Canadian Urological Association best practice report: Bone health in prostate cancer

Question 1

What has led to men diagnosed with prostate cancer living longer?

Answer 1

Advances in treatment.

Question 2

What has become a growing concern due to extended survival of prostate cancer patients?

Answer 2

Increased attention to cancer treatment-induced bone loss and optimizing care of men with castrate-resistant prostate cancer (CRPC) and bony metastases.

Question 3

How does Androgen deprivation therapy (ADT) affect bone health?

Answer 3

ADT with gonadotropin-releasing hormone agonists, antagonists, or orchiectomy decreases bone mineral density (BMD) and increases the risk of fracture.

Question 4

List some risk factors for low BMD in men with prostate cancer.

Answer 4

Advanced age, smoking, low protein intake, family history of osteoporosis, glucocorticoid use, and a prior history of fall or fracture.

Question 5

What significant morbidity is associated with fractures in Canadian men?

Answer 5

One-third of Canadian men who experience a hip fracture die within one year, and hip fracture is an independent risk factor for mortality.

Question 6

What do previous reports suggest about men on ADT in terms of osteoporosis management?

Answer 6

Men on ADT have low rates of osteoporosis screening and infrequently receive interventions to reduce bone loss.

Question 7

Why has the cumulative impact of systemic prostate cancer treatments on bone health become crucial?

Answer 7

It’s an important aspect of patient-centered, comprehensive prostate cancer care.

Question 8

Describe the function and process of bone remodeling.

Answer 8

Bone remodeling is a continuous physiological process whose function is to maintain bone integrity. It involves osteoclast-induced bone breakdown (resorption) and osteoblast-performed bone synthesis (ossification).

Question 9

How do androgens influence osteoblasts and bone density?

Answer 9

Osteoblasts express the androgen receptor. Androgens improve bone density by stimulating osteoblast proliferation and by getting converted peripherally to estrogens, which downregulate osteoclast activity via the RANK pathway.

Question 10

Explain the role of the RANKL/RANK pathway in bone resorption.

Answer 10

When RANKL binds to RANK, osteoclast differentiation, activation, and survival increase. Estrogens inhibit the RANKL/RANK pathway, which reduces osteoclast activity, thus decreasing bone resorption.

Question 11

How does a decrease in androgen levels affect bone density?

Answer 11

When androgen levels are decreased, bone density is reduced through downregulation of osteoblasts and upregulation of osteoclasts.

Question 12

What is the impact of ADT on bone mineral density (BMD)?

Answer 12

ADT reduces testosterone, disrupting bone homeostasis and promoting net bone resorption, thereby reducing BMD. BMD decreases at an accelerated rate in men on ADT compared to healthy controls, especially in the first year of therapy.

Question 13

After 10 years of ADT, what percentage of men might have osteoporosis? And what fracture risk do they face in the first five years?

Answer 13

Up to 85% of men may have osteoporosis after 10 years of ADT, with up to 20% experiencing a fracture within the first five years.

Question 14

How do glucocorticoids affect bone loss?

Answer 14

Glucocorticoids increase bone loss by inducing osteoblast apoptosis and increasing osteoclast survival.

Question 15

What risk is associated with ARAT therapies regarding osteoporotic fracture?

Answer 15

ARAT therapies, such as abiraterone, enzalutamide, apalutamide, and darolutamide, may be associated with an increased risk of osteoporotic fracture. Use of ARATs is linked with a 1.6-fold increased risk of fracture and a 1.8-fold increased risk of falls compared to men not receiving ARATs.

Question 16

Compare the fracture risk in patients receiving abiraterone acetate to those on placebo.

Answer 16

There’s a similar increase in fracture risk in patients receiving abiraterone acetate compared to placebo, with rates being 5.9% vs. 2.3%.

Question 17

Why should physicians managing men with prostate cancer on ADT assess bone health?

Answer 17

With treatment advances leading to longer survival for men with advanced prostate cancer, many patients have prolonged exposure to medications that accelerate bone loss. Assessing bone health can help prevent treatment-induced bone loss.

Question 18

What should men on ADT be evaluated for?

Answer 18

Men on ADT should be evaluated for fracture risk.

Question 19

Name the tools used for estimating fracture risk in men on ADT.

Answer 19

FRAX, CAROC risk assessment tools, and BMD assessment with a DXA scan.

