Risedronate Reduces Osteoclast Precursors and Cytokine Production in Postmenopausal Osteoporotic Women

This paper studies the effect of oral risedronate on osteoclast precursors, osteoclast formation, and cytokine production in 25 osteoporotic women. Risedronate is effective in reducing the number of osteoclast precursors, their formation, vitality, and activity and the level of RANKL and TNF‐α in cultures. Introduction: Bisphosphonates inhibit bone resorption by acting against osteoclasts. Some in vitro studies suggest that they induce osteoclast apoptosis; others suggest that they exert an effect on the production of pro‐osteoclastogenic cytokines. The effect of risedronate on osteoclastogenesis by peripheral blood mononuclear cells (PBMCs) in postmenopausal osteoporosis has not been previously studied. This paper examined the influence of risedronate on the formation of osteoclast precursors and cytokine production within the compass of osteoclastogenesis in osteoporosis. Materials and Methods: This study was conducted on 38 osteoporotic women; 25 patients were treated with risedronate 5 mg/d, whereas 13 were treated with calcium 1 g/d and vitamin D 800 UI/d. The following parameters were assessed: changes in bone turnover, circulating osteoclast precursors, formation of osteoclasts in PBMC cultures, their activity and vitality, and variations in the production of pro‐osteoclastogenic cytokines before and after therapy. Results: After 3 mo of risedronate, there was a significant reduction in the number and degree of differentiation of osteoclast precursors, osteoclast formation, vitality and activity, and in the level of RANKL and TNF in cultures and of TNF and osteoprotegerin (OPG) in serum, whereas in the group treated with calcium and vitamin D, there were no significant changes. Conclusions: Our data show that risedronate is effective in lowering the number of circulating osteoclast precursors, their formation, vitality, and activity in cultures, and in reducing the level of pro‐osteoclastogenic cytokines in culture supernatants and in serum.     

Intermittent Therapy with 1,25 Vitamin D and Calcitonin Prevents Cyclosporin-Induced Alveolar Bone Loss in Rats

Bone loss associated with cyclosporin A (CsA) therapy can result in serious morbidity to patients. Intermittent administration of 1,25 Vitamin D and calcitonin reduces osteopenia in a murine model of postmenopausal osteoporosis. The purpose of this study was to evaluate the effects of this therapeutic approach on CsA-induced alveolar bone loss in rats. Forty male Wistar rats were allocated to four experimental groups according to the treatment received during 8 weeks: (1) CsA (10 mg/kg/day, s.c.); (2) 1,25 Vitamin D (2 μg/kg, p.o.; in weeks 1, 3, 5, and 7) plus calcitonin (2 μg/kg, i.p.; in weeks 2, 4, 6, and 8); (3) CsA concurrently with intermittent 1,25 Vitamin D and calcitonin administration; and (4) the control treatment group (vehicle). At the end of the 8-week treatment period, serum concentrations of bone-specific alkaline phosphatase, tartrate-resistant acid phosphatase (TRAP-5b), osteocalcin, interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) were measured and an analysis of bone volume, bone surface, number of osteoblasts, and osteoclasts was performed. CsA administration resulted in significant alveolar bone resorption, as assessed by a lower bone volume and an increased number of osteoclasts, and increased serum bone-specific alkaline phosphatase, TRAP-5b, IL-1β, IL-6, and TNF-α concentrations. The intermittent administration of calcitriol and calcitonin prevented the CsA-induced osteopenic changes and the increased serum concentrations of TRAP-5b and inflammatory cytokines. Intermittent calcitriol/calcitonin therapy prevents CsA-induced alveolar bone loss in rats and normalizes the production of associated inflammatory mediators.     

