Frequency of zoledronic acid to prevent further bone loss in osteoporotic patients undergoing androgen deprivation therapy for prostate cancer

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVE

To evaluate the efficacy of zoledronic acid (ZA) in osteoporotic patients with prostate cancer receiving either luteinizing hormone‐releasing hormone agonists (LHRHA, which accelerate bone loss) or bicalutamide (which preserves bone mineral density, BMD) as androgen‐deprivation therapy is the mainstay of treatment for advanced prostate cancer, and many patients are osteoporotic at presentation, with others becoming so on treatment.

PATIENTS AND METHODS

Fifty‐eight osteoporotic men with non‐metastatic prostate cancer were followed for 3 years. Patients were randomly assigned to receive either LHRHA (29) or bicalutamide (29). All received 4 mg ZA 3‐monthly for 1 year. BMD was measured by dual energy X‐ray absorptiometry at four times: 1 year before ZA; immediately before ZA; after five infusions; and 1 year afterwards. Bone turnover markers (BTMs) were measured at 3‐monthly intervals on ZA and 1 year later. All patients had radiography of the thoracolumbar spine at baseline and after ZA.

RESULTS

Patients on LHRHA showed a 4.9% decrease in BMD before ZA, a 1.6% increase after ZA and a 3.0% decrease 1 year later, compared to 2.0% increase, 7.8% increase and 1.9% decrease, respectively, in those on bicalutamide. BTMs decreased significantly after ZA. Seven patients (12%) had vertebral fractures at baseline, with none deteriorating at 1 year; two (3.5%) developed mandibular osteonecrosis.

CONCLUSION

Before ZA, BMD decreased on LHRHA, but was maintained on bicalutamide. Treatment with 3‐monthly ZA increased BMD and suppressed BTMs in osteoporotic patients both on LHRHA and bicalutamide, but to a greater extent in the latter. However, 1 year after the last infusion, BMD declined, suggesting that annual administration is inadequate in these patients. The optimum frequency might be related to BMD at time of bisphosphonate initiation.     

Alendronate decreases the fracture risk in patients with prostate cancer on androgen‐deprivation therapy and with severe osteopenia or osteoporosis

OBJECTIVE

To evaluate changes in bone mass and fracture risk in patients with prostate cancer on androgen‐deprivation therapy (ADT) and with a basal T‐score of >?2.0, who were treated with an oral bisphosphonate, as such patients treated with ADT are at increased risk of bone loss and bone fracture.

PATIENTS AND METHODS

We selected 61 patients with prostate cancer treated with ADT; 31 were treated with oral alendronate 70 mg once‐weekly and a control group of 30 were not. At baseline and 12 months we measured bone mineral density (BMD) of the lumbar spine, femoral neck and total hip by dual‐energy X‐ray absorptiometry. All patients had severe osteopenia or osteoporosis at baseline. The risk of femoral neck fracture was calculated at baseline and 12 months (Z‐score 2.7).

RESULTS

Patients treated with alendronate had a significant increase in BMD at the lumbar spine and femoral neck after 1 year of follow‐up, with mean (sd ) values of 1.06 (0.26) vs 1.01 (0.21) g/cm² at baseline (P < 0.001), and 0.75 (0.07) vs 0.73 (0.07) g/cm² (P = 0.03), respectively, while the control group had a significant loss of BMD at the total hip of 0.79 (0.14) vs 0.81 (0.13) g/cm² (P = 0.03). BMD was significantly improved at the three locations in patients treated with alendronate compared with the control group, with differences at the lumbar spine, femoral neck and total hip of 0.05 (0.07) vs 0.01 (0.10) (P = 0.001), 0.01 (0.04) vs ?0.002 (0.03) (P = 0.04) and 0.01 (0.04) vs ?0.01 (0.02) g/cm², respectively (P = 0.001). Patients treated with alendronate had a significant decrease in the fracture risk at the femoral neck, by ?0.54 (1.29) (P = 0.04) after 1 year of follow‐up.

CONCLUSIONS

Treatment with once‐weekly 70 mg alendronate significantly improved the BMD at the lumbar spine and femoral neck in patients with prostate cancer with severe osteopenia or osteoporosis and on ADT, and significantly decreased the risk of femoral neck fracture.     