Question 20

What does the FRAX algorithm provide an estimate of?

Answer 20

An individual’s 10-year fracture risk.

Question 21

What factors does the FRAX algorithm incorporate for fracture risk assessment?

Answer 21

Femoral neck T-score from a DXA scan, age, BMI, glucocorticoid use, prior fracture history, rheumatoid arthritis, smoking, alcohol consumption, parental hip fracture history, and ADT as a secondary cause of osteoporosis.

Question 22

What parameters does the CAROC tool require to estimate fracture risk?

Answer 22

Age, sex, fragility fracture history, glucocorticoid use, and femoral neck T-score from a DXA scan.

Question 23

What areas are BMD measurements taken at, and how are they reported?

Answer 23

Measurements are taken at the lumbar spine and hip, reported as T-scores, which describe the number of standard deviations below or above the mean value for a healthy 30-year-old of similar sex.

Question 24

How is osteoporosis defined based on T-score values?

Answer 24

Osteoporosis is defined as a T-score value 2.5 standard deviations or more below the mean (T≤ - 2.5).

Question 25

How is osteopenia defined based on T-score values?

Answer 25

Osteopenia is defined as a T-score between 1 and 2.5 standard deviations below the mean (T -1 to -2.5).

Question 26

Why might relying solely on BMD scores be problematic in assessing fracture risk?

Answer 26

BMD scores alone may underestimate fracture risk, as many men with fractures have BMD scores that are not in the osteoporotic range. It's recommended to incorporate BMD scores and other patient risk factors in a validated calculator for the best assessment.

Question 27

What is the significance of a previous fracture in assessing the risk for osteoporotic related fracture?

Answer 27

It indicates spontaneous fractures or those induced by minimal trauma that wouldn't normally cause a fracture. This category also includes asymptomatic vertebral fractures.

Question 28

How is glucocorticoid use defined as a risk factor for osteoporotic related fracture?

Answer 28

It refers to the oral intake of glucocorticoids equivalent to ≥5 mg/day of prednisone (FRAX) or ≥7.5 mg of prednisone (CAROC) for more than 3 months.

Question 29

It refers to the oral intake of glucocorticoids equivalent to ≥5 mg/day of prednisone (FRAX) or ≥7.5 mg of prednisone (CAROC) for more than 3 months.

Answer 29

If a mother or father had a history of hip fracture at age less than 80 years, it's considered a risk factor.

Question 30

How do FRAX and CAROC differ in age as a risk factor for osteoporotic related fractures?

Answer 30

FRAX includes ages 40–90 years, while CAROC focuses on ages 50–85.

Question 31

How does BMI influence the risk of osteoporotic related fracture?

Answer 31

A low BMI is associated with a higher risk of fracture.

Question 32

Describe the association between tobacco use and osteoporotic related fractures.

Answer 32

Men who are currently smoking are at an increased risk.

Question 33

What level of alcohol consumption is considered a risk factor for osteoporotic related fractures?

Answer 33

Consumption of 3 or more alcoholic beverages per day.

Question 34

Between rheumatoid arthritis and osteoarthritis, which is a risk factor for osteoporotic related fractures?

Answer 34

Rheumatoid arthritis is a risk factor, while osteoarthritis is not.

Question 35

Fig. 1. Assessment and management of bone health in men on ADT. §Baseline DXA is useful to assess fracture risk. If DXA cannot be performed, fracture risk can be assessed using FRAX or CAROC without DXA. *Non-pharmacological strategies include smoking cessation, moderation of alcohol consumption, exercise, and fall prevention. ¶The Canadian Osteoporosis Society recommends bone targeted agents may be considered in men on ADT with moderate risk of 10-year major osteoporotic fracture (10–20% risk). A shared decision-making approach is appropriate. May consider referral to an osteoporosis expert for patients wishing to discuss further. ‡Evidence to guide the optimal interval to repeat a DXA scan and BMD assessment is limited. The panel recommends clinicians consider repeat DXA every 2–3 years in low-risk patients and every 1–2 years for moderate-risk patients who are not on treatment or when new clinical factors/treatments arise that may impact bone health. Men on bone-targeted therapy may consider a repeat DXA scan to confirm effectiveness of therapy. †Recommend baseline serum calcium and creatinine. ADT: androgen deprivation therapy; BMD: bone mineral density; CAROC: The Canadian Association of Radiologists and Osteoporosis Canada fracture risk assessment; DXA: dual energy X-ray absorptiometry; FRAX: The World Health Organization fracture risk assessment algorithm.

