Bone material properties in actively bone‐forming trabeculae in postmenopausal women with osteoporosis after three years of treatment with once‐yearly Zoledronic acid

Zoledronic acid (ZOL), a third‐generation aminobisphosphonate, showed pronounced antifracture efficacy in a phase III clinical trial [Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly—Pivotal Fracture Trial (HORIZON‐PFT)] when administered yearly (5‐mg infusions of ZOL), producing significant reductions in morphometric vertebral, clinical vertebral, hip, and nonvertebral fractures by 70%, 77%, 41%, and 25%, respectively, over a 3‐year period. The purpose of this study was to analyze the biopsies obtained during the HORIZON clinical trial (152 patients, 82 ZOL and 70 placebo) by means of Raman microspectroscopy (a vibrational spectroscopic technique capable of analyzing undecalcified bone tissue with a spatial resolution of approximately 0.6 µm) to determine the effect of ZOL therapy on bone material properties (in particular mineral/matrix ratio, lamellar organization, carbonate and proteoglycan (based on spectral identification of glycosaminoglycan) content, and mineral maturity/crystallinity) at similar tissue age (based on the presence of tetracycline double labels). The results indicated that while ZOL administration increased the mineral/matrix ratio compared with placebo, it also resulted in mineral crystallites with a quality profile (based on carbonate content and maturity/crystallinity characteristics) of younger (with respect to tissue age) bone. Since the comparisons between ZOL‐ and placebo‐treated patients were performed at similar tissue age at actively forming bone surfaces, these results suggest that ZOL may be exerting an effect on bone matrix formation in addition to its well‐established antiresorptive effect, thereby contributing to its antifracture efficacy. © 2011 American Society for Bone and Mineral Research.     

Differing effects of PTH 1–34, PTH 1–84, and zoledronic acid on bone microarchitecture and estimated strength in postmenopausal women with osteoporosis: An 18‐month open‐labeled observational study using HR‐pQCT

Whereas the beneficial effects of intermittent treatment with parathyroid hormone (PTH) (intact PTH 1–84 or fragment PTH 1–34, teriparatide) on vertebral strength is well documented, treatment may not be equally effective in the peripheral skeleton. We used high‐resolution peripheral quantitative computed tomography (HR‐pQCT) to detail effects on compartmental geometry, density, and microarchitecture as well as finite element (FE) estimated integral strength at the distal radius and tibia in postmenopausal osteoporotic women treated with PTH 1–34 (20 µg sc daily, n = 18) or PTH 1–84 (100 µg sc daily, n = 20) for 18 months in an open‐label, nonrandomized study. A group of postmenopausal osteoporotic women receiving zoledronic acid (5 mg infusion once yearly, n = 33) was also included. Anabolic therapy increased cortical porosity in radius (PTH 1–34 32 ± 37%, PTH 1–84 39 ± 32%, both p < 0.001) and tibia (PTH 1–34 13 ± 27%, PTH 1–84 15 ± 22%, both p < 0.001) with corresponding declines in cortical density. With PTH 1–34, increases in cortical thickness in radius (2.0 ± 3.8%, p < 0.05) and tibia (3.8 ± 10.4%, p < 0.01) were found. Trabecular number increased in tibia with both PTH 1–34 (4.2 ± 7.1%, p < 0.05) and PTH 1–84 (5.3 ± 8.3%, p < 0.01). Zoledronic acid did not impact cortical porosity at either site but increased cortical thickness (3.0 ± 3.5%, p < 0.01), total (2.7 ± 2.5%, p < 0.001) and cortical density (1.5 ± 2.0%, p < 0.01) in tibia as well as trabecular volume fraction in radius (2.5 ± 5.1%, p < 0.05) and tibia (2.2 ± 2.2%, p < 0.01). FE estimated bone strength was preserved, but not increased, with PTH 1–34 and zoledronic acid at both sites, whereas it decreased with PTH 1–84 in radius (?2.8 ± 5.8%, p < 0.05) and tibia (–3.9 ± 4.8%, p < 0.001). Conclusively, divergent treatment‐specific effects in cortical and trabecular bone were observed with anabolic and zoledronic acid therapy. The finding of decreased estimated strength with PTH 1–84 treatment was surprising and warrants confirmation. © 2013 American Society for Bone and Mineral Research.     

