Effects of denosumab on bone mineral density and bone turnover in postmenopausal women

CONTEXT: Denosumab is an investigational fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, a mediator of osteoclastogenesis and osteoclast survival. OBJECTIVE: This study evaluated the ability of denosumab to increase bone mineral density (BMD) and decrease bone turnover markers (BTMs) in early and later postmenopausal women with low BMD. DESIGN AND SETTING: This 2-yr randomized, double-blind, placebo-controlled study was conducted in North America. PARTICIPANTS: Subjects included 332 postmenopausal women with lumbar spine BMD T-scores between -1.0 and -2.5. Interventions: SUBJECTS were randomly assigned to receive denosumab sc, 60 mg every 6 months, or placebo. Randomization was stratified by time since onset of menopause (< or =5 yr or > 5 yr). MAIN OUTCOME MEASURES: The primary end point was the percent change in lumbar spine BMD by dual-energy x-ray absorptiometry at 24 months. Additional end points were percent change in volumetric BMD of the distal radius by quantitative computed tomography; percent change in BMD by dual-energy x-ray absorptiometry for the total hip, one-third radius, and total body; hip structural analysis; percent change in BTMs; and safety. RESULTS: Denosumab significantly increased lumbar spine BMD, compared with placebo at 24 months (6.5 vs. -0.6%; P<0.0001) with similar results for both strata. Denosumab also produced significant increases in BMD at the total hip, one-third radius, and total body (P < 0.0001 vs. placebo); increased distal radius volumetric BMD (P < 0.01); improved hip structural analysis parameters; and significantly suppressed serum C-telopeptide, tartrate-resistant acid phosphatase-5b, and intact N-terminal propeptide of type 1 procollagen. The overall incidence of adverse events was similar between both study groups. CONCLUSIONS: Twice-yearly denosumab increased BMD and decreased BTMs in early and later postmenopausal women.     

Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial

Primary hyperparathyroidism (PHPT) is often associated with reduced bone mineral density (BMD). A randomized, double-blind, placebo-controlled trial was conducted to determine whether alendronate (ALN), 10 mg daily, maintains or improves BMD in patients with PHPT. Eligible patients had asymptomatic PHPT and did not meet surgical guidelines or refused surgery. Forty-four patients randomized to placebo or active treatment arms were stratified for gender. At 12 months, patients taking placebo crossed over to active treatment. All patients were on active treatment in yr 2. The primary outcome index, BMD, at the lumbar spine (LS), femoral neck, total hip, and distal one third radius was measured every 6 months by dual-energy x-ray absorptiometry. Calcium, phosphorous, PTH, bone-specific alkaline phosphatase (BSAP) activity, urinary calcium, and urinary N-telopeptide (NTX) excretion were monitored every 3 months. Treatment with alendronate over 2 yr was associated with a significant (6.85%; micro(d) = 0.052; +/-0.94% se; P < 0.001) increase in LS BMD in comparison with baseline. Total hip BMD increased significantly at 12 months with alendronate by 4.01% (micro(d) = 0.027; +/-0.77% se; P < 0.001) from baseline and remained stable over the next 12 months of therapy. BMD at the one third radius site did not show any statistically significant change in the alendronate-treated group at 12 or 24 months of therapy. At 24 months, the alendronate-treated group showed a 3.67% (micro(d) = 0.022; +/-1.63% se; P = 0.038) gain in bone density at the femoral neck site in comparison with baseline. The placebo group, when crossed over to alendronate at 12 months, showed a significant change of 4.1% (micro(d) = 0.034; +/-1.12% se; P = 0.003) in the LS BMD and 1.7% (micro(d) = 0.012; +/-0.81% se; P = 0.009) at the total hip site in comparison with baseline. There was no statistically significant change seen in the placebo group at 12 months at any BMD site and no significant change at 24 months for the distal one third radius or femoral neck sites. Alendronate was associated with marked reductions in bone turnover markers with rapid decreases in urinary NTX excretion by 66% (micro(d) = -60.27; +/-13.5% se; P < 0.001) at 3 months and decreases in BSAP by 49% at 6 months (micro(d) = -15.98; +/-6.32% se; P < 0.001) and by 53% at 9 and 12 months (micro(d) = -17.11; +/-7.85% se; P < 0.001; micro(d) = -17.36; +/-6.96% se; P < 0.001, respectively) of therapy. In the placebo group, NTX and BSAP levels remained elevated. Serum calcium (total and ionized), PTH, and urine calcium did not change with alendronate therapy. In PHPT, alendronate significantly increases BMD at the LS at 12 and 24 months from baseline values. Significant reductions in bone turnover occur with stable serum calcium and PTH levels. Alendronate may be a useful alternative to parathyroidectomy in asymptomatic PHPT among those with low BMD.     