Question 36

What is the recommendation for initiating treatment to prevent bone loss in patients on ADT?

Answer 36

Treatment should be initiated in patients with osteoporosis (T-score ≤ -2.5), a prior fragility fracture, or a 10-year major osteoporotic fracture risk of >20%.

Question 37

Define a fragility fracture.

Answer 37

It's a fracture from minimal mechanical force (e.g., fall from standing height) that wouldn't ordinarily cause a fracture. It predicts future fractures, independent of FRAX or CAROC score.

Question 38

How often does Osteoporosis Canada recommend BMD surveillance for men on ADT?

Answer 38

Every 1-3 years.

Question 39

In men on ADT at low risk of fracture, how often should a repeat BMD be done?

Answer 39

Every 2-3 years.

Question 40

How often should men on ADT at moderate or high risk of fracture, who aren't receiving pharmacological treatment for bone loss, have a repeat BMD?

Answer 40

Every 1-2 years.

Question 41

For men receiving pharmacological treatment, how soon should a repeat BMD be done to assess treatment efficacy?

Answer 41

Within the first two years.

Question 42

When is it reasonable to stop a bisphosphonate in men on ADT?

Answer 42

After a period of treatment if a repeat risk assessment with FRAX or CAROC shows they're no longer at elevated risk of fracture.

Question 43

When might a patient consider a one-year bisphosphonate holiday?

Answer 43

After three years of intravenous or five years of oral bisphosphonate therapy, provided they don’t have a history of fragility hip or vertebral fracture, have no more than one fragility fracture, hip BMD T-scores > -2.5, and aren't high risk for fracture as per FRAX.

Question 44

Why should denosumab not be discontinued abruptly?

Answer 44

It can lead to rapid bone loss and a risk of rebound fracture. Discontinuation should be done in conjunction with an osteoporosis expert.

Question 45

What is the main purpose of educating patients initiating ADT about cancer treatment-induced bone loss?

Answer 45

To inform them about the potential bone loss due to cancer treatments, its consequences, and prevention strategies. This education empowers patients, increases their autonomy, and improves health outcomes.

Question 46

How does education impact prostate cancer patients in terms of health outcomes?

Answer 46

Education empowers patients, increases their autonomy, and leads to improved health outcomes.

Question 47

Do many patients with prostate cancer have a comprehensive understanding of how cancer treatments may induce bone loss?

Answer 47

No, many patients with prostate cancer have limited knowledge about how cancer treatments can lead to bone loss.

Question 48

What are some effective ways to educate patients about bone health and its relation to prostate cancer treatments?

Answer 48

Educational interventions can be provided through information pamphlets, family physicians, and bone health coordinators. Additionally, online educational materials have been shown to be effective in improving bone health knowledge in prostate cancer survivors.

Question 49

How have online educational materials impacted prostate cancer survivors in terms of bone health knowledge?

Answer 49

Online educational materials have been shown to improve bone health knowledge among prostate cancer survivors. They also offer an easy method to disseminate information.

Question 50

What lifestyle modifications are recommended for patients initiating ADT?

Answer 50

Smoking cessation Moderation of alcohol consumption Weight-bearing and balance exercises Fall prevention strategies

Question 51

How many alcoholic beverages per day are recommended for men with prostate cancer on ADT?

Answer 51

Less than three alcoholic beverages per day.

Question 52

According to a systematic review, how might exercise benefit prostate cancer patients' bone health?

Answer 52

Exercise may help preserve lumbar spine, hip, and femoral shaft BMD.

Question 53

What types of exercises show maximum effects on bone health for men with prostate cancer on ADT?

Answer 53

Moderate-intensity weight-bearing aerobic, resistance, and impact exercises.

Question 54

Did the studies in the systematic review assess exercise as a direct means of reducing the risk of falls or fractures in prostate cancer patients?

Answer 54

No, none of the studies included assessed exercise as a means of directly reducing the risk of falls or fractures.

Question 55

What are some known benefits of physical exercise for prostate cancer patients?

Answer 55

Physical exercise has numerous known health benefits and can improve quality of life measures in prostate cancer patients.

