Anemia

The anemia associated with ADT (continuous or intermittent) is usually the normochromic normocytic type (not microcytic or macrocytic), which is somewhat similar to what is experienced in aging men, except that it occurs within months in those undergoing ADT (acute) compared with decades in those experiencing normal aging (chronic). This acute reduction in hemoglobin occurs in most patients on ADT, with a mean of 10% or greater decrease in hemoglobin and red blood cell counts, but with minimal changes in mean corpuscular volume, and no changes in mean cell hemoglobin, mean cell hemoglobin concentration, or iron levels. Thus, most patients with localized or locally advanced or nonmetastatic prostate cancer do not require treatment with diet, dietary supplements (not iron, B ₁₂ , or folate), or prescription medications for this side effect. If ADT is discontinued, the anemia should dissipate with testosterone normalization. Therefore, just as excessive testosterone levels or testosterone replacement therapy can lead to polycythemia, minimal testosterone levels can lead to anemia. Some preliminary evidence suggests that the hemoglobin changes on average are lower in men without bone metastasis who perform regular resistance exercises. In patients with metastasis, anemia is more likely to become symptomatic during ADT treatment, and some of these individuals may require conventional drug treatment.

Bone and muscle loss

The predicted risk of bone loss may be exaggerated in contemporary patients on ADT because older data are being used. These older studies do not take into account that patients are now more preventive-minded and informed, and use methods to avoid this risk. Older studies involved patients with more advanced disease who were usually not on minimal forms of preventive therapy for bone loss, and yearly rates of spinal bone loss were reported to be as high as 5% to 8.5%, and as much as 2% to 6.5% in the hip. However, research on Japanese patients with prostate cancer found a low rate of osteoporosis (approximately 10%–12%). Patients treated with ADT have significantly reduced bone mineral density (BMD) numbers and T scores and z scores compared with hormone-naïve Japanese patients, but research continues to show no significant increase of osteoporosis prevalence in these men who had been on ADT for a mean of 30.7 months. Heart-healthy lifestyle changes common among the older Japanese population may contribute to this finding.

Additionally, calcium and vitamin D deficiencies and a lack of resistance activity are some of the many factors that can lead to a misrepresentation of the true rate of bone loss associated with ADT. More recent research conducted in the United States and internationally has suggested a reduced risk of bone loss in men receiving calcium and vitamin D supplementation while on ADT ; unfortunately, only a minority (10%–20%) of patients are following these simplistic recommendations, largely because of a lack of education from their providers.

Perhaps if the playing field were leveled in terms of comparing pharmacologic bone preservation therapy with lifestyle changes and supplements in patients with nonmetastatic disease on ADT, this might provide an unbiased assessment of the true need for pharmacologic treatment of this condition. Few older studies have addressed this issue, with some exceptions, including two studies of zoledronic acid in patients with nonmetastatic disease. In these studies, the placebo intervention involved a calcium supplement at a low, inadequate dose (500 mg) and vitamin D intakes of 400 to 500 IU. A rate of bone loss of 2% to 3% was seen in 12 months at the major anatomic sites of interest (spine and hip). In the first study, no participant experienced a clinical or symptomatic fracture, but five new or exacerbated vertebral fractures were diagnosed on imaging in the zoledronic acid group versus three in the placebo group. In the second study, results were similar in terms of fracture incidence, and especially in BMD changes, which were not as excessive as older reports, perhaps because the supplementation in the placebo group was at least minimal. These two studies were too short to report or observe fractures, so little focus was placed on fracture differences, but the lack of fractures should still be of interest to the reader.

Two other studies, one with a weekly oral and another with a 6-month injectable pharmacologic medication, also provide insight into this issue. A randomized 1-year trial of 112 men with nonmetastatic prostate cancer on ADT compared weekly oral alendronate with placebo. Both arms of the study received calcium carbonate with vitamin D (each tablet has 500 mg of calcium and 200 IU of vitamin D) to ensure a total calcium intake greater than 1000 mg/d. At baseline, median duration on ADT was 14 months, and vitamin D levels were greater than 30 ng/mL. BMD changes at the spine were –1.4% for the placebo group, –0.7% at the femoral neck, and –1.8% at the distal radius. One fracture occurred in each group. However, despite no T score differences in the spine among the groups (–0.26), hip BMD and other hip anatomic sites were significantly lower at baseline in the placebo arm, as were measurements at the distal third of the radius.

