Change In Spine Bone Mineral Density Research Articles

Bone mineral density reference norms for Hong Kong Chinese

The aim of this study was to establish bone mineral density (BMD) reference norms for Hong Kong Chinese using Hologic QDR 2000 and 4500 densitometers, and to estimate the prevalence of osteoporosis in the population. Altogether, 4,274 subjects (2,415 females and 1,859 males), aged 9-94 years old, were recruited using a combination of private solicitation and public advertising from schools, community centers, nursing homes, housing estates, and the general community in Hong Kong. Among females, BMD increased by 20% at the total hip and 48% at the lumbar spine between ages 10 and 20 but remained essentially constant between ages 20 and 40. Between ages 40 and 70, BMD declined by 17% at the total hip and 23% at the spine. Total hip BMD continued to drop after age 70 but little change in spine BMD was observed. Among males, BMD increased by 45% at the total hip and 77% at the spine between age 10 and 30. Between ages 30 and 80, total hip BMD decreased by 20%. Lumbar spine BMD decrease was milder, showing a loss of 4% between ages 30 to 50 and remaining relatively constant afterwards. The prevalence of osteoporosis was consistently overestimated when using Hologic-supplied Caucasian cutoffs as compared with local Chinese cutoffs. The prevalence of osteoporosis among Chinese women 50 years or older was 37% and 16% at the spine and total hip, respectively, while that among Chinese men 50 years or older was 7% and 6% at the spine and total hip, respectively. Prior studies have been limited by size or restricted to women. This study represents the largest sample of Hong Kong Chinese amassed to date, provides continuous BMD reference values from ages 10 to 85 for both women and men, and yields more reliable estimates of the prevalence of osteoporosis for the population.

Oral clodronate maintains bone mass in women with primary breast cancer

535 Background: Breast cancer treatments commonly suppress oestrogen levels, accelerate bone loss and increase osteoporosis risk. As hormone replacement is contraindicated, bisphosphonates provide useful alternatives. Oral clodronate (Bonefos) 1600mg reduced the incidence of skeletal metastases and improved overall survival in a double-blind placebo-controlled study of 1069 women with primary breast cancer. We compared the effects of clodronate on spine and hip bone mineral density (BMD) during treatment and over a further 3-year follow-up period. Methods: BMD was measured by dual x-ray absorptiometry (Hologic QDR1000, Bedford, MA) in 498 women at first diagnosis of breast cancer (n=243 and 255 for clodronate and placebo respectively). The effects were estimated by computing annual rates of change in BMD. Results: Over 2 years of treatment, clodronate significantly increased the mean BMD at the spine and total hip while patients in the placebo group demonstrated a significant decrease at both sites (mean between group differences of +0.016, 95%CI 0.010–0.021g/cm2, p<0.0001 for spine and +0.006, 95%CI 0.002–0.010g/cm2, p=0.004 for total hip BMD). During the 3 years of follow-up off treatment, a statistically significant but similar decrease in BMD was observed for both clodronate and placebo groups at all sites. The mean between group difference for annual change in spine BMD was −0.001g/cm2 (95%CI −0.004–0.001, p=0.22) while that for the total hip was 0g/cm2 (95%CI −0.002 −0.002). There were no cases of osteonecrosis. Conclusions: During 2 years of treatment, oral clodronate 1600mg daily has a protective effect on spine and hip bone mass as judged by effects on BMD. After discontinuation, rates of bone loss are similar to, but not greater than, those in placebo-treated women so that at 5 years women previously treated with clodronate still have significantly higher BMD. There may be increased benefit from a longer treatment with clodronate. The optimum duration of treatment with clodronate to protect the skeleton and reduce skeletal metastases remains to be determined. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Berlex/Schering AG, Eli Lilly, Pfizer, Roche AstraZeneca, Berlex/Schering AG, Eli Lilly, Pfizer, Roche, Schering AG Schering AG

Is there Any Interest in Combining Treatments in Osteoporosis?

