AST-induced bone loss in men with prostate cancer: exercise as a potential countermeasure

Abstract

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.

Introduction

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

Table 1 The WHO classification of bone status41

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

Table 2 Summary of studies evaluating BMD loss following AST

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.

Table 3 Fracture rates with androgen suppression treatment

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.

Figure 1
figure1

The interrelationships between androgen suppression treatment (AST) and fracture risk. AST results in severe hypogonadism, which has a deleterious effect on muscle mass leading to a reduction in muscle performance, balance and an increased risk of falls. Hypogonadism also results in estrogen deficiency and both estrogen and testosterone withdrawals lead to reduced bone mineral density (BMD) and an increased risk of sustaining a fracture following trauma, such as a fall. AST administration and muscle weakness contributes to fatigue, which results in a reduction in physical activity, further compromising muscle mass and muscle strength and increasing fall risk, and skeletal unloading reducing BMD.

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.

Figure 2
figure2

Examples of drop jumping off a small step (starting position is panel a and panel b is midflight) and multi-directional jumping from side to side (panel c and panel d).

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.

Table 4 Exercise interventions with bone density as an outcome

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.

Safety aspects

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.

Conclusion

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.

References

  1. 1

    Shahinian VB, Kuo YF, Freeman JL, Orihuela E, Goodwin JS . Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005; 103: 1615–1624.

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Galvao DA, Taaffe DR, Spry N, Joseph D, Newton RU . Cardiovascular and metabolic complications during androgen deprivation: exercise as a potential countermeasure. Prostate Cancer Prostatic Dis 2009; 12: 233–240.

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Levine GN, D′Amico AV, Berger P, Clark PE, Eckel RH, Keating NL et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. CA Cancer J Clin 2010; 60: 194–201.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Saylor PJ, Smith MR . Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol 2009; 181: 1998–2006; discussion 7–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Rashid MH, Chaudhary UB . Intermittent androgen deprivation therapy for prostate cancer. Oncologist 2004; 9: 295–301.

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Galvao DA, Spry NA, Taaffe DR, Newton RU, Stanley J, Shannon T et al. Changes in muscle, fat and bone mass after 36 weeks of maximal androgen blockade for prostate cancer. BJU Int 2008; 102: 44–47.

    Article  PubMed  Google Scholar 

  7. 7

    Taylor LG, Canfield SE, Du XL . Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer. Cancer 2009; 115: 2388–2399.

    Article  PubMed  Google Scholar 

  8. 8

    Smith MR . Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer. Urology 2004; 63: 742–745.

    Article  PubMed  Google Scholar 

  9. 9

    Berruti A, Dogliotti L, Terrone C, Cerutti S, Isaia G, Tarabuzzi R et al. Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy. J Urol 2002; 167: 2361–2367; discussion 7.

    Article  PubMed  Google Scholar 

  10. 10

    Haseen F, Murray LJ, Cardwell CR, O′Sullivan JM, Cantwell MM . The effect of androgen deprivation therapy on body composition in men with prostate cancer: Systematic review and meta-analysis. J Cancer Surviv 2010; 4: 128–139.

    Article  PubMed  Google Scholar 

  11. 11

    Galvao DA, Taaffe DR, Spry N, Joseph D, Turner D, Newton RU . Reduced muscle strength and functional performance in men with prostate cancer undergoing androgen suppression: a comprehensive cross-sectional investigation. Prostate Cancer Prostatic Dis 2009; 12: 198–203.

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Smith MR . Osteoporosis and other adverse body composition changes during androgen deprivation therapy for prostate cancer. Cancer Metastasis Rev 2002; 21: 159–166.

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Shahinian VB, Kuo YF, Freeman JL, Goodwin JS . Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005; 352: 154–164.

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Greenspan SL, Coates P, Sereika SM, Nelson JB, Trump DL, Resnick NM . Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer. J Clin Endocrinol Metab 2005; 90: 6410–6417.

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Daniell HW . Osteoporosis due to androgen deprivation therapy in men with prostate cancer. Urology 2001; 58 (2 Suppl 1): 101–107.

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Daniell HW, Dunn SR, Ferguson DW, Lomas G, Niazi Z, Stratte PT . Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 2000; 163: 181–186.

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Bong GW, Clarke Jr HS, Hancock WC, Keane TE . Serum testosterone recovery after cessation of long-term luteinizing hormone-releasing hormone agonist in patients with prostate cancer. Urology 2008; 71: 1177–1180.

