Assessment of Denosumab in Korean Postmenopausal Women with Osteoporosis: Randomized,Double-Blind,Placebo-Controlled Trial with Open-Label Extension

PurposeThe efficacy and safety of denosumab was compared with placebo in Korean postmenopausal women with osteoporosis in this phase III study.ResultsBaseline demographics were similar in the 62 denosumab- and 64 placebo-treated subjects who completed the double-blind phase. Treatment favored denosumab over placebo for the primary endpoint {mean percent change from baseline in lumbar spine bone mineral density (BMD) at Month 6 [3.2% (95% confidence interval 2.1%, 4.4%; p<0.0001)]}; and secondary endpoints (mean percent change from baseline in lumbar spine BMD at Month 1, total hip, femoral neck, and trochanter BMD at Months 1 and 6, and median percent change from baseline in bone turnover markers at Months 1, 3, and 6). Endpoint improvements were sustained over 12 months in the open-label extension (n=119). There were no new or unexpected safety signals.ConclusionDenosumab was well tolerated and effective in increasing BMD and decreasing bone turnover markers over a 12-month period in Korean postmenopausal women. The findings of this study demonstrate that denosumab has beneficial effects on the measures of osteoporosis in Korean postmenopausal women.     

Treatment of osteoporosis with denosumab

Osteoporosis is a common skeletal disease associated with an imbalance in bone remodeling resulting in a reduction in bone strength and increased fracture risk. The principal regulator of osteoclastic bone resorption is receptor activator of nuclear factor-κB ligand (RANKL), a cytokine member of the tumor necrosis factor family. The binding of RANKL to its receptor on the cell surface of osteoclasts and pre-osteoclasts increases the formation, activity, and survival of osteoclasts. Denosumab is an investigational fully human monoclonal antibody to RANKL. By binding to RANKL, denosumab prevents RANKL from binding to its receptor, resulting in a decrease in bone resorption due to reduction in the formation, activity, and survival of osteoclasts. In postmenopausal women with osteoporosis, denosumab 60 mg by subcutaneous injection every 6 months increased bone mineral density (BMD), reduced bone turnover markers, and reduced the risk of vertebral, hip, and non-vertebral fractures. In postmenopausal women with low BMD, denosumab increased BMD and reduced bone turnover markers. It was well tolerated with a safety profile generally similar to placebo. Denosumab is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis. It may be particularly useful in clinical practice for the treatment of patients with gastrointestinal contraindications or side effects with oral bisphosphonates and for patients with malabsorption.     

Spotlight on Denosumab in Postmenopausal Osteoporosis

Denosumab (Prolia®) is a human recombinant monoclonal antibody that is approved for the treatment of postmenopausal osteoporosis in women at high or increased risk of fracture in the US, the EU, and several other countries. Denosumab has a novel mechanism of action; it binds to receptor activator of nuclear factor κB ligand and inhibits bone resorption by inhibiting osteoclast formation, function, and survival. In postmenopausal women with osteoporosis, denosumab reduced the risk of vertebral, nonvertebral, and hip fractures compared with placebo over 3 years in the large, phase III FREEDOM study. In postmenopausal women with low bone mineral density (BMD) or osteoporosis, treatment with denosumab increased BMD and decreased markers of bone turnover more than alendronate in those who were essentially treatment-naive in the 1-year DECIDE study and also in the 1-year STAND study, in which women were switched from alendronate to denosumab or continued alendronate treatment. Denosumab was generally well tolerated in clinical trials, although long-term effects of very low bone turnover remain to be established. Denosumab is administered once every 6 months via subcutaneous injection, which may be a preferred method of administration and may improve adherence to treatment compared with other osteoporosis treatments. Denosumab is a valuable new option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, and may be useful as a first-line treatment in women at increased risk of fractures who are unable to take other osteoporosis treatments.     