Time to onset of antifracture efficacy and year-by-year persistence of effect of zoledronic acid in women with osteoporosis

Oral bisphosphonates reduce fracture risk in osteoporotic patients but are often associated with poor compliance, which may impair their antifracture effects. This post hoc analysis assessed the time to onset and persistence of the antifracture effect of zoledronic acid, a once-yearly bisphosphonate infusion, in women with osteoporosis. Data from 9355 women who were randomized in two placebo-controlled pivotal trials were included. Endpoints included reduction in the rate of any clinical fracture at 6, 12, 18, 24, and 36 months in the zoledronic acid group compared with placebo, and the year-by-year incidence of all clinical fractures over 3 years. Cox proportional hazards regression was used to determine the timing of onset of antifracture efficacy. A generalized estimating equation model was used to assess fracture reduction for the 3 consecutive years of treatment, thereby evaluating persistence of effect. Safety results from women in the two studies were collated. Zoledronic acid reduced the risk of all clinical fractures at 12 months (hazard ratio [HR] = 0.75, 95% confidence interval [CI] 0.61-0.92, p = 0.0050) with significant reductions maintained at all subsequent time points. Year-by-year analysis showed that zoledronic acid reduced the risk for all clinical fractures compared with the placebo group in each of the 3 years (year 1: odds ratio [OR] = 0.74, 95% CI 0.60-0.91, p = 0.0044; year 2: OR = 0.53, 95% CI 0.42-0.66, p < 0.0001; year 3: OR = 0.61, 95% CI 0.48-0.77, p < 0.0001). This antifracture effect was persistent over 3 years, with the reductions in years 2 and 3 slightly larger than in year 1 (p = 0.097). This analysis shows that zoledronic acid offered significant protection from clinical fractures as early as 12 months. When administered annually, its beneficial effects persisted for at least 3 years.     

The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT)

Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long-term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebo-controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment.     

Once‐yearly zoledronic acid and days of disability,bed rest,and back pain: Randomized,controlled HORIZON Pivotal Fracture Trial

The objective of this study was to determine the effect of once‐yearly zoledronic acid on the number of days of back pain and the number of days of disability (ie, limited activity and bed rest) owing to back pain or fracture in postmenopausal women with osteoporosis. This was a multicenter, randomized, double‐blind, placebo‐controlled trial in 240 clinical centers in 27 countries. Participants included 7736 postmenopausal women with osteoporosis. Patients were randomized to receive either a single 15‐minute intravenous infusion of zoledronic acid (5 mg) or placebo at baseline, 12 months, and 24 months. The main outcome measures were s elf‐reported number of days with back pain and the number of days of limited activity and bed rest owing to back pain or a fracture, and this was assessed every 3 months over a 3‐year period. Our results show that although the incidence of back pain was high in both randomized groups, women randomized to zoledronic acid experienced, on average, 18 fewer days of back pain compared with placebo over the course of the trial (p = .0092). The back pain among women randomized to zoledronic acid versus placebo resulted in 11 fewer days of limited activity (p = .0017). In Cox proportional‐hazards models, women randomized to zoledronic acid were about 6% less likely to experience 7 or more days of back pain [relative risk (RR) = 0.94, 95% confidence interval (CI) 0.90–0.99] or limited activity owing to back pain (RR = 0.94, 95% CI 0.87–1.00). Women randomized to zoledronic acid were significantly less likely to experience 7 or more bed‐rest days owing to a fracture (RR = 0.58, 95% CI 0.47–0.72) and 7 or more limited‐activity days owing to a fracture (RR = 0.67, 95% CI 0.58–0.78). Reductions in back pain with zoledronic acid were independent of incident fracture. Our conclusion is that in women with postmenopausal osteoporosis, a once‐yearly infusion with zoledronic acid over a 3‐year period significantly reduced the number of days that patients reported back pain, limited activity owing to back pain, and limited activity and bed rest owing to a fracture. © 2011 American Society for Bone and Mineral Research.     

