To characterize changes in lean body mass (LBM) in men with prostate cancer receiving androgen-deprivation therapy (ADT).
Patients and Methods
We prospectively evaluated LBM in a prespecified substudy of a randomized controlled trial of denosumab to prevent fractures in men receiving ADT for nonmetastatic prostate cancer. LBM was measured by total-body dual-energy x-ray absorptiometry at study baseline and at 12, 24, and 36 months. The analyses included 252 patients (132, denosumab; 120, placebo) with a baseline and at least one on-study LBM assessment. Patients were stratified by age (< 70 v ≥ 70 years) and by ADT duration (≤ 6 v > 6 months).
Median ADT duration was 20.4 months at study baseline. Mean LBM decreased significantly from baseline, by 1.0% at month 12 (95% CI, 0.4% to 1.5%; P < .001; n = 248), by 2.1% at month 24 (95% CI, 1.5% to 2.7%; P < .001; n = 205), and by 2.4% at month 36 (95% CI, 1.6% to 3.2%; P < .001; n = 168). Men age ≥ 70 years (n = 127) had significantly greater changes in LBM at all measured time points than younger men. At 36 months, LBM decreased by 2.8% in men age ≥ 70 years and by 0.9% in younger men (P = .035). Men with ≤ 6 months of ADT at study entry (n = 36) had a greater rate of decrease in LBM compared with men who had received more than 6 months of ADT at study entry (3.7% v 2.0%; P = .0645).
In men receiving ADT, LBM decreased significantly after 12, 24, and 36 months.
Prostate cancer is both the most common malignancy and the most common cause of cancer death in men. In the United States, there were approximately 217,730 new prostate cancer diagnoses and more than 32,050 deaths in 2010 1. Skeletal complications occur at various points during the disease course, either due to bone metastases directly, or as an unintended consequence of androgen deprivation therapy (ADT). Up to 90% of men with metastatic castration resistant prostate cancer (CRPC) develop bone metastases2,3. Bone metastases are associated with pathologic fractures, spinal cord compression, and bone pain and can require narcotics or palliative radiation for pain relief. Additionally, ADT results in bone loss and fragility fractures.
This review describes the biology of bone metastases, skeletal morbidity in men with prostate cancer, and recent advances in bone targeted therapies to prevent skeletal complications of prostate cancer.
zoledronic acid; denosumab; prostate cancer; bone metastasis; skeletal-related events; Prostate cancer; skeletal complications; bone; side effects of therapy; ADT
Androgen deprivation therapy (ADT) is associated with increased fracture risk. In a recent Phase III trial, toremifene significantly decreased vertebral fractures in men receiving ADT. Similar to other selective estrogen receptor modulators, toremifene was associated with an increase in venous thromboembolic events (VTEs), with the greatest risk in men aged ≥80 years. This post hoc analysis evaluated the efficacy and safety of toremifene in men aged <80 years.
Materials and Methods
This analysis included 847 subjects aged <80 years; 430 received toremifene 80 mg by mouth daily and 417 received placebo for up to 24 months. The primary endpoint was new vertebral fractures. Secondary endpoints included fragility fractures, bone mineral density (BMD), and safety.
Compared with placebo, toremifene decreased the relative risk of new vertebral fractures by 79.5% (95% CI, 29.8%–94.0%; P<0.005). New vertebral fracture incidence was 1.0% with toremifene and 4.8% with placebo (absolute risk reduction, 3.8%). Compared with placebo, toremifene significantly reduced the incidence of a nontraumatic fracture or >7% bone loss by 24 months (P<0.0001). Toremifene also significantly increased BMD at all measured sites (P<0.001 for all comparisons). The incidence of VTEs was similar in the toremifene and placebo groups (2.1% vs 1.0%, respectively; P=0.26). Rates of other adverse events were also similar between groups.
Toremifene significantly decreased new vertebral fractures in men aged <80 years receiving ADT for prostate cancer. The risk of VTEs was lower than in the overall study population, suggesting an improved benefit–risk profile in younger men.
androgen deprivation therapy; osteoporosis; prostate cancer; selective estrogen receptor modulators; toremifene
Men with prostate cancer are at risk of experiencing accelerated bone loss and fractures as a result of androgen deprivation therapy (ADT).
