Bone health in breast cancer

1. Bone health in breast cancer Esmo book

2. In breaast cancer: Survival improvement has necessitated refocus on preserving patients overall health , functional autonomy ,and quality of life throughout the extended disease course . Fracture risk is elevated in patients with newly diagnosed breast cancer compared with age – matched women without breast cancer , and breast cancer itself as well as long – term adjuvant therapies for this disease may further increase the risk of fractures.

3. SKELETAL OUTCOMES Bone loss is most rapid in premenopausal women receiving both ovarian suppression therapy (GnRH agonist) and an AI. 3

4. . As a consequence , the risk of fracture is substantially increased . Fractures may ↑ mortality ,DVT ↓ QoL,Mobility

5. Bone health during adjuvant therapy for early breast cancer Some chemotherapeutic agents may directly affect bone , resulting in a rapid decrease in BMD ; however , indirect effects of chemotherapy may also result in rapid BMD decline . For example , ovarian dysfunction is common with chemotherapy in premenopausal women , leading to premature menopause.

6. The rapid decrease in circulating oestradiol levels from early menopause: leads to BMD decrease approaching 8% on average during the first year (fig)

7. Bone Loss With Cancer Therapies 10 Naturally Occurring Bone Loss CTIBL 7.7 8 7.0 6 4.6 Bone Loss at 1 Yr 4 2.6 2.0 2 1.0 0.5 0 Normal Men[1] Menopausal Women[1] ADT[3] Premature MenopauseSecondary toChemotherapy[5] Postmenopausal Women[1] Al Therapy inPostmenopausalWomen[2] Al Therapy+ GnRHAgonist inPremenopausalWomen[4] 1. Kanis JA. Osteoporosis. 1997:22-55. 2. Eastell R, et al. J Bone Mineral Res. 2002. 3. Maillefert JF, et al. J Urol. 1999;161:1219-1222. 4. Gnant M, et al. Lancet Oncol. 2008;9:840-849. 5. Shapiro CL, et al. J Clin Oncol. 2001;19:3306-3311.

8. Therefore , cancer treatment – induced bone loss • ( CTIBL) is common with both chemo- and endocrine therapies for breast cancer , and can greatly elevate the risk of fractures .

9. Risk factors for fracture in women with early breast cancer Cancer – independent risk factors for fractures include : age (> 65 years ) race (withe ) low body mass index (BMI;<20kg/m), family history of hip fracture , personal history of fragility fracture after age 50 Oral corticosteroid use for longer than 6 months osteoporosis and smoking ( current or history of).

10. Therefore: • Preserving BMD during adjuvant therapy emerging as a major concern in managing patient with Breast Ca. • Because may receive continuously for several years ,they are at high risk of substantial cumulative BMD loss and fracture

11. Recommended skeletal health investigations for woman with early breast cancer

12. chemo chemo ABCSG-12 All pts Ovarian Supp+Tam or AI for 3yrs

13. Z-FAST ZO-FAST EZ-FST Zoledronic acid every 6mo Early vs Delay

14. AI-induced estrogen deficiency • The AIs are divided into steroidal inactivators (exemestane) and nonsteroidal inhibitors (letrozole, anastrozole). • At clinical doses, these third-generation AIs are successful in inhibiting greater than 97 percent of aromataseactivity in vivo . 14

15. …AI-induced estrogen deficiency • In vivo animal studies suggest that exemestane may be more bone sparing than letrozole, owing to its androgenic structure . • However, there are no human trials showing a differential effect of the individual AIs on bone. • The MA-27 trial is a comparative trial of exemestane versus anastrozole as adjuvant therapy in postmenopausal women. The results are likely to provide more conclusive information about the skeletal effects of the steroidal versus nonsteroidal AIs. 15

17. Bone mineral density • In several of the AI trials, BMD and bone turnover markers were evaluated in a subset of women. BMD of the LS and total hip (TH) were significantly reduced in postmenopausal women receiving AIs versus tamoxifen or placebo. 17

18. Bone loss 11.6 % 17.3 % In patients who did not receive ZA • In the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 trial, premenopausal women were randomly assigned to: • tamoxifen plus goserelin • versus • anastrozole plus goserelin . • Half of each group received zoledronic acid (ZA). Significant bone loss occurred in the subset of patients who did not receive ZA (17.3 and 11.6 percent reductions in patients receiving anastrozole/goserelin and tamoxifen/goserelin, respectively). 18

19. Biochemical markers of bone turnover • In several of the trials described above, markers of bone resorption (urine n-telopeptide and serum C-telopeptide [CTX]) (serum bone specific alkaline phosphatase [BALP], N-terminal propeptide of type 1 procollagen [P1NP]) were significantly increased with AI treatment . • In contrast, bone turnover markers remained constant  or decreased with tamoxifen therapy. 19

20. …EVALUATION Normal is a T-score of -1.0 or higher Osteopenia is defined as less than -1.0 and greater than -2.5 Osteoporosis is defined as -2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a thirty year old woman 20 Thus, fracture risk assessment should include evaluation of the following:  • Clinical risk factors for osteoporosis  • Bone mineral density (BMD) measured by dual energy x-ray absorptiometry (DXA)

21. …EVALUATION • We obtain a bone mineral density study (DXA LS and hip) in women who will be starting AIs. 21

22. …EVALUATION • ASCO recommends BMD testing (DXA) for postmenopausal women taking AIs and for premenopausal women who develop treatment-related premature menopause following treatment •  The Belgian Bone Club recommends measuring BMD (DXA) and assessing risk factors for fracture in all women starting AIs or medical castration therapy 22

23. …EVALUATION 23 • A consensus statement from a UK Expert Group recommends measuring BMD within three to six months of commencingAIs in all women except for those ≥75 years of age, in whom the decision to treat can be based upon age and clinical risk factor assessment, independent BMD A recent survey of clinicians in the United Kingdom regarding practice patterns in treatment-induced bone loss in women with breast cancer revealed that a majority ofthem: were not monitoring BMD in women receiving AIs, nor had confidence in their interpretation of DXA scans and knowing when to recommend treatment with bisphosphonates This survey suggests that more work is needed to educate clinicians about these issues.

24. Laboratory evaluation • Laboratory evaluation • In a retrospective study : women (64 with breast cancer, during a six-year interval), 78 percenthad at least one secondary cause of bone loss, other than cancer or cancer-related therapies . • The most common finding was vitamin D insufficiency (38 percent with vitamin D <30 ng/mL . • In women who have low bone mass, laboratory evaluation may help identify other causes of osteoporosis such as renal or liver disease, hyperthyroidism, and hyperparathyroidism 24

25. …Laboratory evaluation 25 • Women with low bone mass (T-score below -2.5) who are initiating or already taking AIs should have the following basic tests: Biochemistry profile, especially calcium, phosphorous, albumin, total protein, creatinine, LFT including ALP, electrolytes)  •   CBC • 25-hydroxyvitamin D

26. PREVENTION AND TREATMENT OF AI-INDUCED BONE LOSS • Nonpharmacologic  • Encourage all women to adopt lifestyle changes that promote not only bone health but overall health as well. These include : • Increasing physical activity including weight bearing exercise, • reducing or stopping smoking, and • Taking calcium and vitamin D supplements . • Adequate calcium and vitamin D intake can result in positive calcium balance and a reduction in the rate of loss of bone. However, the effect upon fracture risk is less clear. 26

27. …Nonpharmacologic  • We suggest 1200 mg of elemental calcium (total diet plus supplement) and 800 international units of vitamin D daily. • In women with low vitamin D levels (25-hydroxyvitamin D level <20 ng/mL), vitamin D supplementation should be provided prior to therapy with bisphosphonates. • Administration of bisphosphonates in the setting of vitamin D deficiency increases the risk of hypocalcemia.

28. Bisphosphonates • Bisphosphonates are specific inhibitors of osteoclast-mediated bone resorption. • They are considered first- line pharmacologic therapy for postmenopausal women with osteoporosis. • Efficacy —  In several randomized trials, bisphosphonates prevented or reduced bone loss in women receiving Ais . • The two largest randomized trials were the Zometa-Femara Adjuvant Synergy Trials (Z-FAST and ZO-FAST) . In both trials, zoledronic acid (4 mg every six months) was evaluated for prevention of AI-induced bone loss. Postmenopausal women with estrogen receptor-positive early-stage breast cancer who were receiving adjuvant letrozole were randomly assigned to immediate treatment with ZA for five years or to delayed administration (when spine or hip T-score decreased to <-2.0 or the occurrence of fracture) . All patients received 500 mg of calcium and 400 to 800 international units of vitamin D. • Results, thus far, are as follows (table 6):  28

29. Z-FAST ZO-FAST EZ-FST Zoledronic acid every 6mo Early vs Delay

30. immediate treatment with ZA for five years or to delayed administration oral risedronate 35 mg/week or placebo ANA=Anastrazole 30

31. …Bisphosphonates  • • After 36 months : At this time point, 15 percent of women in the delayed group required ZA for a T-score decrease to <-2.0. There was no difference in the incidence of fractures between the two groups (5.7 versus 6.3 percent). 31

32. Bisphosphonates • Candidates for therapy — • . In the three-year report from the Z-FAST trial, only 15 percent of subjects in the delayed treatment arm met criteria for receiving ZA, suggesting that treatment of all women regardless of BMD results is unnecessary. 32

33. Bisphosphonates 33 For the prevention of fracture in patients taking AIs, we suggest : bisphosphonates in patients at high risk for fracture, including patients with osteoporosis (T-score <-2.5 or history of fragility fracture) and patients with T-scores between -1.0 and -2.5 who have risks for fracture other than AI therapy .

34. Bisphosphonates 34 Guidelines from societies and expert groups are as follows: Current ASCO guidelines suggest pharmacologic therapy (bisphosphonates) in those with a BMD T-score ≤-2.5. In patients with BMD T-scores above -2.5, annual BMD testing is recommended with initiation of bisphosphonates when BMD T-score falls to <-2.5 . The guidelines are currently being updated, and the recommendations for annual DXA scans and threshold for treatment based on T-scores may change.

35. 35   The UK Expert Group recommends bisphosphonate therapy for elderly women (>75 years) who have one or more risk factors for osteoporotic fracture, regardless of BMD . In addition, they recommend bisphosphonates for postmenopausal women <75 years of age : with T-scores <-2.0(osteoprosis) or if bone loss in women with pre-existing osteopenia (T-score between -1.0 and -2.0) occurs at a rate ≥ to 4 percent per year.

36. 36 Due to the rapid bone loss that occurs in premenopausal women receiving ovarian suppressionwith a GnRH agonist and AI, they recommend bisphosphonates for such women if the T-score is ≤-1.0. In women who are not candidates for bisphosphonates initially, they recommend repeat DXA after 24 months and initiation of bisphosphonates when the above criteria are met.

37. Choice of bisphosphonate and dosing 37   There are currently insufficient data to determine relative efficacy of the individual bisphosphonates. In the Z- and ZO-FAST trials, ZA (4 mg) was administered intravenously every 6 monthsfor five years . However, other bisphosphonates and other schedules may be equally effective. In small trials in postmenopausal women with breast cancer taking AIs, oral risedronate and ibandronate were effective in reducing bone loss. In these trials, bisphosphonates were administered using the same dose and schedule as those used for postmenopausal osteoporosis (without breast cancer)

38. …Choice of bisphosphonate and dosing 38 In healthy postmenopausal women with osteoporosis, ZA (5 mg) administered intravenously once yearly has been shown to prevent fracture. Thus, until additional data are available, choice of bisphosphonate depends upon patient preferences and potential cost issues. We favor weekly oral risedronate or alendronate(osteofos)as initial therapy. However, ZA is an option if the patient does not tolerate an oral bisphosphonate. