4.1. Metabolic syndrome and cardiovascular health
Weight gain and increased body fat mass are common complications of ADT. This weight gain coupled with low activity levels secondary to fatigue and changes in lipid levels may increase the risk of cardiovascular toxicities. Several studies have noted increase in total cholesterol levels, as well as triglyceride levels. In one cross-sectional study, 58 men were investigated for the prevalence of metabolic syndrome [95
]. The sample included 20 patients undergoing ADT for at least 12 months (ADT group), 18 age-matched patients with biochemical recurrence not on ADT, and 20 age-matched controls (control group). The prevalence of metabolic syndrome was higher in the ADT group compared with the non-ADT (p
< .01) and control (p
= .03) groups. Among the components of metabolic syndrome, men on ADT had a higher prevalence of abdominal obesity and hyperglycemia. Androgen-deprived men also had elevated triglycerides compared with controls (p
= .02). The authors concluded that metabolic syndrome was present in more than 50% of the men undergoing long-term ADT, predisposing them to higher cardiovascular risk. In another study of 26 men treated with leuprolide for one year, subcutaneous fat mass in the abdominal area and HDL cholesterol were increased while waist-to-hip ratio, blood pressure, and C-reactive protein did not change significantly. These changes are in contrast to the more recognized “metabolic syndrome” which is characterized by an increased waist-to-hip ratio and blood pressure [96
]. In a larger study, Yannucci et al. measured the fasting serum lipid, glucose and hemoglobin A1C levels in 1102 men at baseline and on ADT treatment at days 85 and 169 [97
]. Significant increases in total cholesterol, triglyceride and high density lipoprotein-cholesterol were observed in patients while on LHRH agonist therapy.
Several recently published studies have demonstrated an increased risk of diabetes and cardiovascular toxicity in men on ADT in population-based analyses. Using Medicare claims, Keating et al. found that GnRH agonist therapy was associated with an increased risk of incident diabetes (adjusted HR, 1.44; p
< .001), coronary artery disease (adjusted HR, 1.16; p
< .001), myocardial infarction (adjusted HR, 1.11; p
= .03), and sudden cardiac death (adjusted HR, 1.16; p
= .004) [98
]. Orchiectomy was significantly associated with diabetes (adjusted HR, 1.34; p
< .001) but not the cardiovascular outcomes. Tsai et al. evaluated the risk of cardiovascular death in 3262 patients treated with radical prostatectomy and 1630 patients treated with external beam radiation therapy, brachytherapy, or cryotherapy for localized prostate cancer [99
]. Competing risks regression analyses were performed to assess whether use of ADT was associated with a shorter time to cardiovascular death after controlling for age (as a continuous variable) and the presence of baseline cardiovascular disease risk factors. Among the 1015 patients who received ADT, the median duration of ADT use was 4.1 months (range = 1.0–32.9 months). Both ADT use (adjusted HR= 2.6; p
= .002) and age (adjusted HR= 1.07; p
= .003) remained associated with statistically significant increased risks of cardiovascular death in patients treated with radical prostatectomy. Among patients 65 years or older treated with radical prostatectomy, the 5-year cumulative incidence of cardiovascular death was 5.5% in those who received ADT and 2.0% in those who did not. Among patients 65 years or older treated with external beam radiation therapy, brachytherapy, or cryotherapy, ADT use was associated with a higher cumulative incidence of death from cardiovascular causes, but the difference did not reach statistical significance. In a third study, Saigal et al. retrospectively examined the cardiovascular risk of 22,816 newly diagnosed men in a population-based registry who were diagnosed between 1992 and 1996 [100
]. The investigators found that newly diagnosed prostate cancer patients who received ADT for at least 1 year were found to have a 20% higher risk of serious cardiovascular morbidity than similar men who did not receive ADT. All the studies conducted so far have been retrospective analyses, and cardiovascular toxicity should be an endpoint studied in any future prospective randomized studies of ADT.
Older patients with prostate cancer have a high prevalence of comorbidities and a higher likelihood of dying from conditions other than prostate cancer. Pre-existing presence of metabolic syndrome and risk factors for cardiovascular toxicity should be assessed prior to initiation of ADT. Focused efforts to reduce cardiac risk factors through diet, exercise, lipid-lowering agents, and other cardioprotective agents (e.g., aspirin, beta-blockers) may help mitigate some of the risks of ADT. In addition, the risks of ADT in potentially causing metabolic syndrome or increasing the risk of cardiovascular toxicity should be explained to the patient and communicated to the patient’s other physicians, including his primary care doctor. If a patient who has underlying cardiac disease must be started on ADT, enlisting the expertise of a cardiologist should be strongly considered along with routine tests to evaluate for worsening of underlying disease.