Involvement of interleukin-6 and prostaglandin E2 in periarticular osteoporosis of postmenopausal women with rheumatoid arthritis

In experimental arthritis, blocking of the receptor activator of nuclear factor κB ligand (RANKL) by osteo-protegerin (OPG) treatment prevents bone loss but not inflammation, suggesting that there are inflammation-related factors that regulate RANKL and OPG. However, it is not known which factors regulate RANKL and OPG in human inflammation-induced bone loss. To clarify the inflammation-related factors that play a role in periarticular osteoporosis in patients with rheumatoid arthritis (RA), the synovial fluid and synovium of the knee joint, and the periarticular cancellous bone of the femoral condyle were collected at surgery from postmenopausal women with RA or osteoarthritis (OA). All patients with RA had radiologic bone loss on the femoral condyles, while such a loss was not observed in patients with OA. The present study examined: (i) tumor necrosis factor α (TNFα), interleukin (IL)-1β and IL-6 levels in synovial fluid; (ii) TNFα, IL-1β and IL-6 messenger RNA (mRNA) expression in the synovium and the cancellous bone that contained bone marrow; and (iii) IL-6 and prostaglandin E₂ (PGE₂) production in cultured osteoblast-lineage cells derived from collagenase-treated cancellous bone fragments. Inflammation of the knee joints in patients with RA was confirmed by significantly higher proinflammatory cytokine levels in the synovial fluid and the synovium than those seen in patients with OA. In patients with RA, mRNA expression of IL-6, but not TNFα and IL-1β, in the cancellous bone and IL-6 and PGE₂ production in the osteoblast-lineage cells were significantly higher than in patients with OA. These findings suggest, for the first time, that IL-6 is involved in periarticular osteoporosis in postmenopausal women with RA. IL-6 and PGE₂ released from osteoblast-lineage cells could be, at least in part, responsible for human inflammation-induced bone loss. Received: August 28, 2000 / Accepted: November 9, 2000     

Risedronate reduces postoperative bone resorption after cementless total hip arthroplasty

Summary Forty-three patients who had undergone cementless THA were randomly assigned to receive no osteoactive drug or oral risedronate for 6 months. Postoperative decrease of BMD in the risedronate group was significantly lower than that seen in the control group in zones 1, 2, 3, 6, and 7. Introduction Proximal bone resorption around the femoral stem often has been observed after total hip arthroplasty (THA), could lead to late stem loosening. We previously reported the efficacy of etidronate on periprosthetic bone resorption after cementless THA. Recently risedronate is suggested to be effective for the prevention and treatment of for osteoporosis. The purpose of the present study was to evaluate the effects of risedronate on periprosthetic bone loss after cementless THA. Methods Forty-three patients who had undergone cementless THA were randomly assigned to receive no osteoactive drug (21 patients) or oral risedronate 2.5 mg/day (22 patients) for 6 months. Three patients were eliminated from the risedronate group because of dyspepsia. Periprosthetic bone mineral density (BMD) in seven regions of interest based on the zones of Gruen et al. was measured with dual energy X-ray absorptiometry at 3 weeks and 6 months postoperatively. Results At 6 months after surgery, postoperative decrease of BMD in the risedronate group was significantly lower than that seen in the control group in zones 1, 2, 3, 6, and 7 (p < 0.05, p < 0.01, p < 0.01, p < 0.05, and p < 0.05, respectively). Conclusion These outcomes suggested that risedronate might reduce the periprosthetic bone resorption after cementless THA.     

Changes in serum levels of receptor activator of nuclear factor-kappaB ligand, osteoprotegerin, IL-6 and TNF-alpha in patients with a concomitant head injury and fracture

Introduction  Several reports indicated that interleukin-6 (IL-6) and tumor necrosis factor α (TNF- α) play important regulatory roles in bone remodeling and homeostasis. In addition, receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) have been shown to be important regulators of osteoclastogenesis during bone remodeling, and their expressions were examined during fracture healing in a mouse model of tibial fracture. However, studies linking RANKL, OPG, IL-6 and TNF-α in patients with head injury and fracture are lacking. Patients and methods  Within the first few hours of admission to hospital and at 4, 8, and 12 weeks after the injury, we evaluated changes in serum levels of RANKL, OPG, IL-6 and TNF-α in 24 male patients with a concomitant head injury and fracture and in 26 male patients with fracture only. These levels were compared with those found in 36 healthy controls. Results  The RANKL/OPG ratios were found to significantly lower in patients with a concomitant head injury and fracture than in the controls immediately after admission and at 4, 8, and 12 weeks after the injury. In addition, RANKL/OPG ratios were significantly lower in patients with a concomitant head injury and fracture than in those with fracture at 8 and 12 weeks after the injury. The serum IL-6 levels were significantly higher in patients with a concomitant head injury and fracture than in the controls upon admission, and at 4, 8, and 12 weeks after the injury. Moreover, the serum IL-6 levels were significantly higher in patients with a head injury and fracture than in those with just a fracture at 4, 8, and 12 weeks after the injury. Conclusions  Based on these changes in the profiles of RANKL, OPG, and IL-6 and the RANKL/OPG ratio, altered repair of a fracture can occur in patients with a concomitant head injury and fracture. J. S. Lee and C. H. Ryu contributed equally to this study.     

