daily for 12 months in a randomized, double-masked, active-controlled fashion. The results showed that both regimens increased bone mineral density (BMD) at hip sites (means: RLX 2.5–4.9%, CCEP 4.6–7.9%, all p<0.005 compared with baseline), and the difference between the two regimens was not significant. The spinal BMD increased significantly in both groups (1.4% with RLX and 6.0% with CCEP, both p<0.01), and more with CCEP (p<0.003). Osteocalcin levels and urinary type I collagen C-telopeptide/creatinine ratios decreased significantly in both regimens, but the decreases were significantly larger with CCEP. Compared with baseline, both RLX and CCEP decreased the total cholesterol (median 4.9% and 8.6% respectively, p<0.001) and LDL-cholesterol (median 11% and 19% respectively, p<0.001), and increased HDL-cholesterol (median 8.6% and 10.7% respectively, p<0.01). Both regimens increased triglyceride levels (median 3.2% and 18.9% respectively, both p<0.05), although to a lesser extent with RLX than with CCEP (p<0.05). Only 3 subjects (3.3%) reported vaginal bleeding in the RLX group, as compared with 31% (7/22) with CCEP (p<0.05). We conclude that in healthy, postmenopausal Taiwanese women, RLX 60 mg given daily has favorable results in BMD, bone turnover and serum lipids, although the dosage we used showed a potency less than that of conventional CCEP. Received: 22 November 2000 / Accepted: 25 June 2001     

Estimation of the Prevalence of Low Bone Density in Canadian Women and Men Using a Population-Specific DXA Reference Standard: The Canadian Multicentre Osteoporosis Study (CaMos)

The Canadian Multicentre Osteoporosis Study (CaMos) is a prospective cohort study which will measure the incidence and prevalence of osteoporosis and fractures, and the effect of putative risk factors, in a random sample of 10 061 women and men aged ≥25 years recruited in approximately equal numbers in nine centers across Canada. In this paper we report the results of studies to establish peak bone mass (PBM) which would be appropriate reference data for use in Canada. These reference data are used to estimate the prevalence of osteoporosis and osteopenia in Canadian women and men aged ≥50 years. Participants were recruited via randomly selected household telephone listings. Bone mineral density (BMD) of the lumbar spine and femoral neck were measured by dual-energy X-ray absorptiometry using Hologic QDR 1000 or 2000 or Lunar DPX densitometers. BMD results for lumbar spine and femoral neck were converted to a Hologic base. BMD of the lumbar spine in 578 women and 467 men was constant to age 39 years giving a PBM of 1.042 ± 0.121 g/cm² for women and 1.058 ± 0.127 g/cm² for men. BMD at the femoral neck declined from age 29 years. The mean femoral neck BMD between 25 and 29 years was taken as PBM and was found to be 0.857 ± 0.125 g/cm² for women and 0.910 ± 0.125 g/cm² for men. Prevalence of osteoporosis, as defined by WHO criteria, in Canadian women aged ≥50 years was 12.1% at the lumbar spine and 7.9% at the femoral neck with a combined prevalence of 15.8%. In men it was 2.9% at the lumbar spine and 4.8% at the femoral neck with a combined prevalence of 6.6%. Received: 23 April 1999 / Accepted: 14 April 2000     

Vitamin D Receptor Gene Polymorphisms and Bone Mineral Density in Elderly Chinese Men and Women in Hong Kong

Although genetic factors have been strongly implicated in determining bone mineral density (BMD), the role of the vitamin D receptor (VDR) polymorphism remains controversial. An overall consensus is difficult, as the populations studied have been heterogeneous with respect to menopausal status and ethnicity. Moreover, some studies have examined only small populations, and relatively few studies have been conducted in Asian populations. There is mounting evidence that calcium homeostasis in Asian populations differs from that in Caucasians. This difference may be mediated, in part, through VDR effects. In a cross-sectional study we have examined the relationship between the VDR polymorphism and BMD in 272 women (mean age 75 years) and 237 men (mean age 73 years) of Chinese origin from Hong Kong. Consistent with other studies in Asian populations we found higher frequencies of the T, b and a alleles compared with those reported in Caucasian populations. Moreover, no significant difference in BMD was observed when subjects were grouped by a combination of the genotypes (bbAATT, bbAaTT, bbaaTT, BbAaTt, BbAATt). These results suggest that VDR polymorphism is not associated with BMD in elderly Hong Kong Chinese men and women. Received: 16 July 1998 / Accepted: 15 February 1999     

