Specific Changes of Urinary Excretion of Cross-Linked N-Telopeptides of Type I Collagen in Pre- and Postmenopausal Women: Correlation with Other Markers of Bone Turnover

Urinary excretion of cross-linked N-telopeptide of type I collagen (NTx) has been reported to be a specific marker of bone resorption [18]. We assessed a new immunoassay for NTx as an indicator of changes in bone resorption caused by spontaneous menopause and compared cross-sectionally the levels of urinary NTx, hydroxylysylpyridinoline (HP), lysylpyridinoline (LP), hydroxyproline (OH-Pr), other serum biochemical indices, and lumbar spine and proximal femur bone mineral density (BMD). Eighty-one Japanese women aged 22–77 participated in this study; 36 were premenopausal and 45 were postmenopausal. Urinary HP, LP, and NTx stayed at low levels in the premenopausal period and rose 21%, 30%, and 67% in the postmenopausal period, respectively. The rise in LP and NTx was statistically significant (P < 0.01), suggesting that NTx is mostly released from bone matrix when bone resorption is accelerated. When premenopausal women were divided into two age groups and postmenopausal women were divided into two groups according to years since menopause (YSM) there were significant differences in LP and NTx between women <4 YSM and women aged <40 and those women aged 41+ (P < 0.01 and P < 0.05, respectively). A significant 110% increase in urinary NTx and a 48% increase in urinary LP were observed in postmenopausal women compared with age-matched premenopausal women aged 45–55. All biochemical markers other than serum PTH correlated significantly with each other (r = 0.243–0.858, P < 0.05–0.0001). Urinary NTx inversely correlated with lumbar spine BMD. When postmenopausal women were divided into three groups, the correlation between bone resorption and formation markers in women 0-1 YSM was greater than in women 2–10 YSM and in women 11 + YSM, indicating that resorption and formation are coupled at the early postmenopausal period. We conclude that urinary NTx is responsive to changes in bone metabolism caused by estrogen deficiency and may be a more sensitive and specific marker than HP, LP, or OH-Pr in the early postmenopausal years. Received: 15 February 1995 / Accepted: 18 October 1996     

Cortical Bone Resorption in Osteoporosis

A study was made of 110 women: 35 healthy premenopausal, 40 healthy postmenopausal, and 35 women diagnosed as having postmenopausal osteoporosis. The postmenopausal women had similar ages and years since menopause (YSM). In all of the women, total bone mass was evaluated by dual-energy X-ray absorptiometry and metacarpal morphometry was evaluated by radiogrammetry on the second metacarpal of the nondominant hand, performed by computed radiography. An external metacarpal diameter of ≥7.4 mm was required as proof of having developed an adequate peak bone mass. The endosteal diameter, which is indicative of bone resorption in both groups of postmenopausal women, obtained in the postmenopausal groups was subtracted from the endosteal diameter obtained in the premenopausal group and the resulting figure was divided by the years since menopause to calculate the rate of cortical bone resorption/year for each group. The endosteal diameters values differed in the three groups studied (P < 0.0001): 3.2 ± 0.7 mm in the healthy premenopausal women; 3.9 ± 0.6 mm in the healthy postmenopausal women; and 4.7 ± 0.5 mm in the osteoporotic postmenopausal women. The rate of cortical bone resorption was 0.068 ± 0.002 mm/YSM (years since menopause) in the osteoporotic postmenopausal women and 0.033 ± 0.003 mm/YSM in the healthy postmenopausal women (P < 0.0001). These figures reflect the importance of bone resorption, as opposed to deficient bone formation, as a cause of osteoporosis. Received: 27 January 1995 / Accepted: 21 August 1996     

Metacarpal Radiogrammetry by Computed Radiography in Postmenopausal Women with Colles' Fracture and Vertebral Crush Fracture Syndrome

Based on the hypothesis that the underlying osteoporotic mechanism of Colles' fracture in postmenopausal women is similar to that of other osteoporotic fractures, that is, cortical bone resorption as opposed to cancellous bone resorption, the rate of corticoendosteal bone loss was compared in 40 normal postmenopausal women [average age 68.4 ± 7.1 years; 20 ± 4 years since menopause (YSM)], in 35 postmenopausal women with Colles' fracture (age 69.4 ± 7.5 years, 22 ± 8 YSM), in 35 normal postmenopausal women with vertebral crush fracture (age 69.4 ± 7.5 years, 22 ± 8 YSM, and in 35 normal premenopausal women (age 36.1 ± 7.9 years). Radiogrammetry by digital radiography of the second metacarpal was used to measure external (ED) and internal (ID) diameter, cortical thickness (CCT), cortical area (CA), and the ratio of cortical area to total area (CA/TA). The ID values of the groups of postmenopausal women were subtracted from the ID value of the premenopausal women and the result was divided by YSM to obtain the rate of corticoendosteal resorption/year (ΔC), CA resorption year (ΔCA) and CA/TA resorption/year (ΔCA/TA). ID, ΔC, ΔCA, and ΔCA/TA all were larger in the postmenopausal women with Colles' and vertebral crush fractures than in the normal postmenopausal women (ANOVA: all P < 0.0001). ID, CCT, ΔC, CA, ΔCA, and ΔCA/TA did not differ between the two groups of postmenopausal women with fractures. ΔC was 87% greater in postmenopausal women with vertebral crush fracture and 116% greater in women with Colles' fracture than in normal postmenopausal women. These results indicate that the loss of cortical bone is an important factor in Colles' fracture in postmenopausal women. Received: 10 October 1996 / Accepted: 15 October 1997     