运动联合利塞膦酸钠治疗绝经后女性骨质疏松症疗效分析

目的观察广场舞运动联合补充利塞膦酸钠防治绝经后骨质疏松症的疗效。方法 168名绝经后骨质疏松症妇女随机分为实验组和对照组,实验组进行广场舞锻炼联合补充利塞膦酸钠治疗,对照组单纯予以补充利塞膦酸钠治疗。实验前及实验干预后6个月和12个月分别检测两组受试者腰椎L1-4、股骨颈部及Ward区骨密度、VAS疼痛评分、骨代谢指标以及不良反应。结果治疗6个月及12个月,两组患者VAS评分不同程度降低,其中以治疗组骨痛的治疗效果要明显优于对照组(P0.05)。治疗12个月后两组腰椎L1-4、股骨颈部及Ward区骨密度明显升高(P0.05),而治疗组明显高于对照组(P0.05)。治疗后6个月及12月,两组血清OC及NTX I较治疗前比较改善明显(P0.05),和对照组比较,治疗组血清OC及NTX I水平改变更为明显(P0.05);而两组不良反应无明显差异(P0.05)。结论广场舞运动结合补充利塞膦酸钠可以有效改善绝经后骨质疏松症,是一种合适的治疗方案。     

跑台运动对去卵巢大鼠骨组织中OPG、RANKL和RUNX2 mRNA表达的影响

目的：观察去卵巢大鼠经跑台运动后其骨组织中OPG、RANKL和RUNX2mRNA表达变化,探讨力学刺激防治绝经后骨质疏松的作用机制。方法：健康3月龄雌性SD大鼠30只,体重（270±10）g,按随机方法平均分为假手术组、去卵巢组和跑台运动组,每组10只。假手术组仅在术中牵动卵巢并不行卵巢切除,其余两组均行卵巢切除术。假手术组和去卵巢组大鼠正常饲养;跑台运动组大鼠在术后1周开始在动物跑台上运动,跑速为18m／min,每次45min,1次／d,6d／周,共训练11周。12周后处死所有动物,取左侧股骨头,脱钙后石腊切片,用倒置相差显微镜观察其组织学变化;取右股骨头提总RNA,实时PCR法检测OPG、RANKL和RUNX2的mRNA表达情况。结果：去卵巢组骨小梁稀疏,骨细胞少,跑台运动组骨小梁粗壮增厚。去卵巢组骨组织中OPG的mRNA表达为（0．131±0．080）,RNAKL的mRNA表达为（8．013±3．550）,RUNX2的mRNA表达为（3．245±5．090）。跑台运动组其骨组织中OPG的mRNA表达为（0．566±0．260）,RANKL的mRNA表达为（5．232±3．670）,RUNX2的mRNA表达为（2．753±3．680）。和去卵巢组比较,跑台运动组的OPG的mRNA表达升高,差异有统计学意义;而RANKL和RUNX2的表达下降,差异无统计学意义。结论：力学刺激能通过促进去卵巢大鼠骨组织中OPG的表达而发挥其抗绝经后骨质疏松的效果,这对今后研究绝经后骨质疏松症的治疗提供了新的思路。     

The Relationships Between the Degree of β-Isomerization of Type I Collagen Degradation Products in the Urine and Aging, Menopause and Osteoporosis with Fractures