We evaluated the effects of denosumab, a fully human monoclonal antibody against RANKL, on preservation of BMD at 3 key skeletal sites (lumbar spine [LS], femoral neck [FN], and total hip [TH]) and the distal radius at 36 months both by responder category and individual responses in a waterfall plot analysis.
Design, Setting, and Participants
This phase 3, randomized, double-blind study of men with non-metastatic prostate cancer receiving ADT investigated the effects of denosumab on bone mineral density (BMD) and fractures. Patients were treated for 36 months.
Subcutaneous denosumab 60 mg (n=734) or placebo (n=734) every 6 months for up to 36 months. Patients were instructed to take supplemental Calcium and vitamin D.
Primary outcome measure: The percentage change from baseline to month 36 in LS, FN, and TH BMD was measured by dual energy x-ray absorptiometry. BMD at the distal 1/3 radius at 36 months was measured in a sub-study of 309 patients.
Results and Limitations
At 36 months, significantly more patients in the denosumab arm had increases of >3% BMD from baseline at each site studied compared with placebo (LS, 78% vs 17%; TH, 48% vs 6%; FN, 48% vs 13%; distal 1/3 radius, 40% vs 7%). The percentage of denosumab patients with bone loss at all 3 key BMD sites at month 36 was 1%, as opposed to 42% in placebo arm. At 36 months 69% of denosumab-treated patients had BMD increases at all three sites (LS, TH or FN) compared with 8% of placebo-treated patients. Lower baseline BMD was associated with higher magnitude lumbar spine, femoral neck, and total hip BMD responses to denosumab.
In men with prostate cancer receiving ADT significantly higher BMD response rates were observed with denosumab vs. placebo.
This study is registered with ClinicalTrials.gov with the identifier NCT00089674.
androgen deprivation; bone mineral density; bone loss; antiresorptive therapy; responder analysis
Previous studies demonstrate that androgen deprivation therapy with gonodotropin-releasing hormone (GnRH) agonists and orchiectomy for prostate cancer is associated with cardiovascular disease. However, few studies have examined its effect on the peripheral vascular system.
To study the risk of peripheral arterial disease and venous thromboembolism associated with androgen deprivation therapy for prostate cancer.
Design, Settings and Participants
Population-based observational study of 182,757 U.S. men aged 66 years and older who were diagnosed with loco-regional prostate cancer from 1992 to 2007, of whom 47.8% received GnRH agonists and 2.2% orchiectomy.
We used Cox proportional hazards models with time-varying treatment variables to assess whether treatment with GnRH agonists or orchiectomy was associated with peripheral arterial disease and/or venous thromboembolism.
Results and limitations
Overall, 47.8% of men received a GnRH agonist during follow-up and 2.2% underwent orchiectomy. GnRH agonist use was associated with an increased risk of incident peripheral arterial disease (adjusted hazard ratio [HR], 1.15, 95% confidence interval [CI] 1.11–1.19) and incident venous thromboembolism (adjusted HR, 1.1, 95% CI 1.04–1.16). In addition, orchiectomy was associated with an increased risk of peripheral arterial disease (adjusted HR, 1.14, 95% CI 1.03–1.27) and venous thromboembolism (adjusted HR, 1.22, 95% CI 1.07–1.40). Limitations include the observational study design, inability to assess the use of oral anti-androgens as monotherapy or combined androgen deprivation.
Androgen deprivation therapy for loco-regional prostate cancer is associated with an increased risk of peripheral artery disease and venous thromboembolism. Additional research is needed to better understand the potential risks and benefits, so that these treatments can be targeted to patients where the benefits are most clear.
Prostate cancer; androgen deprivation therapy; peripheral vascular disease; venous thromboembolism
To investigate associations of baseline CVD risk profile, dosing regimen and treatment duration with incident CVD events during androgen deprivation therapy with degarelix in patients with PCa.
