A Comparison of the Effect of Risedronate and Etidronate on Lumbar Bone Mineral Density in Japanese Patients with Osteoporosis: A Randomized Controlled Trial

To demonstrate the clinical benefit of 2.5 mg daily risedronate in the treatment of involutional osteoporosis, the effect of risedronate on bone mineral density (BMD) of the lumbar spine was compared with that of etidronate, selected as a representative of the bisphosphonates currently marketed in Japan. In this multicenter, randomized, double-masked, active (etidronate) controlled comparative study, a total of 235 Japanese patients with involutional osteoporosis were randomized to receive either treatment with 2.5 mg/day of risedronate for 48 weeks or intermittent treatment with etidronate (4 cycles of 2 weeks of treatment with 200 mg/day followed by 10-week medication-free periods). All patients received 200 mg of calcium supplement daily in the form of the calcium lactate. Bone mineral density of the lumbar spine (L2–L4 BMD) was determined at 12, 24, 36 and 48 weeks by dual-energy X-ray absorptiometry. The primary endpoint was the percent change in L2–L4 BMD from baseline to the time of final evaluation. Changes in biochemical markers of bone turnover and safety profiles were also compared. A significant increase in L2–L4 BMD was observed at 12 weeks after initiation of therapy in both the risedronate (2.8%) and etidronate (1.8%) groups. The increase in L2–L4 BMD at the time of final evaluation in the risedronate group (4.9%) was significantly greater (p = 0.002) than that in the etidronate group (3.1%). The changes in bone resorption markers (urinary total deoxypyridinoline and N-terminal telopeptide of type I collagen) from baseline to 48 weeks were −37.6% and −41.3% for risedronate and −22.5% and −26.6% for etidronate, respectively. New vertebral fractures or deterioration of existing fractures were observed in 2.8% (3/106) of the patients in the etidronate group, while no such cases (0/101) were observed in the risedronate group. No significant difference in the incidence of adverse events was found between two treatments. Daily oral risedronate (2.5 mg) exhibited efficacy superior to that of intermittent cyclical etidronate (200 mg) in increasing L2–L4 BMD, and was well tolerated by Japanese patients with involutional osteoporosis. Received: 7 February 2002 / Accepted: 18 July 2002     

Computed Tomography Image Analysis of the Calcaneus in Male Osteoporosis

The present study aimed to characterize bone microarchitecture assessed by computed tomography (CT) at the calcaneus in male subjects suffering from osteoporosis. Seventy-nine subjects were assessed (45 with osteoporosis and 34 control subjects matched for age). Osteoporosis was defined according to the World Health Organization classification either at the lumbar spine or at the femoral neck. Thirty-three subjects (73%) had a past history of low-energy fracture mainly represented by vertebral fractures (24/33). Nine axial sections (1 mm in width and 2 mm apart) were selected for each subject. Bone microarchitecture analysis was performed using structural (binary and skeletonized images but also skeletonization from gray levels) and fractal analyses. Bone densitometry by dual-energy X-ray absorptiometry (DXA) at the calcaneus was also performed in 73 cases. Bone mineral density (BMD) was decreased in osteoporotic patients compared with controls both at the lumbar spine and hip and also at the calcaneus (p<0.01). Also 14 microarchitectural features among 25 measured were significantly different between the two groups (p<0.01). The odds ratio for fracture per 1 control group standard deviation decrease were also significant for 13 structural features but also for BMD at the calcaneus. The odds ratios after adjustment for BMD at the calcaneus were significant for the following features (p<0.05): number of valleys, 2.8 (1.2–6.9); trabecular partition, 3.3 (1.3–7.9); apparent trabecular spacing, 1.8 (1.0–3.1); trabecular bone pattern factor, 2.2 (1.1–4.3); Euler number, 3.0 (1.1–8.7); node-to-terminus strut count, 3.3 (1.4–7.8); terminus-to-terminus strut count, 2.9 (1.2–6.9); and fractal dimension, 3.7 (1.5–9.7). Few and weak correlations were found between BMD at the calcaneus measured with DXA and features obtained from CT, suggesting that these two methods give different information about bone status. In conclusion, male osteoporosis is a disease characterized by decreased bone mass but also by microarchitectural deterioration of bone tissue which is partly independent of BMD. Received: 24 April 2001 / Accepted: 6 July 2001     

Prevalence of Reduced Bone Mineral Density in Patients with Anti-neutrophil Cytoplasmic Antibody Associated Vasculitis and the Role of Immunosuppressive Therapy: A Cross-Sectional Study