    Article  PubMed  Google Scholar 

  18. 18

    Saylor PJ, Lee RJ, Smith MR . Emerging therapies to prevent skeletal morbidity in men with prostate cancer. J Clin Oncol 2011; 29: 3705–3714.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Saylor PJ, Smith MR . Bone health and prostate cancer. Prostate Cancer Prostatic Dis 2010; 13: 20–27.

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Polascik TJ . Bone health in prostate cancer patients receiving androgen-deprivation therapy: the role of bisphosphonates. Prostate Cancer Prostatic Dis 2008; 11: 13–19.

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Galvao DA, Nosaka K, Taaffe DR, Spry N, Kristjanson LJ, McGuigan MR et al. Resistance training and reduction of treatment side effects in prostate cancer patients. Med Sci Sports Exerc 2006; 38: 2045–2052.

    Article  PubMed  Google Scholar 

  22. 22

    Galvao DA, Taaffe DR, Spry N, Joseph D, Newton RU . Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial. J Clin Oncol 2010; 28: 340–347.

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Segal RJ, Reid RD, Courneya KS, Malone SC, Parliament MB, Scott CG et al. Resistance exercise in men receiving androgen deprivation therapy for prostate cancer. J Clin Oncol 2003; 21: 1653–1659.

    Article  PubMed  Google Scholar 

  24. 24

    Galvao DA, Newton RU, Taaffe DR, Spry N . Can exercise ameliorate the increased risk of cardiovascular disease and diabetes associated with ADT? Nat Clin Pract Urol 2008; 5: 306–307.

    Article  PubMed  Google Scholar 

  25. 25

    NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, March 7–29, highlights of the conference. South Med J 2001; 94: 569–573.

    Google Scholar 

  26. 26

    Johansson H, Oden A, Kanis J, McCloskey E, Lorentzon M, Ljunggren O et al. Low bone mineral density is associated with increased mortality in elderly men: MrOS Sweden. Osteoporos Int 2011; 22: 1411–1418.

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Higano C, Shields A, Wood N, Brown J, Tangen C . Bone mineral density in patients with prostate cancer without bone metastases treated with intermittent androgen suppression. Urology 2004; 64: 1182–1186.

    Article  PubMed  Google Scholar 

  28. 28

    Smith MR, Goode M, Zietman AL, McGovern FJ, Lee H, Finkelstein JS . Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone mineral density and body composition. J Clin Oncol 2004; 22: 2546–2553.

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Morote J, Orsola A, Abascal JM, Planas J, Trilla E, Raventos CX et al. Bone mineral density changes in patients with prostate cancer during the first 2 years of androgen suppression. J Urol 2006; 175: 1679–1683; discussion 83.

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Bergstrom I, Gustafsson H, Sjoberg K, Arver S . Changes in bone mineral density differ between gonadotrophin-releasing hormone analogue- and surgically castrated men with prostate cancer - a prospective, controlled, parallel-group study. Scand J Urol Nephrol 2004; 38: 148–152.

    Article  CAS  PubMed  Google Scholar 

  31. 31

    Preston DM, Torrens JI, Harding P, Howard RS, Duncan WE, McLeod DG . Androgen deprivation in men with prostate cancer is associated with an increased rate of bone loss. Prostate Cancer Prostatic Dis 2002; 5: 304–310.

    CAS  Article  PubMed  Google Scholar 

  32. 32

    Diamond TH, Higano CS, Smith MR, Guise TA, Singer FR . Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: recommendations for diagnosis and therapies. Cancer 2004; 100: 892–899.

    Article  PubMed  Google Scholar 

  33. 33

    Morote J, Morin JP, Orsola A, Abascal JM, Salvador C, Trilla E et al. Prevalence of osteoporosis during long-term androgen deprivation therapy in patients with prostate cancer. Urology 2007; 69: 500–504.

    Article  PubMed  Google Scholar 

  34. 34

    Ettinger MP . Aging bone and osteoporosis: strategies for preventing fractures in the elderly. Arch Intern Med 2003; 163: 2237–2246.

    Article  PubMed  Google Scholar 

  35. 35

    Koot VC, Peeters PH, de Jong JR, Clevers GJ, van der Werken C . Functional results after treatment of hip fracture: a multicentre, prospective study in 215 patients. Eur J Surg 2000; 166: 480–485.

