Oral bisphosphonate prevents bone loss in androgen deprivation therapy for nonmetastatic prostate cancer

We studied the short-term efficacy of alendronate, an oral bisphosphonates, on bone mineral density (BMD) during androgen deprivation therapy (ADT) in 45 nonmetastatic prostate cancer patients at the beginning of ADT (treatment group). All received alendronate five mg daily from the initiation of ADT. Lumber BMD was evaluated by dual energy X-ray absorptiometry, at baseline and after six months of treatment. Historical data on 24 patients with prostate cancer who received ADT without bisphosphonate administration were studied as controls (control group). BMD decreased in 13.9 and 45.8% of the patients in the treatment and control groups, respectively. Mean BMD changes in the lumber spine were +1.6 +/- 3.0% in the treatment group and -1.1 +/- 2.7% in the control group (p = 0.006). No pathological fractures occurred during the study period. No severe adverse effects were observed, but three patients could not continue alendronate treatment because of adverse events. Despite the short-term of this evaluation, our results showed that oral alendronate is an effective and safe treatment for preventing bone loss and increasing BMD in patients receiving ADT for prostate cancer.     

Bone health in men receiving androgen deprivation therapy for prostate cancer

PURPOSE: Patients with recurrent or metastatic prostate cancer generally receive androgen deprivation therapy, which can result in significant loss of bone mineral density. We explored androgen deprivation therapy related bone loss in prostate cancer, current treatments and emerging therapies. MATERIALS AND METHODS: Literature published on the pathogenesis and management of androgen deprivation therapy related bone loss was compiled and interpreted. Recent drug therapy findings were reviewed, including treatment guidelines. RESULTS: Men with prostate cancer often present with bone loss and the initiation of androgen deprivation therapy can trigger further rapid decreases. This results in an increased fracture risk, and greater morbidity and mortality. Early detection of osteoporosis through androgen deprivation therapy screening and prompt initiation of therapy are critical to prevent continued decreases. Lifestyle changes such as diet, supplementation and exercise can slow the rate of bone loss. Pharmacological therapy with oral and intravenous bisphosphonates has been demonstrated to prevent or decrease the bone loss associated with androgen deprivation therapy. However, important differences exist among various bisphosphonates with respect to efficacy, compliance and toxicity. Only zoledronic acid has been shown to increase bone mineral density above baseline and provide long-term benefit by decreasing the incidence of fracture and other skeletal related events in men with bone metastases. CONCLUSIONS: Androgen deprivation therapy associated bone loss adversely affects bone health, patient quality of life and survival in men with prostate cancer. Increased awareness of this issue, identification of risk factors, lifestyle modification and initiation of bisphosphonate therapy can improve outcomes. Education of patients and physicians regarding the importance of screening, prevention and treatment is essential.     

Clinical significance of risedronate for patients with prostate cancer receiving androgen deprivation therapy

PURPOSE: Androgen deprivation therapy (ADT) in patients with prostate cancer is associated with bone loss. We investigated the effectiveness of risedronate about a decreasing bone mineral density in patients with prostate cancer on ADT. MATERIAL AND METHOD: A prospective study was conducted in Kitasato University Hospital from April 2004 to October 2006. A total of 69 men with prostate cancer were assigned to receive either oral risedronate or none during ADT (hormone na?ve). The treatment group was 58 men and taking 2.5 mg risedronate per day. The control group was 11 men. At baseline, we assessed BMD (bone mineral density) by DEXA and urinary NTX, and measured for these changes every 6 months. RESULT: At baseline, each BMDs had no significant difference at the lumber and total hip. At the first 6-month stage, the change in BMD percentage between the 2 groups was statistically significantly different at lumber (p = 0.002) and total hip (p = 0.038). At the 12-month stage, the change in the BMD percentage between the 2 groups was statistically significantly different at the lumber (p = 0.038). And each difference made out that the risedronate group was preserving BMD. In urinary NTX, bone turn over was statistically significantly decreased with the risedronate group compared with the control group at the 12-month stage (p = 0.017). CONCLUSION: We assure the beginning of bone loss at an early date (6 months) with ADT. Daily oral risedronate in patients with receiving ADT reduces bone mineral loss and maintain BMD.     