4.2. Osteoporosis and fractures
Osteoporotic-related fractures are a significant health concern for the elderly with over 1.5 million fractures occurring yearly in the United States. Fractures are associated with back pain, decrease in functional capacity, increased risk for further fractures, higher health care costs, and a higher rate of institutionalization and hospitalizations [101
]. In osteoporosis studies, fractures in men were associated with profound quality of life deficits especially in physical functioning [103
]. In addition, mortality within a year after osteoporotic fracture is markedly increased; in one study, increased odds of death ranged from 1.45 to 3.17 depending on where the fracture occurred [103
]. Lastly, costs for osteoporosis-related fractures are high with persons with fracture having over three times the overall health care costs as persons without osteoporosis [102
]. Overall costs have been estimated at close to $17 billion per year.
An increased risk for loss of bone density, and a subsequent fracture, is a significant concern for older men on ADT. Bone mineral density is most often screened with dual-energy X-ray absorptiometry (DEXA) and the hip, spine, wrist, and femur are the typical locations screened. Screening tests provide a “T
-score” which compares the measured density with that of a younger adult. T
-scores of −1 to −2.5 demonstrate a risk for the disease or osteopenia and osteoporosis is generally demonstrated with T
-scores <−2.5. While loss of bone density does not necessarily lead to osteoporosis or fractures, these are also common additional complications of ADT. In older men, age-related decreases in bioavailable testosterone and estradiol results in bone loss at a rate of approximately 1% per year at baseline [104
]. Annual bone loss with ADT is more rapid; multiple studies have revealed bone loss rates from 1 to 4.6% yearly in men on ADT for nonmetastatic disease [101
]. Although studies are generally small without adequate controls, they typically show statistically significant, clinically important declines in bone density in the lumbar spine, hip, femoral neck, and distal radius with 6–24 months of castration [34
]. On the other hand, in a study which randomized 52 men to bicalutamide or LHRH agonist therapy, bicalutamide was associated with increases in bone mineral density [105
]. Although the rate of bone loss is highest in the first year of therapy, the duration of ADT has been linked to greater magnitude of loss [106
]. In one study of 390 men followed for over 10 years, osteoporosis was prevalent in hormone naive men with prostate cancer (35.4%) and increased to 80% in men on ADT for 10 years [106
]. Other factors that are associated with bone loss in men on ADT include body mass index, alcohol use, and use of preventative modalities such as calcium/vitamin D and exercise. Bone loss can also be linked to other conditions such as hyperthyroidism, liver disease, and vitamin D malabsorption.
Despite increases in prevalence of bone loss and osteoporosis on ADT, there have been no prospective studies evaluating fractures due to ADT, mainly due to the large sample sizes required to study fracture-related endpoints [34
]. However, retrospective studies utilizing large population-based databases have demonstrated that men on ADT are 13–30% more likely to develop a fracture as compared to prostate cancer patients not on ADT [108
]. Age over 65 and comorbidity have been shown to be independent risk factors for fractures in this patient population [110
Given the above, monitoring for bone loss and risk of fractures is imperative in older men on ADT. Patients should undergo complete physical examination and medical history in order to assess for other risk factors for osteoporosis, falls, and fractures. In the elderly, conditions such as falls and reduced muscle strength or sarcopenia contribute to fractures and thus we recommend a baseline comprehensive geriatric assessment (CGA) to assess for these conditions prior to initiation of ADT (see Section 5), which can help with decision-making for treatment initiation and provide targets for multidisciplinary intervention in vulnerable and frail older men [21
]. Because osteoporosis is prevalent in men prior to starting ADT, baseline bone mineral density assessment should be obtained with DEXA scan. Follow-up tests should be performed frequently (every 6–24 months) depending on baseline assessment of BMD and risk factors for development of osteoporosis and fractures (see ) [101
Prevention and treatment of osteoporosis in the older man on ADT.