Denosumab‐mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients

Objective

Periarticular osteoporosis is one of the earliest radiographic signs of bone damage in rheumatoid arthritis (RA). Denosumab, an investigational fully human monoclonal antibody that binds to RANKL, inhibits bone erosion and systemic bone loss in clinical studies of patients with RA. In this hand bone mineral density (BMD) substudy, we investigated the effects of denosumab on hand BMD and its correlation with hand erosion scores.

Methods

Patients receiving methotrexate for erosive RA were randomized in a 1:1:1 ratio to receive subcutaneous placebo, denosumab 60 mg, or denosumab 180 mg at 0 and 6 months. Measurements included BMD (by dual x‐ray absorptiometry [DXA]) of both hands (0, 1, 6, and 12 months), magnetic resonance images of the hands/wrists (0 and 6 months), and radiographs of the hands/wrists and feet (0, 6, and 12 months).

Results

There were 56 patients (13 placebo, 21 denosumab 60 mg, and 22 denosumab 180 mg). Mean changes in hand BMD at 6 and 12 months were: +0.8% and +1.0%, respectively, for denosumab 60 mg; +2.0% and +2.5%, respectively, for denosumab 180 mg; and ?1.2% and ?2.0%, respectively, for placebo. Erosion scores remained near baseline in the denosumab groups and increased from baseline in the placebo group. A negative correlation was observed between hand BMD and erosion scores.

Conclusion

In patients with RA, denosumab provided protection against erosion, and not only prevented bone loss but increased hand BMD as measured by DXA.

     

Bone mineral density in Crohn's disease: a longitudinal study of budesonide,prednisone, and nonsteroid therapy

OBJECTIVE: Corticosteroids may contribute to the bone loss associated with Crohn's disease (CD). We investigated the effect on bone mineral density (BMD) of treatment with budesonide, a steroid with low systemic activity, and compared the outcome with prednisone and nonsteroid therapy in patients with CD. METHODS: Prospective annual BMDs of the lumbar spine (LS) and femoral neck (FN) were measured for 2 yr in 138 patients with quiescent CD treated with mean daily doses of 8.5 mg of budesonide (n = 48), 10.5 mg of prednisone (n = 45), or nonsteroid drugs (n = 45). RESULTS: Between baseline and 1 yr, the mean LS BMD decreased 2.36% in the budesonide group (p < 0.001), 0.61% in the prednisone group (ns), and 0.09% in the nonsteroid group (ns). The difference between budesonide and nonsteroid groups was significant (p = 0.003). In the 2nd yr, LS BMD did not change in the three groups. After 2 yr, FN BMD decreased 2.94% in the budesonide group (p < 0.01), 0.36% in the prednisone group (ns), and 1.05% in the nonsteroid group (ns); the differences among groups were not significant. The proportion of patients with bone loss of >2% per annum at the LS and FN was higher in the budesonide group than in the nonsteroid group (p < 0.001) and prednisone group (p < 0.05). CONCLUSIONS: Patients with CD receiving maintenance treatment for 2 yr with prednisone show little change in BMD, whereas treatment with budesonide may be associated with LS and FN bone loss. Budesonide does not confer an advantage over low-dose prednisone for the preservation of BMD.     

