Bisphosphonates in the treatment of Charcot neuroarthropathy: a double-blind randomised controlled trial.

The purpose of this study is to evaluate the effect of VD supplementation alone on bone turnover markers in younger postmenopausal women. In this double-blind, placebo-controlled trial, 160 women were randomized into the VD group (supplementation with 1000IU of vitamin D3/day, orally; n = 80) or placebo group (n = 80). Women aged 50-65years with amenorrhea ≥ 12months and normal bone mineral density were included. The intervention lasted 9months, and the participants were assessed at the beginning and end of treatment. Serum levels of total calcium, parathormone (PTH), alkaline phosphatase (AP), and 24-h urine calcium were determined. Serum C-terminal telopeptide of type I collagen (s-CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured by immunoassay as markers of bone resorption and formation, respectively. Plasma 25-hydroxyvitamin-D [25(OH)D] concentrations were measured by HPLC. Intention-to-treat analysis was performed using ANOVA, Student's t test, Tukey's test, and gamma distribution. Over the period of 9months, 25(OH)D concentrations increased from 15.0 ± 7.5 to 27.5 ± 10.4ng/mL (+ 45.4%) in the VD group and decreased from 16.9 ± 6.7 to 13.8 ± 6.0ng/mL (- 18.5%) in the placebo group (p< 0.001). There was a decrease (- 21.3%) of PTH levels in the VD group with a significant difference between groups at the end of the study (p< 0.001). No significant differences were observed in the other laboratory parameters (total calcium, AP, and calciuria) in either group (p> 0.05). A comparison of bone turnover markers showed a significant reduction in of s-CTX (- 24.2%, p< .0001) and P1NP (- 13.4%, p= 0.003) levels in the VD group. No significant variations in bone turnover markers were observed in the placebo group (s-CTX, - 6.9%, p= 0.092 and P1NP, - 0.6%, p= 0.918). In younger postmenopausal women with VD deficiency, isolated supplementation with 1000IU of vitamin D3 for 9months is associated with a reduction in bone turnover markers. However, any between-group differences was not observed in bone turnover markers.

To determine the effects of continuation versus discontinuation of alendronate on BMD and markers of bone turnover, we conducted an extension trial in which 1099 older women who received alendronate in the FIT were re-randomized to alendronate or placebo. Compared with women who stopped alendronate, those continuing alendronate for 3 years maintained a higher BMD and greater reduction of bone turnover, showing benefit of continued treatment. However, among women who discontinued alendronate and took placebo in the extension, BMD remained higher, and reduction in bone turnover was greater than values at FIT baseline, showing persistence of alendronate's effects on bone. Prior trials including the Fracture Intervention Trial (FIT) have found that therapy with alendronate increases BMD and decreases fracture risk for up to 4 years in postmenopausal women with low BMD. However, it is uncertain whether further therapy with alendronate results in preservation or further gains in BMD and if skeletal effects of alendronate continue after treatment is stopped. We conducted a follow-up placebo-controlled extension trial to FIT (FIT long-term extension [FLEX]) in which 1099 women 60-86 years of age who were assigned to alendronate in FIT with an average duration of use of 5 years were re-randomized for an additional 5 years to alendronate or placebo. The results of a preplanned interim analysis at 3 years are reported herein. Participants were re-randomized to alendronate 10 mg/day (30%), alendronate 5 mg/day (30%), or placebo (40%). All participants were encouraged to take a calcium (500 mg/day) and vitamin D (250 IU/day) supplement. The primary outcome was change in total hip BMD. Secondary endpoints included change in lumbar spine BMD and change in markers of bone turnover (bone-specific alkaline phosphatase and urinary type I collagen cross-linked N-telopeptide). Among the women who had prior alendronate therapy in FIT, further therapy with alendronate (5 and 10 mg groups combined) for 3 years compared with placebo maintained BMD at the hip (2.0% difference; 95% CI, 1.6-2.5%) and further increased BMD at the spine (2.5% difference; 95% CI, 1.9-3. 1%). Markers of bone turnover increased among women discontinuing alendronate, whereas they remained stable in women continuing alendronate. Cumulative increases in BMD at the hip and spine and reductions in bone turnover from 8.6 years earlier at FIT baseline were greater for women continuing alendronate compared with those discontinuing alendronate. However, among women discontinuing alendronate and taking placebo in the extension, BMD remained higher and reduction in bone turnover was greater than values at FIT baseline. Compared with women who stopped alendronate after an average of 5 years, those continuing alendronate maintained a higher BMD and greater reduction of bone turnover, showing benefit of continued alendronate treatment on BMD and bone turnover. On discontinuation of alendronate therapy, rates of change in BMD at the hip and spine resumed at the background rate, but discontinuation did not result in either accelerated bone loss or a marked increase in bone turnover, showing persistence of alendronate's effects on bone. Data on the effect of continuation versus discontinuation on fracture risk are needed before making definitive recommendations regarding the optimal length of alendronate treatment.