Differences in the Capacity of Several Biochemical Bone Markers to Assess High Bone Turnover in Early Menopause and Response to Alendronate Therapy

We measured bone mineral density (BMD), four markers of bone formation [bone alkaline phosphatase (bAP), osteocalcin (Oc), N- and C-terminal propeptide of type I procollagen (PINP and PICP respectively)] and five markers of bone resorption [serum C-terminal telopeptide of type I collagen (CTx), urinary CTx, N-terminal cross-linked telopeptide (NTx), free and total deoxypyridinoline (fDpd and tDpd respectively)] in 28 healthy premenopausal women (45.7 ± 3.0 years), 15 early (<7 years) healthy menopausal women (53.8 ± 3.1 years) and 20 osteoporotic women (65.3 ± 8.2 years). Bone markers and BMD were also measured in the osteoporotic women 4.1 ± 0.2 and 12.6 ± 1.2 months after the beginning of alendronate therapy (Fosamax, 10 mg/day) respectively (BMD in 16/20). We calculated the intra-individual coefficient of variation (iCV) and the least significant change (LSC) for each bone marker from a subset of 9 healthy premenopausal women (32 ± 5 years) who had a first and a second morning void urine collection (FMV and SMV respectively) and a blood sample on 4 nonconsecutive days (mean interval 14 ± 3 days). None of the bone markers was correlated with BMD (except p= 0.043 between serum Oc and hip BMD). All markers, except fDpd, were increased significantly in early menopausal women when compared with the premenopausal group. Serum CTx presented the highest increase at menopause (+67.8%) and identified the highest rate (11/15) of early menopausal women with bone turnover above the premenopausal range. The iCVs for bone formation markers (7.2–14.4%) were lower than those for bone resorption markers (14.6–22.3%). The iCVs obtained on FMV and SMV were not different. The decrease after 4 months of alendronate was significant for each bone marker but variable from one marker to another. Serum CTx showed the largest decrease (70.8%) and identified the highest number of biologically responding patients (change >LSC; n= 17/20). A significant change in serum CTx after 4 months of alendronate was the best predictor of a significant gain in spine BMD (i.e., ≥27 mg/cm²) after 1 year of therapy, allowing 15 of 16 patients (94%) to be classified correctly (one false-positive). Urinary NTx/Cr was the second best predictor. Despite a moderately high iCV (20.6%), serum CTx appeared the most effective of the markers tested and could be of interest for the detection of high bone turnover and the longitudinal monitoring of alendronate therapy in the individual patient. It must be stressed that serum PINP and urinary NTx and tDpd compared very similarly with serum CTx for monitoring alendronate therapy. Received: 12 April 1999 / Accepted: 13 September 1999     

Baseline BMD and Bone Loss at Distal Radius Measured by Peripheral Quantitative Computed Tomography in Peri- and Postmenopausal Hong Kong Chinese Women

The current study was designed to investigate the rate of bone loss in distal radius and its association with baseline volumetric bone mineral density (BMD) and years since menopause (YSM) in peri- and postmenopausal women using precise and multislice peripheral quantitative computed tomography (pQCT; Densiscan 2000). Two hundred and five healthy Hong Kong Chinese perimenopausal (n = 26) and postmenopausal (n = 179) women within 10 years of the onset of menopause were recruited. Anthropometric parameters and menstrual status were also measured. The linear regression model derived from the baseline volumetric BMD revealed a significant and slightly better correlation with YSM than age, with a YSM-related annual decline of 2.56%, 1.82% and 0.65% in trabecular BMD (tBMD), integral BMD (iBMD) and cortical BMD (cBMD), respectively. Follow-up measurements after a time interval of 12 months showed that the rate of bone loss was higher than the annual decline in BMD calculated from the baseline BMD, with decreases of 2.89%, 2.16% 0.91% in tBMD, iBMD and cBMD, respectively. Baseline BMD was associated with age or YSM (r ranges from −0.283 to −0.502; p<0.001 in all cases), but no relationship was found between annual rate of bone loss and age or YSM. The rate of bone loss did not correlate with baseline volumetric BMD values or YSM after dividing the subjects into fast bone losers (with annual tBMD loss ≥3%), normal bone losers (with annual tBMD loss ≥ 1% but <3%) or slow bone losers (with annual tBMD loss <1%). The rate of bone loss was greater in both trabecular and cortical bone of postmenopausal women within the first 3 menopausal years but was only significant in the iBMD as compared with perimenopausal and postmenopausal women over 7 years after onset of menopause. The percentage distribution of slow and fast bone losers was not found to be associated with YSM. As a total of only 4 fracture cases were documented, the study could not provide conclusive information on whether perimenopausal and early postmenopausal baseline volumetric BMD or rate of bone loss determines the development of osteoporosis or fracture occurrence. Received: 12 November 2001 / Accepted: 18 July 2002     

Increased Serum Levels of N-Telopeptides (NTx) of Bone Collagen in Postmenopausal Nigerian Women

Serum levels of cross-linked N-telopeptides (NTx) of bone collagen, alkaline phosphatase (ALP), and intact parathyroid hormone (PTH) were determined in 64 premenopausal (PRM) and 86 postmenopausal (PSM) women living in northern Nigeria. Serum NTx values were correlated with ALP activity (r = 0.31–0.58, P < 0.01) and PTH (0.32–0.35, P < 0.01)) in all of the subjects studied, and were also related to age (−0.47, P < 0.001) and body mass index (−0.45, P < 0.001) in PRM women. Menopause had the effect of increasing the circulating concentrations of NTx and ALP activity by 15% (P= 0.001) and 11% (P= 0.02), respectively; however, serum levels of PTH were not different between these two groups of women. Compared with Caucasian counterparts matched for age and body mass index, PSM Nigerian women had significantly increased circulating concentrations of NTx (21.7 versus 16.2 nmol BCE/liter, P= 0.01) and demonstrated a trend towards higher ALP activities and PTH levels. These results indicate that (1) discrete reference intervals should be defined for biochemical markers of bone metabolism in African populations, (2) Nigerian women have relatively higher rates of bone turnover, and (3) further investigation of the implications of increased serum NTx should be undertaken using physical methods such as dual X-ray absorptiometry (DXA) and bone ultrasound attenuation. Received: 16 September 1998 / Accepted: 10 January 1999     

Peripheral Volumetric Bone Mineral Density in Pre- and Postmenopausal Chinese Women in Hong Kong

The aim of this cross-sectional study was to use a newly available precise and multislice pQCT (Densiscan 2000) for establishing reference data of volumetric bone mineral density (vBMD) of the distal radius. vBMD of the nondominant wrist was measured in 118 healthy Hong Kong Chinese women aged 41–60. Anthropometric parameters, menstrual status, and handgrip strength were also measured. Results showed that there was a significant age-related decline in trabecular BMD (tBMD), integral BMD (iBMD), and cortical BMD (cBMD), with correlation coefficients ranging from −0.401 to −0.547 (P < 0.001). The annual decline of vBMD was 2.22%, 1.79%, and 0.88% in tBMD, iBMD, and cBMD, respectively. When subjects were divided into premenopausal and postmenopausal groups, we found an age-related decline in tBMD and iBMD, but not in cBMD in both groups. The vBMD values interpreted in mg/cm³ in premenopausal women were 238.4 ± 57.2 in tBMD, 604.6 ± 82.9 in iBMD, 1415.5 ± 129.9 in cBMD, and declined significantly (all P < 0.001) to 193.7 ± 54.7 in tBMD, 500.0 ± 90.3 in iBMD, and 1306.7 ± 153.5 in cBMD in the postmenopausal women. On average, 16.7% of the subjects showed their vBMDs to be below −1 SD and only 1.7% of them lower than −2 SD. Linear regression showed that the annual decline of vBMD was faster in postmenopausal women with 2.42% in tBMD, 1.90% in iBMD, and 0.88% in cBMD compared with 1.91% in tBMD, 0.98% in iBMD, and 0.55% in cBMD in the premenopausal women. After adjustment for age, only the iBMD with dominant trabecular elements showed a significantly accelerated decrease after the onset of menopause (P= 0.008). Weak or no association was found among vBMDs with anthropometric parameters, years since menopause, or handgrip strength. In conclusion, we found a significant age-related decline of vBMDs in Hong Kong Chinese women aged 41–60 years, characterized by the early reduction of metabolically active trabecular bone after entering the fourth decade of life, with an accelerated decline after the onset of menopause. Received: 20 May 1999 / Accepted: 21 January 2000     