Materials and Methods
Data from 1704 subjects who participated in 9 clinical trials was pooled for the analysis. Subjects received treatment with either monthly (20-240 mg) or 3-monthly doses (240-480 mg) of degarelix for an average of 22 months (up to 66 months). Endpoints were ischemic heart disease, cerebrovascular disorders, arterial thrombotic/embolic events, and claudication
First-time CVD events were reported in 92 subjects in the year prior to study entry and 168 subjects after degarelix treatment. Event rates were similar before and after degarelix treatment (5.5 vs. 6.1 per 100 person-years; P=0.45) in the total population and in the subset of men without baseline CVD (5.6 vs. 4.3 per 100 person-years; p=0.11). In contrast, event rates were higher after degarelix treatment (5.3 to 10.5 events per 100 person-years; p=0.0013) in the subset of men with CVD at baseline. In multivariate analysis, CVD at baseline was the strongest independent predictor of events during treatment followed by older age, abstinence to alcohol and obesity (all p<0.05). Dose and schedule of degarelix treatment were not independently associated with CVD events.
In men with PCa, observed rates of CVD events were similar before and after degarelix treatment. Events during degarelix treatment were largely confined to those with pre-existing CVD and further modulated by age and modifiable risk factors.
cardiovascular events; degarelix; long-term treatment; predictors; prostate cancer patients
Effective management of bone metastases in men with castration-resistant prostate cancer (CRPC) remains an important unmet medical need. MET and VEGFR are rational targets for intervention in CRPC. Clinical trials involving agents that inhibit one but not both pathways have reported modest activity and no improvement in overall survival. Cabozantinib is an oral multitargeted tyrosine kinase inhibitor (TKI) that inhibits both MET and VEGFR2. A phase II randomized discontinuation study involving subjects with CRPC demonstrated that cabozantinib therapy is associated with improvement in bone scans, bone turnover markers, and pain response, but with significant adverse events leading to dose reduction and treatment discontinuation. Lower doses of cabozantinib retain high levels of activity with less toxicity. Ongoing phase III clinical trials will define the role of cabozantinib in CRPC. We summarize the rationale for targeting MET and VEGFR pathways in CRPC and the clinical data available to date.
MET; VEGFR; cabozantinib; prostate cancer; bone metastasis
Hyperpolarized (HP) 13C-labeled pyruvate studies with Magnetic Resonance (MR) have been used to observe the kinetics of metabolism in-vivo. Kinetic modeling to measure metabolic rates in-vivo is currently limited because of nonspecific hyperpolarized signals mixing between vascular, extravascular, and intracellular compartments. In this work simultaneous acquisition of both 1H and 13C signals after contrast agent injection is used to resolve specific compartments to improve the accuracy of the modeling. We demonstrate a novel technique to provide contrast to the intracellular compartments by sequential injection of HP [1-13C] pyruvate followed by gadolinium-chelate to provide T1-shortening to extra-cellular compartments. A kinetic model that distinguishes the intracellular space and includes the T1-shortening effect of the gadolinium-chelate can then be used to directly measure the intracellular 13C kinetics.
intracellular; magnetic resonance; metabolism; pyruvate; gadolinium
Whether race influences bone loss and fracture risk during androgen deprivation therapy (ADT) for prostate cancer is unknown. Using data from a prospective, clinical trial, we compared bone mineral density (BMD) and fracture between African American and Caucasian men receiving ADT.
Materials and Methods
Subjects (n=516) were in the placebo group of a two-year randomized placebo controlled fracture prevention trial and were African American (n=68) or Caucasian (n=448). We compared baseline characteristics, changes in BMD, and rates of new fractures between races.
Compared to Caucasian men, African American men had higher baseline hip BMD (0.98 ± 0.15 g/m2 versus 0.91 ± 0.15 g/m2; P=0.001) and similar spine BMD (1.09 ± 0.22 versus 1.11 ± 0.22; P=0.51). There was no difference in prevalent vertebral fractures between African American and Caucasian men (7.4% versus 15.0%; P=0.13). Percentage change in hip BMD at two years was similar between African American and Caucasian men (−2.21 ± 0.59% versus −2.54 ± 0.26%; P=0.65). Changes in BMD of the lumbar spine were also similar between African American and Caucasian men (−1.74 ± 0.69 versus −1.30 ± 0.33%; P=0.64). No new vertebral fractures were reported in African American men versus two fractures in Caucasian men.