We have evaluated the effect of aging, menopause and osteoporosis on the measurements of both nonisomerized type I collagen C-telopeptide breakdown products (α-CTx) by radioimmunoassay (RIA) and β-isomerized type I collagen C-telopeptide breakdown products (β-CTx) by enzyme-linked immunosorbent assay (ELISA). In 86 premenopausal healthy women (PRE), 144 postmenopausal healthy women (POST), 74 patients with vertebral fractures (VX) and 61 patients with hip fractures (HX), urinary CTx excretion was measured by both ELISA and RIA assays. Samples were collected more than 6 months after fracture in the VX group and within 48 h after fracture in the HX group. In all subjects a highly significant correlation was found between α-CTx and β-CTx (r= 0.85). The values of β-CTx in the POST group greatly increased compared with those in the PRE group (% mean increase: 82%), while the values of α-CTx in the POST group moderately increased compared with those in the PRE group (% mean increase: 47%). The values of both α-CTx and β-CTx in the HX group were significantly higher than those in the other groups, but particularly the increase in mean α-CTx (211% for HX versus POST) was very high compared with the increase in mean β-CTx (68% for HX versus POST). Moreover, the α-CTx/β-CTx ratio in the HX group was significantly higher than in the other groups. These results suggest that both assays well reflect the increase in bone resorption associated with high bone turnover, especially, in osteoporotic patients with hip fracture. However, there was a difference between the urinary excretion of α-CTx and β-CTx in patients with hip fracture, so the α-CTx/β-CTx radio might be a good indicator reflecting the characteristics of bone metabolism for osteoporosis with hip fracture. Received: 9 March 1998 / Accepted: 21 September 1998     

Effect of Risedronate on Osteocyte Viability and Bone Turnover in Paired Iliac Bone Biopsies from Early Postmenopausal Women

It is unclear whether standard clinical doses of risedronate affect osteocyte viability. This study examined osteocyte viability and bone remodeling rate in early postmenopausal women (1–5 years after menopause) who were treated with a standard clinical dose of risedronate (5 mg/day, orally) for 1 year. Paired transiliac bone biopsies were obtained from 19 postmenopausal women at baseline and after 1-year treatment with placebo (n = 8, mean age 52.9 ± 3.4 years) or risedronate 5 mg/day (n = 11, mean age 52.5 ± 3.4 years). In these samples, we measured osteocyte- and bone remodeling-related variables in trabecular bone. In both the placebo and risedronate groups, empty lacunae were significantly decreased after 1-year treatment compared to baseline. There were no significant differences in osteocyte-related variables between placebo and risedronate. Risedronate significantly reduced bone-remodeling indices including mineralizing surface (MS/BS), bone formation rate (BFR/BS), and activation frequency (Ac.f). Risedronate treatment caused significantly lower MS/BS and Ac.f than placebo administration. In conclusion, risedronate 5 mg/day effectively inhibited bone remodeling but did not significantly reduce osteocyte viability in trabecular bone.     

Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis

The purpose of this randomized, double-masked, placebo-controlled study was to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis. The study was conducted at 80 study centers in Europe and Australia. Postmenopausal women (n= 1226) with two or more prevalent vertebral fractures received risedronate 2.5 or 5 mg/day or placebo; all subjects also received elemental calcium 1000 mg/day, and up to 500 IU/day vitamin D if baseline levels were low. The study duration was 3 years; however, the 2.5 mg group was discontinued by protocol amendment after 2 years. Lateral spinal radiographs were taken annually for assessment of vertebral fractures, and bone mineral density was measured by dual-energy X-ray absorptiometry at 6-month intervals. Risedronate 5 mg reduced the risk of new vertebral fractures by 49% over 3 years compared with control (p<0.001). A significant reduction of 61% was seen within the first year (p= 0.001). The fracture reduction with risedronate 2.5 mg was similar to that in the 5 mg group over 2 years. The risk of nonvertebral fractures was reduced by 33% compared with control over 3 years (p= 0.06). Risedronate significantly increased bone mineral density at the spine and hip within 6 months. The adverse-event profile of risedronate, including gastrointestinal adverse events, was similar to that of control. Risedronate 5 mg provides effective and well-tolerated therapy for severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures and improving bone density in women with established disease. Received: 29 September 1999 / Accepted: 10 November 1999     