Plasma Leptin Values in Relation to Bone Mass and Density and to Dynamic Biochemical Markers of Bone Resorption and Formation in Postmenopausal Women

After the menopause it has been noted that heavier women conserve bone better than those with lower body weight. The protective effect of obesity on bone mass has been ascribed to a high body fat content. The present study of 54 postmenopausal women was undertaken to determine whether circulating plasma levels of leptin, the newly described hormone produced in adipocytes, were correlated with age-adjusted total body bone mineral content (BMC) or bone mineral density (BMD), or with dynamic biochemical markers of bone resorption or of bone formation. Leptin values were strongly correlated with all measures of adiposity (P < 0.001). Age-adjusted values for BMC and BMD, respectively, were also positively correlated (P < 0.001) with body weight (r = 0.643, r = 0.502), total fat mass (r = 0.557, r = 0.510) and with plasma leptin concentrations (r = 0.480, r = 0.551), confirming a positive relationship between fat mass and bone mass. By contrast, no significant correlations were observed between plasma leptin and dynamic markers of bone resorption (urinary deoxypyridinoline/creatinine r =−0.105, hydroxyproline/creatinine r =−0.193) or formation (plasma osteocalcin r = 0.103). Because there was no evidence for an association between ciculating plasma levels of leptin and biochemical markers of either osteoclastic or osteoblastic activity we conclude it is unlikely that circulating leptin plays any significant direct role in controlling bone cell activity. Our results do not support the hypothesis that leptin mediates the bone-sparing effects of obesity. Received: 23 September 1997 / Accepted: 11 May 1998     

Urinary Excretion of Type I Collagen Degradation Products in Healthy Women and Osteoporotic Patients with Vertebral and Hip Fractures

We have evaluated both the effect of normal aging and menopause on urinary CrossLaps™ (u-CTx) excretion and the bone resorption status by u-CTx in patients with vertebral fracture and hip fracture. In 246 healthy women, 76 patients with vertebral fracture, and 63 patients with hip fracture, u-CTx excretion was measured by ELISA. The age-related changes of u-CTx in healthy females reflected the marked increase of bone resorption associated with modeling at childhood. The values in the subgroups of postmenopausal women 1–3 years since menopause and ≤10 years since menopause were significantly higher than those in the subgroups of premenopausal adult women. The values in the vertebral fracture group were significantly higher than those in the premenopause group, but not those in the postmenopause groups. The values in the hip fracture group were significantly higher than those in the other groups. Of the 70 postmenopausal subjects aged 45–64 years, 43% had u-CTx values more than 2 SD above premenopausal mean. The corresponding values in the patients with vertebral fracture and those with hip fracture were 58% and 64%, respectively. This marker reflects well the increase of bone resorption associated with bone modeling at childhood and with high bone turnover after menopause. The excretions in the patients with hip fracture were much higher than those in the age-matched subjects and also higher than those in the patients with vertebral fracture. These findings indicate that the abnormality of bone resorption in the patients with hip fracture is more severe than in the patients with vertebral fracture. Received: 30 January 1997 / Accepted: 7 August 1997     

Cytokine Production and Bone Mineral Density at the Lumbar Spine and Femoral Neck in Premenopausal Women

Cytokines such as interleukin-1 (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) can influence both bone resorption and bone formation. The objective of this cross-sectional study was to examine the relationship between cytokine production by peripheral blood mononuclear cells (PBMC) and bone mineral density (BMD); the annual rate of change in BMD was examined. Subjects participating in a randomized clinical trial entitled the Women's Healthy Lifestyle Project in Allegheny County, Pennsylvania were used. They included 50 healthy premenopausal women, aged 45–52 years, who had regular menses within the past 3 months and were not on replacement estrogens. Dual-energy X-ray absorptiometry measurements at the AP lumbar spine and femoral neck were made at baseline and at the first annual exam using a Hologic QDR 2000 densitometer. Cytokine production of IL-1β, IL-6, and TNF-α by PBMC was measured at the annual exam. The median values for stimulated cytokine production by PBMC were 3.92 ng/ml, 31.3 ng/ml, and 1.05 ng/ml, for IL-1β, IL-6, and TNF-α, respectively. There were modest correlations between cytokine production and cross-sectional BMD, ranging from r =−0.30 to r =−0.13. Trends of greater spinal bone loss were observed in women with ``high' (≥75th percentile) cytokine production of stimulated IL-1β and IL-6 (IL-1β: ``high' =−1.56% ± 0.70 versus ``low' (<75th percentile) =−0.56% ± 0.35, P= 0.21). In contrast, greater annual gains in femoral neck BMD were observed in those with high cytokine production of IL-1β and IL-6 (IL-1β: high = 3.39% ± 1.16 versus low =−0.85 ± 0.58, P= 0.002). There was no association between stimulated TNF production and annual change in BMD. In this population of healthy premenopausal women, the relationship between cytokine production by PBMC and the rate of change in BMD was significantly different for the lumbar spine and femoral neck, possibly reflecting differences in the proportion of trabecular and cortical bone at these sites. Received: 5 February 1997 / Accepted: 11 May 1998     