Effect of low-dose transdermal E2/NETA on the reduction of postmenopausal bone loss in women

OBJECTIVE: To assess the efficacy of a continuous-combined transdermal patch (estradiol/ norethisterone acetate [E(2)/NETA] 25/125; Estragest TTS, Novartis, Basel, Switzerland) in the reduction of bone loss in postmenopausal women. DESIGN: In a 96-week, double-blind, randomized, multicenter, parallel study, 124 healthy women with an intact uterus more than 4 years after menopause received either transdermal continuous-combined E(2)/NETA (0.025/0.125 mg/day) or placebo patch for 24 treatment cycles; diet was normalized for calcium intake. Lumbar spine bone mineral density (BMD) ranged from 0.969 to 0.805 g/cm2 with a mean annual BMD decrement ranging from 3% to 8% within the last 24 months. BMD at lumbar spine L(2)-L(4) (postero-anterior) and femur were assessed by dual energy x-ray absorptiometry after 6, 12, and 24 cycles. Efficacy variables included measurement of biochemical markers of bone turnover (3, 6, 12, and 24 months). RESULTS: BMD at lumbar spine was significantly higher at all time points in the E(2)/NETA group than in the placebo group (P < 0.0001). Significant increases in BMD (P < 0.0008) from baseline were observed at all sites after 24 months in the E(2)/NETA group compared with placebo, which demonstrated a decrease from baseline. At endpoint, statistically significant decrements in the values of bone remodeling markers were observed (P < 0.05) with E(2)/NETA. CONCLUSIONS: E(2)/NETA 25/125 Estragest TTS was more effective than placebo in reducing the activation frequency of bone remodeling and in preventing bone loss at the spine and hip. Effects on the hip were similar to those observed for higher doses of estrogen.     

Prevention of postmenopausal bone loss with long-cycle hormone replacement therapy

OBJECTIVE: Postmenopausal bone loss and osteoporotic fractures can be prevented by hormone replacement therapy (HRT). However, opposed HRT may increase the risk of breast cancer above that associated with estrogen alone and in non-hysterectomized women estrogen substitution alone increases the risk of uterine cancer, which triggered renewed interest in long-cycle HRT regimens (estrogen replacement therapy with progesterone-free intervals up to 6 months). The effects on bone of such long-cycle HRT regimens are unknown. The objective of the present study was to compare the effects on bone and the endometrium of long-cycle HRT and conventional HRT. METHODS: Seventy-three healthy non-hysterectomized postmenopausal women were randomized to either conventional HRT (estradiol (E2) 2 mg/d during 12 days, E2 2 mg/d plus 1 mg/d of norethisterone acetate (NETA) during 10 days, E2 1 mg/d for 6 days) or long-cycle HRT treatment (two cycles with E2 2 mg/d during 28 days, followed by one cycle of conventional HRT and repeated every 3 months). Primary endpoint was the change in bone mineral density (BMD) at the lumbar spine (LS) over 24 months. RESULTS: BMD at LS increased significantly versus baseline in both treatment groups (conventional HRT +3.8 +/- 0.6%, long-cycle HRT +3.3 +/- 0.5%, p < 0.0001 for both) with no significant difference between treatment groups over 24 months. Similar significant BMD increases versus baseline were observed at the femoral neck, while biochemical markers of bone turnover (osteocalcin and deoxypyridinoline) were significantly decreased over 24 months. There were no endometrial or breast related adverse events reported. CONCLUSION: Long-cycle HRT may be a valid alternative to conventional HRT with regard to protection against postmenopausal bone loss.     

Changes in bone mineral density during and after 3 years' use of tamoxifen or toremifene

OBJECTIVES: To study the effects of tamoxifen and toremifene on bone mineral density (BMD) in postmenopausal women with breast cancer. METHODS: Seventy patients with stage II-III breast cancer were randomized to start either tamoxifen (n = 36; 20 mg per day) or toremifene (n = 34; 40 mg per day) for 3 years. BMD in the lumbar spine and in the proximal femur was measured by dual-energy X-ray absorptiometry both before and during the treatment and 1 year after the discontinuation of the anti-estrogens. RESULTS: The baseline BMD measurements were comparable between the groups. In 3 years, lumbar BMD decreased by 1.7% in tamoxifen (P = 0.048) and 3.0% in toremifene (P = 0.001) users (ns between the groups), and femoral neck BMD by 0.9% (P = 0.040) and 1.3% (P = ns), respectively. The use of hormone replacement therapy (HRT) until the diagnosis of breast cancer was associated with decreases in lumbar BMD during anti-estrogen regimen (4% at 3 years) in contrast to unchanged lumbar BMD in women with no previous use of HRT. During the 1st year after the cessation of anti-estrogen, lumbar BMD did not change at all in either group whereas femoral BMD decreased in both the groups at the rate of 1.5-3.2%, as expected. CONCLUSIONS: We conclude that tamoxifen (20 mg) and toremifene (40 mg) have similar bone-sparing efficacy that in lumbar spine extends up to 1 year after the cessation of these regimens. This effect is not seen in lumbar spine BMD in those postmenopausal women who discontinue HRT at the time of breast cancer diagnosis.     

不同治疗方法对绝经后乳腺癌患者骨密度的影响

目的 探讨不同治疗方法 对绝经后乳腺癌患者骨密度(BMD)的影响.方法 研究分为健康对照组(50例)、肿瘤组[48例,其中24例再行他莫昔芬(TAM)组治疗].采用双能X线骨密度仪(DEXA)测定所有研究对象的基线BMD.肿瘤组术后均进行辅助化疗,其中24例(TAM组)化疗后继续使用TAM行内分泌治疗.用DEXA测量腰椎和左髋部位的BMD,比较肿瘤组化疗前、后以及TAM组行内分泌治疗8个月后BMD变化.结果 肿瘤组化疗后腰椎部位BMD(0.87±0.15)g/cm2比化疗前(0.93±0.15)g/cm2明显降低(P<0.05);TAM组行内分泌治疗8个月后腰椎BMD(0.90±0.04)g/cm2和股骨颈(0.74±0.05)g/cm2等左髋部位的BMD均有明显增加(P<0.05).结论 化疗可能导致绝经后乳腺癌患者BMD的下降,而TAM治疗能缓解化疗引起的BMD降低.     

Oral hormone therapy with 17beta-estradiol and 17beta-estradiol in combination with norethindrone acetate in the prevention of bone loss in early postmenopausal women: dose-dependent effects

OBJECTIVE: A 2-year multicenter, double-blind, randomized, placebo-controlled study examined the efficacy and safety of different doses of 17beta-estradiol (E(2)) alone and continuous-combined oral formulations of E(2) and norethindrone acetate (NETA) versus placebo in the prevention of bone loss in newly menopausal women. DESIGN: Patients were randomized to one of seven groups: placebo, E(2) 0.25 mg, E2 0.5 mg, E(2) 1 mg, E(2) 1 mg/NETA 0.25 mg, E(2) 1 mg/NETA 0.5 mg, or E(2) 2 mg/NETA 1 mg. Treatment was a once-daily tablet taken for 26 months. The primary efficacy endpoint was the change in bone mineral density (BMD) at the lumbar spine, measured by dual-energy x-ray absorptiometry, at screening and at 13, 19, and 26 months. BMD changes at the femoral neck and trochanter were also assessed. Biochemical markers of bone metabolism were measured at baseline, and at 3, 6, 13, 19, and 26 months. Histological diagnoses of endometrial samples were tabulated for each treatment group. RESULTS: A total of 327 women were randomized and 189 women completed the 2-year trial. BMD at the lumbar spine decreased 2.3% in the placebo group. The lowest dose of unopposed E(2) prevented bone loss at the spine and hip. Significant increases in spine BMD compared with placebo occurred in all groups of treatment with E(2) and were more pronounced in the combination groups. Compared with placebo, women receiving active treatment experienced greater reductions in bone resorption markers. The effects were evident by 6 months and generally remained stable thereafter. Adverse events, primarily associated with the endometrium, were the most common reasons for discontinuation. CONCLUSIONS: There is a dose-dependent effect of E(2) on BMD. The addition of NETA seems to enhance the response in BMD observed with E(2). Low doses of E(2) (1 mg and lower) can be considered for the prevention of osteoporosis, while titrating the hormone dose to individual patient's needs.     

The effect of continuous oestradiol with intermittent norgestimate on bone mineral density and bone turnover in post-menopausal women

OBJECTIVE: To assess in post-menopausal women the efficacy and tolerability of a continuous oestradiol/intermittent norgestimate HRT regimen to prevent and to reverse post-menopausal loss of bone mineral density (BMD) and to determine the effects on serum bone turnover markers markers. METHODS: A 1-year, multicentre, international, placebo-controlled, randomised, double-blind clinical trial was conducted in 146 post-menopausal women with an intact uterus in order to assess the effect on bone loss of continuous oral 17beta-oestradiol (1 mg per day) combined with norgestimate (90 microg per day), for 3 consecutive days out of every 6-day treatment period (E2/iNGM). During a second year extension, all women agreeing to continue were on the E2/iNGM regimen. BMD was assessed prior to treatment and after 1 and 2 years or at the end of treatment in women stopping participation prematurely after at least 6 months of treatment. Serum bone turnover markers were determined prior to and at 1 year of treatment Adverse events were collected at three-monthly intervals during clinic visits over the treatment period. RESULTS: BMD in the lumbar spine, the primary endpoint, was evaluable in 117 subjects completing >6 months of treatment. BMD increased on average by 2.4% in women on the intermittent progestin regimen. It decreased by 1.4% in placebo treated women. The change from baseline and the difference between active and placebo treatment (Delta placebo) were highly significant (P < 0.0001). On E2/iNGM, also the BMD in the total hip increased (+1.49%, Delta placebo 3.73%, P < 0.0001). The serum markers for bone formation osteocalcin and type I collagen N-propeptide were significantly reduced compared to baseline by 31 and 44%, respectively and the bone resorption marker C-terminal crosslinked telopeptide of type I collagen by 59%. Minor increases (<10%) of markers in the placebo group were not significant. During a second year extension of the trial, all subjects were on active treatment. Subjects on placebo who lost (median+/-CI 95%) 0.66% (-2.3 to +0.5) of spine BMD during the first year now gained 4.41% (2.7-7.6). They also gained 1.6% (0.1-0.3.6) in the total hip. Subjects continuously on oestradiol/intermittent norgestimate (E2/iNGM) gained an additional 5.7% (2.3-13.5) in the lumbar spine and +0.1% (-0.6 to +2.2) at the total hip. Side effects reported by women on the intermittent progestin regimen significantly in excess over reports from the placebo group were uterine bleeding, abdominal and breast pain, but not headache. Back pain and weight gain was reported by significantly fewer women on active treatment compared to placebo. CONCLUSION: The continuous oestradiol/intermittent norgestimate HRT regimen is well tolerated, reduces bone turnover and prevents post-menopausal bone loss in healthy post-menopausal women.     

Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene

OBJECTIVE: Osteoporosis is a significant health problem in postmenopausal women. Consequently, new and effective therapies are being sought to preserve bone mass and prevent osteoporosis in this population of women. The objective of this study was to compare the effects of lasofoxifene with raloxifene and placebo on indices of bone health in postmenopausal women. DESIGN: A randomized, double-blind, placebo- and active treatment-controlled study of 2 years duration was conducted. Women included 410 postmenopausal women aged 47 to 74 years. The four treatment groups were: lasofoxifene 0.25 mg/day, or 1.0 mg/day, raloxifene 60 mg/day, or placebo daily. All women received daily calcium and vitamin D supplements. The primary endpoint was percent change from baseline to 2 years in lumbar spine bone mineral density (BMD) in all women having baseline and at least one follow-up bone density measurement. Total hip BMD, biochemical markers of bone turnover, low-density lipoprotein cholesterol, and safety were also evaluated in all women. RESULTS: Both doses of lasofoxifene significantly increased lumbar spine BMD compared with raloxifene (P < or = 0.05) and with placebo treatment (P < or = 0.05). Least squares mean increases (95% CI) from baseline in lumbar spine BMD, compared with placebo, were 3.6% (1.9, 5.2) for lasofoxifene 0.25 mg/day, 3.9% (2.4, 5.5) for lasofoxifene 1.0 mg/day, and 1.7% (0.3, 3.0) for raloxifene. The two doses of lasofoxifene and raloxifene were equally effective at increasing total hip BMD. Lasofoxifene and raloxifene significantly reduced the levels of biochemical markers of bone turnover compared with placebo. In general, the effects of lasofoxifene were greater than the responses to raloxifene. At 2 years, lasofoxifene significantly (P < or = 0.05) reduced low-density lipoprotein cholesterol levels by 20.6% and 19.7% with 0.25 mg/day and 1 mg/day, respectively, compared with raloxifene (12.1%) and placebo (3.2%). Lasofoxifene and raloxifene had a similar adverse event profile with low rate of discontinuations due to adverse events. CONCLUSIONS: Lasofoxifene may be an effective and well-tolerated treatment option for the prevention of bone loss in postmenopausal women.     

Denosumab prevents periprosthetic bone mineral density loss in the tibial metaphysis in total knee arthroplasty

BackgroundPeriprosthetic bone quality is one of the most important factors preventing early prosthesis migration and long-term failure. Although denosumab, which binds to the receptor activator of nuclear factor kappa-B ligand (RANKL), has been linked with periprosthetic bone mineral density (BMD), the effectiveness of denosumab against bone loss remains unclear. We hypothesized that denosumab treatment after total knee arthroplasty (TKA) could prevent periprosthetic bone resorption.MethodsIn this prospective cohort study, 28 patients with primary knee osteoarthritis were divided into two groups: denosumab (denosumab and vitamin D) and control (vitamin D only) groups. All patients underwent TKA with the same implant model and received medication after surgery. We used dual-energy X-ray absorptiometry to measure periprosthetic BMD after TKA.ResultsIn the control group, the BMD of the proximal medial tibia decreased drastically at 12 months after TKA (− 19.7%). Denosumab treatment significantly preserved this BMD loss (0.7%). The linear regression analysis revealed that denosumab intervention had the highest significantly positive relationship with BMD.ConclusionsOur results indicate that denosumab treatment significantly reduces periprosthetic BMD loss, even at the early stages after TKA. This therapeutic strategy may facilitate early stable fixation of the prosthesis which, in turn, may help to prevent early implant migration and reduce the need for revision surgery.     

Trait anxiety and tamoxifen effects on bone mineral density and sex hormone- binding globulin

OBJECTIVE: Tamoxifen therapy preserves BMD of the lumbar spine and increases levels of SHBG. We assessed whether trait anxiety, a factor linked with a reactive endocrine system, is associated with differential changes in BMD and SHBG levels in response to tamoxifen therapy. METHODS: Postmenopausal women (N= 140) with axillary-node-negative breast cancer participated in a 2-year randomized, double-blind, placebo-controlled trial of tamoxifen (10 mg twice a day). Levels of BMD and SHBG were assessed at baseline and at 3, 6, 12, 18, and 24 months. RESULTS: Trait anxiety predicted tamoxifen-induced changes in lumbar spine BMD; high levels of trait anxiety were associated with significantly greater lumbar spine BMD at 3, 12, and 24 months (p values <.05) for women on tamoxifen therapy. High anxiety also was associated with lower levels of SHBG for women using tamoxifen at 3, 12, 18, and 24 months (p values <.05). CONCLUSIONS: Trait anxiety is associated with greater preservation of lumbar spine BMD in response to tamoxifen and with a suppression of tamoxifen-induced increases in SHBG. Trait anxiety and other affective traits may serve as indicators of underlying physiological processes that moderate the effects of estrogen receptor modulators (such as tamoxifen) in clinical trials. Such data may help to elucidate the physiological mechanisms responsible for some of the variation in individual responses to treatment.     