Combination therapy includes the concomitant or sequential use of compounds sharing the same mode of action (e.g. two or more inhibitors of bone resorption) or with distinct pathways of activity (e.g. an inhibitor of resorption plus an anabolic agent). Combinatorial use of anti-resorptive agents may generate concerns, due to the risk of inducing oversuppression of bone turnover. However, if low doses of estrogen, used for the management of climacteric symptoms, are insufficient to normalize bone turnover, an addition of a bisphosphonate to HRT can prove to be useful to achieve this objective. Patients pre-treated with inhibitors of resorption, who have no full therapeutic response, are good candidates for the treatment with anabolic agents. The increase in bone turnover that follows the introduction of parathyroid hormone in patients treated with an anti-resorptive agent is similar to that observed in treatment-naive patients and the pattern of bone mineral density (BMD) increase is also identical, with the exception of a 6-month delay in the spine and hip BMD changes observed in prior alendronate-treated subjects. Current data discourage the concomitant use of alendronate and parathyroid hormone since the bisphosphonate appears to blunt, in men and women, the anabolic action of parathyroid hormone. Whether this also applies to other bisphosphonates or inhibitors of resorption remains unknown. The use of an inhibitor of bone resorption after completion of parathyroid hormone treatment seems an appropriate way to maintain the skeletal benefits gained during therapy. Longterm clinical studies, using fractures as an end-point should be initiated to better understand the clinical and pharmaco-economic interest of combination therapies in the management of osteoporosis.

Risk of fracture among women who lose bone density during treatment with alendronate. The Fracture Intervention Trial

It is commonly believed that the response to treatment in patients on alendronate is proportional to the increase in bone mineral density (BMD), and that those who lose BMD during treatment might not respond to treatment. In the Fracture Intervention Trial 6,459 women were randomly assigned to treatment with alendronate or placebo; BMD was measured annually, and new spine fractures were assessed by lateral spine films, taken at baseline and end of follow-up. Among subjects who took at least 70% of the study drug (5,220 women), we compared reductions in risk of spine fractures at end of follow-up (3 or 4 years) within various levels of change in total hip and spine BMD after 1 and 2 years of treatment, after adjustment for differences in characteristics between the treatment and control groups. Women "losing" BMD at the lumbar spine (0% to 4%) while on alendronate had a reduction of 60% in vertebral fracture risk [OR = 0.40 (0.16, 0.99)] compared to their counterparts in the placebo group. The few women that lost more than 4% did not have a significant benefit [OR = 0.15 (0.02, 1.29)]. Those who "gained" BMD (0% to 4%) during treatment had a reduction in risk of 51% [OR = 0.49 (0.30, 0.78)]. Similarly, women who "lost" total hip BMD (0% to 4%) during the first year on alendronate had a 53% decreased risk of vertebral fracture compared to their controls taking placebo [OR = 0.47 (0.27, 0.81)], whereas those "gaining" BMD (0% to 4%) had a comparable risk reduction [OR = 0.49 (0.34, 0.71)]. This was not observed for the few women who lost more than 4% [OR = 0.61 (0.11, 3.45)]. Patients who lost BMD at both the hip and spine were not protected by alendronate. Among patients who adhere to treatment with alendronate, even those who lose BMD benefit from a substantial reduction in risk of vertebral fracture. So, the reduction in bone turnover induced by alendronate might be more important than BMD changes. The few women who lose the most BMD (more than 4% per year) might not benefit from the treatment.

Combination/sequential therapy in osteoporosis

Combination therapy includes the concomitant or sequential use of compounds sharing the same mode of action (eg, two or more inhibitors of bone resorption) or with distinct pathways of activity (eg, an inhibitor of resorption plus an anabolic agent). Combination use of antiresorptive agents may generate concerns, because of the risk of inducing oversuppression of bone turnover. However, if low doses of estrogen, used for the management of climacteric symptoms, are insufficient to normalize bone turnover, the addition of a bisphosphonate to hormone therapy may prove to be useful to achieve this objective. Patients pretreated with inhibitors of resorption, who have not achieved a full therapeutic response, are good candidates for treatment with anabolic agents. The increase in bone turnover that comes after the introduction of parathyroid hormone (PTH) in patients treated with an antiresorptive agent is similar to that observed in treatment-naïve patients and the pattern of bone mineral density (BMD) increase is also identical, with the exception of a 6 month delay in the spine and hip BMD changes observed in prior alendronate-treated subjects. Current data discourage the concomitant use of alendronate and PTH since the bisphosphonate appears to blunt (in men and women) the anabolic action of PTH. Whether this applies to other bisphosphonates or inhibitors of resorption, remains unknown. The use of an inhibitor of bone resorption after completion of PTH treatment seems an appropriate way to maintain the skeletal benefits gained during therapy. Long-term clinical studies, using fractures as an endpoint should be initiated to better understand the clinical and pharmaco-economic interest of combination therapies in the management of osteoporosis.