最大限度雄激素阻断治疗前列腺癌对患者骨密度的影响

目的:探讨最大限度雄激素阻断(MAB)治疗对前列腺癌患者骨密度的影响。方法:对40例因前列腺癌行MAB治疗的患者进行调查,治疗时间7～12个月,分别于治疗前后检测血清前列腺特异性抗原(PSA)、睾酮及血钙、血磷、24 h尿钙、尿磷、碱性磷酸酶、甲状旁腺激素、血常规及肝肾功能,双能X线吸收法测定腰椎、股骨颈骨密度,并进行疼痛评分,比较MAB治疗前后各项指标差异。结果:前列腺癌患者治疗前5例(12.5%)腰椎骨量减少,8例(20.0%)腰椎骨质疏松;13例(32.5%)左股骨颈骨量减少,15例(37.5%)左股骨颈骨质疏松。MAB治疗前患者血清PSA为(52.9±69.9)μg/L,睾酮为(18.9±6.5)nmol/L,治疗后PSA为(1.5±1.6)μg/L,睾酮为(1.9±1.3)nmol/L,与治疗前比较均显著下降(P<0.05)。治疗前血钙为(2.5±0.2)mmol/L,血磷为(1.2±0.2)mmol/L,尿钙为(3.1±1.4)mmol/L,尿磷为(11.5±8.1)mmol/L,治疗后血钙为(2.5±0.1)mmol/L,血磷为(1.2±0.1)mmol/L,尿钙为(2.8±1.2)mmol/L,尿磷为(9.9±4.0)mmol/L,两者比较差异均无统计学意义(P>0.05)。治疗前后碱性磷酸酶、甲状旁腺激素、血常规、肝肾功能差异均无统计学意义(P>0.05)。治疗前腰椎和股骨颈骨密度分别为(1.1±0.1)g/cm2和(0.8±0.2)g/cm2,疼痛评分为(0.6±0.2)分,治疗后腰椎和股骨颈骨密度分别为(1.1±0.2)g/cm2和(0.8±0.1)g/cm2,疼痛评分为(0.7±0.1)分,与治疗前比较差异均无统计学意义(P>0.05)。结论:7～12个月MAB治疗对前列腺癌患者骨密度无明显影响,安全有效,但治疗前应注意监测患者骨密度。     

Risedronate prevents early bone loss and increased bone turnover in the first 6 months of luteinizing hormone‐releasing hormone‐agonist therapy for prostate cancer

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVE

To determine whether increased bone loss and bone turnover during the first 6 months of therapy for prostate cancer with luteinizing hormone‐releasing hormone (LHRH)‐agonist therapy could be prevented by bisphosphonate therapy with risedronate 35 mg/week, as prostate cancer is commonly treated with LHRH agonists and this often leads to rapid bone loss within the first 6 months of therapy.

PATIENTS AND METHODS

A 6‐month randomized, double‐blind, placebo‐controlled trial was conducted, including 40 men aged ≥55 years receiving LHRH‐agonist treatment for 6 months for locally advanced prostate cancer. Bone mineral density (BMD) of the lumbar spine, femoral neck, and total hip was measured every 6 months. In addition, bone turnover markers including N‐telopeptide, serum C‐telopeptide and procollagen peptide, and 25‐OH vitamin D and intact parathyroid hormone were measured at baseline and at 6 months.

RESULTS

After 6 months of LHRH‐agonist therapy, the control group had a significant decline at the spine and hip BMD sites; however, the risedronate group had no bone loss at the hip and an increase at the lumber spine. Markers of bone turnover were increased significantly in the control group but unchanged in the risedronate group.

CONCLUSIONS

LHRH‐agonist treatment for locally advanced prostate cancer produces increased bone turnover and rapid bone loss within the initial 6 months of therapy, and this can be prevented by weekly risedronate treatment.     

Current status of primary pharmacotherapy and future perspectives toward upfront therapy for metastatic hormone‐sensitive prostate cancer

Since 1941, androgen deprivation therapy has been the primary treatment for metastatic hormone‐sensitive prostate cancer. Androgen deprivation therapy consists of several regimens that vary according to therapeutic modality, as well as treatment schedule. Androgen deprivation therapy initially shows excellent antitumor effects, such as relief of cancer‐related symptoms, tumor marker decline and tumor shrinking. However, most metastatic hormone‐sensitive prostate cancer cases eventually develop castration resistance and become lethal. Taxanes, such as docetaxel and cabazitaxel, as well as novel androgen receptor‐targeting agents, such as abiraterone acetate and enzalutamide, have emerged for metastatic castration‐resistant prostate cancer. The concept and principle of primary therapy for metastatic hormone‐sensitive prostate cancer has remained unchanged for decades. Recently, upfront docetaxel chemotherapy has been shown to prolong overall survival in men with metastatic hormone‐sensitive prostate cancer, and would lead to a paradigm shift in primary pharmacotherapy for metastatic hormone‐sensitive prostate cancer. This raises the possibility of upfront use of taxanes, as well as novel androgen receptor‐targeting agents combined with androgen deprivation therapy. The present review summarizes the current status of primary pharmacotherapy for metastatic hormone‐sensitive prostate cancer, and discusses future perspectives in this field.     

雄激素剥夺治疗前列腺癌引起的骨代谢变化

雄激素剥夺治疗(androgen deprivation therapy,ADT)是治疗转移性前列腺癌(PCa)的基石,显著延长了PCa患者生存期.然而在ADT治疗的PCa患者中,每年平均骨密度下降2％～10％,导致骨折发病率、相关发病率和死亡率增加,应该引起临床医师的注意.这种骨代谢状态,目前认为主要是雄激素、雌激素...     

Management of decreased bone mineral density in men starting androgen‐deprivation therapy for prostate cancer

OBJECTIVE

To determine whether clinicians discuss bone‐specific side‐effects with patients on androgen‐deprivation therapy (ADT) for prostate cancer, or prescribe lifestyle and pharmacological interventions for low bone mineral density (BMD), as decreased BMD is a common side‐effect of ADT, leading to increased risk of fracture.

PATIENTS AND METHODS

Sixty‐six men (mean age 70.6 years) with non‐metastatic prostate cancer and starting continuous ADT were enrolled in a prospective longitudinal study. BMD was determined by dual X‐ray absorptiometry (DXA) at baseline. Patients were interviewed to obtain their medical histories, and charts were reviewed to determine whether clinicians documented potential bone side‐effects in clinic notes, and made lifestyle and/or medication recommendations. Both were done at the start of ADT, and 3 and 6 months later. Patients were classified based on DXA T‐score as having normal BMD, as osteopenic, or osteoporotic.

RESULTS

At baseline, 53% of patients had osteopenia and 5% had osteoporosis. Within 6 months of starting ADT, general side‐effects and bone‐specific side‐effects of ADT were documented as being discussed with 26% and 15%, respectively. Clinicians recommended lifestyle interventions to 11% of patients. Pharmacological interventions (calcium, vitamin D, and/or bisphosphonates) were recommended to 18% of all patients within 6 months of starting ADT, and to 26% and 67% of osteopenic and osteoporotic patients, respectively.

CONCLUSIONS

A minority of patients is being informed of bone‐specific side‐effects of ADT. Lifestyle and drug interventions to prevent declines in BMD were recommended uncommonly. Practices around bone health for men starting ADT are suboptimal.     

Effect of androgen deprivation therapy on bone mineral density in prostate cancer patients

Aim: To evaluate the effect of androgen deprivation therapy (ADT) on bone mineral density (BMD) in prostate cancer patients. Methods: Forty-nine prostate cancer patients with their BMD determined were divided into two groups: the non-treated group included 21 patients before the commencement of ADT and the treated group, 28 patients, who had received ADT for more than 1 year. BMD was measured by dual energy X-ray absorptiometry (DEXA) in the lumbar spine (L2-4) and femoral neck. Results: Thirteen (62 %) non-treated and 23 (82 %) treated patients fulfilled the BMD criteria for osteopenia or osteoporosis. Z scores for age-matched control in lumbar spine and femoral neck were -0.9 ± 0.7 and -0.6 ± 0.5, respectively, in the treated group, and -1.8 ± 1.1 and-1.6 ± 1.0 , respectively, in the non-treated group, the differences between the two groups were highly significant (P<0.01). Conclusion: Prostate cancer patients who received ADT for more than 1 year had a significantly lower BMD in the lumbar spine a     

