Efficacy of a multi-component exercise programme and nutritional supplementation on musculoskeletal health in men treated with androgen deprivation therapy for prostate cancer (IMPACT): study protocol of a randomised controlled trial

In Australia, as in other developed countries, prostate cancer (PCa) is the most commonly diagnosed cancer in men [1]. Approximately 1.1 million new cases of PCa are diagnosed worldwide each year [1]. In Australia, a 2014 report estimated that approximately 13% of cancer-related deaths in men were attributed to PCa, which ranks second to lung cancer as the most common cause of cancer-related death in men [2]. Due to medical advancements in both the screening and treatment of PCa, 5-year relative survival rates of all PCa cases are now approaching 100% internationally [3], and thus these patients are living longer, but are susceptible to potential age-related and treatment-related declines in health. Therefore, the clinical paradigm is shifting to an increased focus on improving the quality of years lived.

Various modalities of androgen deprivation therapy (ADT), including those administered as neoadjuvant or adjuvant therapies with other treatments, are commonly used to treat PCa as it improves overall survival, particularly in men with advanced PCa [4‐7]. However, the evidence that ADT prolongs survival in men with localised PCa remains limited and, therefore, debated [8, 9]. Despite this lack of evidence, the use of ADT continues to increase for all stages and grades of PCa [10]. It was estimated that approximately 23,500 Australian men received pharmacological ADT via gonadotropin-releasing hormone (GnRH) agonists in 2008–2009 [11]. After repeating this analysis for 2013–2014, we estimated that approximately 25,500 men are currently receiving ADT via GnRH agonists [12]. Thus, ADT remains the most common cause for severe hypogonadism in men in Australia.

Despite benefits in overall survival in appropriately selected men, the hypogonadism induced via ADT has been associated with numerous adverse effects, particularly with regard to musculoskeletal and cardiometabolic health. It has been reported that within the first 3 to 12 months of ADT, men experience a rapid and dramatic loss in bone mass (up to 11%) and concomitant losses in muscle mass (2–5%) [13‐17] which may explain the observed 23–65% increased fracture risk in this group [18‐20]. There is also a profound gain (up to 15%) in fat mass (FM) which likely contributes to the 10–45% reported increased risk of diabetes, coronary heart disease, myocardial infarction and sudden cardiac death [13, 17, 21‐25]. Thus, there is a need to develop safe and effective interventions to manage the multiple treatment-induced adverse effects of ADT in men with PCa.

Exercise training has been strongly suggested as a viable intervention to ameliorate many of the adverse effects of ADT [17, 26‐28]. In terms of musculoskeletal health outcomes, a number of interventions have shown that progressive resistance training (PRT) can increase muscle strength [29‐33], muscle endurance [30, 34] and balance [30] in men treated with ADT. While there is also some evidence that PRT can improve or preserve lean body mass (LBM) [30, 32, 33, 35], a systematic review found that there was inconclusive findings on the effects of exercise training in men treated with ADT on bone health [26]. To date, only four studies have examined the efficacy of exercise training on areal bone mineral density (aBMD) in ADT-treated men, three of which were conducted over interventional periods of no longer than 20 weeks and observed no benefit [32, 36, 37]. This is perhaps not unexpected given that the typical bone remodelling cycle and new steady state that is measurable takes 6–8 months to complete, and thus it is unlikely that any true physiological skeletal adaptations would occur prior to this period. However, a recent 12-month randomised controlled trial (RCT) also reported no marked skeletal benefits of a targeted PRT and impact-loading exercise programme in men treated with ADT [36]. This may be due to a number of factors. First, the sample size of approximately 25 per group was below the target sample which may have limited the power to detect any between-group differences. Second, the impact exercise programme was non-progressive and only consisted of two-footed jumps (plus 10% body weight), and thus did not incorporate diverse loading patterns which are known to be important for bone remodelling. Third, the mean calcium intake was < 750 mg/day, well below the recommended dietary intake of 1200 mg/day. There is some evidence that insufficient calcium intakes can attenuate the skeletal responses to exercise in older adults [38]. Finally, this study was limited to an assessment of aBMD by dual-energy X-ray absorptiometry (DXA), which provides no information on other determinants of bone strength (e.g. trabecular volumetric BMD (vBMD), cortical structure), which may change following exercise training, independent of aBMD. This is important because the findings from a prospective study using high-resolution, peripheral, quantitative computed tomography (pQCT) found that treatment with ADT for 12 months was associated with losses of up to 11.3% in cortical and 3.5% in trabecular vBMD, which are two- to three-fold greater than changes observed in DXA aBMD [14]. In healthy older men, the findings from an 18-month RCT found that a targeted and progressive multi-component exercise programme incorporating PRT and a diverse range of weight-bearing, impact activities was safe and effective for improving lumbar spine trabecular vBMD and femoral neck aBMD, cross-sectional area and strength as well as muscle strength, mass and size [39]. Further long-term RCTs are required to examine whether similar well-designed and progressive multi-component exercise programmes in combination with adequate nutrition can ameliorate bone and muscle loss in men treated with ADT for PCa.