Furthermore, significantly more patients ( P = .02) in the placebo group had osteopenia or osteoporosis (95% vs 88%). A total of 52% of patients at baseline had osteoporosis compared with 27% treated with the oral drug. Had the participants been able to perform regular resistance exercises and institute heart-healthy lifestyle changes before initiating ADT, it would have been interesting to observe whether any noticeable or tangible differences could be seen between the arms.

Another relevant study involved the use of the recently published, large, 3-year trial of denosumab given every 6 months (n = 734) compared with placebo (n = 734) in men receiving ADT for nonmetastatic prostate cancer. All of the participants were instructed take 1000 mg or more of calcium and 400 IU of vitamin D. This trial represents one of the first long-term randomized studies to provide the placebo arm with realistic and relevant dietary supplementation. Median serum vitamin D levels at baseline were 24 to 25 ng/mL, and increased to 31 ng/mL (normal range) after 36 months. Mean T score was similar in this study compared with the previous study (–0.3), but only 14% to 15% of participants began the trial with osteoporosis (T score <–2.5) at any site, compared with 52% in the placebo arm of the previous trial. Thus, these patients had less-severe bone loss overall compared with the previous study, despite the longer median time on ADT at a baseline of 20 to 21 months.

The primary end point was the percent change in BMD at the lumbar spine at 24 months, and secondary end points included percent change in BMD at the femoral neck and total hip at 24 months, and at all three anatomic locations at 36 months, along with incidence of new fractures. After 24 months a significant loss in lumbar spine BMD was seen in the placebo group, but the actual loss was only 1%, and minimally changed at 36 months. Significant reductions in femoral neck and total hip were also seen, but these losses were only 2% to 3% at 36 months. The largest loss occurred in the distal radius. Incidence of fracture at any anatomic location was lower with denosumab than with placebo, but the difference was not found to be statistically significant at 36 months.

Furthermore, no significant differences were found in the time to first fracture (nonvertebral or vertebral) between the groups. The authors reported that more than one fracture at any location occurred in significantly more patients on placebo than denosumab, and that these patients also had a significantly higher rate of vertebral fractures. However, these are secondary end points, and more participants in the placebo group had a history of vertebral fracture (+2.6%) and osteoporotic fracture (+4.5%) at baseline. The 36-month clinical difference of 2.4% more new vertebral fractures (3.9% vs 1.5%) in the placebo group cannot be fully attributed to the intervention itself, but may also have been from the inequality between groups in terms of vertebral and overall fractures at baseline in favor of denosumab. In other words, the differences between most clinical end points for the calcium and vitamin D group compared with pharmacologic treatment was, in the authors’ opinion, minimal at 36 months. Furthermore, a less than 4% total fracture percentage in the placebo arm (vs 1.9%) over 3 years is low considering that these patients did not make aggressive lifestyle changes or take supplemental preventive therapy before ADT was initiated. Again, this leaves one to ponder how much difference would have really been seen if the placebo group were also assigned to regular resistance and aerobic exercises during this study period or before initiating ADT, interventions that in small studies have been able to maintain BMD alone without supplementation.

Perhaps the most interesting benefit of denosumab may be in men who cannot adequately maintain distal radius density with aggressive lifestyle changes. A slightly higher rate of serious adverse events with denosumab (34.6% vs 30.6%) was also observed in the ADT trial, and an accompanying editorial expressed concerns raised in other studies about a potential negative impact on the immune system. Emerging evidence also has shown that this drug can cause the rare side effect of osteonecrosis of the jaw, and hypocalcemia is not uncommon. Regardless, little doubt exists that preventing osteoporosis with pharmacologic agents such as denosumab in patients with castration-resistant prostate cancer can have a profound impact on skeletal-related events, and the potential increases in radial bone mineral density with this drug cannot be matched by other less-aggressive interventions. However, early use of these drugs in patients without metastasis who are about to begin ADT rather than implement lifestyle changes, supplements (calcium and vitamin D), and resistance exercise should be at least questioned.