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Smith MR, Lee WC, Brandman J, Wang Q, Botteman M, Pashos CL . Gonadotropin-releasing hormone agonists and fracture risk: a claims-based cohort study of men with nonmetastatic prostate cancer. J Clin Oncol 2005; 23: 7897–7903.

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Oefelein MG, Ricchuiti V, Conrad W, Seftel A, Bodner D, Goldman H et al. Skeletal fracture associated with androgen suppression induced osteoporosis: the clinical incidence and risk factors for patients with prostate cancer. J Urol 2001; 166: 1724–1728.

    CAS  Article  PubMed  Google Scholar 

  38. 38

    Townsend MF, Sanders WH, Northway RO, Graham Jr SD . Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate carcinoma. Cancer 1997; 79: 545–550.

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Hatano T, Oishi Y, Furuta A, Iwamuro S, Tashiro K . Incidence of bone fracture in patients receiving luteinizing hormone-releasing hormone agonists for prostate cancer. BJU Int 2000; 86: 449–452.

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Diamond TH, Bucci J, Kersley JH, Aslan P, Lynch WB, Bryant C . Osteoporosis and spinal fractures in men with prostate cancer: risk factors and effects of androgen deprivation therapy. J Urol 2004; 172: 529–532.

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Lopez AM, Pena MA, Hernandez R, Val F, Martin B, Riancho JA . Fracture risk in patients with prostate cancer on androgen deprivation therapy. Osteoporos Int 2005; 16: 707–711.

    CAS  Article  PubMed  Google Scholar 

  42. 42

    Wilcox A, Carnes ML, Moon TD, Tobias R, Baade H, Stamos E et al. Androgen deprivation in veterans with prostate cancer: implications for skeletal health. Ann Pharmacother 2006; 40: 2107–2114.

    Article  PubMed  Google Scholar 

  43. 43

    Malcolm JB, Derweesh IH, Kincade MC, DiBlasio CJ, Lamar KD, Wake RW et al. Osteoporosis and fractures after androgen deprivation initiation for prostate cancer. Can J Urol 2007; 14: 3551–3559.

    PubMed  Google Scholar 

  44. 44

    Krupski TL, Smith MR, Lee WC, Pashos CL, Brandman J, Wang Q et al. Natural history of bone complications in men with prostate carcinoma initiating androgen deprivation therapy. Cancer 2004; 101: 541–549.

    Article  PubMed  Google Scholar 

  45. 45

    Alibhai SM, Duong-Hua M, Cheung AM, Sutradhar R, Warde P, Fleshner NE et al. Fracture types and risk factors in men with prostate cancer on androgen deprivation therapy: a matched cohort study of 19,079 men. J Urol 2010; 184: 918–923.

    Article  PubMed  Google Scholar 

  46. 46

    Melton III LJ, Alothman KI, Khosla S, Achenbach SJ, Oberg AL, Zincke H . Fracture risk following bilateral orchiectomy. J Urol 2003; 169: 1747–1750.

    Article  PubMed  Google Scholar 

  47. 47

    Guise TA, Oefelein MG, Eastham JA, Cookson MS, Higano CS, Smith MR . Estrogenic side effects of androgen deprivation therapy. Rev Urol 2007; 9: 163–180.

    PubMed  PubMed Central  Google Scholar 

  48. 48

    Clarke BL, Khosla S . Androgens and bone. Steroids 2009; 74: 296–305.

    CAS  Article  PubMed  Google Scholar 

  49. 49

    Hamilton EJ, Ghasem-Zadeh A, Gianatti E, Lim-Joon D, Bolton D, Zebaze R et al. Structural decay of bone microarchitecture in men with prostate cancer treated with androgen deprivation therapy. J Clin Endocrinol Metab 2010; 95: E456–E463.

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Vanderschueren D, Vandenput L, Boonen S, Lindberg MK, Bouillon R, Ohlsson C . Androgens and bone. Endocr Rev 2004; 25: 389–425.

    CAS  Article  PubMed  Google Scholar 

  51. 51

    Lee H, McGovern K, Finkelstein JS, Smith MR . Changes in bone mineral density and body composition during initial and long-term gonadotropin-releasing hormone agonist treatment for prostate carcinoma. Cancer 2005; 104: 1633–1637.

    CAS  Article  PubMed  Google Scholar 

  52. 52

    Snow-Harter C, Bouxsein M, Lewis B, Charette S, Weinstein P, Marcus R . Muscle strength as a predictor of bone mineral density in young women. J Bone Miner Res 1990; 5: 589–595.