Peripheral quantitative computed tomography (pQCT) is useful for monitoring bone mineral density of the patients who receive hormone replacement therapy

OBJECTIVE: A forearm fracture (Colles' fracture) is often the first sign of osteoporosis and should alert the patient and physician to the possibility of underlying skeletal fragility. Therefore, the establishment of a more accurate and reliable method for the measurement of bone mineral density (BMD) at the distal radius would be beneficial for the patients who suffer from osteoporosis. The objective of the present study was to evaluate the usefulness of peripheral quantitative computed tomography (pQCT) to assess the change of BMD at the distal radius in early postmenopausal women who receive hormone replacement therapy (HRT). METHODS: Twenty healthy early postmenopausal women who were diagnosed as osteoporosis or osteopenia were randomized to either HRT or placebo treatment. We analyzed BMD of the distal radius by pQCT, lumbar spine by dual-energy X-ray absorptiometry (DXA) and the biochemical markers of bone turn over (osteocalcin, deoxypyridinoline) every 6 months. RESULTS: The placebo group showed a significant decrease from the baseline in the trabecular BMD of the radius at 12 months (7.4+/-2.5%) (p<0.05), whereas the HRT group showed a slight increase (0.7+/-2.2%). The changes in the trabecular BMD of the radius between the HRT and placebo groups were statistically different at 12 months (p<0.05). On the other hand, in the cortical BMD of the radius, no significant differences were seen between the changes of bone densities in the HRT and control groups after 1 year of treatment. pQCT could detect a significant loss of BMD of the radius in early postmenopausal women after 1 year and HRT prevented its loss. CONCLUSION: Our preliminary clinical trial showed that pQCT might be useful for the early detection of bone loss in early postmenopausal women and for the monitoring BMD of the patients who receive HRT.     

Esterified estrogen therapy in postmenopausal women. Relationships of bone marker changes and plasma estradiol to BMD changes: a two-year study

OBJECTIVE: To determine the relationships among bone mineral density changes, bone marker changes, and plasma estrogens in postmenopausal women receiving estrogen replacement therapy. DESIGN: A total of 406 postmenopausal women received 1,000 mg calcium and continuous esterified estrogens (0.3 mg, 0.625 mg, or 1.25 mg) or placebo daily for up to 24 months. Bone mineral density and bone marker measurements were determined at 6-month intervals; plasma estrogens were measured in a subset after 12, 18, and 24 months. RESULTS: Esterified estrogens produced significant increases in bone mineral density (lumbar spine, hip) compared with baseline and placebo at 6, 12, 18, and 24 months. Bone markers decreased from baseline with all esterified estrogen doses relative to placebo. Bone marker changes at 6 months correlated negatively with bone mineral density changes at 24 months (correlation coefficient range = -0.122 to -0.439). The strongest correlation was noted for spine bone mineral density changes and serum osteocalcin. Mean plasma estrogen levels increased with esterified estrogen dose, and bone mineral density changes correlated positively with plasma estrogen levels. Positive bone mineral density changes were noted in treatment groups with plasma estradiol levels at and above 25 pg/mL. CONCLUSIONS: Esterified estrogens, at doses from 0.3 mg to 1.25 mg/day, unopposed by progestin, increase bone mineral density of the spine and hip in postmenopausal women. These bone mineral density changes correlated significantly with bone marker changes at 6 months and with plasma estrogens at 12, 18, or 24 months. Data variability minimizes the predictive value of the bone marker changes in monitoring individual therapy.     

Efficacy of oral etidronate for skeletal diseases in Japan

Etidronate is an oral bisphosphonate compound that is known to reduce bone resorption through the inhibition of osteoclastic activity. The efficacy of etidronate for involutional (postmenopausal and senile) and glucocorticoid-induced osteoporosis, as well as that for other skeletal diseases, was reviewed in Japanese patients. Cyclical etidronate treatment (200 mg or 400mg/day for 2 weeks about every 3 months) increases the lumbar bone mineral density (BMD) in patients with involutional osteoporosis and prevents incident vertebral fractures in patients with glucocorticoid-induced osteoporosis. The losses of the lumbar BMD in patients with liver cirrhosis and the metacarpal BMD in hemiplegic patients after stroke are prevented, and the lumbar BMD is possibly increased, preventing fragile fractures in adult patients with osteogenesis imperfecta type I. Furthermore, proximal bone resorption around the femoral stem is reduced and some complications may be prevented in patients who undergo cementless total hip arthroplasty. Oral etidronate treatment may also help to transiently relieve metastatic cancer bone pain followed by a decrease in abnormally raised bone resorption in patients with painful bone metastases from primary cancer sites, such as the lung, breast and prostate. Thus, oral etidronate treatment is suggested to be efficacious for osteoporosis, as well as other skeletal diseases associated with increased bone resorption, in Japanese patients. Randomized controlled trials needed to be conducted on a large number of patients to confirm these effects.     