When reviewing the data from the four trials of pharmacologic intervention in patients without metastasis, several observations should be considered. As investigators used more appropriate supplementation of calcium and normalization of vitamin D status during the last two pharmacologic trials compared with the first two, reductions in bone loss at the major anatomic sites were progressively less in the placebo arms, and perhaps even stabilized after 1 year (eg, at the lumbar spine, the primary end point of the denosumab trial). Again, this treatment was given without encouraging regular aerobic and resistance exercise, suggesting that a clinical trial of patients without metastasis on ADT with adequate calcium and vitamin D status with aerobic and resistance exercise may compare favorably to pharmacologic intervention over 1 year or more.

Another important factor is that denosumab and zoledronic acid trials have used low to moderate amounts of calcium and vitamin D to enhance the efficacy of the drug itself. Thus, clinicians should encourage calcium and vitamin D supplements in patients on ADT regardless of their bone-preserving drug treatment status. Perhaps more appropriately, they should have the patient meet with a nutritionist to determine their average calcium intake from food, and not exceed the daily 1200 mg requirement with a supplement, regardless of low or average calcium food intake. Furthermore, vitamin D status should be normalized through using approximately 1000 IU/d of vitamin D, and monitoring 25(OH)-vitamin D status to ensure proper levels (30–40 ng/mL or 75–100 nmol/L). Preliminary evidence suggests that daily use of vitamin D supplementation may be more effective at increasing vitamin D serum status than equivalent oral dosing weekly or monthly.

Sarcopenia is simply a progressive reduction in skeletal muscle mass, strength, and quality, and, in some cases, the replacement of these anatomic sites by adipose tissue, which not only occurs with aging but also is accelerated by ADT at upper and lower body sites. Clinical research is also beginning to emerge that sarcopenia can actually improve significantly if men on ADT perform upper and lower body resistance exercises at least twice a week, regardless of the time on ADT. No drug has been able to accomplish these results. Patients must be informed that the only consistent proven treatment for preventing sarcopenia with aging, or during ADT, is regular resistance and aerobic exercise, which also promote heart health. Furthermore, the reductions in skeletal muscle mass and contractile properties with sarcopenia is also associated with increases in insulin resistance, lipids, and fat tissue. Theoretically, the benefits of regular and perhaps even more-intensive resistance activity in men and women could outweigh the benefits of calcium and vitamin D supplementation, as was recently found in a randomized trial of men without prostate cancer. Regardless, clinicians must determine whether the harm outweighs the benefits when beginning a resistance exercise program in a patient who has metastatic disease.

Novel simplistic interventions to combat sarcopenia that could be independently or synergistically beneficial along with resistance activity have been known for some time but not used or encouraged with ADT. For example, because vitamin D receptors are found on muscle tissue, older individuals with normal vitamin D status seem to have a lower risk of sarcopenia. Calcium supplementation may also have this impact for a similar reason, and the combined synergism may reduce the risk of falls. Higher dietary protein intakes beyond the standard, which is currently 0.8 g/kg/d (regardless of age) may stimulate muscle protein synthesis and is safe. Intakes of 1.0 to 1.2, and even 1.5 g/kg/d of protein in some cases (20% of total caloric intake), may benefit older individuals with sarcopenia or may prevent its development. This practice could also favorably impact calcium absorption to improve BMD, maintain nitrogen balance, and avoid compromising renal function.

One of the most interesting, novel, and evolving approaches for preventing sarcopenia is high-quality but diverse amino acid or protein supplementation via low-calorie powders, capsules, or liquids. For example, clinical studies in elderly people have already documented increased lean body mass, reduction in fat mass, and increased handgrip strength, leg strength, and muscle protein synthesis with essential amino acid supplementation for several months. Because small increases in insulin-like growth factor 1 can also occur with protein supplementation (similar to resistance exercise), more research should be conducted on patients with cancer using these interventions, but the overall health benefit seems to trump any specific physiologic concern. The authors believe this is tantamount to the original concern and subsequent debunking of the myth that resistance exercise can exacerbate lymphedema in breast cancer. Additionally, far more concerning interventions in patients with prostate cancer, such as dehydroepiandrosterone supplementation and growth hormone replacement, have failed to provide tangible benefits in elderly patients. In fact, one of the most interesting older studies of growth hormone supplementation found no added benefit, especially in elderly patients engaged in strength training via resistance exercise first for 14 weeks before supplementing with this hormone. Clinicians should promote more heart-healthy and cost-effective interventions that are more promising. For example, fish oil is another supplement that has recently garnered new data regarding sarcopenia prevention through potentially reducing some inflammatory markers.