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a relapsing-remitting disease, which is treated with corticosteroids (CS) in combination with cyclophosphamide. One of the major side-effects of this treatment is osteoporosis, which may result in the increased occurrence of fractures. In the present study we measured the prevalence of reduced bone mineral density (BMD) in a cross-sectional cohort of patients and correlated BMD findings with cumulative doses of CS and/or cyclophosphamide. BMD was measured by dual-energy X-ray absorptiometry (DXA) of the lumbar spine, radius and proximal femur between January 1998 and December 1999. Cumulative doses of CS and cyclophosphamide were calculated by chart review. Ninety-nine consecutive patients (48 men, 51 women) aged 55 ± 16 years (mean ± SD) were studied 50 months (median; range 0–400 months) after a diagnosis of ANCA-associated vasculitis had been made. Sixty-nine patients were treated with 10.7 g (median cumulative dose; range 0.4–67.2g) of CS, and 88 patients were treated with 34.1 g (median cumulative dose; range 0.8–324.3g) of cyclophosphamide. Fifty-seven percent of the patients had osteopenia (T-score: –1 to –2.5 SD), and 21% had osteoporosis (T-score: <−2.5 SD) at least at one site. Thirty-four of 37 (92%) postmenopausal women, 9 of 14 (64%) premenopausal women, and 34 of 48 (71%) men had either osteopenia or osteoporosis. The mean age- and sex-adjusted BMD (Z-score) of the proximal femur in men was found to be significantly lower than zero. Cumulative dose of CS therapy showed an inverse relation with Z-scores at the lumbar spine (p= 0.035) and proximal femur (p = 0.011). Cumulative dose of cyclophosphamide was not correlated with Z-scores. Osteopenia and osteoporosis are thus frequently observed in patients with ANCA-associated vasculities. However, only in men is the mean Z-score significantly lower than zero. Cumulative dose of CS therapy is significantly associated with bone loss at the spine and femur. Received: 26 March 2001 / Accepted: 1 August 2001     

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     

Can the WHO Criteria for Diagnosing Osteoporosis be Applied to Calcaneal Quantitative Ultrasound?

With the increasing number of quantitative ultrasound (QUS) devices in use worldwide it is important to develop strategies for the clinical use of QUS. The aims of this study were to examine the age-dependence of T-scores and the prevalence of osteoporosis using the World Health Organization Study Group criteria for diagnosing osteoporosis and to examine the T-score threshold that would be appropriate to identify women at risk of osteoporosis using QUS. Two groups of women were studied: (i) 420 healthy women aged 20–79 years with no known risk factors associated with osteoporosis; (ii) 97 postmenopausal women with vertebral fractures. All subjects had dual-energy X-ray absorptiometry (DXA) measurements of the spine and hip and QUS measurements on three calcaneal ultrasound devices (Hologic Sahara, Hologic UBA575+, Osteometer DTUone). A subgroup of 102 (76 on the DTUone) healthy women aged 20–40 years was used to estimate the young adult mean and SD for each QUS and DXA measurement parameter to calculate T-scores. The age-related decline in T-scores for QUS measurement parameters was half the rate observed for the bone mineral density (BMD) measurements. The average T-score for a woman aged 65 years was –1.2 for QUS measurements and –1.75 for the BMD measurements. When osteoporosis was defined by a T-score ≤–2.5 the prevalence of osteoporosis in healthy postmenopausal women was 17%, 16% and 12% for lumbar spine, femoral neck and total hip BMD respectively. When the same definition was used for QUS measurements the prevalence of osteoporosis ranged from 2% to 8% depending on which ultrasound device and measurement parameter was used. Four different approaches, based on DXA-equivalent prevalence rates of osteoporosis, were utilized to examine which T-score threshold would be appropriate for identifying postmenopausal women at risk of osteoporosis using QUS measurements. These ranged from –1.05 to –2.12 depending upon the approach used to estimate the threshold and on which QUS device the measurements were performed, but all were significantly lower than the threshold of –2.5 used for BMD measurements. In conclusion, the WHO threshold of T=–2.5 for diagnosing osteoporosis requires modification when using QUS to assess skeletal status. For the three QUS devices used in this study, a T-score threshold of –1.80 would result in the same percentage of postmenopausal women classified as osteoporotic as the WHO threshold for BMD measurements. Corresponding T-score thresholds for individual measurement parameters on the two commercially available devices were –1.61, –1.94 and –1.90 for Sahara BUA, SOS and estimated heel BMD respectively and –1.45 and –2.10 for DTU BUA and SOS respectively Additional studies are needed to determine suitable T-score thresholds for other commercial QUS devices. Received: 25 June 1999 / Accepted: 29 September 1999     

Age-Related Bone Mineral Density, Accumulated Bone Loss Rate and Prevalence of Osteoporosis at Multiple Skeletal Sites in Chinese Women