Bone mineral density in patients with prostate cancer without bone metastases treated with intermittent androgen suppression

Objectives To evaluate prospectively the effects of intermittent androgen suppression (AS) on bone mineral density (BMD) in patients with prostate cancer without bone metastases. Methods A total of 19 hormone-naive patients with Stage D0 disease were treated with a luteinizing hormone-releasing hormone analog and an antiandrogen for 9 months, after which AS was discontinued. When the prostate-specific antigen level reached a predetermined threshold, AS was restarted. BMD was measured at baseline, after 9 months of AS, and at the end of the first off-treatment period or at 1 year, whichever occurred first. Results Of the 19 patients, 17 had normal BMD at baseline; 2 patients with osteopenia at baseline were excluded from the analysis. All but 1 of the 17 patients with normal baseline BMD experienced a decline in BMD in the lumbar spine or hip, or both, during AS. After 9 months, the mean BMD in these patients had decreased by 4.5% at the lumbar spine ( P = 0.0007) and by 2.5% at the hip ( P = 0.00013). After a median off-treatment period of 7.9 months, the mean change in BMD of the lumbar spine and hip relative to the post-AS values was 1.5% ( P = 0.06) and −0.01% ( P = 0.09), respectively. Conclusions The observed loss of BMD during 9 months of AS is significantly greater than the expected 0.5% to 1% annual loss. Interruption of AS attenuated the rate of bone loss, although full recovery to the baseline BMD was not achieved in all patients. These data suggest that men treated with AS should undergo baseline and periodic follow-up BMD assessments, because significant bone loss can occur during the first 9 months of AS.

Prevalence of osteoporosis in men and determinants of changes in bone mass in a non-selected Spanish population.

Osteoporotic studies conducted exclusively in men have been limited by the discrepancies in defining densitometric osteoporosis and, also, because osteoporosis has traditionally been associated only with women. The aims of this study were to describe the prevalence of low bone mineral density (BMD) and osteoporotic fractures as well as the rate of bone loss. The analysis of some risk factors for accelerated bone loss was also evaluated. Men aged 50 years and over, randomly selected from the Oviedo municipal register (n = 308), completed a questionnaire regarding risk factors related to osteoporosis; they underwent two lateral radiographs of the dorsal and lumbar spine and a dual X-ray absorptiometry (DXA) study at the lumbar spine and hip. In the 4th year of the follow-up period, participants were invited to undergo repeats of the same tests that had been carried out in the initial study. The prevalence of densitometric osteoporosis in men older than 50 years, standardized by age, was 8.1% with regard to at least one of the four studied bone areas, with a slight increase with age. The prevalence of osteoporotic fracture, standardized by age, was 24.4%, with a marked increase with age. Osteoporotic prevalent fracture was independently associated only with the rate of change in lumbar spine BMD. From all the osteoporotic risk factors analyzed, only low milk consumption and regular smoking were independently associated with loss of bone mass. In summary, prevalent osteoporotic fracture was independently associated with the rate of change in the lumbar spine BMD but not in the other segments studied. Avoiding smoking and ensuring an adequate milk intake might prevent the loss of bone mass in men.

Hormone Replacement Therapy and Resistance Training Effect on the Musculoskeletal System in Early Postmenopausal Women.

