Androgen suppression treatment (AST) for men with prostate cancer is associated with a number of treatment-related side effects including an accelerated rate of bone loss. This loss of bone is greatest within the first year of AST and increases the risk for fracture. Pharmaceutical treatment in the form of bisphosphonates is currently used to counter the effects of hormone suppression on bone but is costly and associated with potential adverse effects. Recently, exercise has been shown to be an important adjuvant therapy to manage a range of treatment-related toxicities and enhance aspects of quality of life for men receiving AST. We propose that physical exercise may also have an important role in not only attenuating the bone loss associated with AST but in improving bone health and reducing fracture risk. In this review, the rationale underlying exercise as a countermeasure to AST-induced bone loss is provided.
There has been a substantial increase in the use of temporary androgen suppression treatment (AST) in the management of prostate cancer, which is the commonest male cancer. Previously, it was employed mainly to treat symptomatic patients. In the 1990s, there were two major developments that have resulted in a substantial change in the way AST is employed for men with prostate cancer. First, the introduction of the PSA blood test into routine practice, led to both a marked increase in the diagnosis of the disease and substantial downshift in the presentation disease load, resulting in subclinical presentations becoming common.1 Second, adjuvant roles for AST in the management of subclinical disease have become established for localized disease.
However, AST is accompanied by an array of adverse effects that include vasomotor flushing, altered lipoprotein profile, poor balance, metabolic syndrome, cardiovascular complications and increased arterial stiffness.2, 3, 4 In addition, these men are likely to experience detrimental changes in body composition such as increased fat mass and decreased lean mass and muscle strength.5, 6, 7, 8, 9, 10, 11 In men, testosterone suppression results in estrogen deficiency and because of the pivotal role both hormones have in bone metabolism, men receiving AST experience reduced bone mass and have an increased risk for developing osteoporosis and osteoporotic fractures at the hip and spine.12, 13, 14, 15, 16 The increased risk for fracture accompanying treatment is exacerbated by AST-related decreased muscle mass and strength and impaired balance.15 Moreover, these concerns of fracture and reduced neuromuscular function are amplified in those men who do not recover normal testosterone levels following cessation of AST, a risk that increases with age.17
Current clinical guidelines for the management of bone health in this population can include bone mineral density (BMD) screening and monitoring and drug therapies (bisphosphonates).18 Reviews previously published in the Journal have focused on the role that pharmaceutical treatments (bisphosphonates) have in reducing the rate of bone turnover and attenuating bone loss.19, 20 Despite the efficacy of bisphosphonates to improve bone density and therefore reduce fracture risk, they are associated with an increased risk for adverse effects such as an acute phase reaction, which includes gastrointestinal tract symptoms (oral bisphosphonates) and a flu-like illness (intravenous bisphosphonates).19 Recently, evidence has been accumulating regarding the efficacy of exercise, particularly resistance training (also known as strength or weight training), to attenuate the loss of muscle mass and strength associated with AST.21, 22, 23 Exercise has also been recommended as a strategy to ameliorate the increased risk of cardiovascular disease and type II diabetes in men undergoing this form of treatment.24 We propose that physical exercise could also be an effective and safe adjuvant therapy to counter the bone loss associated with AST and thereby reduce the risk for fracture. Moreover, exercise is accompanied by a number of physiological and psychological benefits, which will enhance the patient's overall functioning and quality of life. In this review, we will first discuss the increased risk of osteoporosis and subsequent fracture associated with AST, the mechanisms underpinning the loss of bone mass and then outline the role exercise may have in preventing or attenuating AST-related bone health concerns in men with prostate cancer.