Question 56

What are some recommendations for reducing falls and fractures in prostate cancer patients?

Answer 56

Balance exercises Posture awareness Spine-sparing strategies such as sitting while tying shoes or bending at the knees when lifting.

Question 57

What is the targeted daily calcium intake for patients on ADT?

Answer 57

Patients on ADT should target a calcium intake of 1200 mg/day.

Question 58

What is the recommended range for daily vitamin D intake for patients on ADT?

Answer 58

Patients on ADT should aim for a vitamin D intake of 800–2000 IU daily.

Question 59

What are the potential benefits of calcium and vitamin D supplementation for patients on ADT?

Answer 59

Calcium and vitamin D supplementation may prevent bone loss and reduce the risk of fractures.

Question 60

How does calcium benefit bone health?

Answer 60

Calcium is deposited into bone tissue through ossification by osteoblasts.

Question 61

How is vitamin D synthesized and what is its primary role in relation to calcium?

Answer 61

Vitamin D is synthesized in the skin upon exposure to ultraviolet light and it increases the intestinal absorption of calcium.

Question 62

What was the observed reduction in hip fractures and any fractures with daily supplementation of vitamin D and calcium?

Answer 62

Daily supplementation of vitamin D and calcium reduces hip fracture by 6% and any fracture by 16%.

Question 63

Were any reductions in fractures observed with only vitamin D supplementation?

Answer 63

No reduction in fracture was observed with vitamin D supplementation alone.

Question 64

In patients with prostate cancer on ADT, what are the independent predictors of higher BMD scores during the first year of treatment?

Answer 64

Calcium and vitamin D supplementation.

Question 65

Up to what amount of vitamin D supplementation can be safely done without monitoring?

Answer 65

Supplementation up to 2000 IU per day of vitamin D can be done safely without monitoring.

Question 66

Are lower doses of calcium or vitamin D than the provided targets adequate to prevent treatment-induced bone loss?

Answer 66

No, intake of lower doses of calcium or vitamin D than the provided targets are inadequate to prevent treatment-induced bone loss.

Question 67

What are bone-targeted therapies?

Answer 67

Bone-targeted therapies are pharmacotherapies that actively prevent bone loss by preventing bone resorption.

Question 68

Name the two main drug classifications relevant for patients with cancer treatment-induced bone loss.

Answer 68

Bisphosphonates and Denosumab.

Question 69

How do Bisphosphonates function?

Answer 69

Bisphosphonates are analogues of pyrophosphate that concentrate in the bone and inhibit osteoclast function by reducing osteoclast recruitment to the bone surface. This reduces osteoclast activity and promotes osteoclast apoptosis.

Question 70

Describe the function of Denosumab.

Answer 70

Denosumab is a monoclonal human antibody that binds the RANKL. This prevents the RANKL from activating the RANK receptor on osteoclasts, reducing osteoclast formation, activity, and survival.

Question 71

In which two patient populations should bone-targeted therapies be considered?

Answer 71

Any patient on ADT at elevated risk of osteoporotic fracture. Any man with CRPC and bone metastases regardless of other fracture risks.

Question 72

Does the recommended dosing of bone-targeted therapies differ based on indication?

Answer 72

Yes, recommended dosing of bone-targeted therapies differs based on the indication.

Question 73

In which disease state are there recommendations for routine bone-targeted therapies?

Answer 73

Patients with CRPC and bone metastases are currently the only disease state with recommendations for routine bone-targeted therapies.

Question 74

When should referral to a medical specialist with expertise in osteoporosis be considered?

Answer 74

Referral should be considered if there are: intolerance or contraindications to bone-targeted therapy, fractures, BMD that does not improve or worsens on therapy, or for patients with multiple risk factors, unclear clinical risk factors, or desiring more detailed risk-benefit discussions.

Question 75

Management recommendation for men with castrate-sensitive prostate cancer (CSPC) and non-metastatic CRPC regarding bone-targeted therapies for skeletal-related events (SREs) prevention.

Answer 75

Men with CSPC and non-metastatic CRPC should not receive bone-targeted therapies for the prevention of SREs. Treatment for bone loss prevention should be considered for all men on ADT as per Recommendation 2.

Question 76

Effect of zoledronic acid 4 mg IV every three months on men on ADT.