Surrogates for fracture endpoints in clinical trials.

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.

Initiation of antiretroviral therapy, particularly of regimens that contain tenofovir disoproxil fumarate (TDF), results in increased bone turnover and a reduction in bone mineral density. In addition, TDF has been associated with increased parathyroid hormone (PTH) and efavirenz with reduced vitamin D [25(OH)D] concentrations [1]. The mechanism of bone loss in patients receiving TDF remains incompletely understood. A recent study by Hsieh et al.[2] examined changes in bone-regulatory hormones and bone biomarkers in a single-arm study of 134 antiretroviral therapy-naïve Chinese patients who initiated TDF, lamivudine and efavirenz. Consistent with previous studies, the authors observed statistically significant increases in PTH and bone turnover [collagen type 1 cross-linked C-telopeptide (CTx) and total procollagen type 1 N-terminal propeptide (P1NP)] at 24 and 48 weeks. Although no change in 25(OH)D was observed, vitamin D–binding protein concentrations increased from baseline, prompting the authors to propose a potential role for this plasma protein in TDF-associated bone loss. We recently completed a clinical trial with a similar focus on vitamin D, bone turnover and bone mineral density [3]. Sixty-four patients with well controlled HIV on TDF, emtricitabine and efavirenz were randomized to remain on their treatment or to switch antiretroviral therapy to darunavir/ritonavir for 48 weeks. The switching strategy was associated with significant increases in 25(OH)D concentration, reductions in bone turnover (CTx and P1NP) and a 2–3% increase in bone mineral density at the hip, femoral neck and lumbar spine. Notably, the reductions in CTx and P1NP and the improvement in bone mineral density occurred in the absence of changes in vitamin D–binding protein (Fig. 1), PTH, estimated glomerular filtration rate or renal tubular function [3].Fig. 1: Plasma vitamin D binding protein concentrations in the MIDAS trial [3].DRV/r, darunavir/ritonavir; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate.Our results, as well as those of Hsieh et al.[2], are consistent with a direct effect of TDF on bone [4]. Although the increased bone turnover observed by Hsieh et al. may be the result of increased PTH concentrations with TDF exposure, the reduction in bone turnover markers in our patients who discontinued TDF was not accompanied by a reduction in PTH levels. The improved vitamin D status in our patients who switched therapy may have contributed to the decrease in bone turnover; however, the increase in bone mineral density in those switching off TDF was not explained by the increase in 25(OH)D, and the study by Hsieh et al.[2] demonstrates that TDF-induced increases in bone turnover may occur in the absence of changes in 25(OH)D status. Severe proximal tubulopathy may result in osteomalacia [5]. Both our data and those of Hsieh et al.[2] confirm that TDF-associated changes in bone turnover markers (and in our study, bone mineral density) may occur in the absence of changes in renal tubular function [6]. Moreover, our data do not support the hypothesis that TDF causes an increase in vitamin D–binding protein concentration, nor do they suggest that reductions in vitamin D–binding protein contribute to the improved bone mineral density that was observed following TDF discontinuation. Acknowledgements Conflicts of interest There are no conflicts of interest.