In a clinical trial, African American men receiving ADT for prostate cancer have higher hip BMD and tended to have fewer prevalent vertebral fractures than Caucasian men. Despite lower baseline risk of osteoporosis and fracture, African American men experience a decline in BMD that is similar to Caucasian men.
prostate cancer; androgen deprivation therapy; bone mineral density; fracture; survivorship
Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition may prevent bone metastases. This phase 3 study evaluated denosumab, a fully human anti-RANKL monoclonal antibody, to prevent bone metastasis or death from any cause in men with non-metastatic castration-resistant prostate cancer (CRPC).
Men with non-metastatic CRPC at high risk for bone metastasis (PSA ≥8.0 ng/mL and/or PSA doubling time ≤10.0 months) were enrolled in 319 centers from 30 countries. Patients were randomised 1:1 in blinded fashion using an interactive voice response system to receive monthly subcutaneous denosumab 120 mg or placebo. The primary endpoint was bone metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death.
1432 patients were randomised, 716 to receive denosumab and 716 to receive placebo. Denosumab significantly increased bone metastasis-free survival by a median of 4.2 months over placebo (hazard ratio 0.85 [0.73–0.98]; P=0.028). Denosumab also significantly delayed time to first bone metastasis (hazard ratio 0.84 [0.71–0.98]; P=0.032). Overall survival was similar between groups (hazard ratio 1.01 [0.85–1.20]; P=0.91). Rates of adverse events (AEs) and serious AEs were generally similar between groups, except for osteonecrosis of jaw (ONJ) and hypocalcemia. Yearly cumulative incidence of ONJ for denosumab was: 1%, 3%, 4% in years 1, 2, 3, respectively; overall, less than 5% (n=33). Hypocalcemia occurred in under 2% (n=12) of denosumab and under 1% (n=2) of placebo patients. The blinded treatment phase has been completed.
In men with CRPC, denosumab significantly prolonged bone metastasis-free survival and delayed time to bone metastasis. This is the first large randomised study to demonstrate that targeting the bone microenvironment prevents bone metastasis in men with prostate cancer.
urology/prostate disease; denosumab; prostate cancer; prevention; bone metastasis; survival; hormone refractory; castration-resistant
Abiraterone is an oral inhibitor of CYP17, essential for androgen biosynthesis. This multicenter study assessed its efficacy in patients with CRPC without prior exposure to chemotherapy or CYP17 targeted therapy, and assessed the frequency of interpretation of bone scans discordant with PSA and clinical response.
Patients and Methods
33 patients received abiraterone acetate 1000 mg daily with prednisone 5 mg twice daily in continuous 28-day cycles. Patients were evaluated monthly for efficacy and safety. Bone scan flare was defined as the combination, after 3 months of therapy, of an interpreting radiologist's report indicating “disease progression” in the context of a ≥50% decline in PSA, with scan improvement 3 months later.
A ≥ 50% PSA decline at week 12 was confirmed in 22/33 (67%) patients. PSA declines of ≥ 50% were seen in 26 (79%) patients. Undetectable PSA levels (≤ 0.1 ng/mL) occurred in 2 patients. Median time on therapy and time to PSA progression are 63 and 71 weeks, respectively. Twenty three patients were evaluable for bone scan flare. Progression was indicated in the radiologist's report in 12/23 (52 %), and 10/12 subsequently showed improvement. As prospectively defined, bone scan flare was observed in 10/23 (43.5%) evaluable patients or 10/33 (30%) enrolled patients. Adverse events were typically grade 1/2 and consistent with prior published abiraterone reports.
Clinical response to abiraterone acetate plus prednisone was frequent and durable in men with metastatic CRPC progressing on hormonal therapy with over half of patients on therapy > 1 year. Further investigation is needed to clarify the potential confounding effect of the frequently occurring bone scan flare phenomena on patient management and interpretation of clinical trial results.
abiraterone acetate; castration-resistant prostate cancer; CRPC; hormone-resistant prostate cancer; therapy; efficacy
The prognostic role, in terms of the overall survival outcome, of serum parathyroid hormone evaluated at baseline and after 3 months of zoledronic acid or placebo treatment in hormone-refractory prostate cancer patients with bone metastases enrolled in a randomized clinical trial was assessed.