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Glynn NW, Meilahn EN, Charron M, Anderson SJ, Kuller LH, Cauley JA . Determinants of bone mineral density in older men. J Bone Miner Res 1995; 10: 1769–1777.

    CAS  Article  PubMed  Google Scholar 

  54. 54

    Amin S, Zhang Y, Felson DT, Sawin CT, Hannan MT, Wilson PW et al. Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study. Am J Med 2006; 119: 426–433.

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Freedland SJ, Eastham J, Shore N . Androgen deprivation therapy and estrogen deficiency induced adverse effects in the treatment of prostate cancer. Prostate Cancer Prostatic Dis 2009; 12: 333–338.

    CAS  Article  PubMed  Google Scholar 

  56. 56

    Eakin EG, Youlden DR, Baade PD, Lawler SP, Reeves MM, Heyworth JS et al. Health behaviors of cancer survivors: data from an Australian population-based survey. Cancer Causes Control 2007; 18: 881–894.

    Article  PubMed  Google Scholar 

  57. 57

    Lanyon LE . Using functional loading to influence bone mass and architecture: objectives, mechanisms, and relationship with estrogen of the mechanically adaptive process in bone. Bone 1996; 18 (1 Suppl): 37S–43S.

    CAS  Article  PubMed  Google Scholar 

  58. 58

    Taaffe DR . Sarcopenia—exercise as a treatment strategy. Aust Fam Physician 2006; 35: 130–134.

    PubMed  Google Scholar 

  59. 59

    Newman AB, Simonsick EM, Naydeck BL, Boudreau RM, Kritchevsky SB, Nevitt MC et al. Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability. JAMA 2006; 295: 2018–2026.

    CAS  Article  PubMed  Google Scholar 

  60. 60

    Bylow K, Dale W, Mustian K, Stadler WM, Rodin M, Hall W et al. Falls and physical performance deficits in older patients with prostate cancer undergoing androgen deprivation therapy. Urology 2008; 72: 422–427.

    Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Schmitz KH, Courneya KS, Matthews C, Demark-Wahnefried W, Galvao DA, Pinto BM et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc 2010; 42: 1409–1426.

    Article  PubMed  Google Scholar 

  62. 62

    Moreland J, Richardson J, Chan DH, O′Neill J, Bellissimo A, Grum RM et al. Evidence-based guidelines for the secondary prevention of falls in older adults. Gerontology 2003; 49: 93–116.

    Article  PubMed  Google Scholar 

  63. 63

    Guadalupe-Grau A, Fuentes T, Guerra B, Calbet JA . Exercise and bone mass in adults. Sports Med 2009; 39: 439–468.

    Article  PubMed  Google Scholar 

  64. 64

    Fuchs RK, Bauer JJ, Snow CM . Jumping improves hip and lumbar spine bone mass in prepubescent children: a randomized controlled trial. J Bone Miner Res 2001; 16: 148–156.

    CAS  Article  PubMed  Google Scholar 

  65. 65

    Mackelvie KJ, McKay HA, Khan KM, Crocker PR . A school-based exercise intervention augments bone mineral accrual in early pubertal girls. J Pediatr 2001; 139: 501–508.

    CAS  Article  PubMed  Google Scholar 

  66. 66

    McKay HA, Petit MA, Schutz RW, Prior JC, Barr SI, Khan KM . Augmented trochanteric bone mineral density after modified physical education classes: a randomized school-based exercise intervention study in prepubescent and early pubescent children. J Pediatr 2000; 136: 156–162.

    CAS  Article  PubMed  Google Scholar 

  67. 67

    Huuskonen J, Vaisanen SB, Kroger H, Jurvelin JS, Alhava E, Rauramaa R . Regular physical exercise and bone mineral density: a four-year controlled randomized trial in middle-aged men. The DNASCO study. Osteoporos Int 2001; 12: 349–355.

    CAS  Article  PubMed  Google Scholar 

  68. 68

    Martyn-St James M, Carroll S . Meta-analysis of walking for preservation of bone mineral density in postmenopausal women. Bone 2008; 43: 521–531.

    Article  PubMed  Google Scholar 

  69. 69

    Palombaro KM . Effects of walking-only interventions on bone mineral density at various skeletal sites: a meta-analysis. J Geriatr Phys Ther 2005; 28: 102–107.