We investigated the age-related bone mineral density (BMD), accumulated bone loss rate (ABLR) and the prevalence of osteoporosis at different skeletal sites in Chinese women. BMD was measured at the anteroposterior (AP) spine, supine lateral spine (areal BMD at the midarea [mLat] and the whole region [Lat], volumetric BMD at the middle region [MVD] and total region [TVD]), hip (femoral neck [FN], trochanter [Troc] and Ward’s triangle [Ward’s]) and forearm (radius + ulna ultradistal [RUUD], 1/3 region [RU1/3] and total region [RUT]) using a dual-energy X-ray absorptiometry (DXA) fan-beam bone densitometer (Hologic QDR 4500A) in 2702 females aged from 5 to 96 years old. Data were analyzed by eight different regression models. We found that the cubic regression model was the best for describing age-related changes in BMD. The coefficients of determination (R ²) of the fitting curve were 0.398 to 0.612 (p= 0.000). The data were then analyzed by 5-year age groups. This showed that the earliest peak BMD was at the age of 20–24 years at Troc and Ward’s, and the latest at the age of 40–44 years at RU1/3 and RUT of the distal forearm. Compared with BMD, the ABLRs were highest at Ward’s (−66.2%) and the lowest at RU1/3 of the distal forearm (−31.3%) in subjects over 80 years old. The prevalence of osteoporosis at at least one site in these women was 0.5 ± 0.4% in those 30–39, 4.6 ± 4.4% in those 40–49, 23.9 ± 13.3% in those 50–59, 56.3 ± 20.3% in those 60–69, 71.8 ± 16.7% in those 70–79 and 83.2 ± 12.1% those over 80 years of age, respectively. The prevalence of osteoporosis in these women was 8.6–11.1% at the age of 40–49 and 36.5–40.6% at the age of 50–59 at the lateral spine regions (mLat, Lat, MVD and TVD), and 0.5–3.7% at the age of 40–49 and and 3.9–21.7% at the age of 50–59 years at the other skeletal sites (AP, FN, Troc, Ward’s, RUUD, RU1/3 and RUT). Significant differences were found in the prevalence of osteoporosis between the lateral spine regions and other skeletal sites (p<0.001) at the age of 40–59 years. In summary, we demonstrated significant age-related differences in peak BMD, ABLR and osteoporosis prevalence among various skeletal sites. Our data suggest that the supine lateral spine is the most sensitive site for the diagnosis of osteoporosis, especially in the early menopausal period, although the prevalence of osteoporosis varied with age and with different sites measured. Received: 20 November 2001 / Accepted: 13 February 2002     

Allogeneic Bone Marrow Transplantation is Associated with a Preferential Femoral Neck Bone Loss

Osteoporosis is a major complication of organ transplantation. Little is known about the risk of developing osteoporosis in bone marrow transplant (BMT) recipients. We studied early and late changes in bone mineral density (BMD), as well as biochemical markers of bone remodeling, in patients at the time of allogeneic BMT (alloBMT) and up to 13 years thereafter. In a cross-sectional study, 102 patients (40 women, 62 men, mean age ± SEM, 38.9 ± 1.6 years) were segregated into a first group (A, n= 48) and evaluated before or during the first weeks (mean ± SD 0.3 ± 0.1 month, range –0.5 to 3 months) following alloBMT, and a second group (B, n= 54) studied 60.1 ± 5.6 months (range 6–156 months) following alloBMT. Lumbar spine (LS) BMD was similar in groups A and B and was within normal limits. In contrast, femoral neck (FN) Z- and T-scores were significantly decreased in group B compared with group A (–0.68 ± 0.14 vs –0.03 ± 0.14 SD and –0.84 ± 0.14 vs –0.22 ± 0.14 SD, respectively; p≤0.002). Osteopenia (T-score between –1 and –2.5 SD) was present in 35% of group A and 43% of group B patients (NS). Osteoporosis (T-score <–2.5 SD) was detected in 7% of group B patients, but in none of those in group A (p= 0.05). In a longitudinal study, 56 subjects were evaluated at the time of alloBMT, and 33 and 23 were studied 6 or 12 months later, respectively (13 women, 20 men, 37.5 ± 1.6 years). All were treated with supplements of calcium and vitamin D. Amenorrheic women received hormone replacement therapy (HRT). Three-monthly pamidronate infusions were given to 15 men and 10 non-amenorrheic women who were osteopenic/osteoporotic or had elevated baseline bone turnover markers. Mean baseline LS and FN Z- and T-scores were within normal range. Six months after BMT, FN BMD decreased by 4.2 ± 0.7% (p<0.001), and whole body BMD and bone mineral content by 1.5 ± 0.4% and 3.1 ± 0.6%, respectively (p≤0.0001). Twelve months after the graft, there was no further significant bone loss and only FN BMD decrease remained significantly different compared with baseline (–5.6 ± 1.1%, p≤0.0001). These results indicate that the risk of decreased BMD is higher for the femoral neck than the lumbar spine and whole body levels in patients with allogeneic bone marrow transplantation, and that bone loss occurs mainly during the first 6 months after the graft. Received: 9 February 2001 / Accepted: 23 May 2001     

Sex Difference in the Validity of Vertebral Deformities as an Index of Prevalent Vertebral Osteoporotic Fractures: A Population Survey of Older Men and Women