Influence of Grip Strength on Metacarpal Bone Mineral Density in Postmenopausal Japanese Women: A Cross-Sectional Study

Most published studies on the role of muscle strength in the maintenance of bone mineral density (BMD) focused on the relationship between specific muscle groups and adjacent bones, mostly in young and premenopausal women. This study examined the influence of grip strength on BMD of the metacarpal index in postmenopausal Japanese women. Subjects included 1168 postmenopausal women aged 40–70 years. BMD measurement was done with computed X-ray densitometry (CXD) by analyzing X-ray films of the right second metacarpal index. Grip strength was measured in both the dominant and nondominant hands using a squeeze dynamometer. Grip strength (r = 0.2474; P= 0.0001) and age (r =−0.5443; P= 0.0001) significantly correlated positively and negatively, respectively, with BMD. Physical activity (r = 0.1318; P= 0.0001) also correlated positively with BMD. Breastfeeding (r =−0.1658; P= 0.0001), however, correlated negatively with BMD. Subjects with a history of regular physical activity had higher grip strengths and BMD, than those with no physical activity. Adjustment for age, physical activity, calcium intake, BMI, breastfeeding, testing site, and menopausal type indicated a significant (P for trend = 0.0013) positive association of grip strength with BMD. Subjects with stronger grip strengths had a decreased risk for low BMD. Received: 24 February 1998 / Accepted: 7 August 1998     

Biochemical Markers of Bone Turnover Reflect Femoral Bone Loss in Elderly Women

Although over 90% of hip fractures occur in patients over age 70, few data are available on femoral bone loss in this age group. To examine the relationship between biochemical markers of bone turnover and femoral bone loss in the elderly, 36 female and 17 male, healthy, community-dwelling elderly over age 65 (mean ± SD age: women 71 ± 4 years, men 75 ± 5 years) were followed for 3 years. Annual bone mineral density measurements of the hip and lumbar spine by dual-energy x-ray absorptiometry (DXA) were obtained and biochemical markers of bone resorption (urinary N-telopeptide crosslinks, free pyridinoline, total pyridinoline, total deoxypyridinoline, and hydroxyproline) and bone formation (serum osteocalcin, bone-specific alkaline phosphatase) were obtained at the end of year 3. In elderly women, longitudinal bone loss at the total hip was negatively correlated with markers of bone resorption (r =−0.39 to −0.52, P < 0.05), bone formation (r =−0.38, P < 0.05), and age (r =−0.39, P < 0.05). Markers of bone resorption were correlated with markers of bone formation (r = 0.63 to 0.74, P < 0.01). In multiple regression analysis, urinary N-telopeptide crosslinks (marker of resorption), serum osteocalcin (marker of formation), and serum parathyroid hormone explained 43% of the variability of bone loss at the total hip in women. These parameters were not related to bone loss in men. We conclude that femoral bone loss increases with age in women over 65. Measurements of specific biochemical markers of bone turnover are correlated with longitudinal bone loss in elderly women. These markers may help identify women at greatest risk for bone loss who would benefit most from therapeutic interventions. Received: 28 January 1996 / Accepted: 3 May 1996     

Clinical Observations with a New Specific Assay for Bone Alkaline Phosphatase: A Cross-Sectional Study in Osteoporotic and Pagetic Subjects and a Longitudinal Evaluation of the Response to Ovariectomy,Estrogens, and Bisphosphonates