Comparison of effect of treatment with etidronate and alendronate on lumbar bone mineral density in elderly women with osteoporosis

The purpose of this open-labeled prospective study was to compare the treatment effects of cyclical etidronate and alendronate on the lumbar bone mineral density (BMD), bone resorption, and back pain in elderly women with osteoporosis. Fifty postmenopausal women with osteoporosis, age ranging from 55 to 86 years (mean: 70.7 years), were randomly divided into two groups with 25 patients in each group: the cyclical etidronate group (etidronate 200 mg daily for 2 weeks every 3 months) and the alendronate group (5 mg daily). The BMD of the lumbar spine (L1-L4) measured by DXA, the urinary cross-linked N-terminal telopeptides of type I collagen (NTX) level measured by the enzyme-linked immunosorbent assay, and back pain evaluated by the face scale score were assessed at baseline, 6 months, and 12 months. There were no significant differences in baseline characteristics including age, body mass index, years since menopause, lumbar BMD, urinary NTX level, and face scale score between the two treatment groups. Etidronate treatment sustained the lumbar BMD following a reduction in the urinary NTX level and improved back pain, while alendronate treatment reduced the urinary NTX level more significantly, resulting in an increase in the lumbar BMD, and similarly improved back pain. No serious adverse events were observed in either group. This study confirmed that alendronate treatment had a greater efficacy than etidronate treatment in increasing the lumbar BMD through the reduction of bone resorption in elderly women with osteoporosis.     

Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years

OBJECTIVE: Raloxifene hydrochloride (60 mg/day) is a selective estrogen receptor modulator indicated for the prevention and treatment of postmenopausal osteoporosis. Raloxifene treatment for 3 years increases bone mineral density (BMD) and, unlike tamoxifen (a triphenylethylene selective estrogen receptor modulator), does not stimulate the endometrium in healthy postmenopausal women. The effect of longer duration of treatment with raloxifene is not known. Therefore, the main objectives of these analyses are (1) to compare the effect of 5 years of treatment with raloxifene (60 mg/day) with placebo in terms of the likelihood of developing osteoporosis and (2) to evaluate the effect of 5 years of raloxifene treatment on the endometrium and incidence of vaginal bleeding. DESIGN: The current analyses include integrated data from two identically designed, prospective, double-blinded trials including postmenopausal women (mean age, 55 years) randomly assigned to either placebo (n = 143) or raloxifene (60 mg/day; n = 185). Osteoporosis and osteopenia were diagnosed according to World Health Organization criteria, using the manufacturer's database for the lumbar spine and the National Health and Nutrition Examination Survey's 1998 reference base for the hip. Endometrial thickness was determined using transvaginal ultrasonography. Clinical diagnoses of endometrial hyperplasia or endometrial cancer were confirmed by blinded review of histopathology reports. RESULTS: Compared with the case of placebo, raloxifene treatment for 5 years reduced bone turnover markers (osteocalcin: -10.9%, P < 0.001; bone-specific alkaline phosphatase: -7.2%, P = 0.042; urinary C-telopeptide: -11.1%, P = 0.034) and was associated with increased BMD in the lumbar spine (2.8%; P < 0.001) and total hip BMD (2.6%; P < 0.001). Women taking raloxifene were less likely to develop osteoporosis (relative risk [RR] for raloxifene v placebo: 0.13; 95% CI: 0.00, 0.37; P = 0.001) or osteopenia (RR: 0.23; 95% CI: 0.00, 0.81; P = 0.038) at the lumbar spine and were more likely to convert to normal BMD status at the lumbar spine (RR: 4.01; 95% CI: 1.34, 11.23; P = 0.043) and total hip (RR: 3.92; 95% CI: 1.12,14.27; P = 0.011) at 5 years, compared with the case of placebo. Raloxifene also significantly reduced total cholesterol (-5.5%; P < 0.001) and low-density lipoprotein cholesterol (-8.7%; P < 0.001), compared with the case of placebo. No significant changes in high-density lipoprotein cholesterol (P = 0.257) or triglycerides (P = 0.620) were detected. Incidence of hot flashes was higher among women taking raloxifene compared with those taking placebo [raloxifene, 47 (28.8%); placebo, 21 (16.8%); P = 0.017]. Women taking placebo or raloxifene reported a similar incidence of vaginal bleeding (P = 0.999) or of mean endometrial thickness of more than 5 mm at baseline and at each visit, up to the 5-year endpoint (P >/= 0.349). No diagnoses of endometrial hyperplasia or endometrial cancer were made in either treatment group. CONCLUSIONS: Five years of raloxifene treatment in healthy postmenopausal women preserves BMD, significantly reduces the likelihood of development of osteoporosis, and was not associated with an increased rate of vaginal bleeding, endometrial hyperplasia, or endometrial carcinoma, compared with the case of placebo.     