The National Osteoporosis Foundation (NOF) recommends treatment for people with a T
-score of −2 with no risk factors, and for T
-scores below −1.5 with risk factors [113
]. Risk factors for osteoporosis or fractures for prostate cancer patients include planned long-term ADT use, low body mass index, cigarette smoking, alcohol use, family history of osteoporosis or fractures, and previous history of fractures. All patients who are to undergo ADT should be counseled on smoking cessation, alcohol in moderation, and the benefits of exercise. Exercise, specifically weight-bearing and muscle-strengthening exercises, have been shown to increase BMD and reduce fracture risk in osteoporotic persons, although most of the studies were conducted in postmenopausal women [113
]. Resistance exercise training for men on ADT can improve muscular strength [115
]. Although no study has demonstrated reduced fracture risk in men on ADT as a result of exercise, experts in the field currently recommend that men on ADT be encouraged to actively participate in a regular exercise program that includes resistance training and weight-bearing exercise [40
]. In older patients, it is imperative to assess fall risk, need for assistive devices, and conduct a home safety evaluation. Our research team found that close to 20% of men over the age of 70 report falls in the last 3 months, which exceeds the baseline risk for age-equivalent men [116
]. A fall assessment includes a multidisciplinary objective evaluation of physical performance and a comprehensive fall history [117
]. Prostate cancer specialists should enlist the expertise of health care professionals with specialized expertise in the care of older persons in order to provide the best care to the patient. When customizing an exercise program to prevent fracture risk in older persons, balance training as well as weight training should be recommended. Balance training and Tai Chi Chuan have been shown to reduce fall and fracture risk and improve BMD in frail older persons [118
There are effective pharmaceutical interventions to help prevent and treat osteoporosis in men on ADT. Daily calcium (1500 mg in split doses) and vitamin D (800 IU) can both increase BMD and reduce the risk of fractures in older men with osteoporosis, and should be included in any osteoporosis prevention regimen [120
]. These supplements may be useful in treating osteopenia and osteoporosis for men on ADT and they have minimal side effects. Medical options for treatment of osteoporosis include bisphosphonates, estrogen, and selective estrogen receptor modulators (SERMs). Bisphosphonates inhibit osteoclast activity thereby reducing bone resorption and are available in oral and intravenous formulations. Several randomized studies have shown that intravenous bisphosphonates (pamidronate or zolendronic acid) given every 3–4 months significantly prevented bone loss after 1 year in men with nonmetastatic prostate cancer on ADT [121
]. Zoledronic acid (4 mg IV every 3 months) also has been shown to significantly improve bone mineral density at 1 year [123
]. One study of 22 men on ADT who received zolendronic acid at 4 mg yearly also revealed statistically significant and clinically meaningful benefits in terms of prevention of bone loss [124
]. Alendronate may be a possibility as an oral option, although few studies have been conducted with this agent in men on ADT [125
]. It is important to note that studies thus far have not demonstrated prevention or improvement in risk or rate of fractures, although it has been shown that increasing BMD with bisphosphonate therapy reduces osteoporotic fractures in postmenopausal women [127
]. Prior to initiation of bisphosphonate therapy, risk for side effects should be carefully considered. Bisphosphonate-induced nephrotoxicity can be a significant concern for cancer patients and health care professionals. Clinically significant deterioration in renal function is a risk with some bisphosphonates, requiring renal function monitoring and drug discontinuation [128
]. In addition, renal impairment can progress to renal failure, prompting the need for renal dialysis and even death. Approximately 7% of the people with pre-existing chronic kidney disease would be at a greater risk for renal deterioration during long-term bisphosphonate therapy [129
]. Other side effects can include a flu-like syndrome usually with the first infusion and a rare but significant potential complication of osteonecrosis of the jaw. Given this last concern, men starting ADT should have all dental work completed prior to initiation of bisphosphonates.
Besides bisphosphonate therapies, other options include estrogen therapy and SERMs. Estrogen therapy is associated with decreases in markers of bone resorption and prevention of bone loss in men on ADT; however, the studies are small and estrogen carries with it the risk of cardiotoxicity and thromboembolism. On the other hand, SERMs, such as raloxifene and toremifene, have beneficial effects on the bone, without significant cardiac toxicity. Smith et al. showed that raloxifene increases BMD in men on ADT [130
]. One challenge, however, is the frequency of significant hot flashes associated with SERMs. Like with the bisphosphonates, more studies are needed to examine the impact of these drugs on fractures in men on ADT.
In summary, osteoporosis and fractures are important potential complications of ADT and may negatively impact QOL. Osteoporosis is a common scenario at baseline in frail older persons and is considered a geriatric syndrome. Geriatric syndromes in the elderly are associated with an increased risk of mortality [131
]. As a result, the decision to start ADT in an older person should include an evaluation of bone mineral density and fall risk. A recent study of physician care practices revealed that only 9% of men on ADT had undergone a DEXA scan and only 15% received at least one intervention for prevention and treatment of ADT [132
]. In another study of 174 men on ADT, only 34% received recommended osteoporosis management [133
]. Intervention efforts to educate cancer specialists should also be undertaken in order to improve outcomes of this population.