The purpose of this study was to examine the serum levels of bone alkaline phosphatase (BALP) measured with a new assay in normal and in osteoporotic women, and to evaluate prospectively its responsiveness to changes of bone metabolism. The following groups of subjects were studied: (1) 95 healthy women (44–75 years) (22 pre- and 73 postmenopausal) and 35 osteoporotic women [vertebral bone mineral density (BMD) more than 2.5 SD below the normal adult mean]; (2) 10 women (44–50 years) ovariectomized (OVX) for benign uterine diseases, examined before and 12 months after surgery; (3) 16 OVX women (36–54 years), examined before and after 12 months of transdermal estrogen replacement therapy (50 μg/day); (4) 12 previously untreated pagetic patients (4 women and 8 men, 50–80 years), examined before and 3 months after the I.V. administration of clodronate (600 mg) or alendronate (5 mg) for 2 consecutive days. The median BALP value was 11.6 U/liter (25–75th percentiles: 10.5–12.7; range 7.7–19.3) in healthy premenopausal (PreMP) women and significantly higher (median: 16.8 U/liter; 25–75th percentile: 13.8–21.8; P < 0.01) in postmenopausal (PostMP) women. There was a clear age-related increase in normal subjects (r = 0.43; P < 0.001). In the osteoporotic group, BALP levels, as well as other biochemical parameters of bone turnover, were not significantly different from those of normal women when adjusted for age. In OVX women, BALP levels showed a marked increase 12 months after surgery (median: 113%; 25–75th percentile: 87–139%), significantly higher than the increase of total ALP (median: 43%; 25–75th percentile: 25–66%; P < 0.001), and similar to the increases of serum osteocalcin and urinary hydroxyproline. Transdermal estrogen treatment prevented the BALP increase, even if no reduction was observed; total ALP showed a similar behavior. The basal levels of BALP were significantly elevated in pagetic patients (median: 91 U/liter; range 18–610 U/liter) and correlated to the scintigraphic extent of the disease (r = 0.76; P < 0.01). Three months after the I.V. administration of bisphosphonates, the decrease of BALP was more marked than that of total ALP (median: −54% versus −41%; P < 0.05). In conclusion, these results suggest that BALP measurement with this immunoassay may be clinically useful, and more sensitive than total ALP, in the assessment of bone turnover during changes of the estrogen status as well as in monitoring the effects of treatments that modify the metabolic activity of the skeleton. Received: 25 January 1996 / Accepted: 3 May 1996     

Not All Postmenopausal Women on Chronic Steroid and Estrogen Treatment are Osteoporotic: Predictors of Bone Mineral Density

Chronic steroid use results in osteoporosis, and postmenopausal women are believed to be at a high risk for steroid-induced bone loss. The purpose of this study was to determine predictors of bone mineral density (BMD) in postmenopausal women on both chronic steroid and hormone replacement therapy. Seventy-six postmenopausal women (≥3 years postmenopausal, ≥2 years of steroid treatment of ≥5 mg/day of prednisone, and ≥1 year of hormone replacement therapy) were recruited into this study. Measurements of BMD of the lumbar spine and femoral neck were obtained in all subjects. Risk factors for osteoporosis were obtained by questionnaire. Discriminant analysis was performed to determine predictors of BMD. Osteoporosis, defined by a T score of <−2.5, was present in the lumbar spine or femoral neck in 34 of the 76 subjects. Based on these criteria, women with osteoporosis were significantly older, were more years postmenopausal, and had a lower body mass index (BMI) than women who did not have osteoporosis. Predictors of osteoporosis for both the femoral neck and spine included a low BMI (P < 0.05), more years postmenopausal (P < 0.01), and more years on steroids (P < 0.01). Low BMI was the only significant predictor of osteoporosis in the lumbar spine (P < 0.05), whereas for the femoral neck both years on steroids (P < 0.05) and BMI (P < 0.05) were significant predictors of low BMD. In summary, not all postmenopausal women on chronic steroid and hormone replacement therapy are osteoporotic but a low BMI, more years on steroids, and more years postmenopausal were significant predictors of osteoporosis in these subjects. Received: 8 November 1997 / Accepted: 21 May 1997     

Longitudinal Alveolar Bone Loss in Postmenopausal Osteoporotic/Osteopenic Women

The purpose of this 2-year longitudinal clinical study was to investigate alveolar (oral) bone height and density changes in osteoporotic/osteopenic women compared with women with normal lumbar spine bone mineral density (BMD). Thirty-eight postmenopausal women completed this study; 21 women had normal BMD of the lumbar spine, while 17 women had osteoporosis or osteopenia of the lumbar spine at baseline. All subjects had a history of periodontitis and participated in 3- to 4-month periodontal maintenance programs. No subjects were current smokers. All patients were within 5 years of menopause at the start of the study. Four vertical bitewing radiographs of posterior sextants were taken at baseline and 2-year visits. Radiographs were examined using computer-assisted densitometric image analysis (CADIA) for changes in bone density at the crestal and subcrestal regions of interproximal bone. Changes in alveolar bone height were also measured. Radiographic data were analyzed by the t-test for two independent samples. Osteoporotic/osteopenic women exhibited a higher frequency of alveolar bone height loss (p<0.05) and crestal (p<0.025) and subcrestal (p<0.03) density loss relative to women with normal BMD. Estrogen deficiency was associated with increased frequency of alveolar bone crestal density loss in the osteoporotic/osteopenic women and in the overall study population (p<0.05). These data suggest that osteoporosis/osteopenia and estrogen deficiency are risk factors for alveolar bone density loss in postmenopausal women with a history of periodontitis. Received: 9 April 1998 / Accepted: 18 August 1998     

The Effectiveness of Cyclic and Continuous Oral Clodronate Therapy on Bone Density and Markers in Osteopenic Postmenopausal Women