Early and rapid bone mineral density loss of the proximal femur in men

CONTEXT: The changes in bone mineral density (BMD; grams per square centimeter), a well-known predictor of future fracture risk, are not well investigated in young men. OBJECTIVE: The objective of the study was to investigate the changes in BMD in men between 17 and 26 yr of age. DESIGN: This was a longitudinal study. PARTICIPANTS: Participants included 107 healthy males with a mean age of 17 yr at baseline. BMD was also measured in 81 of their fathers at a mean age of 50 yr. MAIN OUTCOME MEASURES: BMD of the total body, proximal femur, and lumbar spine was measured at baseline and after mean periods of 27, 66, and 92 months in the young cohort. RESULTS: BMD of the total body and lumbar spine initially increased to reach a plateau during the study period. At the proximal femur, peak values were obtained at 19 yr of age, followed by significant losses of almost 0.02 g/cm(2) per year (P < 0.001). At this site, the fathers' BMD indicated a further loss of about 0.0085 g/cm(2) per year up to the age of 50 yr. The BMD development at all sites was positively associated with physical activity (P < 0.05). However, changes in physical activity, weight, and height did not explain the local BMD loss seen at the proximal femur. CONCLUSION: Early losses of BMD at the proximal femur were found in this male sample. The results indicate that 25% of peak BMD at this site may be lost by the age of 50 yr in men. We suggest that bone remodeling may be regulated differently at the proximal femur than at other sites.     

Risedronate reverses bone loss in postmenopausal women with low bone mass: results from a multinational, double-blind, placebo-controlled trial. BMD-MN Study Group

Our objective was to investigate the efficacy and tolerability of risedronate in postmenopausal women with low bone mass. Women with a mean lumbar spine T-score of -2 or less (n = 543) received 24 months of placebo or risedronate (2.5 or 5 mg/day). All received calcium (1 g/day). The principal outcome measures were bone mineral density (BMD) at the lumbar spine, femoral neck, and femoral trochanter. At 24 months, lumbar spine BMD increased from baseline by 4% with 5 mg risedronate and 1.4% in the 2.5-mg group, compared with no change with placebo. Efficacy was similar in women who were less than 5 yr and more than 5 yr postmenopausal. At 24 months, risedronate (5 mg) had also increased BMD at the femoral neck and trochanter, whereas BMD decreased in the placebo group. BMD increases were seen at all three sites with risedronate (5 mg) after only 6 months of therapy. Risedronate was well tolerated; upper gastrointestinal adverse events were similar to placebo. We conclude that risedronate (5 mg) increases BMD rapidly and effectively and is well tolerated in postmenopausal women with low bone mass, regardless of time since menopause.     

Annual zoledronate increases bone density in highly active antiretroviral therapy-treated human immunodeficiency virus-infected men: a randomized controlled trial

CONTEXT: Recent studies have reported low bone mineral density (BMD) in HIV-infected patients. Annual iv administration of 4 mg zoledronate has been shown to increase BMD and suppress bone turnover in postmenopausal women. OBJECTIVE: The objective of the study was to determine whether annual administration of 4 mg zoledronate will increase BMD in HIV-infected men receiving highly active antiretroviral therapy. DESIGN AND SETTING: A 2-yr randomized placebo-controlled trial was conducted in a clinical research center. PARTICIPANTS: A total of 43 HIV-infected men were treated with highly active antiretroviral therapy for at least 3 months, with BMD T score less than -0.5. INTERVENTION: Participants received annual iv administration of 4 mg zoledronate or placebo. All participants took 400 mg/d calcium and 1.25 mg/month vitamin D. MEASUREMENTS: BMD at the lumbar spine, total hip and total body, and bone turnover markers were measured. RESULTS: At the lumbar spine, BMD increased by 8.9% over 2 yr in the zoledronate group compared with an increase of 2.6% in the control group (P<0.001). At the total hip, BMD increased by 3.8% over 2 yr in the zoledronate group compared with a decrease of 0.8% in the control group (P<0.001). At the total body, BMD increased by 2.3% over 2 yr compared with a decrease of 0.5% in the control group (P<0.001). Urine N-telopeptide decreased by 60% at 3 months in the zoledronate group and thereafter remained stable. CONCLUSIONS: Annual administration of zoledronate is a potent and effective therapy for the prevention or treatment of bone loss in HIV-infected men. The current data provide the first trial evidence of the BMD effects of annual zoledronate beyond 1 yr in any population, as well as being the first reported trial in men.     

Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. Phase III Osteoporosis Treatment Study Group

We report here the second 2-yr extension of a clinical trial among postmenopausal women; 235 women continued blinded treatment with 5 or 10 mg alendronate daily, and 115 women who had been treated with alendronate for 5 yr were switched to blinded placebo. Continuous treatment with alendronate (10 mg daily) for 7 yr increased lumbar spine bone mineral density (BMD) by 11.4% compared to baseline. After the initial 18 months, each additional year of treatment through yr 7 increased spine BMD by 0.8% for the 10-mg dose and 0.6% for the 5-mg dose, with significant increases during yr 6-7. Previously reported increases in BMD at other skeletal sites and decreases in biochemical markers of bone turnover remained stable during yr 6-7. Among women previously taking alendronate for 5 yr who were switched to placebo, there was no significant decline in BMD at the spine or hip, whereas small, but significant, decreases in BMD at the forearm and total body and small increases in biochemical markers were observed. The safety and tolerability profiles were similar to those of placebo. This is the largest published long-term study of antiresorptive therapy. Our findings indicate that long-term alendronate treatment is well tolerated and effective for 7 yr. Increases in spinal BMD continue for at least 7 yr, and other skeletal benefits are maintained. Discontinuation does not lead to accelerated bone loss, but continuous treatment yields better skeletal benefits than shorter treatment.     

Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60

Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency.     

The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years

Context: Primary hyperparathyroidism (PHPT) often presents without classical symptoms such as overt skeletal disease or nephrolithiasis. We previously reported that calciotropic indices and bone mineral density (BMD) are stable in untreated patients for up to a decade, whereas after parathyroidectomy, normalization of biochemistries and increases in BMD ensue. Objective: The objective of the study was to provide additional insights in patients with and without surgery for up to 15 yr. Design: The study had an observational design. Setting: The setting was a referral center. Patients: Patients included 116 patients (25 men, 91 women); 99 (85%) were asymptomatic. Intervention: Fifty-nine patients (51%) underwent parathyroidectomy and 57 patients were followed up without surgery. Main Outcome Measure: BMD was measured. Results: Lumbar spine BMD remained stable for 15 yr. However, BMD started to fall at cortical sites even before 10 yr, ultimately decreasing by 10 +/- 3% (mean +/- sem; P < 0.05) at the femoral neck, and 35 +/- 5%; P < 0.05 at the distal radius, in the few patients observed for 15 yr. Thirty-seven percent of asymptomatic patients showed disease progression (one or more new guidelines for surgery) at any time point over the 15 yr. Meeting surgical criteria at baseline did not predict who would have progressive disease. BMD increases in patients who underwent surgery were sustained for the entire 15 yr. Conclusions: Parathyroidectomy led to normalization of biochemical indices and sustained increases in BMD. Without surgery, PHPT progressed in one third of individuals over 15 yr; meeting surgical criteria at the outset did not predict this progression. Cortical bone density decreased in the majority of subjects with additional observation time points and long-term follow-up. These results raise questions regarding how long patients with PHPT should be followed up without intervention.     

Prevention of postmenopausal bone loss: six-year results from the Early Postmenopausal Intervention Cohort Study

We report the effect of continuous treatment with alendronate for 6 yr vs. placebo in the Early Postmenopausal Intervention Cohort study. A total of 1609 healthy, early postmenopausal women were recruited; we describe results for the 585 women who received continuous placebo or alendronate (2.5 or 5 mg) daily for 6 yr. Bone mineral density (BMD) was evaluated at the lumbar spine, hip, forearm, and total body at baseline and annually thereafter. Bone turnover markers were measured every 6 months from baseline to yr 2 and annually thereafter. Adverse experiences, including upper gastrointestinal events and fractures, were recorded throughout the study. Women receiving placebo experienced progressive decreases in BMD at all skeletal sites. Patients receiving alendronate experienced significant gains in spine and hip BMD that were maintained through yr 6. Significantly greater, dose-related decreases in bone turnover markers in the alendronate groups vs. placebo occurred within the first year and were sustained through yr 6. Women receiving alendronate had adverse experience incidences similar to those receiving placebo. Fractures occurred in 11.5, 10.3, and 8.9% of women taking placebo, 2.5 mg alendronate, or 5 mg alendronate daily, respectively. Therapy with alendronate is an effective and promising strategy for the prevention of postmenopausal osteoporosis.     

Age-related changes in bone density among healthy Greek males.