Hip and spine strength effects of adding versus switching to teriparatide in postmenopausal women with osteoporosis treated with prior alendronate or raloxifene

Many postmenopausal women treated with teriparatide for osteoporosis have previously received antiresorptive therapy. In women treated with alendronate (ALN) or raloxifene (RLX), adding versus switching to teriparatide produced different responses in areal bone mineral density (aBMD) and biochemistry; the effects of these approaches on volumetric BMD (vBMD) and bone strength are unknown. In this study, postmenopausal women with osteoporosis receiving ALN 70 mg/week (n = 91) or RLX 60 mg/day (n = 77) for ≥18 months were randomly assigned to add or switch to teriparatide 20 µg/day. Quantitative computed tomography scans were performed at baseline, 6 months, and 18 months to assess changes in vBMD; strength was estimated by nonlinear finite element analysis. A statistical plan specifying analyses was approved before assessments were completed. At the spine, median vBMD and strength increased from baseline in all groups (13.2% to 17.5%, p < 0.01); there were no significant differences between the Add and Switch groups. In the RLX stratum, hip vBMD and strength increased at 6 and 18 months in the Add group but only at 18 months in the Switch group (Strength, Month 18: 2.7% Add group, p < 0.01 and 3.4% Switch group, p < 0.05). In the ALN stratum, hip vBMD increased in the Add but not in the Switch group (0.9% versus –0.5% at 6 months and 2.2% versus 0.0% at 18 months, both p ≤ 0.004 group difference). At 18 months, hip strength increased in the Add group (2.7%, p < 0.01) but not in the Switch group (0%); however, the difference between groups was not significant (p = 0.076). Adding or switching to teriparatide conferred similar benefits on spine strength in postmenopausal women with osteoporosis pretreated with ALN or RLX. Increases in hip strength were more variable. In RLX‐treated women, strength increased more quickly in the Add group; in ALN‐treated women, a significant increase in strength compared with baseline was seen only in the Add group.     

Effect of raloxifene after recombinant teriparatide [hPTH(1–34)] treatment in postmenopausal women with osteoporosis

Summary Loss of bone mineral density occurs after discontinuation of teriparatide, if no subsequent treatment is given. Sequential raloxifene prevented rapid bone loss at lumbar spine and further increased bone mineral density (BMD) at femoral neck, whether raloxifene was started immediately or after a one-year delay following teriparatide treatment. Introduction We compared the sequential effects of raloxifene treatment with a placebo on teriparatide-induced increases in bone mineral density (BMD). A year of open-label raloxifene extended the study to assess the response with and without delay after discontinuation of teriparatide. Methods Following a year of open-label teriparatide 20 μg/day treatment, postmenopausal women with osteoporosis were randomly assigned to raloxifene 60 mg/day (n = 157) or a placebo (n = 172) for year 2, followed by a year of open-label raloxifene. BMD was measured by dual energy x-ray absorptiometry. Results The raloxifene and placebo groups showed a decrease in lumbar spine (LS) BMD in year 2 for raloxifene and placebo groups (−1.0 ± 0.3%, P = 0.004; and −4.0 ± 0.3%, P < 0.001, respectively); the decrease was less with raloxifene (P < 0.001). Open-label raloxifene treatment reversed the LS BMD decrease with a placebo, resulting in similar decreases 2 years after randomization (−2.6 ± 0.4% (raloxifene-raloxifene) and −2.7 ± 0.4% (placebo-placebo). At study end, LS and femoral neck (FN) BMD were higher than pre-teriparatide levels, with no significant differences between the raloxifene-raloxifene and placebo-raloxifene groups, respectively (LS: 6.1 ± 0.5% vs. 5.1 ± 0.5%; FN: 3.4 ± 0.6% vs. 3.0 ± 0.5%). Conclusion Sequential raloxifene prevented rapid bone loss at the LS and increased FN BMD whether raloxifene was started immediately or after a one-year delay following teriparatide treatment. Preliminary data presented previously at the International Osteoporosis Foundation World Congress on Osteoporosis, Toronto Canada June 2–6, 2006, abstract published: Adami S, Munoz-Torres M, Econs MJ, Sipos A, Xie L, Dalsky GP, McClung M, Felsenberg D, Brown JP, Brandi ML, San Martin J. Effect of raloxifene after teriparatide treatment in postmenopausal women with osteoporosis. Osteoporos Int. 2006;17(Suppl 2):S137.     