Clinical guidelines for optimising bone health in men on ADT recommend calcium and vitamin D treatment [11]. While direct evidence from RCTs to support their role in preventing bone loss in this group is lacking, a review based on secondary analyses of clinical trials reported that treatment with 500–1000 mg/day of calcium and 200–500 IU/day of vitamin D in ADT-treated men was inadequate to prevent bone loss [40]. In healthy older adults, there is level-1 evidence that calcium (>1000 mg/day) plus vitamin D (> 800 IU/day) can reduce fracture risk [41]. Studies have also shown that 2000 IU/day of vitamin D can improve muscle strength and function [41, 42], and that daily consumption of calcium-vitamin D fortified milk for 2 years prevented aBMD loss at multiple sites in healthy men aged older than 50 years [43]. While a systematic review and meta-analysis of prospective studies reported that increased dairy or calcium intake was associated with an increased risk of PCa, no association was observed with supplemental or non-dairy calcium, which suggest that other components of dairy rather than fat and calcium may increase PCa risk [44]. In line with these mixed findings, supplementation at doses < 1500 mg/day have been shown to either have no influence on PCa progression [45], reduce PCa risk [46] or decrease PSA velocity [47]. In addition, in men diagnosed with PCa, total milk/dairy intake after diagnosis was not associated with a greater risk of lethal PCa, with evidence of a decreased risk in those with a high intake of low-fat dairy [48].

There is also evidence that increased dietary protein in older adults can have favourable effects on both health, particularly when combined with calcium and vitamin D at recommended levels [38]. This has been attributed to several factors: a higher protein intake can increase serum insulin-like growth factor-1 (IGF-1), enhance intestinal calcium absorption, suppress parathyroid hormone levels as well as increase muscle mass and strength, which may improve bone health via increased loading on bone [49]. There is also evidence in older adults without PCa that higher protein intakes (> 1.2 g/kg) can enhance weight loss, offset muscle loss, improve lipid profiles and insulin sensitivity [50]. While this is not a universal finding, this could be explained by the modest level of protein intake achieved in some studies and/or the type (quality) of protein consumed. Currently there are no guidelines with regard to dietary protein for men with PCa using ADT.

It is well known that PRT stimulates muscle protein synthesis (MPS), but in a fasted state it also accelerates muscle protein breakdown (MPB) [51]. Ingestion of a high-quality, rapidly digested, protein-rich source, such as whey-protein, post-exercise can attenuate the increase in MPB and stimulate MPS to enhance the anabolic benefits of PRT [51]. Thus, combining PRT with whey-protein ingestion may represent an optimal strategy to enhance muscle hypertrophy. While questions still remain in terms of the optimal dose of protein needed to elicit a synergistic response with PRT, emerging evidence indicates that 20–40 g of high-quality protein be consumed early after a bout of PRT to enhance muscle mass and/or strength [51]. Moreover, Hanson et al. [52] recently demonstrated that consumption of 40 g of whey-protein alone, or following a single session of unilateral knee extension exercises, increased MPS beyond basal rates in men treated with ADT; albeit these increments were suboptimal when compared to healthy, age-matched men. However, a critical, but as yet unanswered, question is whether ingestion of a whey-protein-, vitamin D- and calcium-enriched drink with PRT can improve the multiple musculoskeletal health outcomes in ADT-treated men.

Therefore, the primary aim of this 12-month RCT is to determine whether a multi-component exercise programme targeting muscle and bone health combined with a protein-, calcium- and vitamin D-enriched drink can enhance hip and lumbar spine aBMD in men with PCa currently treated with ADT. The secondary aims are to examine the effects of the intervention on tibial and radial bone structure and strength, total body and regional body composition, muscle strength and function, as well as cardiometabolic health, catabolic/inflammatory and anabolic/anti-inflammatory cytokines, health-related quality of life (HR-QoL) and cognitive function.

This trial will be the first to assess the efficacy of combining a targeted, bone-specific, resistance and impact exercise training programme with nutritional supplementation on musculoskeletal health in men treated with ADT for PCa. Importantly, this is one of the few known trials to examine such a lifestyle intervention over an extended period of time (52 weeks) in this population group, with a focus on both DXA areal bone density and pQCT measures of bone structure and cortical and trabecular volumetric BMD, all of which are important determinants of whole bone strength. There are currently no established guidelines for specifically managing the large range of adverse effects observed in men treated with ADT [28]. Current guidelines mainly focus on pharmacological interventions for bone health, such as antiresorptive therapy with bisphosphonates, which have been extensively evaluated and shown to prevent losses in bone density commonly reported with ADT [11, 99‐101]. However, these drugs have no effect on ameliorating the many other adverse effects associated with ADT. In terms of muscle health, functional capacity and cardiometabolic risk, the guidelines are less evidence-based within this specific clinical population group [11, 99], and commonly recommend more generic exercise guidelines for cancer survivors [102‐105]. A recent study evaluating the most robust ADT-specific guidelines [11] in a cohort of 113 men commencing ADT concluded that over a 2-year follow-up, despite maintaining bone density at the lumbar spine and reducing various cardiometabolic risk markers via additional therapies (e.g. statins), bone losses were still reported at the total hip, and risk factors of cardiometabolic risk, such as waist circumference, increased. Therefore, further well-designed, long-term trials are needed to inform ADT-specific exercise training guidelines for managing bone health and cardiometabolic risk. Furthermore, there are limited guidelines on addressing declines in HR-QoL and the large range of additional ADT-induced adverse effects. We expect that the findings from this study will provide a unique opportunity to explore whether combining exercise training with nutritional supplementation may also be effective at ameliorating multiple ADT-induced adverse effects when compared to usual care.