Osteoporosis in men is increasingly recognized as a problem in clinical medicine, but it has received much less attention than its counterpart in women. It is termed idiopathic if no known cause of bone disease can be identified clinically or in the laboratory. The true incidence of idiopathic osteoporosis (IO) in males is difficult to estimate because population characteristics and referral patterns differ so widely. The aim of this study was to investigate the incidence of IO in healthy Greek male volunteers by measuring bone mineral density (BMD) at four skeletal sites and examining the relations among age, BMI, and bone status. This type of information has not yet been published. We considered osteoporosis to be present when the BMD was less than or equal to -2.5 SD from the average value for healthy young men. Three hundred and sixty-three normal male volunteers were investigated. The mean age was 51.3+/-8.7 yr, and BMI was 27.5+/-3.7 kg/m2. In all subjects BMD at four skeletal sites - lumbar spine (LS), femoral neck (FN), Ward's triangle (WT), and finally trochanter (T) - was measured using dual-energy X-ray absorptiometry (DEXA). T-score, Z-score and g/cm2 values were estimated. Forty-four subjects (11%) had BMD< or =-2.5 SD (T-score). The mean age and BMI for the men with decreased BMD was 54.8+/-6.4 yr and 26.3+/-3.3 kg/m2, whereas mean age and BMI for those with normal BMD was 51.0+/-8.9 yr and 27.6+/-3.6 kg/m2, respectively. These differences were statistically significant (p<0.001 and p<0.05, respectively). A positive correlation was found between BMI and bone density (g/cm2) at three skeletal sites: LS (r=0.235, p<0.001), WT (r=0.126, p<0.001) and FN (r=0.260, p<0.001). A positive correlation was also found between BMI and T-score at all skeletal sites studied: LS (r=0.276, p<0.001), WT (r=0.133, p<0.05), FN (r=0.233, p<0.001), and T (r=0.305, p<0.001). Finally, a positive correlation was also found between BMI and Z-score: LS (r=0.256, p<0.001), WT (r=0.117, p<0.005), FN (r=0.240, p<0.001), and T (r=0.187, p<0.001). A negative correlation was found between age and bone density (g/cm2) at FN (r=-0.157, p<0.01) and WT (r=-0.183, p<0.001). The same was true between age and T-score at FN only (r=0.137, p<0.05). Furthermore, a similar correlation was found between age and Z-score at LS (r=0.174, p<0.001). When ANOVA one-way analysis was used, a significant difference was found between the different age groups and BMD (g/cm2) at FN, T, and WT (p<0.001 for all sites). For T-score, a significant difference between age groups was found only at FN (p<0.005). Finally, a significant difference in Z-score was found at FN (p<0.001) and LS (p<0.005). When multiple regression analysis was applied, it was found that BMD (g/cm2) at two sites, FN and WT, independently correlated with age and BMI (FN: p<0.001 for both, WT: p<0.01 and p<0.05, respectively). Finally, we found an accelerated trend toward decreased BMD (g/cm2), when the odds ratio was applied. In conclusion, this study demonstrated that 11% of otherwise healthy Greek men had BMD less than or equal to -2.5 SD. A strong association was found between BMD (g/cm2) and age at three skeletal sites when ANOVA one-way analysis was applied. Moreover, BMD was positively correlated with BMI and negatively correlated with age. Currently available data are sparse and much more research is needed to increase our understanding concerning the etiology of this condition as well as illuminating the relationship between bone density and fracture.     

Comparison of weekly treatment of postmenopausal osteoporosis with alendronate versus risedronate over two years

OBJECTIVE: A 1-yr extension of the Fosamax Actonel Comparison Trial was completed to compare changes in bone mineral density (BMD), bone turnover, and upper gastrointestinal tolerability over 2 yr of treatment. DESIGN: This was a randomized, double-blind extension conducted at 72 U.S. sites. PATIENTS AND METHODS: Of the 1053 women who completed yr 1, 833 postmenopausal women with low BMD entered the extension, continuing their same treatment allocation [once-weekly (OW) alendronate 70 mg or OW risedronate 35 mg]. Changes in BMD at the hip trochanter, total hip, femoral neck, and lumbar spine and in markers of bone turnover were compared at 24 months. Tolerability was assessed by adverse experience reporting. RESULTS: Alendronate produced greater increases from baseline in BMD at 24 months than did risedronate at the trochanter (alendronate, 4.6%; risedronate, 2.5%, P < 0.001) as well as at all other BMD sites. Significantly more alendronate than risedronate patients had measured BMD increases of 0% or more and 3% or more at all BMD sites (P < 0.001), and fewer alendronate patients had measured decreases of 3% or more at all BMD sites. Significantly greater reductions in all biochemical markers of bone turnover occurred with alendronate, compared with risedronate. No differences were seen in occurrence or discontinuations due to upper gastrointestinal adverse experiences. CONCLUSIONS: Patients receiving 70 mg OW alendronate had greater gains in BMD, were more likely to maintain or gain BMD, and had greater reductions in bone turnover markers than patients receiving 35 mg OW risedronate after 24 months, with no differences in upper gastrointestinal tolerability.     