    Article  PubMed  Google Scholar 

  70. 70

    Borer KT . Physical activity in the prevention and amelioration of osteoporosis in women: interaction of mechanical, hormonal and dietary factors. Sports Med 2005; 35: 779–830.

    Article  PubMed  Google Scholar 

  71. 71

    Nikander R, Gagnon C, Dunstan DW, Magliano DJ, Ebeling PR, Lu ZX et al. Frequent walking, but not total physical activity, is associated with increased fracture incidence: a 5-year follow-up of an Australian population-based prospective study (AusDiab). J Bone Miner Res 2011; 26: 1638–1647.

    Article  PubMed  Google Scholar 

  72. 72

    Hurley BF, Hanson ED, Sheaff AK . Strength training as a countermeasure to aging muscle and chronic disease. Sports Med 2011; 41: 289–306.

    Article  PubMed  Google Scholar 

  73. 73

    Taaffe DR, Cauley JA, Danielson M, Nevitt MC, Lang TF, Bauer DC et al. Race and sex effects on the association between muscle strength, soft tissue, and bone mineral density in healthy elders: the Health, Aging, and Body Composition Study. J Bone Miner Res 2001; 16: 1343–1352.

    CAS  Article  PubMed  Google Scholar 

  74. 74

    Peterson SE, Peterson MD, Raymond G, Gilligan C, Checovich MM, Smith EL . Muscular strength and bone density with weight training in middle-aged women. Med Sci Sports Exerc 1991; 23: 499–504.

    CAS  Article  PubMed  Google Scholar 

  75. 75

    Karlsson MK, Johnell O, Obrant KJ . Bone mineral density in weight lifters. Calcif Tissue Int 1993; 52: 212–215.

    CAS  Article  PubMed  Google Scholar 

  76. 76

    Suominen H . Muscle training for bone strength. Aging - Clin Exp Res 2006; 18: 85–93.

    Article  PubMed  Google Scholar 

  77. 77

    Vincent KR, Braith RW . Resistance exercise and bone turnover in elderly men and women. Med Sci Sports Exerc 2002; 34: 17–23.

    Article  PubMed  Google Scholar 

  78. 78

    Kohrt WM, Bloomfield SA, Little KD, Nelson ME, Yingling VR . Physical activity and bone health. Med Sci Sports Exercise 2004; 36: 1985–1996.

    Article  Google Scholar 

  79. 79

    Maddalozzo GF, Snow CM . High intensity resistance training: effects on bone in older men and women. Calcif Tissue Int 2000; 66: 399–404.

    CAS  Article  PubMed  Google Scholar 

  80. 80

    Menkes A, Mazel S, Redmond RA, Koffler K, Libanati CR, Gundberg CM et al. Strength training increases regional bone mineral density and bone remodeling in middle-aged and older men. J Appl Physiol 1993; 74: 2478–2484.

    CAS  Article  PubMed  Google Scholar 

  81. 81

    Nelson ME, Fiatarone MA, Morganti CM, Trice I, Greenberg RA, Evans WJ . Effects of high-intensity strength training on multiple risk factors for osteoporotic fractures: a randomized controlled trial. JAMA 1994; 272: 1909–1914.

    CAS  Article  PubMed  Google Scholar 

  82. 82

    Kerr D, Morton A, Dick I, Prince R . Exercise effects on bone mass in postmenopausal women are site-specific and load-dependent. J Bone Miner Res 1996; 11: 218–225.

    CAS  Article  PubMed  Google Scholar 

  83. 83

    Kerr D, Ackland T, Maslen B, Morton A, Prince R . Resistance training over 2 years increases bone mass in calcium-replete postmenopausal women. J Bone Miner Res 2001; 16: 175–181.

    CAS  Article  PubMed  Google Scholar 

  84. 84

    Newton RU, Taaffe DR, Spry N, Gardiner RA, Levin G, Wall B et al. A phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for prostate cancer. BMC Cancer 2009; 9: 210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Taaffe DR, Robinson TL, Snow CM, Marcus R . High-impact exercise promotes bone gain in well-trained female athletes. J Bone Miner Res 1997; 12: 255–260.

    CAS  Article  PubMed  Google Scholar 

  86. 86

    Taaffe DR, Snow-Harter C, Connolly DA, Robinson TL, Brown MD, Marcus R . Differential effects of swimming versus weight-bearing activity on bone mineral status of eumenorrheic athletes. J Bone Miner Res 1995; 10: 586–593.