Osteoporosis and fractures during and following AST
Osteoporosis is characterized by decreased BMD and altered micro-architecture, resulting in compromised bone strength and increased risk for fracture.25 At present, the gold standard to measure BMD and diagnose osteoporosis is by a dual energy X-ray absorptiometry scan of the hip (femoral neck) and lumbar spine. The World Health Organization (WHO) defines osteoporosis as bone density 2.5 s.d. or more below the mean for young adults (Table 1).25 Low BMD has shown to be a strong predictor of fracture risk and mortality in older men.26
AST rapidly decreases testosterone levels to a hypogonadal state and, as a result, a number of studies involving men receiving AST have demonstrated an accelerated bone loss.6, 9, 14, 15, 27, 28, 29, 30, 31 A summary of the studies that reported rates of bone loss as a percentage is shown in Table 2. Although the annual rate of bone loss experienced during AST is the greatest in the first year, with average rates of 1.8–6.5% at the hip and 2–8% at the lumbar spine,32 the rate of bone loss remains elevated thereafter relative to the rate of bone loss seen in healthy older men, which is approximately 0.5–1% per annum.33
The clinically important consequences of low BMD are subsequent vertebral and hip fractures, which result in decreased levels of independence, physical function and quality of life for the individual. Hip fractures are the most severe outcome of low BMD because of the associated morbidity, loss of independence and mortality.34 Following a hip fracture less than half (39%) of surviving patients are able to recover their pre-fracture level of mobility and fewer still (25%) regain their former functional status (affecting mobility, social function and activities of daily living) 1-year post fracture.35
It is well established that men receiving AST for their prostate cancer have an increased risk for fracture (Table 3).13, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 Further, within the first 5 years of therapy >20% of men will sustain a fracture.13 Data from cohort studies have revealed a positive relationship between both the duration of AST40 and number of doses administered13 and fracture risk. Using the Surveillance, Epidemiology and End Results Medicare data on 50 613 men with prostate cancer, Shahinian et al.13 reported a linear trend (P<0.001) between the number of doses received after diagnosis and the occurrence of any fracture. This finding is of particular significance to men diagnosed with prostate cancer and administered AST at a relatively young age (<60 years) who therefore may experience the side effects of castrate levels of testosterone for extended durations.
Mechanisms for bone loss during and following AST
Estrogens and androgens have complex roles in the regulation of bone metabolism. In men, estrogens are derived through the aromatization of testosterone,47 and both estrogen and testosterone have important direct and indirect roles in influencing body composition and bone metabolism.48 Consequently, sex hormone deficiency induced by AST results in decreased bone density48 and micro-architectural decay.49
Testosterone-induced adverse effects
In men, testosterone may act directly on bone via androgen receptors or indirectly via aromatization to estrogen.50 The principal role of testosterone in bone metabolism is in the accumulation of peak bone mass during development, however, in adult men testosterone also stimulates bone formation and downregulates osteoclastic activity and hence bone resorption. Testosterone also directly influences changes in body composition by its effects on skeletal muscle. The loss of lean mass and BMD as well as an increase in fat mass following AST are well documented,6, 8, 10, 51 and although both fat mass and lean mass are both positively associated with bone density because of the effects of gravitational loading on the skeleton,52, 53 the relationship between lean mass and BMD is more powerful owing to the added effect of muscle pull on the skeleton.
Estrogen-induced adverse effects
In men, the reduction of testosterone results in estrogen deficiency. Therefore, men receiving AST experience a decrease in estrogen that parallels, but is slightly less than, the reduction in testosterone. Estrogen deficiency results in a disproportionate lifespan between the osteoblasts and osteoclasts and leads to greater bone resorption than formation47 resulting in a net loss of bone density and increased risk for fracture.54 Consequently, men receiving hormone suppression therapy for prostate cancer experience a greater loss of BMD and increased risk for fracture than both cancer survivors not receiving AST and healthy older men experiencing age-related hypogonadism.47, 55 Estrogen patches have been prescribed for men receiving AST in an attempt to attenuate bone loss, however, this treatment can produce further unwanted side effects such as breast swelling and tenderness of the nipple (∼17–42% of cases).47
Other factors associated with bone loss and fracture
It has been reported that men with prostate cancer are more likely to be sedentary or less physically active than those without cancer.56 Bone-loading activities are integral to stimulate positive changes in bone metabolism and conversely if the skeletal system is not subjected to weight-bearing activity bone loss occurs.57 In addition, physical inactivity also leads to loss of muscle tissue (known as sarcopenia).58 Therefore, age-related loss of muscle mass or sarcopenia, which is exacerbated in men undertaking AST, is further accentuated in men who are insufficiently physically active before, during or after treatment. Further, sarcopenia results in decreased muscle strength and balance and combined with an accelerated rate of bone loss, men receiving AST are at an increased risk for falls and fracture. We have recently reported that men on AST not only had significantly reduced muscle strength but also poorer lower extremity functional performance measures such as walking speed compared with healthy age-matched controls.11 Slower walking speed is associated with mobility limitations and disability eventually leading to increased morbidity,59 decreased quality of life and increased dependence on health-care resources. Similarly, Bylow et al.60 reported that older men with prostate cancer receiving AST had significant functional and physical impairment and were more likely to have had a fall in the previous 3 months compared with similarly aged men. A summary of the interrelated factors associated with bone loss and fracture as a result of AST is shown in Figure 1.
Exercise as a potential countermeasure
A recent consensus statement by the American College of Sports Medicine (ACSM)61 on exercise and cancer reported exercise to be safe and effective to reduce many of the side effects associated with prostate cancer treatment and androgen suppression. A total of 12 intervention studies on exercise in prostate cancer survivors/patients indicated strong evidence supporting a number of clinically important outcomes including improvements in aerobic fitness and muscle strength, body composition, quality of life and physical function and reductions in reported fatigue levels. Despite the well-known detrimental effects of AST on bone, there is generally an absence of published exercise trials in this population. In non-prostate cancer populations, regular physical exercise is recognized as the most valuable lifestyle intervention to both optimize the accrual of bone density during puberty and attenuate the bone loss commonly associated with aging. Furthermore, exercise can have a major role in modifying falls risk factors and preventing falls in older adults.62 We propose exercise may also be beneficial for men with prostate cancer on AST where decreased bone density and an increased risk for fracture are well-established treatment side effects.
There is strong evidence that exercise (resistance training and high-impact loading exercises) involving mechanical loading of the skeleton from ground reaction forces (GRF) and muscle pull can positively influence bone health.63 A large number of intervention trials have shown that it is beneficial for children and adolescents to engage in exercise involving moderate to high-impact activities (jumping, skipping and hopping) to maximize peak bone mass.64, 65, 66 Examples of drop jumping and multi-directional jumping are shown in Figure 2. In trials involving adults, much of the focus has been on attenuating post-menopausal bone loss in older women.63 To this end, low-impact weight-bearing aerobic exercise (walking) is commonly advocated as a strategy to manage age-related bone loss, yet results from long-duration walking interventions do not support its inclusion in these recommendations.67 Two recent meta-analyses on the effect of walking on bone mass concluded that regular walking failed to produce a significant effect on the preservation of BMD in post-menopausal women at the clinically relevant sites of the hip and spine.68, 69 However, mechanical loads placed on the bone involving novel or unusual distributions, high strains and strain rates have been shown to be particularly osteogenic.70 The limited effect that walking interventions have had on attenuating BMD loss is most likely due to the habitual nature of walking and that the relatively low GRFs do not reach a sufficient intensity to augment bone density. Therefore, walking to improve bone health is not supported by current scientific evidence. Moreover, results from a recent Australian cohort study of 4909 men and women aged 50 years and older found that there was not only no beneficial effects of regular physical activity on fracture incidence but that more frequent walking was associated with an increased fracture risk.71 Nevertheless, despite its inability to stimulate bone gain, walking should be encouraged to men with prostate cancer in order to minimize the damaging effects physical inactivity and sedentary behavior have on body composition (fat and muscle mass) and the cardiovascular system.
Resistance training programs
The benefits of resistance training for healthy individuals and those with chronic diseases are well documented.72 Prostate cancer is largely an age-related disease and consequently, in addition to the detrimental effects of AST on physical function, most men with prostate cancer are likely to have decreased functional reserve capacities and be at an increased risk for falls and fracture. Resistance training has been shown to be a safe and effective management strategy to counter these age-related issues in older adults without prostate cancer.72 Therefore, resistance training may be even more relevant for this clinical population because of the increased risk for fracture these men encounter because of the combination of the deleterious effects of AST and age-related physical decline.