Is twice-yearly denosumab beneficial in postmenopausal women with osteopenia but no history of fracture?

This Practice Point commentary discusses the findings and limitations of the first randomized, placebo-controlled trial of twice-yearly denosumab to be performed in postmenopausal women with low BMD but no previous fracture. Bone et al. found that treatment with denosumab significantly increased BMD at all sites measured and reduced the levels of bone turnover markers when compared with placebo. Despite these beneficial effects, denosumab was associated with increased rates of sore throat, rash and infections requiring hospitalization. Furthermore, the study was limited by lack of information on antifracture efficacy, although such information will presumably be forthcoming in the near future. Here, I highlight how denosumab therapy differs from other antiresorptive agents with respect to mechanism of action and effects on BMD. The findings of Bone et al. suggest that denosumab might represent a novel anti-osteoporosis agent. Nonetheless, further investigations of efficacy and long-term safety are needed before denosumab can be adopted into routine clinical practice.     

Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone

Older men, particularly those with low serum testosterone (T) levels, might benefit from T therapy to improve bone mineral density (BMD) and reduce fracture risk. Concerns exist, however, about the impact of T therapy on the prostate in older men. We hypothesized that the combination of T and finasteride (F), a 5 alpha-reductase inhibitor, might increase BMD in older men without adverse effects on the prostate. Seventy men aged 65 yr or older, with a serum T less than 12.1 nmol/liter on two occasions, were randomly assigned to receive one of three regimens for 36 months: T enanthate, 200 mg im every 2 wk with placebo pills daily (T-only); T enanthate, 200 mg every 2 wk with 5 mg F daily (T+F); or placebo injections and pills (placebo). Low BMD was not an inclusion criterion. We obtained serial measurements of BMD of the lumbar spine and hip by dual x-ray absorptiometry. Prostate-specific antigen (PSA) and prostate size were measured at baseline and during treatment to assess the impact of therapy on the prostate. Fifty men completed the 36-month protocol. By an intent-to-treat analysis including all men for as long as they contributed data, T therapy for 36 months increased BMD in these men at the lumbar spine [10.2 +/- 1.4% (mean percentage increase from baseline +/- SEM; T-only) and 9.3 +/- 1.4% (T+F) vs. 1.3 +/- 1.4% for placebo (P < 0.001)] and in the hip [2.7 +/- 0.7% (T-only) and 2.2 +/- 0.7% (T+F) vs. -0.2 +/- 0.7% for placebo, (P < or = 0.02)]. Significant increases in BMD were seen also in the intertrochanteric and trochanteric regions of the hip. After 6 months of therapy, urinary deoxypyridinoline (a bone-resorption marker) decreased significantly compared with baseline in both the T-only and T+F groups (P < 0.001) but was not significantly reduced compared with the placebo group. Over 36 months, PSA increased significantly from baseline in the T-only group (P < 0.001). Prostate volume increased in all groups during the 36-month treatment period, but this increase was significantly less in the T+F group compared with both the T-only and placebo groups (P = 0.02). These results demonstrate that T therapy in older men with low serum T increases vertebral and hip BMD over 36 months, both when administered alone and when combined with F. This finding suggests that dihydrotestosterone is not essential for the beneficial effects of T on BMD in men. In addition, the concomitant administration of F with T appears to attenuate the impact of T therapy on prostate size and PSA and might reduce the chance of benign prostatic hypertrophy or other prostate-related complications in older men on T therapy. These findings have important implications for the prevention and treatment of osteoporosis in older men with low T levels.     