0757 Evidence suggests that hormone replacement therapy (HRT) in combination with resistance training may promote greater increases in bone mass (BMD) and strength than either resistance training or HRT alone. PURPOSE: To investigate the interactive effects of HRT and a 1-yr site-specific resistance-training program (two free weight exercises squat and deadlift) two days per week a strategy to increase strength and reverse or attenuate accelerated bone loss at the spine in early postmenopausal women. METHODS: Participants from a group of self selected HRT or no-HRT (n = 148) early postmenopausal women were randomly assigned to either 1) no HRT plus resistance training (n = 28); 2) HRT plus resistance training (n = 33); 3) HRT no resistance training (n = 32); or 4) control (no HRT no resistance training group (n = 29). Mean age and months post menopause did not differ between groups (52.1 + 3.0 yr and 25.8 + 9.9 months, respectively). Body composition and bone mineral density (BMD) of the spine were assessed by Dual Energy X-Ray Absorptiometry (Hologic), and upper and lower body peak force by isokinetic dynamometry (KinCom 500H, Chattex Corp.), at baseline and month 12. Data were analyzed using a 4 (group: no HRT plus exercise, HRT plus resistance training, HRT no resistance training, no HRT no resistance training) × 2 (time: baseline and month 12) repeated measures multivariate analysis of variance. Multivariate analysis revealed main effects for group (P <. 007), time, (P <. 001), and the group by time interaction (P <. 001) (Table 1). RESULTS: One year of resistance training produced changes in spine BMD of + 0.43% and + 0.56%, lower body strength of + 35.4% and + 25.4%, upper body strength of + 37.3% and + 41.1% and lean mass of +3.9% and + 4.2% for the no HRT plus resistance training and HRT plus resistance training groups, respectively. In contrast, women in the HRT no resistance training and no HRT no resistance training experienced declines in spine BMD of −1.4% and −3.6%, lower body strength of – 2.2% and −7.1%; respectively, and increases in upper body strength of + 11.8% and + 7.8%, and lean mass of + 2.6% and +1.2% respectively. CONCLUSION: Regardless of HRT status, free weight squats and deadlifts performed two days per week reversed bone loss at the spine. Moreover, resistance training was more effective than hormone replacement therapy in preventing bone loss at the spine and increasing lower and upper body strength and lean mass in Vol. 36 No. 5 Supplement this group of early postmenopausal women. Funded by: American Federation for Aging Research and Erkkila Foundation

Compliance with pharmacologic therapy for osteoporosis.

There is little information available concerning compliance with pharmacologic therapy for osteoporosis in the usual care setting. We evaluated 176 consecutive, previously untreated women whose physicians initiated treatment for osteoporosis following a bone mineral density (BMD) test obtained as part of routine medical practice. All patients were contacted >/=1 year after the initial BMD test and offered a follow-up BMD. Compliance with therapy was defined as the percent of time that a patient filled a prescription for osteoporosis treatment. Ninety-three (53%) patients received estrogen (ERT), 93 (53%) bisphosphonates, 8 (5%) calcitonin, and 17 (10%) received more than one therapy. Ninety-one of the 176 (52%) agreed to a follow-up BMD at a mean of 590 days after the first study (participants); 85 declined a follow-up BMD (refusers). Participants and refusers were similar for age, treatment patterns, and compliance with therapy. For all patients, compliance for those given bisphosphonate was similar to those given ERT (70.7% (95% CI 63.5-77.9%) versus 69.2% (95% CI 61.7-76.8%). For participants, the change in spine BMD was similar for those treated with bisphosphonate [mean increase 3.53 (+/-2.64)%/year (mean+/-SD)] and those treated with ERT [mean increase 3.00 (+/-2.75)%/year]. For those participants whose compliance with therapy was >/=66%, the mean increase in spine bone density was 3.80 (+/-2.59)%/year compared to 2.11 (+/-2.64)%/year ( p<0.005) for those whose compliance was <66%. Compliance with ERT and bisphosphonate therapy initiated in routine practice after a BMD was similar over a mean of 590 days. Compliance less than 66% with drug treatment results in suboptimal improvement in bone density.

Surrogates for fracture endpoints in clinical trials.

Surrogates for fracture endpoints in clinical trials.