Potential Role of Pancreatic and Enteric Hormones in Regulating Bone Turnover

BackgroundEmerging data suggest that type 2 diabetes mellitus (T2D) is associated with an increased risk for fractures despite relatively normal or increased bone mineral density (BMD). Although the mechanism for bone fragility in T2D patients is multifactorial, whether glycemic control is important in generating this impairment in bone metabolism remains unclear. The purpose of our study is to identify a hemoglobin A1c (A1c) threshold level by which reduction in bone turnover begins in men with T2D.MethodA cross-sectional analysis of baseline data was obtained from 217 men, ages 35–65, regardless of the presence or absence of hypogonadism or T2D, who participated in 2 clinical trials. The following data were obtained: A1c by HPLC, testosterone and estradiol by LC/MS, bone turnover markers Osteocalcin [OC], C-terminal telopeptide [CTx], and sclerostin by ELISA, and BMD by DXA. Patients were grouped into 4 categories based of A1c (group I: <6%, group II: 6.0–6.4%, group III: 6.5–6.9%, and group IV: ≥7%). Threshold models were fit to the data using nonlinear regression and group comparisons among the different A1c categories performed by ANOVA.ResultsThreshold model and nonlinear regression showed an A1c cut-off of 7.0, among all choices of A1cs, yields the least sum of squared errors. A comparison of bone turnover markers revealed relatively lower OC (p = 0.002) and CTx (p = 0.0002) in group IV (A1c ≥7%), compared to the other groups. An analysis of men with T2D (n = 94) showed relatively lower OC (p=0.001) and CTx (p=0.002) in those with A1c ≥7% compared to those with <7%, respectively. The significance between groups persisted even after adjusting for medications and duration of diabetes.ConclusionAn analysis across our entire study population showed a breakpoint A1c level of 7% or greater is associated with lower bone turnover. Also in men with T2D, an A1c ≥7% is associated with low bone turnover.

To evaluate the effects of alfacalcidol on bone turnover in elderly women with osteoporosis, an open-label, prospective, calcium-controlled study was conducted. A total of 80 patients with osteoporosis were divided into two groups: the control group, group C (mean age, 78.0 years), in which patients were given calcium, and group D (mean age, 77.4 years), in which the patients were given alfacalcidol 1 micro g/day together with calcium for 6 months. Calcium regulation, lumbar bone mineral density (LBMD), and markers for bone turnover were assessed. A significant increase in urinary calcium/creatinine ratio (90% increase from baseline at 3 months; P = 0.0083, and 60% at 6 months; P = 0.0091) and a significant decrease in serum parathyroid hormone (30% decrease from baseline at 6 months; P < 0.0001) was observed in group D compared with the corresponding changes in group C. Significant decreases of bone resorption markers (deoxypyridinoline and N-telopeptide) at 6 months (about 15% decrease from the baseline values) were observed in group D compared with the corresponding changes in group C. The changes in bone formation markers (bone-derived alkaline phosphatase and osteocalcin) in group D were significantly different at 6 months (-21.5%; P = 0.0047 and -13.4%; P = 0.0032, respectively) from the values in group C. The magnitudes of the decrease in bone turnover markers were highly correlated with the corresponding baseline values, suggesting that alfacalcidol treatment effectively reduces bone turnover in patients with high bone turnover rates. The LBMD in group D increased by 1.7% and that in group C decreased by 1.6% ( P = 0.0384). The changes in calcium metabolism and LBMD were in good agreement with those in previous reports. Although the changes in bone turnover markers in group D were slight, significant reduction in bone turnover with alfacalcidol treatment, together with the change in calcium metabolism, may account for the effects of alfacalcidol on BMD and on fracture prevention reported previously. In conclusion, alfacalcidol reduces bone turnover in elderly women with high-bone-turnover osteoporosis, and it may have beneficial effects on bone.