There are numerous cross-sectional reports of a muscle–bone relationship in which muscle strength predicts bone density.73, 74 Furthermore, studies involving athletic individuals who participate in resistance training such as weightlifting, demonstrate that these athletes have greater BMD than those involved in non-resistance based training such as running or non-athletic individuals.75 Although cross-sectional studies help to highlight the relationship between muscle strength and bone density, a clearer picture of the effect of physical exercise on bone is best examined via exercise interventions. A previous review of exercise trials found resistance training to produce favorable effects on bone density.76 Successful resistance training interventions in older men and women have generally involved high-intensity (70–90% 1-RM, where RM refers to the maximum number of repetitions that can be performed at a given resistance load) progressive resistance training77, 78, 79, 80, 81 performed 2–3 times per week. Details of a sample of these resistance training studies are shown in Table 4, with gains reported of ∼1–3%. However, moderate-intensity strength training does not illicit the same increases in BMD as high-intensity training.82, 83 This supports the prescription of activities involving high-resistance loads rather than exercise involving low-to-moderate resistance loads to enhance bone health.
We have previously reported that men on AST undertaking a 20-week high-intensity resistance training program preserved their whole body and hip BMD.21 Further, this program improved muscle strength (40–96%), balance (8%) and physical performance (5–27%). This is an important outcome as the loss in muscle mass and performance are known risk factors for falls, fracture and decreased independence, and improvements of these factors in conjunction with the preservation of bone mass decreases the risk for fracture. Importantly, participants PSA levels did not rise throughout the exercise regimen indicating that exercise can be safely prescribed without negatively affecting the disease status of men with prostate cancer. However, it should be noted that this was a single-group study with a small number of participants and, consequently, we are currently undertaking a yearlong randomized controlled trial in a large cohort of men on AST with BMD as the primary outcome to confirm and extend these findings.84
Isolated impact loading and multi-modal exercise programs
Apart from the osteogenic effects of muscle pull on the skeleton induced by resistance training, physical activity also influences bone cell behavior via compressive forces on the weight-bearing skeleton. As such, there has been substantial interest surrounding the effect of different types of weight-bearing activities involving large GRFs and the effect they may have on both stimulating bone accrual and managing bone loss. Results from studies comparing the incidental effect of high- versus low-impact sports on BMD in several populations of athletes indicate that those sports imparting higher-impact forces on the weight-bearing skeleton are more osteogenic than those involving lower-impact forces.85, 86 A number of high-quality intervention studies investigating the effect high-impact exercises such as multi-directional jumping and stepping87 or in a multi-modal program with resistance training88, 89, 90 have demonstrated positive skeletal benefits (Table 4). Reported increases in BMD at the measured sites (lumbar spine and femoral neck) in these trials range from 1 to 3.8% over the duration of the studies (4 to 18 months).
Several studies have investigated the effect of different modes of weight-bearing impact exercise on bone in pre-menopausal women.87, 91, 92, 93 Generally these trials found weight-bearing impact activities (jumping and skipping) to improve BMD at the hip (Table 4). The activities involved in the trials involved peak GRFs ranging from approximately 2 to 6 times body weight. A similar impact-loading exercise regimen produced positive effects on BMD in women and men aged over 50.94 Although there is currently no consensus as to the optimal training frequency, Bailey and Brooke-Wavell93 found daily sessions of brief hopping (50 hops) to induce greater increases in femoral neck BMD than sessions undertaken 4 days a week and that less frequent hopping was ineffective.
In cancer survivors, Winters-Stone et al.95 recently reported the results of their randomized controlled trial that examined the effect of a targeted exercise program of resistance training and impact-loading activities on the bone health of women (⩾50 years) with breast cancer. Following the 12-month intervention, women in the exercise group maintained BMD at the lumbar spine compared with controls (0.47% versus −2.13%). Similarly, Saarto et al.96 found that a 12-month impact-loading exercise program that included jumping, stepping, hopping and leaping preserved hip BMD in premenopausal breast cancer survivors whereas those in the control group lost 1.4%. Importantly, there were no reported injuries or adverse events associated with participation in either of these training programs indicating that resistance training and impact-loading exercise can be safe and feasible for individuals with cancer and also an effective method of managing the bone loss associated with cancer treatments.
Although it seems that there may be a threshold number of loading cycles or jumps beyond which there is little additional effect, this number has not been determined in human trials. The number of jumps per session shown to be effective range from 10 to 100 making it difficult to ascertain the optimal number of cycles; however, brief exposure (40–50 cycles) of high magnitude jump-type exercises appears adequate to elicit beneficial effects.