Bisphosphonates have been used effectively to treat established osteoporosis and prevent postmenopausal bone loss. However, the optimal manner of its administration—whether cyclic or continuous—has not been well established. This study investigated the efficacy of cyclic and continuous oral administration of clodronate in 54 newly identified osteopenic postmenopausal women in a randomized, double-blind, crossover fashion. The participants were randomly separated into two groups. The cyclic group (n = 29) received 800 mg twice daily of oral clodronate for 2 weeks every 3 months for the first 12 months followed by placebo for the second 12 months. The continuous group (n = 25) received placebo in the first 12 months and ingested 400 mg of clodronate once daily for the second 12 months. The urinary amino-terminal (NTX™) and carboxy-terminal (CrossLaps™) cross-linked fragments of type I collagen, both markers of bone resorption, showed a marked decrease (25–50%) with both regimens during the period of active treatment. In the cyclic group, the levels of these two markers increased in the second 12 months with placebo, but did not return to the baseline completely. However, bone mineral density (BMD), determined by dual-energy X-ray absorptiometry (DXA), showed no significant change of BMD at various sites after 1 year of active treatment in both groups. Thoracic and lumbar spine X-ray showed no new vertebral fracture in either group after 2 years of treatment. With the two treatment protocols in this study, oral clodronate was effective in decreasing postmenopausal bone resorption, causing no significant changes in BMD at various sites. Received: 16 April 1997 / Accepted: 1 October 1998     

The Decrease in Serum Bone-Specific Alkaline Phosphatase Predicts Bone Mineral Density Response to Hormone Replacement Therapy in Early Postmenopausal Women

Hormone replacement therapy (HRT) prevents bone loss in postmenopausal women. Up to 20% of women demonstrate no increase in bone mineral density (BMD) on HRT. We examined whether early changes in serum bone alkaline phosphatase (B-ALP) predict long-term BMD changes in postmenopausal women on HRT. Ninety women within 1 year of menopause were randomly assigned to continuous or sequential estrogen/progestin (beta estradiol/norethisterone acetate) if naturally postmenopausal, or beta estradiol if within 1 month of surgical menopause. Spine, femoral neck BMD (DXA), and B-ALP were determined over 2 years. The mean percent BMD changes were 3.8%, 2.9%, 1.6% in the spine and 2.4%, 4.0%, 1.1% in the femoral neck in sequential, continuous, and estrogen alone treatment groups, respectively, significantly different from zero except for femoral neck BMD change in the estrogen alone group. HRT was associated with spine and femoral neck BMD loss in 17.4% and 25.3% of women, respectively. In estrogen/progestin-treated women, baseline B-ALP correlated with spine BMD change (r = 0.42, P < 0.01). At 3 months, B-ALP dropped significantly in the estrogen/progestin-groups with a maximal decrease at 12 months, but no change from baseline in the estrogen alone group. Using quartile analysis, women with the greatest drop in B-ALP (≥50%) at 6 months demonstrated the greatest gain in spine BMD at 2 years. A 40% decrease at 6 months in B-ALP had a 56% sensitivity, 83% specificity, 95% positive predictive value for spine BMD gain at 2 years. The decrease in B-ALP can be used to monitor BMD response to HRT. Received: 6 January 1999 / Accepted: 13 August 1999     

Loss of Bone Mineral Density in Women Athletes During Aging

Total and regional bone mineral density (BMD) by dual-energy-X-ray absorptiometry (DXA) and bone turnover were tested in 50 highly trained women athletes and 21 sedentary control women (18–69 years; BMI < 25 kg/m²). VO_2max (ml · kg⁻¹· min⁻¹) and lean tissue mass (DXA) were significantly higher in the athletes versus controls (both P < 0.0001). Total body BMD did not decline significantly with age in the athletes whereas lumbar spine (L₂–L₄) BMD approached statistical significance (r =−0.26; P= 0.07). Significant losses of the femoral neck (r =− 0.42), Ward's triangle (r =−0.53), and greater trochanter BMD (r =−0.33; all P < 0.05) occurred with age in the athletes. In the athletes, total body BMD, L₂–L₄ BMD, and BMD of all sites of the femur were associated with lean tissue mass (r = 0.32 to r = 0.57, all P < 0.05) and VO_2max (r = 0.29 to r = 0.48, all P < 0.05). Femoral neck and greater trochanter BMD were higher in the athletes than in controls (both P < 0.05) and lumbar spine and Ward's triangle BMD approached statistical significance (both P= 0.07). Bone turnover was assessed by serum bone-specific alkaline phosphatase (B-ALP), urinary deoxypyridinoline cross-links (Dpd), and urinary aminoterminal cross-linked telopeptides (NTX). There were no relationships between B-ALP or Dpd with age whereas NTX increased with age (r = 0.46, P < 0.05) in the entire group. Levels of B-ALP and NTX were negatively associated with total body, L₂–L₄, femoral neck, Ward's triangle, and greater trochanter BMD (P < 0.05). B-ALP and Dpd were not significantly different between athletes and controls whereas NTX was lower in the athletes than in controls (P < 0.001). The high levels of physical activity observed in women athletes increase aerobic capacity and improve muscle mass but are not sufficient to prevent the loss of bone with aging. Received: 28 November 1997 / Accepted: 8 April 1998     