Evidence that Treatment with Risedronate in Women with Postmenopausal Osteoporosis Affects Bone Mineralization and Bone Volume

Risedronate is used in osteoporosis treatment. Postmenopausal women enrolled in the Vertebral Efficacy with Risedronate Therapy trial received either risedronate (5 mg/day) or placebo for 3 years. Subjects received calcium and vitamin D supplementation if deficient at baseline. Lumbar spine bone mineral density (BMD) was measured at baseline and at 3 years. Quantitative back-scattered electron imaging (qBEI) was performed on paired iliac crest biopsies (risedronate, n = 18; placebo, n = 13) before and after treatment, and the mineral volume fraction in the trabecular bone was calculated. Combining dual-energy X-ray absorptiometric values with the mineral volume fraction for the same patients allowed us to calculate the relative change in trabecular bone volume with treatment. This showed that the effect on BMD was likely to be due partly to changes in matrix mineralization and partly due to changes in bone volume. After treatment, trabecular bone volume in the lumbar spine tended to increase in the risedronate group (+2.4%, nonsignificant) but there was a significant decrease (−3.7%, P < 0.05) in the placebo group. Calcium supplementation with adequate levels of vitamin D led to an ∼3.3% increase in mineral content in the bone material independently of risedronate treatment. This increase was larger in patients with lower matrix mineralization at baseline and likely resulted from correction of calcium/vitamin D deficiency as well as from reduced bone remodeling. Combining BMD and bone mineralization density distribution data show that in postmenopausal osteoporosis 3-year treatment with risedronate preserves or may increase trabecular bone volume, unlike placebo. This analysis also allows, for the first time, separation of the contributions of bone volume and matrix mineralization to the increase in BMD.     

绝经后骨质疏松及骨量减少患者治疗前后骨密度变化的研究

目的 观察利塞膦酸钠防治绝经后骨质疏松症的疗效。方法 绝经后骨质疏松症48例,对照组24例,服安慰剂,实验组24例,服利塞膦酸钠5 mg/d,两组每日均服凯思立D 1片,2组共观察6月。结果 利塞膦酸钠组腰椎、股骨颈及大粗隆的骨密度均明显升高(P<0.05),实验组总有效率为80.95％,明显高于对照组的45.45％(P<0.01)。结论 利塞膦酸钠能明显提高绝经后骨质疏松症患者的骨密度,副作用轻。     

Vitamin D status and response to treatment in post-menopausal osteoporosis

Summary  Treatment with anti-resorptive agents over 13 months was associated with for three to fivefold lower bone mineral density changes and 1.5-fold increased risk of incidence fracture in vitamin D insufficient as compared to vitamin D repleted postmenopausal osteoporotic women. Introduction  Several drugs were registered for the treatment of osteoporosis on the basis of clinical trials in which vitamin D repletion was a pre-requisite inclusion criteria and vitamin D supplements were used as adjunctive therapy. However, in routine clinical practice these supplements are not consistently recommended. Methods  We studied 1515 women with postmenopausal osteoporosis under treatment with anti-resorbing agents (alendronate, risedronate, raloxifene) for 13.1 months with an adherence > 75%. The patients were classified as vitamin D deficient (N = 514) or vitamin D repleted (N = 1001) according to risk factors (N = 1062) or the level of 25(OH) vitamin D [25(OH)D] above or below 50 nmol/l (N = 453). Results  Vitamin D deficient and vitamin D repleted subjects differed significantly for annualized spine and hip bone mineral density (BMD) changes adjusted for all available confounding factors (type of treatment, age, global calcium intake, baseline BMD values). One hundred fifty one patients suffered from a new incident clinical fracture. The adjusted odds ratio for incident fractures in vitamin D deficient as compared to vitamin D repleted women was 1.77 (1.20 – 2.59, 95% CI; p = 0.004). Conclusions  Optimal vitamin D repletion seems to be necessary to maximize the response to anti-resorbers in terms of both BMD changes and anti-fracture efficacy.     