Answer 76

Increased BMD by 5.6% in one year, compared to a decrease in BMD of 2.2% in the placebo group.

Question 77

Findings of systematic review of bisphosphate use in men with prostate cancer.

Answer 77

Improvements in BMD observed, but no significant change in fracture risk.

Question 78

Effect of denosumab 60 mg SC every six months on patients on ADT.

Answer 78

Increased BMD by 5.6% compared to a 1% decrease in the placebo group in two years. Reduced vertebral fracture risk from 3.6% to 1.5% in men on ADT without metastases at 36 months.

Question 79

Number Needed to Treat (NNT) for denosumab to reduce vertebral fracture risk.

Answer 79

48.

Question 80

Comparison between denosumab and oral bisphosphonate alendronate.

Answer 80

Significant improvement in lumbar BMD at 24 months with denosumab (5.6% vs. -1.1%), with a non-statistically significant decrease in vertebral fracture risk.

Question 81

Definition of SREs.

Answer 81

Pathological fracture, spinal cord compression from cancer, or the need for radiation or surgery to manage pain or reduce future fracture risk.

Question 82

Recommendation for bone-targeted therapies in non-metastatic CSPC.

Answer 82

Only indicated in men who are at increased risk of osteoporotic fracture.

Question 83

Findings from the CALGB 90202 study regarding zoledronic acid in metastatic CSPC.

Answer 83

Early treatment with zoledronic acid in metastatic CSPC showed no difference than placebo in preventing fractures or improving survival.

Question 84

Results from the STAMPEDE trial about zoledronic acid with and without docetaxel.

Answer 84

No improvement in SREs.

Question 85

ZAPCA trial findings comparing zoledronic acid to placebo.

Answer 85

No difference in time to treatment failure or first SRE.

Question 86

Recommendation for bone-targeted therapies in metastatic CSPC.

Answer 86

Only indicated in men who are at increased risk of osteoporotic fracture.

Question 87

What is the recommendation regarding bone-targeted therapies for the prevention of skeletal-related events (SREs) in men with castrate-sensitive prostate cancer (CSPC) and non-metastatic CRPC?

Answer 87

Men with CSPC and non-metastatic CRPC should not receive bone-targeted therapies for the prevention of SREs.

Question 88

In the context of non-metastatic CRPC, what was the outcome of using denosumab 120 mg SC every four weeks regarding bone metastasis?

Answer 88

Denosumab 120 mg SC every four weeks delayed the time to first bone metastasis in patients with non-metastatic CRPC and a prostate-specific antigen (PSA) doubling time of <10 months. However, it did not improve progression-free or overall survival (NNT= 20).

Question 89

What happened with the randomized trial of zoledronic acid for the prevention of first bone metastasis in men with prostate cancer?

Answer 89

The trial was terminated due to the low observed event rate.

Question 90

Have zoledronic acid and denosumab been approved in Canada for the prevention of bony metastases in men with prostate cancer?

Answer 90

No, neither zoledronic acid nor denosumab has been approved in Canada for this purpose, due to uncertain clinical benefit with a definite risk of complications.

Question 91

Which patient populations should not receive bone-targeted therapies for the prevention of skeletal-related events (SREs)?

Answer 91

Men with castrate-sensitive prostate cancer (CSPC) and non-metastatic CRPC.

Question 92

What should be considered in all men on ADT to prevent bone loss?

Answer 92

Treatment for the prevention of bone loss as per Recommendation 2.

Question 93

For men with CRPC and bone metastases, which treatments are recommended to prevent SREs?

Answer 93

Denosumab 120 mg SC every four weeks (preferred) or zoledronic acid 4 mg IV every four weeks.

Question 94

Why are bone-targeted therapies indicated in men with CRPC and bone metastases?

Answer 94

To reduce skeletal-related events (SREs).

Question 95

How does zoledronic acid at 4 mg IV every four weeks impact SREs in comparison to placebo?

Answer 95

Reduces SREs from 49% to 38% at 24 months (NNT=9).

Question 96

How did denosumab compare to zoledronic acid in a randomized controlled trial regarding SREs?

Answer 96

Denosumab was superior, prolonging the time to first SRE by 3.6 months (NNT=20).

Question 97

How does the efficacy of zoledronic acid given at 12-week intervals compare to four-week dosing for SRE prevention?