Charcot neuroarthropathy is one of the most devastating complications of diabetes causing much discomfort and disability and sometimes leading to amputation. The current therapies are disappointing and fail to address the underlying disease process. In order to try and halt the underlying bone resorption we have studied the action of the bisphosphonate, pamidronate, in six diabetic patients with active Charcot neuroarthropathy. The treatment was associated with improvement in the patients' symptoms and a reduction in Charcot activity as measured by temperature of the affected foot which fell from 3.4 +/- 0.7 (SE) degrees C to 1.0 +/- 0.5 degrees C above the intact foot (p = 0.05). There was a significant reduction in bone turnover as judged by alkaline phosphatase activity which fell by 25 +/- 3% (p < 0.001). These preliminary data suggest that bisphosphonates may be the first definitive treatment for active Charcot neuroarthropathy and that controlled trials are now indicated.

Objective To investigate the effects of vitamin D deficiency on bone turnover and bone mineral density in patients with a blunted PTH response as compared to patients with vitamin D deficiency and secondary hyperparathyroidism.Method A total of 542 postmenopausal women [mean age (64.0 ± 10.8) years] were evaluated by assessing serum calcium,phosphate,alkaline phosphatase,25-hydroxy vitamin D (25-OHD),PTH,bone turnover markers such as osteocalcin,C-terminal telopeptide of type Ⅰ collagen(CTX) and procollagen type Ⅰ amino-terminal propeptide(PINP),and bone mineral density of lumber spine,total hip and femur neck etc.Result (1) The prevalence of vitamin D deficiency in this cohort was 24％.Mean 25-OHD varied across seasons (P =0.023) ; women who paid visits during winter and spring yielded significantly lower levels of 25-OHD than those who had their visit during the fall (P =0.012 and P =0.039).Serum PTH and bone turnover markers did not vary by season.(2) All subjects could be divided into four groups occording to their serum 25-OHD and PTH levels.Group 1:25-OHD＜ 10 ng/ml and PTH ≥ 65 pg/ml (7.0％),group 2:25-OHD ＜ 10 ng/ml and PTH ＜ 65 pg/ml (17.0％),group 3:25-OHD ≥ 10 ng/ml and PTH＜65 pg/ml (73.6％),group 4:25-OHD ≥ 10 ng/ml and PTH ≥ 65 pg/ml (2.4％).Blunted PTH response was found in 70.8％ of patients with vitamin D deficiency.Patients with vitamin D deficiency and a blunted PTH response were characterized by a lowered serum calcium,a reduction in bone turnover (serum CTX and serum osteocalcin),but protection in bone density as compared to those with vitamin D deficiency and secondary hyperparathyroidism.(3) As for spine bone mineral density,the significant independent predictors were body mass index(r2 =0.370,P＜0.01),age(r2 =-0.158,P＜0.01),PTH(r2 =-0.121,P＜0.05),and serum CTX(r2 =-0.118,P＜0.05).For femoral neck bone mineral density,the significant independent predictors were years since menopause(r2 =-0.201,P＜O.01) and body mass index(r2 =0.139,P＜0.05).And for hip bone mineral density,the significant independent predictors were age (r2 =-0.239,P＜0.01) and body mass index (r2 =0.239,P＜0.01).There was little correlation between 25-OHD and bone mineral density.Conclusion This study identifies a high prevalence of vitamin D deficiency in healthy postmenopausal women in shanghai,and a distinct group of patients with vitamin D deficiency and a blunted PTH response as shown by disruption in calcium homeostasis but protection against PTH-mediated bone loss.Compared with hip,spine bone mineral density is more sensitive to higher serum PTH and higher bone turnover. Key words: 25-hydroxy vitamin D; Serum parathyroid hormone; Hyperparathyroidism; Bone turnover; Bone mineral density