Effect of teriparatide [rhPTH(1-34)] on BMD when given to postmenopausal women receiving hormone replacement therapy.

The effects of teriparatide when given in combination with HRT were studied in postmenopausal women with low bone mass or osteoporosis. The data provide evidence that the adverse event profile for combination therapy with teriparatide + HRT together is consistent with that expected for each treatment alone and that the BMD response is greater than for HRT alone. INTRODUCTION: Teriparatide [rhPTH(1-34)], given as a once-daily injection, activates new bone formation in patients with osteoporosis. Hormone replacement therapy (HRT) prevents osteoporosis by reducing bone resorption and formation. Combination therapy with these two compounds, in small clinical trials, increased BMD and reduced vertebral fracture burden. The purpose of this study was to determine whether teriparatide provided additional effect on BMD when given in combination with HRT. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled study was conducted in postmenopausal women with either low bone mass or osteoporosis. Patients were randomized to placebo subcutaneous plus HRT (n = 125) or teriparatide 40 microg/day (SC) plus HRT (TPTD40 + HRT; n = 122) for a median treatment exposure of 13.8 months. Approximately one-half of the patients in each group were pretreated with HRT for at least 12 months before randomization. Patients received 1000 mg calcium and 400-1200 IU of vitamin D daily as oral supplementation. BMD was measured by DXA. RESULTS: Compared with HRT alone, TPTD40 + HRT produced significant (p < 0.001) increases in spine BMD (14% versus 3%), total hip (5.2% versus 1.6%), and femoral neck (5.2% versus 2%) at study endpoint. BMD, in whole body and ultradistal radius, was higher, and in the one-third distal radius was lower, in the combination therapy but not in the HRT group. Serum bone-specific alkaline phosphatase and urinary N-telopeptide/Cr were increased significantly (p < 0.01) in the women receiving TPTD40 + HRT compared with HRT. A similar profile of BMD and bone markers was evident in both randomized patients as well as in subgroups of patients not pretreated or pretreated with HRT. Patients tolerated both the treatments well. Nausea and leg cramps were more frequently reported in the TPTD40 + HRT group. CONCLUSIONS: Adding teriparatide, a bone formation agent, to HRT, an antiresorptive agent, provides additional increases in BMD beyond that provided by HRT alone. The adverse effects of teriparatide when added to HRT were similar to the adverse effects described for teriparatide administered alone. Whether teriparatide was initiated at the same time as HRT or after at least 1 year on HRT, the incremental increases over HRT alone were similar.     

Effects of teriparatide [recombinant human parathyroid hormone (1-34)] on cortical bone in postmenopausal women with osteoporosis.

Treatment with teriparatide (rDNA origin) injection [teriparatide, recombinant human parathyroid hormone (1-34) [rhPTH(1-34)]] reduces the risk of vertebral and nonvertebral fragility fractures and increases cancellous bone mineral density in postmenopausal women with osteoporosis, but its effects on cortical bone are less well established. This cross-sectional study assessed parameters of cortical bone quality by peripheral quantitative computed tomography (pQCT) in the nondominant distal radius of 101 postmenopausal women with osteoporosis who were randomly allocated to once-daily, self-administered subcutaneous injections of placebo (n = 35) or teriparatide 20 microg (n = 38) or 40 microg (n = 28). We obtained measurements of moments of inertia, bone circumferences, bone mineral content, and bone area after a median of 18 months of treatment. The results were adjusted for age, height, and weight. Compared with placebo, patients treated with teriparatide 40 microg had significantly higher total bone mineral content, total and cortical bone areas, periosteal and endocortical circumferences, and axial and polar cross-sectional moments of inertia. Total bone mineral content, total and cortical bone areas, periosteal circumference, and polar cross-sectional moment of inertia were also significantly higher in the patients treated with teriparatide 20 microg compared with placebo. There were no differences in total bone mineral density, cortical thickness, cortical bone mineral density, or cortical bone mineral content among groups. In summary, once-daily administration of teriparatide induced beneficial changes in the structural architecture of the distal radial diaphysis consistent with increased mechanical strength without adverse effects on total bone mineral density or cortical bone mineral content.     