Vitamin D supplementation and bone mineral density in early postmenopausal women

Increased vitamin D intake may preserve or increase bone mineral density (BMD) in older persons. A 2-y double-blind study was undertaken to determine whether weekly administration of 10 000 units of vitamin D(2) maintained or increased BMD in younger postmenopausal women more efficiently than did calcium supplements alone. One hundred eighty-seven women who were >or= 1 y postmenopausal were randomly assigned to take either 1000 mg Ca/d after the evening meal or 1000 mg Ca/d plus 10 000 U vitamin D(2)/wk in a double-blind, placebo-controlled format. The BMD of the proximal forearm, lumbar spine, femoral neck, Ward's triangle, and femoral trochanter was measured at 6-mo intervals by osteodensitometry. During the 2-y period, there was no significant difference in the change in BMD at any site between the subjects taking calcium supplements and those taking calcium plus vitamin D(2). Both groups significantly (P < 0.005) gained BMD in Ward's triangle and the femoral trochanter but significantly (P < 0.005) lost bone in the proximal radius. There was no significant change in the lumbar spine or femoral neck BMD. In younger postmenopausal women ( age: 56 y) whose average baseline serum 25-hydroxyvitamin D concentration was well within the normal range, the addition of 10 000 U vitamin D(2)/wk to calcium supplementation at 1000 mg/d did not confer benefits on BMD beyond those achieved with calcium supplementation alone.

1120 Hepatitis C treatment practice patterns in the United States: a national survey

PURPOSE: Previously we have reported a significant increase in bone mineral density (BMD) of the spine and the hip and reductions in biochemical indices of bone turnover in postmenopausal women with osteoporosis treated with alendronate at various doses over 1 to 2 years. We have followed BMD and biochemical parameters in these patients for 1 or 2 years after discontinuation of alendronate to determine resolution of alendronate effects.PATIENTS AND METHODS: Participants received daily oral doses of placebo, 5 or 10 mg of alendronate for 2 years, or 20 or 40 mg of alendronate for 1 year followed by 1 year of placebo. No treatment was given in the third year of study.RESULTS: Lumbar spine BMD changes in the 5- and 10-mg groups (−1.4 and −0.4%) were similar to those in the placebo group (−1.2%) 1 year after discontinuation of drug and lumbar spine BMD changes in the 20- and 40-mg groups (−1.2% and 0.8%) were similar to those in the placebo group (−0.9%) 2 years after discontinuation of drug. BMD of the total hip followed the same pattern of resolution. The difference in BMD between alendronate and placebo groups at the end of alendronate treatment was maintained up to 2 years. Residual reductions in the bone resorption markers urinary deoxypyridinoline (d-Pyr) and collagen type 1 cross-linked N telopeptides and the bone formation markers serum bone-specific alkaline phosphatase and osteocalcin remained for 1 year after discontinuation of 5 and 10 mg of alendronate and for 2 years after discontinuation of 20 and 40 mg of alendronate, other than return of D-Pyr to baseline 1 year after cessation of treatment with the 5- and 10-mg doses.CONCLUSIONS: A residual decrease in bone turnover may be found up to 2 years after discontinuation of alendronate. Accelerated bone loss is not observed when treatment is discontinued. However, continuous therapy with alendronate is required to achieve a continuous gain in BMD.

Osteopenia in exercise-associated amenorrhea using ballet dancers as a model: a longitudinal study.

Few longitudinal studies have investigated the effects of amenorrhea and amenorrhea plus exercise on bone mineral density (BMD) of young women. We carried out a 2-yr comparison of dancers and nondancers, both amenorrheic and normal, that investigated the role of hypothalamic amenorrhea on bone in this context. We studied 111 subjects (mean age, 22.4 +/- 4.6 yr; age of menarche, 14.1 +/- 2.2 yr), including 54 dancers, 22 with hypothalamic amenorrhea, and 57 nondancers, 22 with hypothalamic amenorrhea. Detailed hormonal and nutritional data were obtained in all groups to determine possible causal relationship to osteoporosis. The amenorrheic groups, dancers and nondancers, both showed reduced BMD in the spine, wrist, and foot, which remained below controls throughout the 2 yr. Only amenorrheic dancers showed significant changes in spine BMD (12.1%; P < 0.05) but still remained below controls, and within this subgroup, only those with delayed menarche showed a significant increase. The seven amenorrheic subjects (three dancers and four nondancers) who resumed menses during the study showed an increase in spine and wrist BMD (17%; P < 0.001) without achieving normalization. Delayed menarche was the only variable that predicted stress fractures (P < 0.005), which we used as a measure of bone functional strength. Analysis of dieting and nutritional patterns showed higher incidence of dieting behavior in this group, as manifested by higher Eating Attitudes Test scores (16.3 +/- 2.00 vs. 11.5 +/- 1.45; P < 0.05) and higher fiber intakes (30.7 +/- 3.00 vs. 17.5 +/- 2.01 g/24 h; P < 0.001). We concluded that low bone mass occurs in young women with amenorrhea and delayed menarche, both exercisers and nonexercisers. Crucial bone mass accretion may be compromised by their reproductive and nutritional health.