Morphometric methods have been developed for standardized assessment of vertebral deformities in clinical and epidemiologic studies of spinal osteoporosis. However, vertebral deformity may be caused by a variety of other conditions. To examine the validity of morphometrically assessed vertebral deformities as an index of osteoporotic vertebral fractures, we developed an algorithm for radiological differential classification (RDC) based on a combination of quantitative and qualitative assessment of lateral spinal radiographs. Radiographs were obtained in a population of 50- to 80-year-old German women (n= 283) and men (n = 297) surveyed in the context of the European Vertebral Osteoporosis Study (EVOS). Morphometric methods (Eastell 3 SD and 4 SD criteria, McCloskey) were validated against RDC and against bone mineral density (BMD) at the femur and the lumbar spine. According to RDC 36 persons (6.2%) had at least one osteoporotic vertebral fracture; among 516 (88.9%) nonosteoporotics 154 had severe spondylosis, 132 had other spinal disease and 219 had normal findings; 14 persons (2.4%) could not be unequivocally classified. The prevalence of morphometrically assessed vertebral deformities ranged from 7.3% to 19.2% in women and from 3.5% to 16.6% in men, depending on the stringency of the morphometric criteria. The agreement between RDC and morphometric methods was poor. In men, 62–86% of cases with vertebral deformities were classified as nonosteoporotic (severe spondylosis or other spinal disease) by RDC, compared with 31–68% in women. Among these, most had wedge deformities of the thoracic spine. On the other hand, up to 80% of osteoporotic vertebral fractures in men and up to 48% in women were missed by morphometry, in particular endplate fractures at the lumbar spine. In the group with osteoporotic vertebral fractures by RDC the proportion of persons with osteoporosis according to the WHO criteria (T-score <−2.5 SD) was 90.0% in women and 86.6% in men, compared with 67.9–85.0% in women and 20.8–50.0% in men with vertebral deformities by various methods. Although vertebral deformities by most definitions were significantly and inversely related to BMD as a continuous variable in both sexes [OR; 95% CI ranged between (1.70; 1.07–2.70) and (3.69; 1.33–10.25)], a much stronger association existed between BMD and osteoporotic fractures defined by RDC [OR; 95% CI between (4.85; 2.30–10.24) and (15.40; 4.65–51.02)]. In the nonosteoporotic group individuals with severe spondylosis had significantly higher BMD values at the femoral neck (p <0.01) and lumbar spine (p <0.0004) compared with the normal group. On the basis of internal (RDC) and external (BMD) validation, we conclude that assessment of vertebral osteoporotic fracture by quantitative methods alone will result in considerable misclassification, especially in men. Criteria for differential diagnosis as used within RDC can be helpful for a standardized subclassification of vertebral deformities in studies of spinal osteoporosis. Received: 5 February 1999 / Accepted: 24 June 1999     

Long-Term Follow-up of Bone Mass after Orthotopic Liver Transplantation: Effect of Steroid Withdrawal from the Immunosuppressive Regimen

Glucocorticoids have been suggested to play a major role in transplantation-related osteopenia. In this study we assess the long-term changes and the effect of steroid withdrawal from the standard immunosuppressive regimen on bone mineral density (BMD) after orthotopic liver transplantation (OLT). Sixty-nine non-osteoporotic patients (20 women, 49 men), aged 48 ± 9.5 years (mean ± SD), and with a follow-up of 58.3 ± 23.2 months (range 24–121 months) were studied. Immunosuppressive treatment consisted of prednisone, cyclosporin A and azathioprine. In 41 patients (group A), prednisone was tapered and withdrawn after 36.2 ± 19.3 months (range 13–79 months), whereas in 28 patients (group B) prednisone was maintained. BMD in the spine (L1–L4) was serially measured by dual-energy X-ray absorptiometry (Hologic QDR 1000w) at baseline, before steroid withdrawal and at the end of study. Age- and sex-matched Z-scores of BMD were calculated. No differences were found in age, body mass index, time since OLT, or baseline BMD between the two groups. BMD had significantly increased in both groups at the end of follow-up period (group A, +8.1 ± 8.7%; group B, +3.2 ± 8.0%, p<0.05). However, the Z-score was significantly higher in group A than in group B at the end of study (–0.44 ± 1.05 vs –0.99 ± 0.77; p<0.05). BMD recovery was lower in pre-OLT biliary cirrhosis patients. Bone mass improvement was independent of the time since OLT in both groups, and of the time of steroid withdrawal in group A. Our data confirm that steroid withdrawal accelerates the recovery of bone mass in patients who have undergone a successful liver transplantation. Received: 17 April 2001 / Accepted: 1 August 2001     

Pregnancy-Associated Osteoporosis: Does the Skeleton Recover?

Osteoporosis in pregnancy is a rare clinical problem of unknown cause. If the bone loss results from the pregnancy alone it should improve toward normal after delivery; in contrast, where bone density was low before pregnancy, due to some other secondary cause, significant postpartum improvement might not be expected. Thirteen women (age 23–37 years) with pregnancy-associated osteoporosis presenting with either pain in the back and vertebral collapse (8 subjects) or pain in the hip (5 subjects) had consecutive dual-energy X-ray absorptiometry measurements of bone mineral density (BMD) for up to 8 years after an affected pregnancy. The BMD results were expressed as a Z-score in relation to an age-matched mean. The mean initial (0–6 months postpartum) BMD was low in both groups and at both sites. In the back pain group the mean spine Z-score (L1–L4) was –3.34 (range –2.25 to –4.66) and mean total hip Z-score was –2.41 (range –1.44 to −3.82). In the hip pain group the mean spine Z-score was –2.00 (range –1.48 to –2.65) and mean hip Z-score was –2.19 (range –1.12 to –3.26). Subsequent mean hip and spine BMD increased significantly toward the lower end of the normal range. We conclude that a reversible part of the bone loss is related to the pregnancy itself. A low BMD before pregnancy cannot be excluded. Knowledge that the bone density increases after an affected pregnancy, combined with the known rarity of recurrent symptoms in subsequent pregnancies, is important in prognosis. Received: 29 June 1999 / Accepted: 16 November 1999     