Secondary hyperparathyroidism is frequent in prostate cancer patients with bone metastases, and this condition is worsened by the administration of potent bisphosphonates. Serum parathyroid hormone (PTH) elevation can impair the efficacy of these drugs in terms of survival.
The prognostic role of elevated serum PTH levels at baseline and after 3 months of zoledronic acid administration was assessed prospectively in 643 bone metastatic prostate cancer patients enrolled in a prospective randomized, placebo-controlled study.
On multivariate analysis, after adjusting for major prognostic factors and bone turnover markers, elevated baseline serum PTH level was negatively associated with overall survival (hazard ratio [HR], 1.448; 95% confidence interval [CI], 1.045–2.006; p < .03) in zoledronic acid–treated patients but not in placebo-treated patients. In patients with normal baseline PTH levels, there was a trend but insignificant association between zoledronic acid administration and a better survival outcome than with placebo (HR, 0.81; 95% CI, 0.65–1.01; p = .065), whereas a trend in the opposite direction was observed in patients with elevated PTH levels (HR, 1.45; 95% CI, 0.87–2.39; p = .151); interaction test, p = .040. Elevated serum PTH level after 3 months of zoledronic acid treatment was not significantly associated with survival outcome.
Secondary hyperparathyroidism has a negative prognostic impact in metastatic prostate cancer patients undergoing zoledronic acid administration. Counteracting elevated PTH levels by adequate doses of vitamin D may improve the efficacy of this drug.
Bone metastasis; Parathyroid hormone; Prostate cancer; Zoledronic acid
Purpose of review
The aim of this review is to summarize new concepts and concerns regarding treatment-related osteoporosis, diabetes, and cardiovascular disease in men receiving androgen deprivation therapy for prostate cancer.
Gonadotropin-releasing hormone agonists increase bone turnover, decrease bone mineral density, and increase fracture risk. Bisphosphonates, selective and estrogen receptor modulators significantly increase bone mineral density during androgen deprivation therapy. Ongoing randomized controlled trials will assess efficacy of denosumab, toremifene, and zoledronic acid to prevent fractures in this setting. Gonadotropin-releasing hormone agonists also increase fat mass, decrease insulin sensitivity, and increase serum lipoproteins. In contrast to the classical metabolic syndrome, however, the phenotype of men during androgen deprivation therapy is characterized by increased high-density lipoprotein cholesterol and preferential accumulation of subcutaneous fat. Gonadotropin-releasing hormone agonists are associated with greater risk of incident diabetes and cardiovascular disease in men with prostate cancer.
Androgen therapy increases risk of fractures, diabetes mellitus, and cardiovascular disease in men with prostate cancer. Current and planned studies will evaluate strategies to prevent these treatment-related adverse effects.
cardiovascular disease; diabetes; gonadotropin-releasing hormone agonists; obesity; osteoporosis; prostate cancer
The intended therapeutic effect of gonadotropin-releasing hormone (GnRH) agonists is hypogonadism, a major cause of acquired osteoporosis in men. Consistent with this observation, GnRH agonists increase bone turnover and decrease bone mineral density, a surrogate for fracture risk. Large claims-based analyses and other retrospective studies provide compelling evidence that GnRH agonists increase risk of clinical fractures. Estrogens play a central role in homeostasis of the normal male skeleton, and estrogen deficiency rather than testosterone deficiency seems to be primarily responsible for the adverse skeletal effects of GnRH agonists. In randomized controlled trials, bisphosphonates (pamidronate and zoledronic acid) and selective estrogen receptor modulators (raloxifene and toremifene) increased bone mineral density in GnRH agonist – treated men. Two ongoing large randomized placebo-controlled studies will prospectively define fracture outcomes in men with prostate cancer and assess the efficacy of novel pharmacologic interventions (AMG162, toremifene) during GnRH agonist treatment.
Gonadotropin-releasing hormone (GnRH) agonists decrease bone mineral density (BMD) and increase fracture risk in men with prostate cancer. Annual zoledronic acid increases BMD in postmenopausal women, but its efficacy in hypogonadal men is not known.
Patients and Methods
In a 12-month study, 40 men with nonmetastatic prostate cancer who were receiving a GnRH agonist and had T scores more than −2.5 were randomly assigned to zoledronic acid (4 mg intravenously on day 1 only) or placebo. BMD of the posteroanterior lumbar spine and proximal femur were measured by dual-energy x-ray absorptiometry.