Comparative study of the protective effect of different intravenous bisphosphonates on the decrease in bone mineral density in patients submitted to radical prostatectomy undergoing androgen deprivation therapy. A prospective open-label controlled study

OBJECTIVES: To establish whether androgen deprivation therapy (ADT) promotes osteoporosis and osteopenia METHODS: Ninety-four prostatectomized men with rising prostrate-specific antigen (PSA) were enrolled into the placebo group (31), monthly i.v. clodronate (39) or monthly i.v. zoledronic acid (24) groups for 36 months. Dual-energy X-ray absorptiometry measured the bone density in the lumbar (L2-L4) area. chi(2) and anova tests were used to analyze data.. RESULTS: After 6 months of androgen deprivation, 17 of the 31 control cases developed osteopenia in the lumbar area. At 12 months, nine control cases had osteoporosis with 13 additional cases of osteopenia. At the end of the 36-month study period, the untreated group showed an average bone mineral density (BMD) loss of -1.82 (+/-0.94) with 13 cases of osteopenia and 18 cases of osteoporosis. The clodronate group had two cases of osteoporosis out of 39 subjects after 6 months of ADT with 28 developing osteopenia and seven cases of osteoporosis after 36 months of follow up. Mean BMD loss in this group was -0.72 (+/-0.34). The zoledronic acid studied arm had seven cases of osteopenia after 6 months of ADT while 20 and five cases developed osteopenia and osteoporosis, respectively, after 36 months of follow up. The former group had a mean bone loss of -0.88 (+/-0.32). There was statistical difference for BMD loss in the treated groups starting at 6 months in comparison to the control group. CONCLUSIONS: Six months of ADT promoted impressive bone loss in the lumbar area of the non-treated patients. This tendency is progressive and may be delayed by i.v. bisphosphonates.     

Carbon‐ion radiation therapy for prostate cancer

In 1994, carbon‐ion radiotherapy was started at the National Institute of Radiological Sciences using the Heavy‐Ion Medical Accelerator in Chiba. Between June 1995 and March 2000, two phase I/II dose escalation studies (protocols 9402 and 9703) of hypofractionated carbon‐ion radiotherapy for both early‐ and advance‐stage prostate cancer patients had been carried out to establish radiotherapy technique and to determine the optimal radiation dose. To validate the feasibility and efficacy of hypofractionated carbon‐ion radiotherapy, a phase II study (9904) was initiated in April 2000 using the shrinking field technique and the recommended dose fractionation (66 gray equivalents in 20 fractions over 5 weeks) obtained from the phase I/II studies, and was successfully completed in October 2003. The data from 175 patients in the phase II study showed the importance of an appropriate use of androgen deprivation therapy according to tumor risk group. Since November 2003, carbon‐ion radiotherapy for prostate cancer was approved as “Highly Advanced Medical Technology” from the Ministry of Health, Labor, and Welfare, and since then approximately 1100 patients have received carbon‐ion radiotherapy as of July 2011. In this review, we introduce our steps thorough three clinical trials carried out at National Institute of Radiological Sciences, and show the updated data of carbon‐ion radiotherapy obtained from approximately 1000 prostate cancer patients. In addition, our recent challenge and future direction will be also described.     

~(153)Sm-EDTMP治疗前列腺癌骨转移的疗效观察

目的:通过对比研究153Sm-EDTMP和唑来膦酸治疗前列腺癌骨转移,以了解153Sm-EDTMP治疗前列腺癌骨转移的疗效。方法:确诊前列腺癌骨转移患者55例,分两组,一组31例用153Sm-EDTMP按37.0 MBq/kg体重静脉注射治疗,一组24例用唑来膦酸4 mg加入0.9%氯化钠注射液100 ml中缓慢静滴。治疗前及治疗后1～2个月行99mTc-MDP骨扫描检查。结果:153Sm-EDTMP组疼痛缓解有效率为83.9%,骨代谢改变有效率为64.5%。唑来膦酸组疼痛缓解有效率为58.3%,骨代谢改变有效率为33.3%。经χ2检验,两组疼痛缓解有效率比较χ2=4.448,P=0.035,骨代谢改变有效率比较χ2=5.263,P=0.022,均有显著性差异。结论:153Sm-EDTMP是治疗前列腺癌骨转移较理想的药物。