Circulating levels of inflammatory markers predict change in bone mineral density and resorption in older adults: a longitudinal study

CONTEXT: IL-1, IL-6, and TNF-alpha play an important role in the pathogenesis of osteoporosis in animals; however, evidence that these play a similar role in bone loss in human studies is limited. OBJECTIVE: Our objective was to determine the associations between serum markers of inflammation and changes in bone mineral density (BMD) and urinary pyridinoline (PYR) to creatinine (Cr) ratio over 2.9 yr in older adults. METHODS: A total of 168 randomly selected subjects (mean 63 yr, range 52-78, 48% female) was studied. BMD was measured by dual-energy x-ray absorptiometry at baseline (mean T score: -0.18 to -0.61) and 2.9 yr later. Serum high-sensitivity (hs) C-reactive protein (CRP), IL-6, TNF-alpha, and the urinary PYR/Cr ratio were measured on both occasions. RESULTS: The mean annual loss of BMD was 0.15, 0.15, and 0.34% at total body, spine, and hip, respectively. Change in total body BMD was associated with baseline hs-CRP, IL-6, and TNF-alpha, as well as change in hs-CRP (beta: -0.41%/U, 95% confidence interval -0.68%, -0.15%) and IL-6 (beta: -0.62%/U, 95% confidence interval -1.01%, -0.23%). If these markers were put in the same predictive model, only IL-6 remained largely unchanged. Changes in other BMD sites were significantly predicted by IL-6 (hip and spine) and TNF-alpha (spine only). Finally, change in the PYR/Cr ratio was positively associated baseline IL-6, hs-CRP, and their changes (all P < 0.05) in women, but not men. CONCLUSIONS: Variation within the low levels of inflammatory markers observed in this study, especially IL-6, predicts bone loss and resorption, suggesting that targeted antiinflammatory therapy has potential for the prevention of osteoporosis.     

Predicting bone loss following orthotopic liver transplantation

BACKGROUND: Hepatic osteodystrophy occurs in the majority of patients with advanced chronic liver disease with the abnormalities in bone metabolism accelerating following orthotopic liver transplantation (OLT). AIMS: To examine changes in bone mineral density (BMD) following OLT and to investigate factors that lead to bone loss. METHODS: Twelve patients had BMD (at both the lumbar spine (LS) and femoral neck (FN)) and biochemical markers measured preoperatively and for 24 months following OLT. RESULTS: BMD was low in 75% of patients prior to OLT and decreased significantly from baseline at the LS at three months and the FN at six months. BMD began to increase thereafter at both sites, approaching baseline values at the LS by 12 months. Bone formation markers, osteocalcin and procollagen type I carboxy propeptide, decreased immediately post-OLT, with a concomitant increase seen in the resorption markers pyridinoline and deoxypyridinoline. This resulted in a negative uncoupling index early post-OLT, that rebounded to positive values after six months. There was a significant correlation between the change in the uncoupling index between six and three months which preceded the increase in BMD at 12 months. The decrease in BMD recorded early post-OLT correlated with vitamin D levels at three months. CONCLUSIONS: Results suggest that increased resorption and inadequate formation are the major contributors to additional bone loss following OLT. Non-invasive biochemical markers precede later changes in BMD in this patient group following OLT and may have a role in investigating and planning intervention strategies to prevent bone loss in future studies.     

Efficacy of Denosumab for Osteoporosis in Patients with Rheumatic Diseases

Objective Denosumab, an anti-RANKL monoclonal antibody, was reported to improve bone mineral density (BMD) and reduce fracture risk, offering favorable efficacy against postmenopausal osteoporosis. However, some patients have experienced a reduced BMD despite denosumab therapy. Methods We performed an observational study to clarify the clinical efficacy of denosumab for osteoporosis in rheumatic disease patients. Serum levels of bone turnover markers and lumber BMD in 100 rheumatic disease patients were examined at baseline and 6 and 12 months after denosumab therapy. The independent influence of changes in the BMD was examined by multiple regression analyses adjusted for patient characteristics and bone turnover markers. Results As bone resorption markers, serum levels of N-telopeptide crosslinked of type I collagen (NTx) and tartrate-resistant acid phosphatase isoform 5b were statistically decreased after 12 months. As bone formation markers, serum levels of osteocalcin, procollagen type I N-terminal peptide, and bone alkaline phosphatase were significantly decreased after 12 months. The mean BMD was significantly increased after 12 months. However, in 10 patients, the BMD decreased. A multivariate analysis of factors related to BMD changes highlighted a young age, low prednisolone dosage, and reduction in NTx. Conclusions Denosumab increases the BMD to combat osteoporosis in rheumatic disease patients, and potential predictors of a better response to denosumab include a young age, reduction in bone turnover markers, and low-dose glucocorticoid use.     