Bone and muscle loss

The predicted risk of bone loss may be exaggerated in contemporary patients on ADT because older data are being used. These older studies do not take into account that patients are now more preventive-minded and informed, and use methods to avoid this risk. Older studies involved patients with more advanced disease who were usually not on minimal forms of preventive therapy for bone loss, and yearly rates of spinal bone loss were reported to be as high as 5% to 8.5%, and as much as 2% to 6.5% in the hip. However, research on Japanese patients with prostate cancer found a low rate of osteoporosis (approximately 10%–12%). Patients treated with ADT have significantly reduced bone mineral density (BMD) numbers and T scores and z scores compared with hormone-naïve Japanese patients, but research continues to show no significant increase of osteoporosis prevalence in these men who had been on ADT for a mean of 30.7 months. Heart-healthy lifestyle changes common among the older Japanese population may contribute to this finding.

Additionally, calcium and vitamin D deficiencies and a lack of resistance activity are some of the many factors that can lead to a misrepresentation of the true rate of bone loss associated with ADT. More recent research conducted in the United States and internationally has suggested a reduced risk of bone loss in men receiving calcium and vitamin D supplementation while on ADT ; unfortunately, only a minority (10%–20%) of patients are following these simplistic recommendations, largely because of a lack of education from their providers.

Perhaps if the playing field were leveled in terms of comparing pharmacologic bone preservation therapy with lifestyle changes and supplements in patients with nonmetastatic disease on ADT, this might provide an unbiased assessment of the true need for pharmacologic treatment of this condition. Few older studies have addressed this issue, with some exceptions, including two studies of zoledronic acid in patients with nonmetastatic disease. In these studies, the placebo intervention involved a calcium supplement at a low, inadequate dose (500 mg) and vitamin D intakes of 400 to 500 IU. A rate of bone loss of 2% to 3% was seen in 12 months at the major anatomic sites of interest (spine and hip). In the first study, no participant experienced a clinical or symptomatic fracture, but five new or exacerbated vertebral fractures were diagnosed on imaging in the zoledronic acid group versus three in the placebo group. In the second study, results were similar in terms of fracture incidence, and especially in BMD changes, which were not as excessive as older reports, perhaps because the supplementation in the placebo group was at least minimal. These two studies were too short to report or observe fractures, so little focus was placed on fracture differences, but the lack of fractures should still be of interest to the reader.

Two other studies, one with a weekly oral and another with a 6-month injectable pharmacologic medication, also provide insight into this issue. A randomized 1-year trial of 112 men with nonmetastatic prostate cancer on ADT compared weekly oral alendronate with placebo. Both arms of the study received calcium carbonate with vitamin D (each tablet has 500 mg of calcium and 200 IU of vitamin D) to ensure a total calcium intake greater than 1000 mg/d. At baseline, median duration on ADT was 14 months, and vitamin D levels were greater than 30 ng/mL. BMD changes at the spine were –1.4% for the placebo group, –0.7% at the femoral neck, and –1.8% at the distal radius. One fracture occurred in each group. However, despite no T score differences in the spine among the groups (–0.26), hip BMD and other hip anatomic sites were significantly lower at baseline in the placebo arm, as were measurements at the distal third of the radius.

Furthermore, significantly more patients ( P = .02) in the placebo group had osteopenia or osteoporosis (95% vs 88%). A total of 52% of patients at baseline had osteoporosis compared with 27% treated with the oral drug. Had the participants been able to perform regular resistance exercises and institute heart-healthy lifestyle changes before initiating ADT, it would have been interesting to observe whether any noticeable or tangible differences could be seen between the arms.