EFFECTS OF GYMNASTICS TRAINING ON VOLUMETRIC AND AREAL SPINE BMD

PURPOSE: Bone gains and losses have been reported in gymnasts following seasonal training and detraining periods however, reports of seasonal changes in the spine of gymnasts has been limited to areal calculations from anterior-posterior (AP) projections using dual energy x-ray absorptiometry. Our aim was to assess the effects of gymnastics training on areal and volumetric measures of spinal bone mineral density (BMD) in gymnasts and controls. METHODS: Subjects consisted of 9 intercollegiate gymnasts and 15 normally active controls. Height (by stadiometer) and BMD and weight (by DXA, QDR-4500/A, Hologic Inc., Waltham, MA) were assessed at the beginning and end of an academic year (9 months). During this time gymnasts engaged in their competitive training season whereas controls were normally active. Lumbar spine measurements included areal BMD (G/CM2) in the AP projection and volumetric BMD (G/CM3) from coupled AP and lateral projections. Compared to controls, gymnasts were slightly older (19.33 ± 0.37 vs. 18.33 ± 0.13, p < .01) and had a later age at menarche (14.44 ± 0.63 vs. 11.93 ± 0.33, p < 0.01) but BMI was similar between groups (gym = 23.9 ± 0.58 con = 23.0 ± 0.65) and did not change over the academic year. Furthermore, groups did not differ for calcium intake and the average values were close to or within the RDA (gym = 943.9 ± 99.5 con = 1145.9 ± 141.9). By ANCOVA, adjusting for initial BMD values, 9-month changes in areal and volumetric BMD were not significantly different between groups (Table 1). However, compared to controls, changes in areal and volumetric BMD were more than 5- and 10-fold greater in gymnasts (Table 1). In conclusion, while we did not observe significant differences between groups for 9-month change in areal or volumetric spine BMD, we attribute the non-significant findings to low power, due to the small sample size, and short follow up period.Table 1: Lumbar Spine Areal and Volumetric BMD in Gymnasts (n = 9) and Controls (n = 15) (mean ± SE)

Seasonal changes in calciotropic hormones, bone markers, and bone mineral density in elderly women.

Seasonal variation of serum vitamin D metabolites, PTH, bone turnover markers, and bone mineral density (BMD), adjusted for confounding variables, was studied in a cross-sectional population of 251 ambulatory elderly women aged 65-77 yr. A significant (P < 0.05) seasonal change was observed in serum 25 hydroxyvitamin D (25OHD), bone resorption marker (urine N-telopeptide), and BMD of the spine, total body, and mid-radius. Serum 25OHD was significantly lower (P < 0.05) in winter (December, January, February, March) compared with summer (June, July, August, September), with the nadir in February (68.4 +/- 6.74 nmol/liter) and the zenith in August (85.6 +/- 5.12 nmol/liter). Mean serum PTH levels were higher in winter when serum 25OHD was low, and mean serum PTH was lower in summer when serum 25OHD was high, although the seasonal change in serum PTH was not significant. The change in serum 1,25-dihydroxy vitamin D(3) paralleled that of serum 25OHD levels, but the seasonal effect was not significant. Mean 24-h urine N-telopeptide showed a significant seasonal change (P < 0.05); it was about 24% higher in February (zenith) compared with that in August (nadir). The zenith month of urine N-telopeptide levels corresponded to the nadir month of serum 25OHD levels and vice versa. A significant (P < 0.05) inverse correlation was observed between 24-h urine N-telopeptides and serum 25OHD levels. There was a significant (P < 0.05) seasonal change in mean BMD of spine, total body, and mid-radius. These changes paralleled those in serum 25OHD levels. Spine BMD was 8.4% higher in August (zenith) compared with that in February (nadir), whereas total body BMD and mid-radius BMD were 6.1 and 7.6% higher, respectively, in July (zenith) compared with that in January (nadir). There was a nonsignificant increase of 3.6% in total hip BMD. In summary (see Fig. 5), the seasonal changes in vitamin D metabolism in elderly women are closely associated with small changes in serum PTH, changes in bone resorption, and BMD.