Randomized Trial of Alendronate Plus Vitamin D<Subscript>3</Subscript> Versus Standard Care in Osteoporotic Postmenopausal Women with Vitamin D Insufficiency

Vitamin D insufficiency is common in patients with osteoporosis. We conducted a randomized trial comparing alendronate 70 mg combined with vitamin D₃ 5,600 IU in a single tablet (ALN/D5600, n = 257) with standard care chosen by the patients’ personal physicians (n = 258) in patients with postmenopausal osteoporosis (BMD T score ≤2.5 or ≤1.5 and a prior fragility fracture) who had vitamin D insufficiency (serum 25[OH]D values 8–20 ng/ml) and who were at risk of falls. Virtually all patients randomized to standard care received bisphosphonate therapy, and in approximately 70% of cases this was combined with vitamin D supplements. However, only 24% took ≥800 IU/day of supplemental vitamin D. At 6 months the proportion of patients with vitamin D insufficiency was 8.6% in the ALN/D5600 group compared with 31.0% in the standard care group (P < 0.001). Those in the ALN/D5600 group also had a greater reduction in urinary NTX/creatinine ratio (−57% vs. −46%, P < 0.001) and bone-specific alkaline phosphatase (−47% vs. −40%, P < 0.001). In the ALN/5600 group, by 12 months the increase in BMD was greater at the lumbar spine (4.9% vs. 3.9%, P = 0.047) and the total hip (2.2% vs. 1.4%, P = 0.035), significantly fewer patients were vitamin D—insufficient (11.3% vs. 36.9%, P < 0.001), and bone turnover marker (BTM) results were similar to those at 6 months. There was no difference between groups in those who experienced falls or fractures, and adverse events were similar. Based on the finding that ALN/D5600 was more effective than standard care at correcting vitamin D insufficiency, increasing BMD, and reducing BTMs in this patient group, greater attention needs to be directed toward optimizing the treatment of osteoporosis and correcting vitamin D deficiency in postmenopausal women.     

Effect of daily oral minodronate on vertebral fractures in Japanese postmenopausal women with established osteoporosis: a randomized placebo-controlled double-blind study

Summary  A randomized placebo-controlled trial was conducted to examine the effect of daily oral 1 mg minodronate on vertebral fractures in 704 postmenopausal women with established osteoporosis for 24 months. Minodronate treatment reduced vertebral fractures by 59% without serious adverse events. Minodronate is a safe and effective bisphosphonate for osteoporosis treatment. Introduction  Minodronate increases bone mineral density (BMD) in postmenopausal osteoporotic patients. However, its efficacy in reducing osteoporotic fractures has not been tested. Methods  To examine anti-fracture efficacy and safety of daily oral minodronate in postmenopausal women with established osteoporosis, a randomized, double-blind, placebo-controlled trial was conducted in 704 postmenopausal women (55 to 80 years) with one to five vertebral fractures and low BMD. Subjects were randomly assigned to receive daily oral 1 mg minodronate (n = 359) or placebo (n = 345) for 24 months, with daily supplements of 600 mg calcium and 200 IU vitamin D₃. Results  Daily 1 mg minodronate for 24 months reduced the risk of vertebral fractures by 59% (95% CI, 36.6–73.3%). Furthermore, when fractures during the first 6 months were eliminated, the risk of vertebral fractures from 6 to 24 months was reduced by 74% in minodronate-treated group. Minodronate treatment also reduced height loss. Bone turnover markers were suppressed by about 50% after 6 months of minodronate treatment and remained suppressed thereafter. The overall safety profile including gastrointestinal safety was similar between the two groups. Conclusions  Daily oral minodronate is safe, well-tolerated, and is effective in reducing vertebral fracture risk in postmenopausal women with established osteoporosis. ClinicalTrials.gov Identifier: NCT00212667.     