Comparison of Serum and Urine Assays for Biochemical Markers of Bone Resorption in Postmenopausal Women with and without Hormone Replacement Therapy and in Men

Biochemical markers of bone resorption have been used to characterize metabolic bone disease and assess therapeutic response. Most studies have used the urinary measurement of collagen crosslinks, but serum assays have recently been developed that may have less analytic and biologic variability. In the present study, we measured urine and serum N- and C-terminal crosslinked telopeptides of type I collagen (NTX and CTX) and serum bone sialoprotein (BSP) in postmenopausal women with or without hormone replacement therapy (HRT) and in men of similar age. In these populations, the variability of serum and urine markers was similar, except that serum NTX showed somewhat lower variability in postmenopausal women. Urine and serum assays correlated well with one another and were significantly lower in postmenopausal women on HRT compared with untreated women. The difference in women on HRT was similar for sNTX, uNTX and BSP (35–40%) and greater for sCTX and uCTX (52–53%). There was an inverse correlation between markers and bone mineral density, largely attributable to the high correlation in women not on HRT. Fractional excretion of NTX and CTX were estimated at 0.20 ± 0.07 and 0.44 ± 0.11, respectively. These values were independent of the concentration of the marker or of creatinine in the urine. We conclude that serum markers are useful measures of bone resorption in these populations, in whom the use of such markers is likely to be helpful in the management of osteoporosis. Received: 23 August 1999 / Accepted: 30 November 1999     

Skeletal Site Bone Mineral Density Heterogeneity in Women and Men

The heterogeneity of skeletal bone mineral density, measured on a single dual-energy X-ray absorptiometer, was examined in a large cohort of 7050 women and 702 men referred for investigation of osteoporosis. The men were significantly older (64.8 +/- 13.2 vs 60.2 +/- 11.5 years) and had an increased prevalence of nontraumatic fractures (ODR: 2.18; 95% CI: 1.82-2.61). The detection rate (sensitivity) for any osteoporosis (spine or hip) in women was 87.1% and 45.1% when assessed at the anteroposterior (AP) spine and femoral neck respectively. The corresponding osteoporosis detection rate in men was 69.3% and 67.5% at the AP spine and femoral neck respectively. Age-related AP spine degenerative changes increased significantly and at a similar rate for both women and men. Misclassification, that is osteoporosis (T-score < -2.5) at one site and normal (T-score > -1) bone mass at the other, was low in both genders (< 4.5%), but 3.1 (95% CI: 2.1-4.6) times more likely in women when the diagnosis was based on the femoral neck compared with the AP spine. Our findings suggest that there are significant age- and gender-related bone mineral density differences between the spine and hip skeletal sites which have to be considered if only one site is selected for investigation.     

Diurnal Variation of Bone Mineral Turnover in Elderly Men and Women

The diurnal variation of markers of bone mineral metabolism have been documented in pre- and early postmenopausal women. Such rhythms have clinical implications for timing of sample collection and assessment of therapeutic intervention. To examine the diurnal variation of bone turnover in the elderly, we examined markers of bone formation [serum osteocalcin (OC) and bone-specific alkaline phosphatase (B-ALP)]; a marker of bone resorption (urinary N-telopeptide cross-linked collagen type 1 [NTX]); and serum calcium and parathyroid hormone (PTH) over 24 hours. Subjects were healthy community-dwelling elderly who were on no medications known to significantly alter bone mineral metabolism. Subjects included 14 women [74 ± 6 years (mean ± SD)] and 14 men (80 ± 5 years). Over the 24-hour sampling period, mean serum OC, B-ALP, and calcium values were similar in elderly men and women. However, mean serum PTH was significantly higher in elderly men compared with women (P < 0.05). The magnitude of the diurnal variation of urinary NTX was significantly higher in women compared with men (P < 0.05). There was a significant diurnal variation for serum OC, B-ALP, calcium, PTH, and urinary NTX in both elderly men and women. The magnitude of the diurnal variation was approximately 10–20% of mean value for OC and B-ALP, 30% for PTH, and up to 40% for urinary NTX. We conclude that there is significant diurnal variation in the markers of bone mineral metabolism for elderly men and women. The peak value, which on average would be 20% higher than the mean value for urinary NTX, highlights the importance of the timing of sample collection for appropriate interpretation of therapeutic response. In addition, gender-related differences, including relatively higher levels of serum PTH and lower levels of urinary NTX in elderly men, may help explain differences in rates of bone loss in this age group. Received: 21 June 1996 / Accepted: 18 October 1996     

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