Ethnic and Gender Differences in Bone Mineral Density and Bone Turnover in Young Adults: Effect of Bone Size

Generally, the incidence of osteoporotic fracture is lower in black populations and in men. These effects of ethnicity and gender may result from differences in peak bone mineral density (PBMD) and bone turnover (BT), which in turn are affected by bone size. Therefore, the aims of this study were to examine the effects of ethnicity and gender on bone mineral density (BMD) and BT in young African-Caribbean and Caucasian adults, and to adjust for the effect of bone size on BMD and BT. BMD was measured at the lumbar spine, L2–L4 (LS), total body (TB) and femoral neck (FN) by dual-energy X-ray absorptiometry in 44 blacks (16 men, 28 women) and 59 whites (28 men, 31 women) ages 20–37 years. We measured serum bone-specific alkaline phosphatase (BAP) and serum osteocalcin (OC) as markers of bone formation and urinary immunoreactive free deoxypyridinoline (ifDpd) and crosslinked N-telopeptide of type I collagen (NTx) as markers of bone resorption. To adjust the data for any differences in bone size, we calculated: (a) bone mineral apparent density (BMAD), an estimated volumetric bone density which attempts to normalize BMD measurements for bone size; and (b) bone resorption markers as a ratio to total body bone mineral content (TB BMC). Two-way analysis of variance was used to compare the effects of race and gender, and to test for any interaction between these two factors. Blacks had higher BMD compared with whites at the TB (p<0.001), LS (p= 0.0001) and FN (p= 0.0005). This increase remained significant at the LS only after calculating BMAD. Men had higher BMD at all sites (except at the LS). This increase was no longer significant at the FN after calculating BMAD, and LS BMAD was actually greater in women (p<0.0001). Blacks and whites had similar concentrations of turnover markers, but men had higher bone turnover markers than women (BAP, p<0.0001; OC, p= 0.002; ifDpd, p= 0.03; NTx, p<0.0001). This increase in bone resorption markers was no longer significant after adjusting for TB BMC (except for NTx in whites). We conclude that the skeletal advantage in blacks during young adulthood is not explained by bone size. However, it seems probable that bone size effects partially explain gender differences in BMD and bone turnover. Received: 2 February 1999 / Accepted: 2 December 1999     

Comparison of Three Bone Densitometry Methods in Osteoporotic Women

Three techniques of bone mass measurement were evaluated in the diagnosis of postmenopausal osteoporosis; the overlap in the measurements and the capacity for discriminating was determined among 51 postmenopausal normal (mean age 66.6 ± 8.4 years) and 42 postmenopausal osteoporotic women (mean age 68.5 ± 7.5 years). All bone mass was evaluated by total body bone mineral content (BMC_TB), density (BMD_TB), ultrasound bone velocity (UBV) in proximal phalanxes 2–5 of the nondominant hand (UBV = mean value of all ultrasound measurements), and peripheral quantitative computed tomography of the nondominant forearm (pQCT). BMC_TB was found to be significantly better (P < 0.0001) for diagnosing postmenopausal osteoporosis than the other methods; both cortical and trabecular pQCT measurements were more discriminating than the corresponding UBV measurements (P < 0.001). T-score values in normals, subjects versus osteoporotic ones were BMC_TB−1.15 ± 0.79 versus −3.17 ± 0.74; BMD_TB−1.01 ± 0.97 versus −3.28 ± 0.81; UBV −1.51 ± 1.02 versus −2.34 ± 1.21; trabecular-pQCT −0.40 ± 0.72 versus −1.57 ± 0.37; cortical-pQCT −1.00 ± 0.87 versus −2.67 ± 0.53; and total-pQCT −0.65 ± 1.01 versus −2.34 ± 0.27, respectively. The overlap in values between the postmenopausal normal and postmenopausal osteoporotic groups was 50% with UBV, 6% with BMC_TB, 9% with BMD_TB, 25% with cortical pQCT, and 42% with trabecular pQCT. BMC_TB, BMD_TB, UBV, and pQCT correlated well with each other as measurements of bone mass, but BMC_TB was more discriminating than the other measurements in the diagnosis of osteoporosis. Received: 7 June 1995 / Accepted: 21 May 1997