Physical training increases osteoprotegerin in postmenopausal women

The purpose of this study was to explore whether mechanical loading by exercise over a 1–year period in postmenopausal women had an effect on the receptor activator for nuclear factor kappa B ligand/osteoprotegerin (RANKL/OPG) system or the levels of the Wnt-signaling antagonist sclerostin. A total of 112 postmenopausal were randomized to either sedentary life (controls) or physical activity (training group). Ninety-two women fulfilled the study protocol. The training program consisted of three fast 30-min walks and one or two 1-h aerobic training sessions per week. The effect on the bone mineral density of the hip assessed with dual X-ray absorptiometry was positive as reported earlier. Blood samples were taken from participants at baseline and after 1 year and serum levels of OPG, RANKL and sclerostin were quantified together with the bone metabolism markers C-terminal telopeptide of collagen type I (CTX) and bone-specific alkaline phosphatase (BALP). The results were analyzed using an analysis of covariance model using baseline values as the covariate. The training group displayed a clear mean increase of OPG +7.55 pg/ml compared to controls (p = 0.007). The mean changes for RANKL +0.19 pg/ml (square-root transformed data) and sclerostin +0.62 pmol/l were non-significant (p = 0.13 and p = 0.34). The changes in bone turnover markers CTX and BALP showed a tendency to decrease in the training group versus controls but the changes were small and non-significant. Although our study is limited in number of participating women, we have been able to show an OPG-associated, and RANKL- and sclerostin-independent, training-induced inhibition of postmenopausal bone loss.     

The efficacy and tolerability of risedronate on bone mineral density and bone turnover markers in osteoporotic Chinese women: a randomized placebo-controlled study

Osteoporosis has become an important health problem in postmenopausal Asian populations as the prevalence of hip and vertebral fractures in some Asian countries has risen to approach that of Caucasian populations. Risedronate, a pyridinyl-bisphosphonate agent, is a potent inhibitor of bone resorption. Risedronate increases bone mineral density (BMD), reduces markers of bone turnover, and reduces the risk of fractures in Caucasian postmenopausal women. To determine the efficacy and tolerability of risedronate in Chinese, a multicenter, randomized, double blind, placebo controlled study was performed in Hong Kong. Sixty-five (65) postmenopausal osteoporotic Southern Chinese women, aged 67+/-6 years, were randomly assigned to receive either risedronate 5 mg daily (n=31) or placebo (n=34) for 12 months. All women received calcium carbonate 500 mg daily and vitamin D 400 IU daily. Mean baseline BMD T-score at the spine and total hip was -3.4 and -2.6, respectively. A significant increase in spine BMD was already evident at month 3 of risedronate treatment (P<0.001). Risedronate significantly increased BMD and reduced bone turnover markers as compared with placebo. The risedronate group had significant increase in BMD at 12 months at both the spine and hip when compared with the placebo group (L1-4 6.6% vs. 0.4%, P<0.001; total hip 2.7% vs. 0.3, P<0.0001; femoral neck 1.8% vs. 1.1%, P<0.02; trochanter 4% vs. 1.1%, P<0.0001, respectively). Significant changes in urine N-telopeptide (NTx) and serum osteocalcin were evident as early as 1 and 3 months, respectively, with risedronate treatment. No significant changes were seen in both BMD and bone markers in the placebo group. Risedronate was well tolerated without major adverse effects. We conclude that risedronate is an effective and well-tolerated agent for the treatment of postmenopausal osteoporosis in Asian population.     

Effects of risedronate or alfacalcidol on bone mineral density,bone turnover,back pain,and fractures in Japanese men with primary osteoporosis: results of a two-year strict observational study

Although osteoporosis in men is already a major public health problem, there is still a dearth of data about the effects of risedronate in male osteoporosis, especially in Japanese with primary osteoporosis. Therefore, the objective of our study was to investigate the effects of risedronate on bone mineral density (BMD), bone turnover, back pain, and fractures in these patients prospectively for two years (at baseline, three months, six months, twelve months, and twenty-four months) both longitudinally and compared with those of alfacalcidol. The subjects enrolled for this study were 66 Japanese male patients with untreated primary osteoporosis (mean age 63.52 ± 8.7 years), who were divided into two groups (44 with risedronate and 22 with alfacalcidol). We measured BMD by dual energy X-ray absorptiometry at three sites—the lumbar spine, femoral neck, and distal radius. Risedronate treatment significantly increased BMD at the lumbar spine and at the femoral neck, reduced bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx), and reduced back pain, both longitudinally and compared with alfacalcidol treatment. We observed a lower rate of incident fracture in risedronate users. However, multiple logistic regression analysis revealed that this trend was not statistically significant, possibly because of the small number of patients enrolled. These potentially beneficial effects of risedronate on bone in male patients with primary osteoporosis suggest the possibility that osteoporosis should be treated with risedronate regardless of gender in order to effectively prevent subsequent osteoporotic fractures.     