Another relevant study involved the use of the recently published, large, 3-year trial of denosumab given every 6 months (n = 734) compared with placebo (n = 734) in men receiving ADT for nonmetastatic prostate cancer. All of the participants were instructed take 1000 mg or more of calcium and 400 IU of vitamin D. This trial represents one of the first long-term randomized studies to provide the placebo arm with realistic and relevant dietary supplementation. Median serum vitamin D levels at baseline were 24 to 25 ng/mL, and increased to 31 ng/mL (normal range) after 36 months. Mean T score was similar in this study compared with the previous study (–0.3), but only 14% to 15% of participants began the trial with osteoporosis (T score <–2.5) at any site, compared with 52% in the placebo arm of the previous trial. Thus, these patients had less-severe bone loss overall compared with the previous study, despite the longer median time on ADT at a baseline of 20 to 21 months.

The primary end point was the percent change in BMD at the lumbar spine at 24 months, and secondary end points included percent change in BMD at the femoral neck and total hip at 24 months, and at all three anatomic locations at 36 months, along with incidence of new fractures. After 24 months a significant loss in lumbar spine BMD was seen in the placebo group, but the actual loss was only 1%, and minimally changed at 36 months. Significant reductions in femoral neck and total hip were also seen, but these losses were only 2% to 3% at 36 months. The largest loss occurred in the distal radius. Incidence of fracture at any anatomic location was lower with denosumab than with placebo, but the difference was not found to be statistically significant at 36 months.

Furthermore, no significant differences were found in the time to first fracture (nonvertebral or vertebral) between the groups. The authors reported that more than one fracture at any location occurred in significantly more patients on placebo than denosumab, and that these patients also had a significantly higher rate of vertebral fractures. However, these are secondary end points, and more participants in the placebo group had a history of vertebral fracture (+2.6%) and osteoporotic fracture (+4.5%) at baseline. The 36-month clinical difference of 2.4% more new vertebral fractures (3.9% vs 1.5%) in the placebo group cannot be fully attributed to the intervention itself, but may also have been from the inequality between groups in terms of vertebral and overall fractures at baseline in favor of denosumab. In other words, the differences between most clinical end points for the calcium and vitamin D group compared with pharmacologic treatment was, in the authors’ opinion, minimal at 36 months. Furthermore, a less than 4% total fracture percentage in the placebo arm (vs 1.9%) over 3 years is low considering that these patients did not make aggressive lifestyle changes or take supplemental preventive therapy before ADT was initiated. Again, this leaves one to ponder how much difference would have really been seen if the placebo group were also assigned to regular resistance and aerobic exercises during this study period or before initiating ADT, interventions that in small studies have been able to maintain BMD alone without supplementation.

Perhaps the most interesting benefit of denosumab may be in men who cannot adequately maintain distal radius density with aggressive lifestyle changes. A slightly higher rate of serious adverse events with denosumab (34.6% vs 30.6%) was also observed in the ADT trial, and an accompanying editorial expressed concerns raised in other studies about a potential negative impact on the immune system. Emerging evidence also has shown that this drug can cause the rare side effect of osteonecrosis of the jaw, and hypocalcemia is not uncommon. Regardless, little doubt exists that preventing osteoporosis with pharmacologic agents such as denosumab in patients with castration-resistant prostate cancer can have a profound impact on skeletal-related events, and the potential increases in radial bone mineral density with this drug cannot be matched by other less-aggressive interventions. However, early use of these drugs in patients without metastasis who are about to begin ADT rather than implement lifestyle changes, supplements (calcium and vitamin D), and resistance exercise should be at least questioned.

When reviewing the data from the four trials of pharmacologic intervention in patients without metastasis, several observations should be considered. As investigators used more appropriate supplementation of calcium and normalization of vitamin D status during the last two pharmacologic trials compared with the first two, reductions in bone loss at the major anatomic sites were progressively less in the placebo arms, and perhaps even stabilized after 1 year (eg, at the lumbar spine, the primary end point of the denosumab trial). Again, this treatment was given without encouraging regular aerobic and resistance exercise, suggesting that a clinical trial of patients without metastasis on ADT with adequate calcium and vitamin D status with aerobic and resistance exercise may compare favorably to pharmacologic intervention over 1 year or more.