Treatment of Postmenopausal Women with Osteoporosis or Low Bone Density with Raloxifene

Raloxifene, a selective estrogen receptor modulator (SERM), has been shown to improved bone mineral density (BMD) and serum lipid profiles in healthy postmenopausal women. The objective of this study was to examine the effects of raloxifene on BMD, biochemical markers of bone metabolism and serum lipids in postmenopausal women with low bone density or osteoporosis. This Phase II, multicenter, 24-month, double-masked study assessed the efficacy and safety of raloxifene in 129 postmenopausal women (mean age ± SD: 60.2 ± 6.7 years) with osteoporosis or low bone density (baseline mean lumbar spine BMD T-score: −2.8). Women were randomly assigned to one of three treatment groups: placebo, 60 mg/day raloxifene-HCl (RLX 60) or 150 mg/day raloxifene-HCl (RLX 150) and concomitantly received 1000 mg/day calcium and 300 U/day vitamin D₃. At 24 months, BMD was significantly increased in the lumbar spine (+3.2%), femoral neck (+2.1%), trochanter (+2.7%) and total hip (+1.6%) in the RLX 60 group compared with the placebo group (p<0.05). The RLX 150 group had increases in BMD similar to those observed with RLX 60. A greater percentage of raloxifene-treated patients, compared with those receiving placebo, had increased BMD (p<0.05). Serum bone-specific alkaline phosphatase activity, serum osteocalcin, and urinary type I collagen:creatinine ratio were significantly decreased in the RLX-treated groups, compared with the placebo group (p<0.01). RLX 60 treatment significantly decreased serum levels of triglycerides, and total- and LDL-cholesterol levels (p<0.01). The rates of patient discontinuation and adverse events were not significantly different among groups. In this study, raloxifene increased bone density, decreased bone turnover, and improved the serum lipid profile with minimal adverse events, and may be a safe and effective treatment for postmenopausal women with osteoporosis or low bone density. Received: 26 December 1998 / Accepted: 31 March 1999     

Prophylactic Use of Alfacalcidol in Corticosteroid-Induced Osteoporosis

One hundred and forty-five patients suffering from diseases requiring long-term treatment with high doses of corticosteroids (30 mg/day or greater of prednisolone) were recruited to the study. Patients had to be steroid naive on entry to the study (not more than 15 days of treatment with a corticosteroid within the previous 24 months). Patients were randomized to receive either 1 mg/day alfacalcidol or placebo capsules for 12 months. Bone mineral density (BMD) of the lumbar spine was assessed by dual-photon absorptiometry on entry and after 3, 6 and 12 months’ treatment. Safety was monitored by the recording of all adverse events reported by patients and the regular screening of blood samples for hematology and serum biochemistry. Of the 145 patients, 74 were randomized to alfacalcidol and 71 to placebo. The treatment groups were well matched at baseline with no significant differences in demographic, clinical or biochemical parameters. The mean equivalent dose of prednisolone at baseline was 46.6 mg/day and 46.3 mg/day for the alfacalcidol and placebo group respectively. From the 145 patients randomized to treatment, 71 (38 who received alfacalcidol and 33 who received placebo) provided BMD data both at baseline and at 3, 6 and 12 months. The percentage change in BMD after 6 months’ treatment was –2.11% in the alfacalcidol group and –4.00% in the placebo group (p= 0.39). After 12 months the percentage change in BMD was +0.39% (CI: –4.28 to 4.81) in the alfacalcidol group and –5.67% (CI: –8.13 to –3.21) in the placebo group, this difference (6.06%, CI: 0.88 to 11.24) being statistically significant (p= 0.02). An intention to treat analysis also showed a significant difference between the two treatment groups in alfacalcidol’s favor (3.81%, p= 0.01; CI: 0.92 to 6.70). There was no significant difference between the two treatment groups in the corticosteroid dose at any time point during the study. Serum calcium was measured throughout and there were no significant differences between the two treatment groups at any visit. This study suggests that alfacalcidol can prevent corticosteroid-induced bone loss from the lumbar spine. Long-term use of alfacalcidol was not associated with any significant adverse effects in this diverse group of patients. Received: 22 May 1997 / Accepted: 27 April 1998     

Short-Term Increases in Bone Turnover Markers Predict Parathyroid Hormone-Induced Spinal Bone Mineral Density Gains in Postmenopausal Women with Glucocorticoid-Induced Osteoporosis