Effects of calcium and vitamin D supplementation on hip bone mineral density and calcium-related analytes in elderly ambulatory Australian women: a five-year randomized controlled trial

CONTEXT: Effects of long-term calcium, with or without vitamin D, on hip bone mineral density (BMD) and bone turnover in sunny climates have not been reported. OBJECTIVE: The aim was to evaluate the effect of vitamin D added to calcium supplementation on hip dual-energy x-ray absorptiometry BMD and calcium-related analytes. DESIGN, SETTING, AND PARTICIPANTS: The study was a 5-yr randomized, controlled, double-blind trial of 120 community-dwelling women aged 70-80 yr. INTERVENTIONS: The interventions were 1200 mg/d calcium with placebo vitamin D (Ca group) or with 1000 IU/d vitamin D2 (CaD group), or double placebo (control). MAIN OUTCOME MEASURES: Hip BMD, plasma 25-hydroxyvitamin D, biomarkers of bone turnover, PTH, and intestinal calcium absorption were measured. RESULTS: Hip BMD was preserved in CaD (-0.17%) and Ca (0.19%) groups but not controls (-1.27%) at yr 1 and maintained in the CaD group only at yr 3 and 5. The beneficial effects were mainly in those with baseline 25-hydroxyvitamin D levels below the median (68 nmol/liter). At yr 1, compared with controls, the Ca and CaD groups had 6.8 and 11.3% lower plasma alkaline phosphatase, respectively (P相似文献   

Effect of discontinuation of estrogen,calcitriol, and the combination of both on bone density and bone markers

In a 5-yr randomized prospective study we examined the treatment effect of estrogen replacement therapy/hormone replacement therapy (ERT/HRT), calcitriol, ERT/HRT and calcitriol, or placebo for 3 yr and the effect of discontinuation of therapy for 2 more yr on bone mineral density (BMD), calciotropic hormones, markers of bone remodeling, and calcium absorption in 489 elderly women. The treatment phase of the study was double-blinded. After discontinuing therapy for 2 yr, there was rapid bone loss in all 3 treatment groups, and most of the decrease in BMD occurred in the first year. In the ERT/HRT group, spine BMD increased 5.5% in yr 3, decreased 3.2% in yr 4, and decreased 0.7% in yr 5; femoral neck BMD increased 3.7% in yr 3, decreased 2.5% in yr 4, and decreased 0.4% in yr 5; total body BMD increased 2.1% in yr 3, decreased 1.4% in yr 4, and decreased 0.6% in yr 5. In the combination group, spine BMD increased 7.1% in yr 3, decreased 4.3% in yr 4, and decreased 0.3% in yr 5; femoral neck BMD increased 4.5% in yr 3, decreased 3.0% in yr 4, and decreased 0.01% in yr 5; total body BMD increased 2.2% in yr 3, decreased 1.5% in yr 4, and decreased 0.6% in yr 5. In the calcitriol group, spine BMD increased 1.8% in yr 3, decreased 1.8% in yr 4, and showed no change in yr 5; femoral neck BMD increased 0.2% in yr 3, decreased 0.2% in yr 4, and decreased 0.6% in yr 5; total body BMD decreased 0.4% in yr 3, decreased 0.6% in yr 4, and decreased 0.4% in yr 5. Compared with placebo, all treated groups at yr 5 had significantly higher total body BMD; only the combination group had significantly higher spine BMD (3.4%; P < 0.001) and total hip BMD (2.4%; P < 0.01.) compared with the placebo group. Compared with baseline, only spine BMD in the combination group was significantly higher (2.6%; P < 0.001) at yr 5. The increase in calcium absorption and the decrease in serum PTH levels in the calcitriol groups were reversed after discontinuation of treatment, and the decrease in bone markers was reversed in the hormone-treated groups. These results suggest that discontinuation of ERT/HRT and/or calcitriol therapy in elderly women leads to a decrease in much of the BMD gained on treatment; however, in the combination group there was a statistically significant residual effect on spine BMD.