Placebo-controlled multicenter study of oral alendronate in postmenopausal osteoporotic women. FOSIT-Study-Group. Fosamax International Trial

OBJECTIVES: To evaluate effects on bone mineral density (BMD), safety, and tolerability of a single daily dose of alendronate (10 mg), administered for 1 year to postmenopausal women with osteoporosis. METHODS: This interim analysis includes the first approximately 20% of patients to complete treatment in a large, placebo-controlled study (the Fosamax International Trial (Fosit)), which enrolled 1908 patients from 34 countries. Patients < or = 85-year-old with osteoporosis (lumbar spinal BMD > or = 2 S.D. below mean for mature premenopausal Caucasian women) were randomly assigned to treatment with alendronate or placebo once daily in the morning; all patients received supplemental calcium (500 mg/day). Dual-Energy X-ray Absorptiometry (DXA) was used to measure BMD in spine and proximal femur. RESULTS: A total of 297 patients had BMD data available for analysis. Patients treated with alendronate showed progressive increase of BMD during treatment. At 12 months, mean BMD had increased significantly (P < 0.001) at the lumbar spine (5.6%), trochanter (3.6%), and femoral neck (2.6%) in the alendronate group. Increases in BMD were significantly (P < 0.001) greater than in the placebo group at all sites. Among 442 patients assessed for safety, there were no statistically or clinically significant differences between treatment groups in the incidence of adverse events, including upper gastrointestinal adverse events, or laboratory abnormalities. CONCLUSIONS: Results of this multinational study show that oral alendronate, administered as 10 mg once daily for 1 year, is generally well tolerated and produces significant, progressive increases in BMD at the lumbar spine and proximal femur of postmenopausal women with osteoporosis.     

Dual X-ray absorptiometry detects disease- and treatment-related alterations of bone density in prostate cancer patients

Metastatic bone disease is an important clinical problem which has proven difficult to study because of a lack of noninvasive investigative modalities. Here we show that dual-energy X-ray absorptiometry (DXA) scanning provides clinically useful information about the status of metastatic bone lesions in cancer patients undergoing palliative treatment. In the study group of 21 patients, a significant increase in metastatic bone mineral density (BMD) was confirmed in prostate (n=14) relative to breast (n=7) cancer patients. With respect to the prostate cancer cohort, further increases in lesional BMD were evident in all evaluable patients in whom biochemical progression occurred; conversely, lesional BMD declined in patients who had a partial response to therapy. BMD of uninvolved bone decreased with all types of androgen-deprivation therapy regardless of whether patients responded or relapsed. We conclude that BMD changes in both lesional and uninvolved bone are readily detectable in metastatic prostate cancer, and propose that DXA scanning represents a promising new approach to monitoring the natural history and therapeutic course of this disease. This revised version was published online in July 2006 with corrections to the Cover Date.