The purpose of this study was to test the ability of early changes in markers of bone turnover to predict subsequent changes in bone mineral density (BMD) induced by parathyroid hormone fragment, PTH (1–34), in postmenopausal osteoporotic women treated with estrogen and glucocorticoids. Forty-nine postmenopausal women with chronic, inflammatory diseases and BMD T-scores ≤–2.5 at the lumbar spine or femoral neck who were concurrently treated with estrogen ≥ 1 year and prednisone 5–20 mg/day for ≥ 1 year participated. Subjects were randomized to treatment with human PTH (1–34) 400 IU/day or to a control group for 1 year and followed for an additional year. Serum and urine were collected at baseline and 1, 3, 6, 9, 12, 18 and 24 months for measurement of bone alkaline phosphatase (BAP), osteocalcin (OC) and deoxypyridinoline (DPD). We constructed an Uncoupling Index (UI) from all three markers (UI = [Z _BAP+Z _OC]/2 –Z _DPD, where the Z-score for each marker in each subject was calculated from the mean and standard deviation of the study population at baseline). BMD of the lumbar spine and hip was measured at baseline and every 6 months thereafter by dual-energy X-ray absorptiometry (DXA) and annually by quantitative computed tomography (QCT; spine only). BMD of the spine, but not hip (total, femoral neck or trochanter), and levels of all three markers increased significantly as a result of PTH treatment (p<0.01 compared with controls). The resorption response lagged behind that of formation as evidenced by a significant increase (p<0.05) in the UI for the first 9 months of treatment. The UI values and changes from baseline to 1, 3 and 6 months in BAP, OC and DPD were correlated with the 12- and 24-month changes in spine BMD measured both with QCT and with DXA (Spearman’s rank coefficients ≤0.76; p<0.05). Most PTH-treated subjects could be identified as biochemical responders by least significant change analysis. Following 1 month of therapy, BAP and OC identified 65% and 81% as responders, respectively. The responder rates were 79%, 79% and 75% for BAP, OC and DPD, respectively by 6 months. Responders exhibited a high level of diagnostic accuracy for predicting a gain in BMD (areas under the receiver operating characteristic curves exceeding 0.79 for QCT and 0.70 for DXA), but not the magnitude of the gain. These data suggest that serial bone marker measurements may be useful in identifying skeletal responders to an anabolic therapy, such as PTH, in estrogen-replete postmenopausal women with glucocorticoid-induced osteoporosis. Received: 27 July 1999 / Accepted: 2 November 1999     

Daily treatment with parathyroid hormone is associated with an increase in vertebral cross-sectional area in postmenopausal women with glucocorticoid-induced osteoporosis

 Daily treatment with hPTH (1–34) is associated with a significant increase in bone formation which results in large gains in lumbar spine bone mass. However, bone formation is known to occur on trabecular, endocortical and periosteal surfaces. The purpose of this study was to determine whether daily treatment with hPTH (1–34) for 1 year was associated with a change in vertebral cross-sectional area, or vertebral size, as measured by serial quantitative computed tomography scans. Fifty-one postmenopausal women treated chronically with both glucocorticoids and hormone replacement therapy (HRT) were randomized to either daily hPTH (1–34) for 1 year and HRT or to a control group treated with only HRT. Measurements of bone density of the spine were obtained every 6 months by dual-energy X-ray absorptiometry (DXA) and annually by QCT of the L1 and L2 vertebrae. Vertebral cross-sectional area (VCSA) was obtained from the QCT scans. In addition, we estimated the vertebral compressive strength (VSFOM, g²/cm⁴ = trabecular BMD² × VCSA). After 1 year of hPTH (1–34) treatment, VCSA increased 4.8% (p < 0.001), and 1 year after treatment was discontinued VCSA was still 2.6% higher than the baseline value (p < 0.05). The control group had no change in VCSA. In addition, estimated vertebral compressive strength increased more than 200% over baseline levels in the hPTH (1–34) treatment group and no change was observed in the control group. In summary, daily treatment with hPTH (1–34) for 1 year increased vertebral size as measured by VCSA and this increase was maintained after hPTH (1–34) was discontinued. Since vertebral fracture risk is related to both bone size and bone mass, we cautiously speculate that the increase in vertebral size associated with hPTH (1–34) treatment is at least partially responsible for increased vertebral bone strength and reduction of fracture risk associated with this therapy in postmenopausal osteoporosis. Received: 26 March 2002 / Accepted: 9 August 2002 Acknowledgement This work was supported by Public Health Service Grants 1-R01-46661, and the Rosalind Russell Arthritis Research Center.     