雄激素剥夺治疗对老年前列腺癌患者骨量丢失的影响

目的：了解雄激素剥夺治疗（ androgen deprivation therapy ,ADT）对老年前列腺癌患者骨量丢失的影响。方法选取36例接受ADT（至少半年）的前列腺癌患者为ADT组及22例口服非那雄胺治疗（至少半年）的良性前列腺增生患者为非ADT组。两组患者在治疗前后均完善血钙、血磷、血清白蛋白、糖化血红蛋白（GHb）、碱性磷酸酶（ALP）、血肌酐（Cr）、前列腺特异性抗原（PSA）、睾酮、雌二醇（E2）等基础资料检测,并在治疗后进行骨密度（ bone mineral density,BMD）的测定,使用随机提供的T值作为参照标准对骨质疏松进行诊断。结果 ADT组治疗后睾酮明显下降,与 ADT前及非 ADT组差异有统计学意义（ P ＜0．01）;ADT组BMD较非ADT组低,在全身骨成分、腰椎（L1－4）、前臂骨两组 BMD差异有统计学意义（ P ＜0．05）,股骨颈BMD在ADT组较非ADT组低,但差异不明显（ P ＞0．05）;ADT组骨质疏松发生率为50．0％,非ADT组为22．7％,两组有统计学差异（ P ＜0．05）。结论 ADT可能加快老年前列腺癌患者骨量丢失,使骨质疏松的发生率升高。在对前列腺癌患者采取去势治疗前,建议先完善BMD的测定,对有明显骨量丢失或有高骨质风险的患者,建议采取适当的干预措施,以减缓骨量丢失。     

Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer

PURPOSE: A multicenter double-blind, randomized, placebo controlled clinical trial was performed to assess the effect of zoledronic acid, a potent new bisphosphonate, on bone mineral density during androgen deprivation therapy for nonmetastatic prostate cancer. MATERIALS AND METHODS: Men with M0 (no distant metastases) prostate cancer beginning androgen deprivation therapy were randomly assigned to receive 4 mg. zoledronic acid or placebo intravenously every 3 months for 1 year. The primary efficacy variable was the percent change from baseline to 1 year in bone mineral density of the lumbar spine as measured by dual energy x-ray absorptiometry. RESULTS: A total of 106 men were enrolled in the trial. Mean bone mineral density in the lumbar spine increased by 5.6% in men receiving zoledronic acid and decreased by 2.2% in those given placebo (mean difference 7.8%, 95% confidence interval 5.6%-10.0%, p <0.001). Mean bone mineral density of the femoral neck, trochanter and total hip also increased in the zoledronic acid group and decreased in the placebo group. Zoledronic acid was well tolerated. CONCLUSIONS: Zoledronic acid increases bone mineral density in the hip and spine during androgen deprivation therapy for nonmetastatic prostate cancer.     

Risedronate prevents persistent bone loss in prostate cancer patients treated with androgen deprivation therapy: results of a 2-year follow-up study

Androgen deprivation therapy (ADT) for prostate cancer (PCa) causes bone loss. Although we reported previously that risedronate significantly recovers bone mineral density (BMD) for up to 12 months, there have been no reports with longer follow-up periods to date. This study extended our earlier series extending the follow-up period to 24 months. Eligible patients had histologically confirmed PCa without lumbar spine metastasis and underwent ADT. Lumbar spine BMD, urinary deoxypyridinoline (uDPD) and serum bone alkaline phosphatase were measured at 6, 12 and 24 months. Among the total of 96 patients, we analyzed 26 and 18 patients in risedronate administration and control groups, respectively. BMD relative to the young adult mean ratio, uDPD and serum bone alkaline phosphatase of the risedronate administration group recovered significantly after 24 months compared with the control group (P<0.0001, P=0.0001, and P<0.0001, respectively). Transient blurred vision, malaise and vertigo were observed in 1 patient each among the 46 patients treated with risedronate within 28 days after first administration. Oral administration of risedronate is safe and effective for the recovery of ADT-induced bone loss in PCa patients even at 24 months after commencement of treatment.     

前列腺癌雄激素剥夺治疗与骨质丢失

目的前列腺癌是男性泌尿系统常见的恶性肿瘤之一。我国前列腺癌的发病率在迅速上升。 目前绝大多数患者采取雄激素剥夺治疗,与化疗相比,雄激素剥夺治疗的毒副作用较轻,更容易被患 者接受,但仍会引起一系列的不良反应,本文将对前列腺癌雄激素剥夺治疗后骨质丢失的情况及防治 策略进行综述。     

Preventing bone loss during androgen deprivation therapy for prostate cancer: early experience with neridronate

OBJECTIVE: Androgen-deprivation therapy (ADT) is the usual treatment for locally advanced or metastatic prostate cancer. Osteoporosis is a common complication of ADT. The aim of our study was to evaluate the efficacy of neridronate, a relatively new bisphosphonate to prevent bone loss during androgen ablation. METHODS: Sixty patients with prostate cancer and osteoporosis were enrolled and randomly assigned to 2 different treatment regimes: group A (30 patients) treated with maximum androgenic blockage (MAB), and group B (30 patients) treated with bicalutamide 150 mg. Each group was divided in 2 subgroups A1-A2 and B1-B2. All patients received calcium and cholecalciferol supplements (500 mg of elemental calcium and 400 IU cholecalciferol) daily. The A2 and B2 subgroups were also treated with neridronate (25 mg intramuscular monthly). Lumbar and femoral bone mineral density (BMD) was evaluated by dualenergy X-ray absorptiometry (DXA), both at baseline and after one year of treatment. Deoxypyridinoline (DPD) and bone-alkaline phosphatase (B-ALP) were determined at the beginning, midstudy and at the end. RESULTS: Patients treated only with calcium and cholecalciferol (A1, B1 subgroups) showed a marked bone loss after 6, and 12 months, with increased levels of DPD and BALP, compared to baseline values. Patients treated with neridronate (A2 et B2 subgroups) showed unchanged levels of these markers. After one year of treatment, lumbar and total hip BMD decreased significantly in patients treated only with calcium and cholecalciferol (A1 subgroup: -4.9% and -1.9% respectively). BMD did not change significantly at any site in patients treated also with neridronate (A2 subgroup: +1% and +0.8% respectively). Lumbar and total hip BMD did not change significantly (-1.5% and -1% respectively) in B1 subgroup. In B2 subgroup an important increase in lumbar spine and the total hip BMD was shown (+2.5% and 1.6% respectively). No relevant side effects were recorded during our study. CONCLUSION: In conclusion, neridronate is an effective and safe treatment in preventing bone loss in men receiving ADT for prostate cancer.     

Individual variations of serum testosterone in patients with prostate cancer receiving androgen deprivation therapy

OBJECTIVE

To analyse individual variations in serum testosterone level, the cumulative rate of ‘breakthrough’ increases over castrate levels, and to evaluate whether the increases can be predicted.

PATIENTS AND METHODS

Serum testosterone levels were determined every 6 months over 3 years in 73 consecutive patients with prostate cancer who were medically castrated, prospectively enrolled in a single tertiary academic centre. Patients recruited for this study were being treated with a 3‐monthly depot of luteinizing hormone‐releasing hormone agonist over 6–48 months. Serum testosterone was measured using a chemiluminescent assay with a lower sensitivity level of 15 ng/dL and interassay coefficient of variation of 25% at low testosterone concentrations.

RESULTS

Individual variations could not be explained by the interassay variation coefficient in 26% of the patients. The rate of breakthrough increases >50 ng/dL increased from 12.3% at the first determination to 24.7% at the third, then remaining stable. The rate of breakthrough increases of 20–50 ng/dL increased from 27.4% at the first determination to 31.5% at the second, and then remained stable. A first determination of <20 ng/dL provided an 11.4% probability for future increases of >50 ng/dL, with a 5.7% probability if two consecutive determinations were <20 ng/dL and a null probability when three consecutive determinations were <20 ng/dL.

CONCLUSIONS

Individual variations in serum testosterone level cannot be explained by the coefficient of variation of the assay in a quarter of patients who are medically castrated. Breakthrough increases over castrate levels increase over time and those of >50 ng/dL can be predicted from the previous levels.     

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.     

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     

Increased risk of a herpes zoster attack in patients receiving androgen deprivation therapy for prostate cancer

This study aimed to examine the association of herpes zoster (HZ) with androgen deprivation therapy (ADT) use among patients with prostate cancer (PC), using a population‐based data set. The study sample for this study was retrieved from the Taiwan Longitudinal Health Insurance Database 2005. We selected 877 patients with PC who had received ADT as the study group, while 849 patients with PC who had not received ADT served as the comparison group. Each study patient was individually tracked for a 3‐year period to discriminate those who subsequently received a diagnosis of HZ. Of the total 1,726 sampled patients, the incidence rate of HZ per 100 person‐years was 1.80 (95% CI: 1.41–2.25) during the 3‐year follow‐up period. In particular, incidence rates of HZ per 100 person‐years were 2.36 (95% CI: 1.75–3.13) and 1.24 (95% CI: 0.81–1.81), respectively, for patients with PC who had and those who had not received ADT. Furthermore, Cox proportional hazard regressions showed that the adjusted hazard ratio for an HZ attack during the 3‐year follow‐up period for patients with PC who had received ADT was 1.88 (95% CI: 1.13–3.11) than those who had not received ADT. We concluded that patients with PC who had received ADT had an increased risk of HZ.     

Reversibility of androgen deprivation therapy in patients with prostate cancer

PURPOSE: We determined the duration of testosterone suppression and recovery in patients with prostate cancer treated with a hydrogel implant releasing the gonadotropin releasing hormone (GnRH) agonist histrelin or treated with a depot GnRH agonist. MATERIALS AND METHODS: Luteinizing hormone (LH) and testosterone (T) responses were monitored in 3 groups. Group 1 comprised 7 patients treated with histrelin implant, which is inserted into the arm of the patient while under local anesthesia, and suppresses LH and testosterone. Following implant removal antiandrogens (flutamide or bicalutamide) were administered. Group 2 comprised 8 patients treated with long-term depot GnRH super agonists which were later withheld and patients were given bicalutamide. Group 3 consisted of 7 patients treated with bicalutamide. RESULTS: In group 1 LH and T were in the castration range while implants were in place. LH increased 1 to 6 weeks after implant removal followed by an increase in T. In 7 of 8 patients in group 2, LH, T and prostate specific antigen remained suppressed for 9 months. In 6 of 7 group 3 patients LH and T increased with a decrease in prostate specific antigen. CONCLUSIONS: Despite continuous prolonged T suppression for up to 3 years due to histrelin implant, LH and T increased rapidly following implant removal, indicating that suppression is reversible. In view of the 9-month suppression of LH and T after the last depot GnRH injection in 7 of 8 patients, it is possible to space GnRH agonist administration at longer intervals. However, T must be monitored to determine that suppression is maintained.     

Denosumab and changes in bone turnover markers during androgen deprivation therapy for prostate cancer

Androgen deprivation therapy (ADT) for prostate cancer increases fracture risk, decreases bone mineral density, and increases bone turnover markers (BTMs) including serum type 1 C‐telopeptide (sCTX), tartrate‐resistant alkaline phosphatase 5b (TRAP‐5b), and procollagen‐1 N‐terminal telopeptide (P1NP). In a prespecified exploratory analysis of a phase 3, multicenter, double‐blind study, we evaluated the effects of denosumab (60 mg subcutaneously every 6 months for 3 years) versus placebo (1468 patients, 734 in each group) on BTM values. BTMs were measured at baseline, month 1, and predose at months 6, 12, 24, and 36 in the overall population. BTMs at month 1 are also reported for subgroups based on age (< 70 years versus ≥ 70 years), prior duration of ADT (≤ 6 months versus >6 months), and baseline BTM (≤ median versus > median BTM values). Treatment with denosumab provided a rapid and sustained decrease of BTM values compared with placebo. The median change in sCTX levels at month 1 was ?90% in the denosumab group and ?3% in the placebo group (p < 0.0001). The median change in TRAP‐5b levels at month 1 was ?55% in the denosumab group and ?3% in the placebo group (p < 0.0001). The maximal median change in P1NP was ?64% in the denosumab group and ?11% in the placebo group, (p < 0.0001). Significantly greater decreases in BTM for denosumab were also seen in subgroup analyses based on age, prior ADT treatment, and baseline BTM values. Suppression of bone turnover markers was consistent with marked increases in bone mineral density reported previously. © 2011 American Society for Bone and Mineral Research     

Fracture risk in patients with prostate cancer on androgen deprivation therapy

Although a decrease in bone mass is a well-known side effect of hormone therapy for prostate carcinoma, its clinical significance is unclear, as there is only scanty information about the incidence of fractures. Therefore, the aim of this study was to determine the risk of non-metastatic fractures in patients with prostate cancer undergoing androgen deprivation therapy. We performed a retrospective cohort study that comprised 288 patients with cancer who were subjected to androgen deprivation therapy (ADT). All were given LHRH agonists, and most of them also received peripheral androgen receptor blockers. The results were compared with a control group of 300 men that were not receiving ADT. The incidence rates of peripheral and vertebral fractures in the group of men on ADT were 1.9 and 0.8 per 100 patient-years, respectively. Incidence rates in the control group were 0.5 and 0.2, respectively. In the whole study group, 35 patients had at least one fracture during follow-up (25 on ADT, ten controls). Thus, the number of patients with at least one fracture was significantly higher in the group on ADT (P=0.001 by the log-rank test). The unadjusted risk ratio was 4.2 (CI 2.0–8.9). A similar value (risk ratio 3.6; CI 1.6–7.7, P=0.001) was found after it was adjusted for other factors, such as age or prior fractures. Therefore, ADT is associated with a fourfold increase in the incidence rate of both peripheral and vertebral fractures. Although the absolute incidence remains relatively small, preventive measures should be considered for high-risk patients.