Another important factor is that denosumab and zoledronic acid trials have used low to moderate amounts of calcium and vitamin D to enhance the efficacy of the drug itself. Thus, clinicians should encourage calcium and vitamin D supplements in patients on ADT regardless of their bone-preserving drug treatment status. Perhaps more appropriately, they should have the patient meet with a nutritionist to determine their average calcium intake from food, and not exceed the daily 1200 mg requirement with a supplement, regardless of low or average calcium food intake. Furthermore, vitamin D status should be normalized through using approximately 1000 IU/d of vitamin D, and monitoring 25(OH)-vitamin D status to ensure proper levels (30–40 ng/mL or 75–100 nmol/L). Preliminary evidence suggests that daily use of vitamin D supplementation may be more effective at increasing vitamin D serum status than equivalent oral dosing weekly or monthly.

Sarcopenia is simply a progressive reduction in skeletal muscle mass, strength, and quality, and, in some cases, the replacement of these anatomic sites by adipose tissue, which not only occurs with aging but also is accelerated by ADT at upper and lower body sites. Clinical research is also beginning to emerge that sarcopenia can actually improve significantly if men on ADT perform upper and lower body resistance exercises at least twice a week, regardless of the time on ADT. No drug has been able to accomplish these results. Patients must be informed that the only consistent proven treatment for preventing sarcopenia with aging, or during ADT, is regular resistance and aerobic exercise, which also promote heart health. Furthermore, the reductions in skeletal muscle mass and contractile properties with sarcopenia is also associated with increases in insulin resistance, lipids, and fat tissue. Theoretically, the benefits of regular and perhaps even more-intensive resistance activity in men and women could outweigh the benefits of calcium and vitamin D supplementation, as was recently found in a randomized trial of men without prostate cancer. Regardless, clinicians must determine whether the harm outweighs the benefits when beginning a resistance exercise program in a patient who has metastatic disease.

Novel simplistic interventions to combat sarcopenia that could be independently or synergistically beneficial along with resistance activity have been known for some time but not used or encouraged with ADT. For example, because vitamin D receptors are found on muscle tissue, older individuals with normal vitamin D status seem to have a lower risk of sarcopenia. Calcium supplementation may also have this impact for a similar reason, and the combined synergism may reduce the risk of falls. Higher dietary protein intakes beyond the standard, which is currently 0.8 g/kg/d (regardless of age) may stimulate muscle protein synthesis and is safe. Intakes of 1.0 to 1.2, and even 1.5 g/kg/d of protein in some cases (20% of total caloric intake), may benefit older individuals with sarcopenia or may prevent its development. This practice could also favorably impact calcium absorption to improve BMD, maintain nitrogen balance, and avoid compromising renal function.

One of the most interesting, novel, and evolving approaches for preventing sarcopenia is high-quality but diverse amino acid or protein supplementation via low-calorie powders, capsules, or liquids. For example, clinical studies in elderly people have already documented increased lean body mass, reduction in fat mass, and increased handgrip strength, leg strength, and muscle protein synthesis with essential amino acid supplementation for several months. Because small increases in insulin-like growth factor 1 can also occur with protein supplementation (similar to resistance exercise), more research should be conducted on patients with cancer using these interventions, but the overall health benefit seems to trump any specific physiologic concern. The authors believe this is tantamount to the original concern and subsequent debunking of the myth that resistance exercise can exacerbate lymphedema in breast cancer. Additionally, far more concerning interventions in patients with prostate cancer, such as dehydroepiandrosterone supplementation and growth hormone replacement, have failed to provide tangible benefits in elderly patients. In fact, one of the most interesting older studies of growth hormone supplementation found no added benefit, especially in elderly patients engaged in strength training via resistance exercise first for 14 weeks before supplementing with this hormone. Clinicians should promote more heart-healthy and cost-effective interventions that are more promising. For example, fish oil is another supplement that has recently garnered new data regarding sarcopenia prevention through potentially reducing some inflammatory markers.