Mean (± SE) BMD of the posteroanterior lumbar spine decreased by 3.1% ± 1.0% in men assigned to placebo and increased by 4.0% ± 1.0% in men assigned to zoledronic acid (P < .001). BMD of the total hip decreased by 1.9% ± 0.7% in men assigned to placebo and increased by 0.7% ± 0.5% in men assigned to zoledronic acid (P = .004). Similar between-group differences were observed for the femoral neck and trochanter. Serum N-telopeptide, a marker of osteoclast activity, decreased significantly after zoledronic acid treatment.
In men receiving a GnRH agonist, a single treatment with zoledronic acid significantly increased BMD and durably suppressed serum N-telopeptide levels for 12 months. Annual zoledronic acid may be a convenient and effective strategy to prevent bone loss in hypogonadal men.
Gonadotropin-releasing hormone (GnRH) agonists are the mainstay of treatment for recurrent and metastatic prostate cancer. GnRH agonists are also an important part of therapy for many men with localized or locally advanced prostate cancer. Although GnRH agonists improve survival in certain settings, they involve adverse effects including vasomotor flushing, obesity, and osteoporosis. This article describes the evidence that GnRH agonists increase risk for diabetes and cardiovascular disease and reviews the potential mechanisms for treatment-related morbidity.
To evaluate effects of obesity on sex steroid levels during treatment with a gonadotropin-releasing hormone agonist in men with prostate cancer.
Forty-nine hormone-naïve men with recurrent or locally advanced prostate cancer were included in the analyses. All subjects were treated with leuprolide 3-month depot for 48 weeks. Serum levels of estradiol, sex hormone – binding globulin, total testosterone, and free testosterone were assessed at baseline, 24 weeks, and 48 weeks. Subjects were categorized by body mass index (BMI) and percent body fat.
Pretreatment serum sex hormone – binding globulin and total testosterone levels were significantly lower in overweight and obese men than in men with normal BMI. In the overall study population, mean serum testosterone concentrations decreased from 372 ±18 ng/dL at baseline to 13 ± 1ng/dL at week 48 (P < 0.001). Free testosterone decreased from 6.75 ± 0.33 ng/dL at baseline to 0.21 ± 0.02 ng/dL at week 48 (P < 0.001). During treatment with leuprolide, obese men had significantly higher total and free testosterone levels than men with normal BMI. Compared with normal men, total and free testosterone levels during treatment were 1.8-fold and 2.3-fold higher in obese men. Similar results were observed when subjects were categorized by body fat.
Despite lower pretreatment serum testosterone levels, obese men have higher total and free testosterone levels during leuprolide treatment than men with normal BMI. These differences may contribute to the association between obesity and increased prostate cancer mortality.
Inflammatory and angiogenic biomarkers were measured in androgen deprivation therapy–treated and control groups of men with prostate cancer. Significantly higher concentrations of some inflammatory biomarkers were found in the treatment group.
Angiogenesis and inflammation are both important to the pathogenesis of malignancies. Androgen deprivation therapy (ADT) for prostate cancer causes drastic hormonal changes that alter both disease and host factors. We measured inflammatory and angiogenic biomarkers in ADT-treated and control groups of men with prostate cancer.
Materials and Methods.
Baseline and 12-week plasma samples were collected from 37 ADT-naïve men with locally advanced or recurrent prostate cancer. Of those, 23 initiated ADT with a gonadotropin-releasing hormone (GnRH) agonist and 14 served as nontreatment controls. Samples were tested for a panel of angiogenic and inflammatory biomarkers.
The treatment group had significantly higher concentrations of the inflammatory biomarkers interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and stromal cell–derived factor (SDF)-1α. None of the angiogenic biomarkers were significantly different between the groups at baseline. Among patients with a short prostate-specific antigen (PSA) doubling time (<6 months), the proangiogenic factor basic fibroblast growth factor (bFGF) was lower at baseline. In the treatment group, plasma placental growth factor (PlGF) increased and IL-6 decreased after 12 weeks of ADT. Moreover, the treatment group continued to have significantly higher concentrations of the inflammatory biomarkers IL-1β, IL-8, and SDF-1α as well as bFGF than controls.