Effects of teriparatide [rhPTH (1-34)] treatment on structural geometry of the proximal femur in elderly osteoporotic women

Introduction: We evaluated effects of teriparatide (rDNA origin) injection [teriparatide, rhPTH (1–34), TPTD] on hip structure among a subset 558 postmenopausal women enrolled in the Fracture Prevention Trial. Methods: Patients were randomized to once-daily, self-administered subcutaneous injections of placebo (N = 189), teriparatide 20 μg (TPTD20; N = 186), or 40 μg (TPTD40; N = 183) for a median of 20 months. Repeated dual energy X-ray absorptiometry (DXA) hip scans were analyzed with the Hip Structure Analysis (HSA) program to derive structural geometry. Results and conclusions: There were no significant differences in age or body size between groups at baseline, 1 year, or study termination. At the femoral neck, teriparatide increased bone mass and improved bone geometric strength in both treatment groups compared to the placebo group, with the response being dose-related. The mean difference (95% CI) in bone cross-sectional area (CSA) in the TPTD20 was 3.5% (1.8% to 5.3%), and 6.3% (4.5% to 8.2%) in TPTD40 at study termination, compared to placebo controls. Teriparatide treatment increased bending strength, with the mean difference in section modulus being 3.6% (1.4% to 5.8%) and 6.8% (4.6% to 9.1%) greater in the TPTD20 and TPTD40 groups, respectively. Compared to placebo, local cortical instability characterized by the buckling ratio decreased by 5.5% (3.5% to 7.5%) and 8.6% (6.6% to 10.5%) in the TPTD20 and TPTD40 groups, respectively, during the study period. The changes at the intertrochanteric region were comparable to those at the narrow neck although between-group differences were slightly smaller. Except for an inconsequential (1%) improvement in section modulus in TPTD20, teriparatide effects did not reach significance at the femoral shaft. In conclusion, teriparatide treatment improved axial and bending strength, and increased cortical thickness and stability at the femoral neck and intertrochanteric region. Teriparatide treatment effects were not apparent at the purely cortical femoral shaft.     

Relationship of changes in total hip bone mineral density to vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis treated with once-yearly zoledronic acid 5 mg: the HORIZON-Pivotal Fracture Trial (PFT)

Measurements of change in bone mineral density (BMD) are thought to be weak predictors of treatment effect on the reduction of fracture risk. In this study we report an alternative year-on-year approach for the estimation of treatment effect explained by BMD in which we examine the relationship between fracture risk and the most recent change in BMD. We studied 7736 postmenopausal women (ages 65 to 89 years) who were participants in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) and were randomized to either intravenous administration of zoledronic acid or placebo. The percentage of treatment effect explained by change in total hip BMD was estimated using the alternative year-on-year approach and the standard approach of looking at change over 3 years. We also studied a subset of 1132 women in whom procollagen type 1 amino-terminal propeptide (PINP) was measured at baseline and 12 months, to estimate the percentage of treatment effect explained by change in PINP. Regardless of the method used, the change in total hip BMD explained a large percentage of the effect of zoledronic acid in reducing new vertebral fracture risk (40%; 95% CI, 30% to 54%; for the 3-year analysis). The treatment effects for nonvertebral fracture were not statistically significant for the year-on-year analysis but 3-year change in BMD explained 61% (95% CI, 24% to 156%) of treatment effect. Change in PINP explained 58% (95% CI, 15% to 222%) of the effect of zoledronic acid in reducing new vertebral fracture risk. We conclude that our estimates of the percentage of treatment effect explained may be higher than in previous studies because of high compliance with zoledronic acid (due to its once-yearly intravenous administration). Previous studies may have underestimated the relationship between BMD change and the effect of treatment on fracture risk.     

Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis

Though osteonecrosis of the jaw (ONJ) is temporally‐associated with the use of nitrogen‐containing bisphosphonates (N‐BPs), a cause‐and‐effect relationship has not yet been established. We hypothesize that ONJ is a two‐stage process in which: (1) risk factors initiate pathologic processes in the oral cavity that lead to a supranormal rate of hard tissue necrosis; and (2) powerful antiresorptives reduce the rate of removal of necrotic bone sufficiently to allow its net accumulation in the jaw. To test this hypothesis, we used the rice rat model of periodontitis. At age 28 days, rats (n = 15/group) were placed on a high‐sucrose and casein diet to exacerbate the development of periodontitis. Animals were injected subcutaneously (SC) biweekly with vehicle or alendronate (ALN, 15 µg/kg), or IV once monthly with vehicle, a low dose (LD) of zoledronic acid (ZOL), or a high dose (HD) of ZOL and sacrificed after 6, 12, 18, and 24 weeks. Mandibles and maxillae were analyzed to determine the effects on the: (1) progression of periodontitis; (2) integrity of alveolar bone; (3) status of bone resorption and formation; (4) vascularity; and (5) osteocyte viability. We found that only HD‐ZOL induced ONJ‐like lesions in mandibles of rice rats after 18 and 24 weeks of treatment. These lesions were characterized by areas of exposed necrotic alveolar bone, osteolysis, a honeycomb‐like appearance of the alveolar bone, presence of bacterial colonies, and periodontal tissue destruction. In addition, inhibition of bone formation, a paradoxical abolition of the antiresorptive effect of only HD‐ZOL, increased osteocyte necrosis/apoptosis, and decreased blood vessel number were found after 18 and/or 24 weeks. Our study suggests that only HD‐ZOL exacerbates the inflammatory response and periodontal tissue damage in rice rats, inducing bone lesions that resemble ONJ. © 2012 American Society for Bone and Mineral Research.     

唑来膦酸连续2年治疗绝经后女性骨质疏松临床观察

目的：观察唑来膦酸连续2年治疗绝经后女性骨质疏松的疗效、急性发热反应情况及其相关因素分析。方法回顾性分析我科2010年7月至2013年7月连续2年静脉使用唑来膦酸5mg滴注治疗绝经后女性骨质疏松患者共46人。年龄60～74岁,平均年龄（66．87±6．77）岁。观察每次急性期发热出现比例及每例患者前后2次药物输注后发热出现情况。比较治疗第1年、第2年骨质疏松差异及甲状旁腺激素、血清钙差异。结果46例患者中第1次输注唑来膦酸共观察到20人发热,占43．4％,次年输注唑来膦酸仅1例出现发热,发热组治疗前甲状旁腺激素水平显著高于无发热组（ P＜0．05）。第2次输注前甲状旁腺激素、血清钙较第1年输注前均无显著差异（ P＞0．05）,第2次输注前骨密度监测腰椎及全髋T值较第1次有所改善（P＜0．05）。结论绝经后女性骨质疏松患者连续静脉用唑来膦酸治疗对骨密度有改善,首次治疗出现急性期发热反应并不少见,但均为一过性,次年均可耐受。治疗前PTH水平可能与发热反应相关。     

The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis.

Teriparatide [rhPTH(1-34)] increases bone mineral density and reduces the risk of vertebral fracture in women. We randomized 437 men with spine or hip bone mineral density more than 2 SD below the young adult male mean to daily injections of placebo, teriparatide 20 microg, or teriparatide 40 microg. All subjects also received supplemental calcium and vitamin D. The study was stopped after a median duration of 11 months because of a finding of osteosarcomas in rats in routine toxicology studies. Biochemical markers of bone formation increased early in the course of therapy and were followed by increases in indices of osteoclastic activity. Spine bone mineral density was greater than in placebo subjects after 3 months of teriparatide therapy, and by the end of therapy it was increased by 5.9% (20 microg) and 9.0% (40 microg) above baseline (p < 0.001 vs. placebo for both comparisons). Femoral neck bone mineral density increased 1.5% (20 microg; p = 0.029) and 2.9% (40 microg; p < 0.001), and whole body bone mineral content increased 0.6% (20 microg; p = 0.021) and 0.9% (40 microg;p = 0.005) above baseline in the teriparatide subjects. There was no change in radial bone mineral density in the teriparatide groups. Bone mineral density responses to teriparatide were similar regardless of gonadal status, age, baseline bone mineral density, body mass index, smoking, or alcohol intake. Subjects experienced expected changes in mineral metabolism. Adverse events were similar in the placebo and 20-microg groups, but more frequent in the 40-microg group. This study shows that teriparatide treatment results in an increase in bone mineral density and is a potentially useful therapy for osteoporosis in men.     