Answer 97

Zoledronic acid at 12-week intervals was found to be non-inferior to four-week dosing for the prevention of SREs.

Question 98

How did denosumab at 12-week intervals compare to its four-week dosing regarding health-related quality of life and assessment of fractures?

Answer 98

Denosumab at 12-week intervals was non-inferior for health-related quality of life but was underpowered for assessment of fractures.

Question 99

Denosumab at 12-week intervals was non-inferior for health-related quality of life but was underpowered for assessment of fractures.

Answer 99

Yes, an ongoing trial (NCT02051218) is exploring the role of every 12-week denosumab in metastatic CRPC patients.

Question 100

Before initiating bone-targeted therapies, what baseline evaluations should a patient undergo?

Answer 100

Dental exam, assessment of renal function, and serum calcium.

Question 101

What is ONJ?

Answer 101

Osteonecrosis of the jaw. It's a potential complication of bone-targeted therapies.

Question 102

How common is ONJ with osteoporotic treatment doses of bone-targeted therapies?

Answer 102

Very rare.

Question 103

Which patients have a higher risk of ONJ?

Answer 103

Patients with CRPC and bony metastases receiving bone-targeted therapy for the prevention of SREs. Other risk factors include prior head and neck radiotherapy, glucocorticoid exposure, diabetes, poor dental hygiene, and invasive dental procedures.

Question 104

What was the ONJ incidence after one year of therapy on monthly denosumab or zoledronic acid when standardized for exposure time?

Answer 104

1.1% for denosumab and 0.7% for zoledronic acid per 100 years of exposure.

Question 105

How does the risk of ONJ change with time on denosumab?

Answer 105

The incidence increased to 4.1% per 100 years of exposure, suggesting the risk of ONJ increases with time.

Question 106

Why is zoledronic acid distinct from denosumab in the context of renal failure?

Answer 106

Zoledronic acid requires dose adjustments for renal failure and it's recommended to cease therapy with a creatinine clearance (CrCl) <30 mL/min.

Question 107

How often does severe hypocalcemia occur in patients on bone-targeted therapies?

Answer 107

In less than 1% of patients.

Question 108

What are the risk factors for severe hypocalcemia?

Answer 108

Osteoblastic metastasis, vitamin D deficiency, and renal insufficiency.

Question 109

When can periodic calcium monitoring be considered?

Answer 109

In patients with metastatic CRPC receiving treatment to prevent SREs and in patients with borderline renal function.

Question 110

What is the recommendation regarding the combination of radium-223 and ARAT therapies for patients with prostate cancer?

Answer 110

Combining radium-223 and ARAT therapies should be avoided due to increased fracture risk until further data is available.

Question 111

What is radium-223 and its significance in the context of prostate cancer?

Answer 111

Radium-223 is an alpha-emitting radiopharmaceutical that has been shown to improve overall survival in men with CRPC and symptomatic bony metastases.

Question 112

What did the ERA 223 study reveal about the combination of radium-223 and abiraterone?

Answer 112

The combination of radium-223 and abiraterone increased the risk of overall fracture (29% vs. 11%) and non-pathological fracture (49% vs. 17%) compared to abiraterone alone.

Question 113

How common was the use of additional supportive bone-targeted therapies in the ERA 223 study population?

Answer 113

The overall use of additional supportive bone-targeted therapies in the study population was low, at 40%.

Question 114

What did the post-hoc analysis of the ERA 223 study determine about bone-targeted therapies?

Answer 114

The post-hoc analysis determined that the use of bone-targeted therapies decreased the risk of fracture.

Question 115

What is the primary objective of the PEACE III study (NCT02194842)?

Answer 115

PEACE III is an ongoing study assessing the combination of radium-223 and enzalutamide with protocol changes to include routine bone-targeted therapies.

Question 116

What did the interim analysis of PEACE III reveal about fracture risk?

Answer 116

The interim analysis of PEACE III showed a three-fold higher risk of fracture with combination treatment that was reversed with mandatory bone-targeted therapy administration.

Question 117

Why is bone health assessment and bone-targeted therapies crucial for men with CRPC and bony metastases?

Answer 117

The results from studies like ERA 223 and PEACE III stress the ongoing importance of bone health assessment and bone-targeted therapies in men with CRPC and bony metastases.