These men were characterized by elevations in several traditional markers of aggressive disease and also by higher levels of several inflammatory biomarkers. Although ADT decreased IL-6 levels, IL-1β, IL-8, and SDF-1α remained significantly higher than in controls. The role of these biomarkers should be further explored.
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 pre-specified 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) vs. placebo (1468 patients, 734 in each group) on BTM values. BTMs were measured at baseline, month 1, and pre-dose 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 vs. ≥ 70 years), prior duration of ADT (≤6 months vs. >6 months), and baseline BTM (≤ median vs. >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 <.0001). The median change in TRAP-5b levels at month 1 was −55% in the denosumab group and −3% in the placebo group (p <.0001). The maximal median change in P1NP was −64% in the denosumab group and −11% in the placebo group, (p <.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.
(5) denosumab; androgen deprivation therapy; bone turnover markers; prostate cancer
Gonadotropin-releasing hormone agonists increase fat mass, decrease insulin sensitivity, and increase serum triglycerides–changes suggestive of the classic metabolic syndrome. These analyses were designed to assess the effects of gonadotropin-releasing hormone agonist treatment on other markers of the metabolic syndrome including adiponectin, resistin, and plasminogen activator inhibitor type 1 (PAI-1) levels and to evaluate relationships between changes in adipocytokines, body composition, and insulin sensitivity.
In this prospective 12-week study, 25 nondiabetic men with locally advanced or recurrent prostate cancer and no radiographic evidence of metastases were treated with leuprolide depot and bicalutamide. Outcomes included changes from baseline to week 12 in body composition, insulin sensitivity, and levels of adiponectin, resistin, and PAI-1.
Mean (± SE) percentage fat body mass increased by 4.3 ± 1.3% from baseline to week 12 (P=0.002). Insulin sensitivity index decreased by 12.9 ± 7.6% (P=0.02). Serum adiponectin levels increased by 37.4 ± 7.2% from baseline to week 12 (P<0.001). In contrast, serum resistin levels did not change significantly. Changes in adiponectin were associated with changes lean mass (r=0.448; P=0.02) and fat mass (r=−0.383; P=0.06) but not changes in insulin sensitivity.
Combined androgen blockade with leuprolide and bicalutamide significantly increased serum adiponectin levels but did not alter PAI-1 or resistin levels. This pattern of metabolic changes appears distinct from the classic metabolic syndrome.
prostate cancer; GnRH agonist; obesity; insulin resistance; adiponectin; resistin
In men with prostate cancer, gonadotropin-releasing hormone (GnRH) agonists increase fat mass, decrease insulin sensitivity, and increase triglycerides, features that are shared with metabolic syndrome. To the authors’ knowledge, however, less is known regarding the effects of GnRH agonists on other attributes of the metabolic syndrome.
In an open-label prospective study, 26 men with recurrent or locally advanced prostate cancer were treated with leuprolide for 12 months. Outcomes included changes in blood pressure, body composition, lipids, adipocytokines, and C-reactive protein.
The mean weight, body mass index, and waist circumference increased significantly from baseline to Month 12 (P < .001 for each comparison). Fat mass increased by 11.2% ± 1.5% (P < .001) and the percentage lean body mass decreased by 3.6% ± 0.5% (P < .001). The total abdominal fat area increased by 16.5% ± 2.6% (P < .001), with the accumulation of subcutaneous fat accounting for 94% of the observed increase. The waist-to-hip ratio and blood pressure did not change significantly. Serum high-density lipoprotein (HDL) cholesterol concentrations increased significantly (P = .002). Serum adiponectin levels increased by 36.4 ± 5.9% from baseline to Month 3 and remained significantly elevated through Month 12 (P < .001). Resistin and C-reactive protein levels did not change significantly.