The purpose of the present study was to compare the effect of alendronate treatment on lumbar bone mineral density (BMD) and bone turnover in men and postmenopausal women with osteoporosis. Sixty men with primary or secondary osteoporosis and 318 women with postmenopausal osteoporosis were treated with alendronate. The primary end points were lumbar BMD and urinary cross-linked N-terminal telopeptides of type I collagen (NTX) and serum alkaline phosphatase (ALP) levels. The secondary end point was the incidence of vertebral and nonvertebral fractures. Forty-seven (78.3%) men and 254 (79.9%) women who could complete the 12-month trial were analyzed. The mean ages of men and postmenopausal women were 69.1 and 70.4 years, respectively. Both men and postmenopausal women showed higher levels of urinary NTX as compared with normal range of premenopausal women. Alendronate treatment decreased urinary NTX level by 39.2% in men and 45.4% in postmenopausal women at 3 months and serum ALP level by 17.8 and 21.0%, respectively, at 12 months. Following reduction in bone turnover markers, lumbar BMD increased 5.8 and 7.6% in men and postmenopausal women, respectively, at 12 months. Reduction in urinary NTX level and increase in lumbar BMD were smaller in men than in postmenopausal women. The incidence of vertebral and nonvertebral fractures was 10.6 and 8.5%, respectively, in men and 8.3 and 7.5%, respectively, in postmenopausal women, with no significant difference in these incidences between them. These results suggested that alendronate treatment effectively increased lumbar BMD from baseline in men with primary or secondary osteoporosis following reduction in bone turnover, although its efficacy did not appear to be greater than in postmenopausal women with osteoporosis.

The purpose of the present study was to compare the effect of alendronate treatment on lumbar bone mineral density (BMD) and bone turnover in men and postmenopausal women with osteoporosis. Sixty men with primary or secondary osteoporosis and 318 women with postmenopausal osteoporosis were treated with alendronate. The primary end points were lumbar BMD and urinary cross-linked N-terminal telopeptides of type I collagen (NTX) and serum alkaline phosphatase (ALP) levels. The secondary end point was the incidence of vertebral and nonvertebral fractures. Forty-seven (78.3%) men and 254 (79.9%) women who could complete the 12-month trial were analyzed. The mean ages of men and postmenopausal women were 69.1 and 70.4 years, respectively. Both men and postmenopausal women showed higher levels of urinary NTX as compared with normal range of premenopausal women. Alendronate treatment decreased urinary NTX level by 39.2% in men and 45.4% in postmenopausal women at 3 months and serum ALP level by 17.8 and 21.0%, respectively, at 12 months. Following reduction in bone turnover markers, lumbar BMD increased 5.8 and 7.6% in men and postmenopausal women, respectively, at 12 months. Reduction in urinary NTX level and increase in lumbar BMD were smaller in men than in postmenopausal women. The incidence of vertebral and nonvertebral fractures was 10.6 and 8.5%, respectively, in men and 8.3 and 7.5%, respectively, in postmenopausal women, with no significant difference in these incidences between them. These results suggested that alendronate treatment effectively increased lumbar BMD from baseline in men with primary or secondary osteoporosis following reduction in bone turnover, although its efficacy did not appear to be greater than in postmenopausal women with osteoporosis.

The objective of the study was to evaluate the effects of alendronic acid once weekly relative to risedronic acid once weekly on bone mineral density (BMD), markers of bone turnover and tolerability in the treatment of osteoporosis in postmenopausal women. This was a randomised, double-masked, double-dummy multicentre international study (75 centres in 27 countries in Europe, the Americas and Asia-Pacific). A total of 1303 women were screened and 936 with low bone density (T-score < or = -2.0 at the spine, hip trochanter, total hip or femoral neck) were randomised; 91% (n = 854) completed the study. Patients were randomised to treatment with either active alendronic acid 70 mg weekly (Fosamax) and placebo identical to risedronic acid weekly or active risedronic acid 35 mg weekly (Actonel) and placebo identical to alendronic acid weekly for 12 months. The primary efficacy endpoint was the percentage change from baseline in hip trochanter BMD at 12 months. Secondary endpoints included the percentage change from baseline in lumbar spine, total hip and femoral neck BMD; biochemical markers of bone turnover (including serum bone-specific alkaline phosphatase [BSAP] and urinary type I collagen N-telopeptides [NTx]); and safety and tolerability as assessed by reporting of adverse experiences. Alendronic acid produced greater increases in BMD than did risedronic acid at 12 months at all sites measured. Mean percentage increases from baseline in hip trochanter BMD at month 12 were 3.56% and 2.71% in the alendronic acid and risedronic acid groups, respectively (treatment difference [95% CI]: 0.83% [0.22, 1.45; p = 0.008]). Mean percentage increases from baseline were greater with alendronic acid than risedronic acid at the lumbar spine, total hip and femoral neck BMD at month 12 (p = 0.002, p < 0.001, p = 0.039, respectively). Increases in BMD with alendronic acid compared with risedronic acid were also significantly greater at 6 months at the trochanter and total hip. There was a greater reduction in bone turnover with alendronic acid compared with risedronic acid: NTx decreased 58% with alendronic acid compared with 47% with risedronic acid at 12 months (p < 0.001); and BSAP decreased 45% with alendronic acid compared with 34% with risedronic acid at 12 months (p < 0.001). Overall tolerability and upper gastrointestinal tolerability were similar for both agents. Alendronic acid once weekly produced greater BMD increases at both hip and spine sites and greater reductions in bone turnover relative to risedronic acid once weekly. Both agents were well tolerated with no significant difference in upper gastrointestinal adverse experiences. Clinicians should consider these results when making treatment decisions for postmenopausal women with osteoporosis.

Bone in diabetes mellitus is characterized by an altered microarchitecture caused by abnormal metabolism of bone cells. Together with diabetic neuropathy, this is associated with serious complications including impaired bone healing culminating in complicated fractures and dislocations, especially in the lower extremities, so-called Charcot neuroarthropathy (CN). The underlying mechanisms are not yet fully understood, and treatment of CN is challenging. Several in vitro and in vivo investigations have suggested positive effects on bone regeneration by modifying biomaterials with sulfated glycosaminoglycans (sGAG). Recent findings described a beneficial effect of sGAG for bone healing in diabetic animal models compared to healthy animals. We therefore aimed at studying the effects of low- and high-sulfated hyaluronan derivatives on osteoclast markers as well as gene expression patterns of osteoclasts and osteoblasts from patients with diabetic CN compared to non-diabetic patients with arthritis at the foot and ankle. Exposure to sulfated hyaluronan (sHA) derivatives reduced the exaggerated calcium phosphate resorption as well as the expression of genes associated with bone resorption in both groups, but more pronounced in patients with CN. Moreover, sHA derivatives reduced the release of pro-inflammatory cytokines in osteoclasts of patients with CN. The effects of sHA on osteoblasts differed only marginally between patients with CN and non-diabetic patients with arthritis. These results suggest balancing effects of sHA on osteoclastic bone resorption parameters in diabetes.

Alendronate and raloxifene are antiresorptive agents with different mechanisms of action, each used to treat osteoporosis in postmenopausal women. This study was undertaken to compare the efficacy and tolerability of alendronate to raloxifene in postmenopausal women with low-bone density. Randomized, double-masked, double-dummy multicentre international study. Clinical trial centres in Europe, South America and Asia-Pacific. A total of 487 postmenopausal women with low bone density, based on bone mineral density (BMD) of the lumbar spine or hip (T-score < or =-2.0). Interventions. Patients received either alendronate 70 mg once weekly and daily placebo identical to raloxifene or raloxifene 60 mg daily and weekly placebo identical to alendronate for 12 months. Evaluations included BMD of the lumbar spine and hip and markers of bone turnover at 6 and 12 months and adverse event reporting. Alendronate demonstrated substantially greater increases in BMD than raloxifene at both lumbar spine and hip sites at 12 months. Lumbar spine BMD increased 4.8% with alendronate vs. 2.2% with raloxifene (P < 0.001). The increase in total hip BMD was 2.3% with alendronate vs. 0.8% with raloxifene (P < 0.001). Reductions in bone turnover were significantly larger with alendronate than raloxifene. Overall tolerability was similar, however, the proportion of patients reporting vasomotor events was significantly higher with raloxifene (9.5%) than with alendronate (3.7%, P = 0.010). The proportion of patients reporting gastrointestinal events was similar between groups. In postmenopausal women with low bone density, improvements in BMD and markers of bone turnover were substantially greater during treatment with alendronate compared to raloxifene.