Association of a G2014A Transition in Exon 8 of the Estrogen Receptor-α Gene with Postmenopausal Osteoporosis

We report the association of a newly identified synonymous G2014A single nucleotide polymorphism (SNP) which does not alter the amino acid sequence in exon 8 of the estrogen receptor-α (ERα) gene with osteoporosis in Thai postmenopausal women. Subjects consisted of 228 postmenopausal women aged more than 55 years divided into two groups – with vertebral or femoral osteoporosis (n= 106) or without osteoporosis (n= 122) – according to bone mineral density (BMD) criteria. The exon 8 G2014A SNP, which is 6 nucleotides upstream from the end of the stop codon, was identified by PCR-RFLP. Data are expressed as the mean and 95% CI. The allele frequency of the G2014A polymorphism was 26.4% in osteoporotic subjects and was significantly higher than that in non-osteoporotic women (15.2%) (p<0.05). By stepwise logistic regression analysis, it was found that the G2014A polymorphism was related to the presence of osteoporosis (odds ratio 2.7 per A allele, 95% CI 1.49–4.76) independently of body weight (odds ratio 0.93 per kg, 95% CI 0.89–0.96) and years since menopause (odds ratio 1.12 per year, 95% CI 1.08–1.19). In a multiple linear regression model, L2–L4 BMD of osteoporotic subjects was associated with body weight (p<0.05), endogenous estradiol levels (p<0.05) and the G2014A genotype (p<0.001), while it was related only to body weight (p<0.05) and estradiol levels in non-osteoporotic women (p<0.05). We conclude that a G2014A SNP in exon 8 of ERα is associated with the presence and severity of postmenopausal osteoporosis. Linkage disequilibrium between this polymorphism and the 3′-untranslated region of the ERα gene which may participate in the regulation of ERα gene expression remains to be determined. Received: 17 October 2000 / Accepted: 11 June 2001     

The Role of Serum TGF-β Isoforms as Potential Markers of Osteoporosis

Osteoporosis is a major public health problem characterized by low bone mineral density (BMD) that presently has no biochemical test useful for its diagnosis. The cytokine TGF-β has been postulated to play a role in controlling bone density by regulating the fine balance between bone matrix deposition by osteoblasts and its resorption by osteoclasts. We explored whether measurement of serum levels of different TGF-β isoforms could be useful as a clinical tool in osteoporosis. We measured the concentration of TGF-β1 antigen using the BDA19 capture sandwich enzyme-linked immunosorbent assay (ELISA), TGF-β2 antigen concentration using a Quantikine sandwich ELISA kit and TGF-β3 antigen concentration using a modified version of the TGF-β1 Quantikine sandwich ELISA kit. Subjects were 41 women with osteoporosis (with nontraumatic vertebral fracture or lumbar spine BMD Z-score <−1.5 SD) and a total of 199 control women from different sources. Serum concentrations of TGF-β1 and TGF-β2 were similar in all groups. However, detectable levels of TGF-β3 (>0.2 ng/ml) were found in 35 of 41 patients with osteoporosis (median 7.2 (5.2–8.9) ng/ml) compared with 11 of 36 controls or 24 of 89 healthy women of unknown bone density. Differences among the groups could not be accounted for by age, weight, medications, use of hormone replacement therapy or the presence of osteoarthritis. Using the optimal cut-off of ≥2 ng/ml, the test was able to detect an individual with low spine BMD (Z-score <−1.5) with a sensitivity of 84% and a specificity of 53%, with similar results for the femoral neck. The odds ratio for osteoporosis associated with a positive test at this level was 5.93 (95% CI 2.41–11.59), and 4.1 (95% CI 1.66–10.11) using the WHO cut-off of T-score <−2.5. Serum TGF-β3 concentration is raised in osteoporotic women and the test appears to have potential as a marker for osteoporosis. The underlying mechanisms and the relationships between TGF-β3 and bone turnover and fractures remain to be explored. Received: 4 April 1998 / Accepted: 21 September 1998     

Regular Physical Exercise and Bone Mineral Density: A Four-Year Controlled Randomized Trial in Middle-aged Men. The DNASCO Study

The aim of the study was to investigate the effects of regular aerobic exercise training on bone mineral density (BMD) in middle-aged men. A population based sample of 140 men (53–62 years) was randomly assigned into the exercise and reference groups. BMD and apparent volumetric BMD (BMD_vol) of the proximal femur and lumbar spine (dual-energy X-ray absorptiometry, DXA) and anthropomorphic measurements were performed at the randomization and 2 and up to 4 years later. The participation rate was 97% and 94% at the second and third BMD measurements, respectively. As another indication of excellent adherence and compliance, the cardiorespiratory fitness (aerobic threshold) increased by 13% in the exercise group. The 2% decrease in the reference group is regarded as an age-related change in cardiorespiratory fitness. Regardless of the group, there was no association between the increase in aerobic threshold and change in BMD. In the entire group, age-related bone loss was seen in the femoral neck BMD and BMD_vol (p<0.01). BMD and BMD_vol values increased with age in L2–L4 (p<0.004). An increased rate of bone loss at the femoral neck was observed in men with a low energy-adjusted calcium intake (p = 0.003). Men who increased their alcohol intake during the intervention showed a decrease in the rate of bone loss at the femoral neck (p = 0.040). A decrease in body height associated with decreased total femoral BMD (r= 0.19, p = 0.04) and the change in body height was a predictor of bone loss in the femoral neck (β= 0.201). Long-term regular aerobic physical activity in middle-aged men had no effect on the age-related loss of femoral BMD. On the other hand, possible structural alterations, which are also essential for the mechanical strength of bone, can not be detected by the DXA measurements used in this study. The increase seen in lumbar BMD reflects age-related changes in the spine, thus making it an unreliable site for BMD follow-up in men. Received: August 2000 / Accepted: November 2000     