rhPTH(1-34)治疗糖皮质激素诱发大鼠骨质疏松症的实验研究

目的 观察重组人甲状旁腺激素(1-34)[recombinant human parathyroid hormone(1-34),rh-PTH(1-34)]对糖皮质激素引起的大鼠继发性骨质疏松症(OP)的治疗作用。方法 应用肌肉注射地塞米松(dexamethasone.DEX)方法,建立模拟糖皮质激素引起的继发性OP大鼠模型。给予皮下注射5、10、20和40μg·kg-1·d-1rhVTH(1-34)治疗8周。观察骨量、骨生物力学、骨形态计量及骨代谢相关血尿生化指标,综合评价PTH对糖皮质激素诱发OP的治疗效果。结果显示肌注地塞米松大鼠的骨量、骨生物力学较对照组显著性下降,表明诱导大鼠骨质疏松模型成立。不同剂量咖治疗均能显著增加模型大鼠的腰椎与股骨骨密度、股骨干重与灰重,提高股骨三点弯曲最大载荷、提高腰椎骨小梁面积百分比及矿化沉积率(P<0.05-0.001),并呈一定剂量效应关系。血钙、磷无明显变化。结论外源性PTH对糖皮质激素诱发的大鼠OP具有显著治疗作用。     

甲状旁腺激素（1-34)、雷奈酸锶、唑来膦酸对绝经后骨质疏松症的疗效对比研究

目的比较甲状旁腺激素(1-34)(PTH)、雷奈酸锶(SR)、唑来膦酸(ZA)对绝经后妇女骨质疏松的疗效。方法 150例绝经后骨质疏松症患者被随机分为三组:PTH组、SR组和ZA组,进行开放、对比研究。SR组每天口服雷奈酸锶2 g/d;PTH组每天皮下注射20μg的PTH(1-34);ZA组给予唑来膦酸5 mg静脉滴注。治疗前、后6个月及1年分别测定两组患者腰背部自发性疼痛的VAS评分、L_(1-4)椎体、股骨颈、Wards三角的BMD值,并观察治疗期间三组骨质疏松性骨折的发生率及服药后的不良反应。结果治疗后PTH组和SR组VAS评分明显改善,低于ZA组;PTH组L_(1-4)椎体、股骨颈、Wards三角的BMD值在治疗后6月及12月较治疗前上升显著,明显优于SR组及ZA组(P0.05)。骨质疏松脆性骨折的发生率PTH组低于SR组及ZA组。三组药品不良反应发生率比较,差异无统计学意义(P0.05)。结论 PTH、SR和ZA都可以有效降低VAS评分,提高骨密度,降低骨质疏松脆性骨折的发生率,且药物副反应少,其中以PTH效果最佳。     

PTH对骨髓细胞骨代谢相关基因表达的影响

目的观察大鼠骨髓微环境骨代谢相关基因表达变化,拟探讨外源性甲状旁腺激素（Parathyroidhormone PTH）治疗骨质疏松的分子机制.方法给予卵巢摘除（ovariectomy OVX）诱导的骨质疏松（Osteoporosis OP）大鼠每天20 μg/kg重组人甲状旁腺激素[rhPTH（1-34）]治疗8周,采用RT-PCR方法检测大鼠骨髓细胞骨代谢相关基因的表达,比较PTH用药前、后及停药后各基因表达的变化.结果显示用药后骨髓细胞中成骨活性基因ALP、BGP、Cbf α1表达均持续显著升高（P＜0.05～0.001）;破骨细胞调节基因M-CSF与RANKL表达变化无统计学意义;OPG与TRAF-6表达呈双相波动（P＜0.05～0.01）;RANKL/OPG比值在用药1周时增加（P＜0.05）;IL-6表达呈早期短时升高（P＜0.01）.结论PTH对骨质疏松的治疗作用可能与其持续增强骨髓细胞的成骨活性基因表达,调节破骨细胞分化和功能成熟基因表达有关.     