The skeletal site-differential changes in bone mineral density following bone marrow transplantation: 3-year prospective study.

Loss of bone mass is usually detected after bone marrow transplantation (BMT) during the early post-transplant period. However, little is known about the long-term effects of BMT on bone metabolism. We have prospectively investigated 11 patients undergoing BMT. Bone mineral density (BMD) was measured before BMT, and 1, 2, and 3 yr after BMT. Serum markers of bone turnover were serially measured before BMT and 1, 2, 3, 4, and 12 weeks, 6 months, and 1 yr after BMT. The mean change in the lumbar spine (L2-4) BMD, calculated as the percent change from the baseline to the level at 1, 2, and 3 yr was -4.7% (NS), -1.1% (NS), and +6.4% (p<0.05), respectively. The mean change in the total proximal femur BMD from the baseline to the level at 1, 2, and 3 yr was -8.5% (p<0.01), -8.7% (p<0.05) and -5.6% (p<0.05), respectively. In summary, there was little decline in lumbar BMD at 1 yr following BMT and gradual recovery until 3 yr. In contrast, femoral BMD decreased much more than the lumbar area at 1 yr and did not recover until 3 yr. The mechanism of skeletal site-selective differences in the changes of BMD needs to be elucidated.

Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment

We present the 5-year results of the effect of adjuvant chemotherapy on bone mineral density (BMD) and the efficacy of clodronate in the prevention of bone loss in 73 premenopausal women with primary breast cancer. All patients were treated with cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. The patients were randomised to oral clodronate 1600 mg daily for 3 years or to a control group. At 5 years, patients were divided into those with preserved menstruation and those with amenorrhoea. Changes in BMD correlated significantly with the menstrual function after chemotherapy. The change in the lumbar spine BMD at 3 and 5 years were +0.6 and −1.3% in the menstruating group and −7.5 and −10.4% in the amenorrhoeic group ( P=0.0001 and 0.0001, respectively), and in femoral neck +1.7 and −0.3%, and −3.5 and −5.8% ( P=0.002 and P=0.001, respectively). Three-year clodronate treatment significantly reduced the bone loss in the lumbar spine −3.0% compared with controls −7.4% at three years ( P=0.003), but no significant difference was found in the femoral neck: −1.7% versus −2.8%, respectively ( P=0.86). These differences between the study groups were still seen at 5 years: in the lumbar spine −5.8% versus −9.7% ( P=0.008) and femoral neck −3.5% versus −5.1% ( P=0.91). In conclusion, chemotherapy-induced ovarian failure in premenopausal women caused a temporary accelerated bone loss of the lumbar spine. Adjuvant clodronate treatment significantly reduced this bone loss. Two years after the termination of treatment, the bone loss was still significantly less in the clodronate group compared with the control group.

Prevention of Bone Loss with Tibolone in Postmenopausal Women: Results of Two Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Studies

Tibolone, a novel compound with tissue-specific effects, has been found to have antiresorptive properties in bone. To confirm the efficacy of tibolone and determine its minimum effective dose for prevention of bone loss in early postmenopausal women, two randomized, double-blind, placebocontrolled, dose-finding studies were performed. Seven hundred seventy healthy women postmenopausal within 1–4 yr, with normal bone density for their age, were treated for 2 yr with 0.3, 0.625, 1.25, or 2.5 mg tibolone daily or placebo. All subjects took supplemental calcium carbonate (500 mg daily). Bone mineral density (BMD) of the lumbar spine and right proximal femur was measured by dual-energy x-ray absorptiometry for up to 2 yr. At each dose level, except the lowest (0.3 mg), tibolone produced a progressive increase in lumbar spine and total hip BMD over the 2-yr treatment period; at 0.3 mg, total hip density was maintained. However, only the doses 1.25 mg and 2.5 mg produced a progressive increase in femoral neck BMD. The differences in mean percent change from baseline in spine and total hip density were significant (P< 0.05) for all tibolone dose groups compared with placebo at all time points. Tibolone was well tolerated, with a similar overall incidence of adverse events compared with placebo. Tibolone 1.25 mg per day is recommended because it shows a positive and statistically significant change in BMD of spine and femoral neck.