Intermittent Oral Disodium Pamidronate in Established Osteoporosis: A 2 Year Double-Masked Placebo-Controlled Study of Efficacy and Safety

The effect of oral pamidronate on bone mineral density and its adverse effect profile was investigated by a double-masked placebo-controlled study of 122 patients aged 55–75 years with established vertebral osteoporosis. Patients on active therapy received disodium pamidronate 300 mg/day (group A) for 4 weeks every 16 weeks, 150 mg/day (group B) for 4 weeks every 8 weeks or placebo (group C). All patients additionally received 500 mg of calcium and 400 IU vitamin D daily. Dual-energy X-ray absorptiometry measurements of the spine, hip, forearm and total body were performed at baseline and 6-monthly for 2 years using a Hologic QDR 1000 device at two sites. Serum osteocalcin and urinary deoxypyridinoline were measured at the above visits and at 3 months. The percentage change (SEM) in spine bone mineral density (BMD) at 2 years based on intention-to-treat analysis was 4.64 (1.01) in group A, 6.10 (0.87) in group B and 1.13 (1.32) in group C. Analysis of variance showed significant increases in group A and B compared with placebo (p<0.01). There were also significant rises in femoral neck BMD for group A (p = 0.005), trochanter BMD for groups A and B (p<0.01) and total-body BMD for groups A and B (p<0.001). There was a significant reduction in serum osteocalcin and urinary deoxypyridinoline for groups A and B (p<0.01). There was an excess of gastrointestinal side-effects in the treated groups, particularly group A. We conclude that intermittent pamidronate therapy can prevent bone loss at both the lumbar spine and femoral neck in patients with established vertebral osteoporosis, although due to gastrointestinal side-effects the 300 mg dose in particular does not appear suitable for clinical usage. Received: 12 January 1999 / Accepted: 30 August 1999     

Inappropriate Reference Range for Peak Bone Mineral Density in Dual-energy X-ray Absorptiometry: Implications for the Interpretation of T-scores

An inappropriate reference range for peak bone mineral density (BMD) may result in identification of an incorrect proportion of subjects with osteopenia and osteoporosis at dual-energy X-ray absorptiometry (DXA). In this study, we assessed the prevalence of low BMD in Turkish young adults with respect to local population reference range T-scores and the US reference range T-scores. The BMD values of lumbar spine (L1–L4) and proximal femur (femoral neck, intertrochanter, trochanter, Ward”s triangle and total) were measured by DXA in 323 healthy young adults (171 women, 152 men) aged 19–25 years. The World Health Organization criteria for the diagnosis of osteopenia (−2.5 <T-score <−1) and osteoporosis (T-score ≤−2.5) were applied. In women, the means of the US reference range T-scores were significantly lower than zero at the spine and proximal femoral sites (p<0.0001). In men, the means of the US reference range T-scores were significantly lower than zero at the spine, femoral neck, intertrochanter, total femur (p<0.0001) and trochanter (p<0.05), but not at Ward”s triangle (p=0.92). When the diagnoses were based on local population reference range T-scores instead of the US reference range T-scores, the prevalence of low BMD (T-score <−1) in women fell from 50.3% to 14.0% at the lumbar spine and from 60.8% to 14.6% at the femoral neck, and in men from 42.8% to 15.8% at the lumbar spine and from 30.9% to 17.1% at the femoral neck. Our data suggest that individual populations should use their own reference range T-scores to avoid misdiagnoses of osteopenia and osteoporosis by DXA. Received: 4 November 1999 / Accepted: 29 March 2000     

Age and Sex Differences in the Bone Mineral Density of the Distal Forearm Based on Health Check-up Data of 6343 Japanese

Bone mineral density (BMD) predicts osteoporotic fractures. The incidence of osteoporotic fractures in Japan is lower than among Caucasians, but fewer data on the BMD of Asians have been reported. This study attempted to clarify the age and sex differences in the forearm BMD of healthy adult Japanese and to assess racial differences between Japanese and Caucasians. The subjects were 6343 healthy adult Japanese (5281 females, 1062 males) who underwent a health check-up at a health care service center between February 1995 and August 1999. Subjects’ age ranged from 15 to 80 years. The BMD of the distal radius and ulna of the non dominant forearm was measured by dual-energy X-ray absorptiometry. Overall, the forearm BMD of men was greater than that of women in all age groups. Peak BMD was 0.484 g/cm² in the 40–44 year age group of women and 0.590 g/cm² in the 30–34 year age group of men. The forearm BMD of women under 50 years of age (the average age at menopause) increased slightly with age (2.0%/decade, p<0.0001), but it did not among their male counterparts. After 50 years of age, BMD of the women decreased linearly (–1.6%/year, p<0.0001) with age, the rate of decrease being 1.7-fold faster than in their male counterparts. Rates of gain and loss of forearm BMD differ between the sexes. In comparison with data previously reported, we did not find any evidence of racial differences in BMD as an explanation for the lower incidence of osteoporotic fractures in Japan. Received: 23 November 1999 / Accepted: 17 March 2000