    CAS  Article  PubMed  Google Scholar 

  87. 87

    Heinonen A, Kannus P, Sievanen H, Oja P, Pasanen M, Rinne M et al. Randomised controlled trial of effect of high-impact exercise on selected risk factors for osteoporotic fractures. Lancet 1996; 348: 1343–1347.

    CAS  Article  PubMed  Google Scholar 

  88. 88

    Cheng S, Sipila S, Taaffe DR, Puolakka J, Suominen H . Change in bone mass distribution induced by hormone replacement therapy and high-impact physical exercise in post-menopausal women. Bone 2002; 31: 126–135.

    CAS  Article  PubMed  Google Scholar 

  89. 89

    Kukuljan S, Nowson CA, Bass SL, Sanders K, Nicholson GC, Seibel MJ et al. Effects of a multi-component exercise program and calcium-vitamin-D3-fortified milk on bone mineral density in older men: a randomised controlled trial. Osteoporos Int 2009; 20: 1241–1251.

    CAS  Article  PubMed  Google Scholar 

  90. 90

    Erickson CR, Vukovich MD . Osteogenic index and changes in bone markers during a jump training program: a pilot study. Med Sci Sports Exerc 2010; 42: 1485–1492.

    Article  PubMed  Google Scholar 

  91. 91

    Bassey EJ, Rothwell MC, Littlewood JJ, Pye DW . Pre- and postmenopausal women have different bone mineral density responses to the same high-impact exercise. J Bone Miner Res 1998; 13: 1805–1813.

    CAS  Article  PubMed  Google Scholar 

  92. 92

    Kato T, Terashima T, Yamashita T, Hatanaka Y, Honda A, Umemura Y . Effect of low-repetition jump training on bone mineral density in young women. J of Appl Physiol 2006; 100: 839–843.

    Article  Google Scholar 

  93. 93

    Bailey CA, Brooke-Wavell K . Optimum frequency of exercise for bone health: randomised controlled trial of a high-impact unilateral intervention. Bone 2010; 46: 1043–1049.

    Article  PubMed  Google Scholar 

  94. 94

    Welsh L, Rutherford OM . Hip bone mineral density is improved by high-impact aerobic exercise in postmenopausal women and men over 50 years. Euro J Appl Physiol Occupation Physiol 1996; 74: 511–517.

    CAS  Article  Google Scholar 

  95. 95

    Winters-Stone KM, Dobek J, Nail L, Bennett JA, Leo MC, Naik A et al. Strength training stops bone loss and builds muscle in postmenopausal breast cancer survivors: a randomized, controlled trial. Breast cancer Res Tr 2011; 127: 447–456.

    Article  Google Scholar 

  96. 96

    Saarto T, Sievanen H, Kellokumpu-Lehtinen P, Nikander R, Vehmanen L, Huovinen R et al. Effect of supervised and home exercise training on bone mineral density among breast cancer patients. A 12-month randomised controlled trial. Osteoporos Int 2012; 23: 1601–1612.

    CAS  Article  PubMed  Google Scholar 

  97. 97

    Martyn-St James M, Carroll S . A meta-analysis of impact exercise on postmenopausal bone loss: the case for mixed loading exercise programmes. Br J Sports Med 2009; 43: 898–908.

    CAS  Article  PubMed  Google Scholar 

  98. 98

    Chodzko-Zajko WJ, Proctor DN, Fiatarone Singh MA, Minson CT, Nigg CR, Salem GJ et al. American college of sports medicine position stand exercise and physical activity for older adults. Med Sci Sports Exerc 2009; 41: 1510–1530.

    Article  Google Scholar 

  99. 99

    Oefelein MG, Ricchiuti V, Conrad W, Resnick MI . Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol 2002; 168: 1005–1007.

    Article  PubMed  Google Scholar 

  100. 100

    Barry MJ, Gallagher PM, Skinner JS, Fowler Jr FJ . Adverse effects of robotic-assisted laparoscopic versus open retropubic radical prostatectomy among a nationwide random sample of medicare-age men. J Clin Oncol Off J Am Soc Clin Oncol 2012; 30: 513–518.

    Article  Google Scholar 

  101. 101

    Pilepich MV, Caplan R, Byhardt RW, Lawton CA, Gallagher MJ, Mesic JB et al. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85-31. J Clin Oncol 1997; 15: 1013–1021.

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to K A Bolam.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Keywords

  • androgen suppression
  • bone density
  • fracture risk
  • physical exercise

Further reading

Search

Quick links