COL1A1 Sp1 Polymorphism Predicts Perimenopausal and Early Postmenopausal Spinal Bone Loss

Genetic factors play an important role in the pathogenesis of osteoporosis but the genes that determine susceptibility to poor bone health are defined incompletely. Previous work has shown that a polymorphism that affects an Spl binding site in the COLIA1 gene is associated with reduced bone mineral density (BMD) and an increased risk of osteoporotic fracture in several populations. Data from cross-sectional studies have indicated that COLIA1 Sp1 alleles also may be associated with increased rates of bone loss with age, but longitudinal studies, which have examined bone loss in relation to COLIA1 genotype, have yielded conflicting results. In this study, we examined the relationship between COLIA1 Sp1 alleles and early postmenopausal bone loss measured by dual-energy X-ray absorptiometry (DXA) in a population-based cohort of 734 Scottish women who were followed up over a 5- to 7-year period. The distribution of genotypes was as expected in a white population with 484 "SS" homozygotes (65.9%); 225 "Ss" heterozygotes (30.7%), and 25 "ss" homozygotes (3.4%). Women taking hormone-replacement therapy (HRT; n = 239) had considerably reduced rates of bone loss at the spine (-0.40 +/- 0.06%/year) and hip (-0.56 +/- 0.06%/year) when compared with non-HRT users (n = 352; spine, -1.36 +/- 0.06%/year; hip, -1.21 +/- 0.05%/year; p < 0.001 for both sites). There was no significant difference in baseline BMD values at the lumbar spine (LS) or femoral neck (FN) between genotypes or in the rates of bone loss between genotypes in HRT users. However, in non-HRT users (n = 352), we found that ss homozygotes (n = 12) lost significantly more bone at the lumbar site than the other genotype groups in which ss = -2.26 +/- 0.31%/year compared with SS = -1.38 +/- 0.07%/year and Ss = -1.22 +/- 0.10%/year (p = 0.004; analysis of variance [ANOVA]) and a similar trend was observed at the FN in which ss = -1.78 +/- 0.19%/year compared with SS = -1.21 +/- 0.06%/year and Ss = -1.16 +/- 0.08%/year (p = 0.06; ANOVA). The differences in spine BMD loss remained significant after correcting for confounding factors. Stepwise multiple regression analysis showed that COLIA1 genotype independently accounted for a further 3.0% of the variation in spine BMD change after age (4.0%), weight (5.0%), and baseline BMD (2.8%). We conclude that women homozygous for the Sp1 polymorphism are at significantly increased risk of excess rates of bone loss at the spine, but this effect may be nullified by the use of HRT.

Bone mineral metabolism in adults with β‐thalassaemia major and intermedia

Bone disease is an important cause of morbidity in older patients with beta-thalassaemia major and intermedia. We studied 27 women and 23 men with beta-thalassaemia major (37) and intermedia (13) whose mean age was 32.3 +/- 9.7 years. Bone mineral density (BMD) of the lumbar spine, femoral neck and distal radius was determined by dual-energy X-ray absorbiometry (DXA). The longitudinal change in BMD over a mean of 5.6 years was determined in 19 patients. Serum 25-hydroxyvitamin D, insulin growth factor-1 (IGF-1), bone formation markers bone-alkaline phosphatase, osteocalcin and the resorption marker urinary N-telopeptide cross-linked type 1 collagen (NTx) were determined. The BsmI vitamin D receptor (VDR) gene polymorphism was analysed. Reduced BMD (Z-score < -2) was present in 89%, 62% and 73% of patients in the spine, hip and radius respectively. Vitamin D deficiency was found in 62%, decreased IGF-1 in 72% and increased urinary NTx in 84% of patients. Serum IGF-1 correlated with spine and hip BMD (r = 0.4, r = 0.39, P < 0.01 respectively), and NTx correlated with the hip BMD Z-score (r = 0.35 P < 0.05). The mean annual percentage change in spine BMD was -1.36%. Patients with the VDR BB genotype had lower spine BMD than patients with the bb genotype. In conclusion, bone loss continues in adult thalassaemia patients and is associated with increased bone resorption and decreased IGF-1. The BsmI VDR gene polymorphism is associated with osteopenia in thalassaemia.