Lack of Bone Neoplasms and Persistence of Bone Efficacy in Cynomolgus Macaques After Long‐Term Treatment With Teriparatide [rhPTH(1‐34)]

In rats, teriparatide [rhPTH(1‐34)] causes marked increases in bone mass and osteosarcoma. In primates, teriparatide causes lesser increases in bone mass, and osteosarcomas have not been reported. Previous studies in primates were not designed to detect bone tumors and did not include a prolonged post‐treatment observation period to determine whether tumors would arise after cessation of treatment. Ovariectomized (OVX), skeletally mature, cynomolgus monkeys (n = 30 per group) were given teriparatide for 18 mo at either 0 or 5 μg/kg/d subcutaneously. After 18 mo of treatment, subgroups of six monkeys from both groups were killed and evaluated, whereas all remaining monkeys entered a 3‐yr observation period in which they did not receive teriparatide. Surveillance for bone tumors was accomplished with plain film radiographs, visual examination of the skeleton at necropsy, and histologic evaluation of multiple skeletal sites. Quantitative assessments of bone mass, architecture, and strength were also performed. After the 18‐mo treatment period, vertebral BMD, BMC, and strength (ultimate load) were increased by 29%, 36%, and 52%, respectively, compared with OVX controls. Proximal femur BMD, BMC, and strength were also increased by 15%, 28% and 33%, respectively. After 3 yr without treatment, no differences in bone mass or strength at the vertebra were observed relative to OVX controls; however, the femoral neck showed significant persistence in stiffness (20%), BMC (14%), and trabecular BV/TV (53%), indicating a retention of teriparatide efficacy at the hip. Radiographs and histology did not identify any bone proliferative lesions or microscopic lesions of osteosarcoma at the end of the treatment or observation period. These data indicate that teriparatide did not induce bone proliferative lesions over a 4.5‐yr interval of observation, including 18 mo of treatment and 3 yr of follow‐up observation. Bone analyses confirmed that teriparatide caused increases in bone mass and strength, consistent with previous studies. During the withdrawal phase, beneficial effects of teriparatide treatment on the vertebra were lost; however, some of the beneficial effects on the proximal femur persisted for 3 yr after cessation of treatment. Although the lack of bone tumors in this study provides some additional reassurance regarding the safety of teriparatide for the primate skeleton, the small group size and other limitations of this, or any other animal study, limit the ability to draw definitive conclusions regarding the risk of bone tumor developments in patients.     

Effects of denosumab on bone turnover markers in postmenopausal osteoporosis

Denosumab, a fully human monoclonal antibody to RANKL, decreases bone remodeling, increases bone density, and reduces fracture risk. This study evaluates the time course and determinants of bone turnover marker (BTM) response during denosumab treatment, the percentage of denosumab‐treated women with BTMs below the premenopausal reference interval, and the correlations between changes in BTMs and bone mineral density (BMD). The BTM substudy of the Fracture REduction Evaulation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Trial included 160 women randomized to subcutaneous denosumab (60 mg) or placebo injections every 6 months for 3 years. Biochemical markers of bone resorption (serum C‐telopeptide of type I collagen [CTX] and tartrate‐resistant acid phosphatise [TRACP‐5b]) and bone formation (serum procollagen type I N‐terminal propeptide [PINP] and bone alkaline phosphatase [BALP]) were measured at baseline and at 1, 6, 12, 24, and 36 months. Decreases in CTX were more rapid and greater than decreases in PINP and BALP. One month after injection, CTX levels in all denosumab‐treated subjects decreased to levels below the premenopausal reference interval. CTX values at the end of the dosing period were influenced by baseline CTX values and the dosing interval. The percentage of subjects with CTX below the premenopausal reference interval before each subsequent injection decreased from 79% to 51% during the study. CTX and PINP remained below the premenopausal reference interval at all time points in 46% and 31% denosumab‐treated subjects, respectively. With denosumab, but not placebo, there were significant correlations between CTX reduction and BMD increase (r = ?0.24 to ?0.44). The BTM response pattern with denosumab is unique and should be appreciated by physicians to monitor this treatment effectively. © 2011 American Society for Bone and Mineral Research.