Although a number of exercise studies have shown isolated high-impact loading activities can lead to increases in BMD, an emerging body of evidence suggests that targeted multi-modal exercise programs (combining high-intensity resistance training and high-impact weight-bearing activity) are most effective at improving bone density.88, 97 Consequently, we propose that exercise regimens incorporating progressive high-impact loading exercises such as jumping, skipping, bounding and hopping in addition to progressive high-intensity resistance training could be an effective, feasible and inexpensive adjuvant therapy to manage the bone loss and increased fracture risk associated with androgen suppression therapy for men with prostate cancer.
Exercise is regarded as a safe and effective means to enhance physical and physiological function in people at all ages and for those with chronic conditions. Furthermore, participation in physical exercise has shown to be safe after most types of cancer treatments.61 The Consensus Statement released by the ACSM Roundtable on Exercise Guidelines for Cancer survivors reported that the accumulated evidence from trials involving resistance and aerobic exercise showed that there was consistent and a high level of evidence (evidence category A) that exercise is safe in prostate cancer survivors.61 Moreover, both resistance training and aerobic exercise have been shown to not adversely affect PSA.21, 22 In older persons and in men with localized prostate cancer, resistance training is particularly well tolerated and can confer an array of health benefits.61, 98 High-impact exercise has also been shown in both breast cancer survivors and non-prostate cancer populations to be well tolerated and has the potential to both prevent bone loss and increase bone mass.87, 89, 93, 95, 96 Although high-impact exercises are particularly beneficial, activities involving high peak GRFs are not currently recommended for those with established osteoporosis because of their increased risk for fracture. Further, jumping exercises are currently not advised for those with advanced metastatic bone disease because of the increased fracture risk associated with this stage of disease progression.99 In addition, incontinence is a recognized issue for men with prostate cancer100 and men with incontinence may not choose to undertake impact-loading exercise because of the increased pressure it may have on their pelvic floor and bladder control. Finally, although rare, vertigo and more commonly dizziness are recognized side effects of AST and may influence safety should those patients be willing to perform impact-loading exercises.101 These patients will need to be carefully screened and supervised before and during exercise participation to ensure that a fall does not result.
There appears to be a strong rationale to support the addition of high-impact exercise to current exercise guidelines for men on AST. However, until studies trialing this type of exercise in this population are completed, caution must be exercised when prescribing, progressing and supervising jumping type exercise. Where appropriate, clinicians should refer patients to qualified health professionals, such as exercise physiologists, trained to prescribe exercise for individuals with chronic disease and associated co-morbidities. The ACSM (www.acsm.org) provides registered professionals with University qualifications in exercise science. Similarly, other countries, such as Australia, New Zealand and United Kingdom have organizations (Exercise and Sports Science Australia, ESSA—www.essa.org.au/, Sport and Exercise Science New Zealand, SESNZ—www.sesnz.org.nz/ and British Association of Sport and Exercise Science, BASES—www.bases.org.uk/) that provide registered exercise professionals with University qualifications who are specialists in supervising and prescribing exercise for this population.
Androgen suppression therapy for men with prostate cancer results in an array of adverse effects including substantial bone loss. Physical exercise, specifically impact-loading exercise, has the potential to preserve or augment bone density in this patient population. Combining this form of training with resistance exercise would result in improved physical function, bone density and a reduction in falls risk, therefore reducing the risk for fracture. Consequently, for those individuals willing and able to perform physical exercise, impact-loading and resistive training should be considered as a strategy to counter the bone loss and fracture risk associated with androgen suppression. No other therapy has the potential to address the vast array of adverse effects associated with AST as does physical exercise and should be recommended when possible in men undergoing this form of treatment.
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The authors declare no conflict of interest.
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Bolam, K., Galvão, D., Spry, N. et al. AST-induced bone loss in men with prostate cancer: exercise as a potential countermeasure. Prostate Cancer Prostatic Dis 15, 329–338 (2012). https://doi.org/10.1038/pcan.2012.22
- androgen suppression
- bone density
- fracture risk
- physical exercise
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