The term metabolic syndrome does not appear to adequately describe the effects of GnRH agonists in men with prostate cancer. In contrast to the metabolic syndrome, GnRH agonists increase subcutaneous fat mass, HDL cholesterol, and adiponectin, and do not alter the waist-to-hip ratio, blood pressure, or C-reactive protein level.
prostate cancer; metabolic syndrome; gonadotropin-releasing hormone; metabolic changes
Skeletal morbidity is a prominent burden to men with advanced prostate cancer throughout the natural history of the disease. Bone metastases can cause pain and greatly elevate the risk for fractures and other structural complications. Distinct from the problem of metastases, treatment-related osteoporosis and associated fragility fractures are potential complications of androgen-deprivation therapy. Bone-targeted therapies for prostate cancer have therefore been the focus of considerable research and drug development efforts. The osteoclast is a validated therapeutic target in the management of prostate cancer. Osteoclast inhibition with zoledronic acid (a bisphosphonate) or with denosumab (a monoclonal antibody to RANK ligand) reduces risk for skeletal events in men with castration-resistant prostate cancer metastatic to bone. Osteoclast inhibition with any of several bisphosphonates improves bone mineral density, a surrogate for osteoporotic fracture risk. Denosumab and toremifene (a selective estrogen receptor modulator) have each been shown to reduce osteoporotic fracture risk among men receiving androgen-deprivation therapy. Beta-emitting radiopharmaceuticals reduce pain due to metastatic disease. Investigations involving alpha-emitting radium-223, endothelin-A receptor antagonists atrasentan and zibotentan, proto-oncogene tyrosine-protein kinase (SRC) inhibitor dasatinib, and tyrosine kinase inhibitor cabozantinib (XL184) are ongoing in clinical trials and are also discussed.
Hormone ablation therapy (HALT) for breast or prostate cancer accelerates the development of osteoporosis in both men and women by causing estrogen deficiency, which increases the risk for fracture by promoting bone resorption mediated by osteoclasts. Denosumab, a fully human monoclonal antibody that inhibits osteoclast formation and function, increases bone mass in patients undergoing hormone ablation therapy. In the HALT study of 1,468 men with prostate cancer on androgen-deprivation therapy, denosumab significantly reduced the risk of new vertebral fractures, increased bone mineral density (BMD), and reduced markers of bone turnover. In a study of 252 women with breast cancer undergoing adjuvant aromatase inhibitor (AI) therapy, denosumab increased BMD at 12 and 24 months, overall and in all patient subgroups. The overall rates of adverse events were similar to placebo. Clinicians should consider fracture risk assessment and therapies such as denosumab to increase bone mass in patients on hormone ablation therapy who are at high risk for fracture.
denosumab; treatment-induced bone loss; hormone-ablation therapy; breast cancer; prostate cancer
Disrupted skeletal homeostasis is common in patients with prostate cancer. Low bone density is common at diagnosis, and fracture risk is further elevated by the effects of androgen-deprivation therapy. Later in the disease course, bone metastases can result in skeletal morbidity. Although prostate-specific antigen (PSA) levels can provide important insights into overall disease progression, convenient, noninvasive tools for monitoring skeletal health are lacking. Biochemical markers released into serum and urine as a result of bone turnover might fulfill this unmet need. The objectives of this article are to assess current evidence examining the potential utility of bone turnover markers for monitoring skeletal health. bone disease progression, and response to antiresorptive therapies in the prostate cancer setting.
Published articles and abstracts from major oncology or urology congresses pertaining to the use of bone turnover markers to monitor skeletal health and disease progression were identified and assessed for relevance and methodologic stringency.
Several randomized trials and correlative studies support the utility of bone marker level changes to assess disease progression in the metastatic setting, bone health during hormonal therapy, and response to bisphosphonate therapy. The available data support potential associations between levels of the collagen type I telopeptides (NTX and CTX) and the severity of metastatic bone disease as well as outcomes during antiresorptive therapy. Evidence linking bone marker level changes with early diagnosis of skeletal metastases is emerging. Although several markers have shown promising results in correlative studies, results from ongoing prospective trials are needed to establish the role of bone markers in this setting.
Bone marker levels reflect ongoing skeletal metabolism and can provide important insights into bone health and response to bisphosphonate therapy in patients with prostate cancer. The data supporting a role for bone markers to monitor skeletal disease progression and response to zoledronic acid therapy are especially strong. Bone marker assessments may complement established diagnostic and monitoring paradigms in prostate cancer.
Bisphosphonate; Bone loss; Bone metastases; Bone mineral density; Bone turnover markers; Prostate cancer