Relationships between insulin-like growth factor-I (IGF-I) and OPG, RANKL, bone mineral density in healthy Chinese women

Summary Serum IGF-I level was negatively correlated with OPG and OPG/RANKL ratio, but positively correlated with RANKL. Serum OPG level in the highest quintile of IGF-I was significantly lower than that in the lowest. We conclude that the effect of IGF-I on bone remodeling may be mediated by the OPG/RANKL system. Introduction Insulin-like growth factor I (IGF-I) is an important factor in coupling bone remodeling, activating both formation and resorption. Compared with the many studies on the role of IGF-I in bone formation, the information regarding its effects on bone resorption is limited and conflicting. The balance of the two peptides produced by osteoblasts, osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL), is critical for the bone resorption process. Our study was designed to analyze the relationships of serum concentrations of IGF-I with OPG, RANKL, OPG/RANKL ratio as well as BMDs in healthy Chinese women. Methods BMDs at lumbar spine and proximal femur in 504 pre- and postmenopausal women were measured by DXA. Serum levels of IGF-I, OPG and RANKL were also measured. Pearson’s correlation and partial correlation analysis, ANOVA, covariance analysis and stepwise multiple regression analysis were used as appropriate. Results Age was negatively correlated with serum levels of IGF-I (r = −0.702, p < 0.001). IGF-I was negatively correlated with OPG and OPG/RANKL ratio, but positively correlated with RANKL. The relationship between IGF-I and BMDs disappeared after adjustment for age. In postmenopausal women, IGF-I was lower in women with osteoporosis than in those with normal BMD (p = 0.056), but no differences were found among OPG, RANKL and OPG/RANKL ratio. Serum levels of OPG in the highest quintile of IGF-I were significantly lower than those in the lowest quintile of IGF-I, while no difference was found in RANKL. In the multiple regression analysis model, serum levels of IGF-I were the main determinants of the bone mass in Chinese women. Conclusions In conclusion, the relationship between decreasing IGF-I and BMDs in healthy Chinese women influenced by age, whereas the effect of IGF-I on bone remodeling (bone resorption) may be mediated by the OPG/RANKL system.     

Skeletal deterioration induced by RANKL infusion: a model for high-turnover bone disease

Summary RANKL was administered continuously to rats for 28 days to investigate its potential as a disease model for the skeletal system. Bone turnover rates, bone material, structural and mechanical properties were evaluated. RANKL infusion caused overall skeletal complications comparable to those in high bone-turnover conditions, such as postmenopausal osteoporosis. Introduction RANKL is an essential mediator for osteoclast development. No study has examined in detail the direct skeletal consequences of excess RANKL on bone turnover, mineralization, architecture, and vascular calcification. We, therefore, administrated soluble RANKL continuously into mature rats and created a bone-loss model. Methods Six-month-old Sprague-Dawley (SD) rats were assigned to three groups (n = 12) receiving continuous administration of saline (VEH) or human RANKL (35 μg/kg/day, LOW or 175 μg/kg/day, HI) for 28 days. Blood was collected routinely during the study. At sacrifice, hind limbs and aorta were removed and samples were analyzed. Results High dose RANKL markedly stimulated serum osteocalcin and TRAP-5b levels and reduced femur cortical bone volume (−7.6%) and trabecular volume fraction (BV/TV) at the proximal tibia (−64% vs. VEH). Bone quality was significantly degraded in HI, as evidenced by decreased femoral percent mineralization, trabecular connectivity, and increased endocortical bone resorption perimeters. Both cortical and trabecular bone mechanical properties were reduced by high dose RANKL. No differences were observed in the mineral content of the abdominal aorta. Conclusions Continuous RANKL infusion caused general detrimental effects on rat skeleton. These changes are comparable to those commonly observed in high-turnover bone diseases such as postmenopausal osteoporosis.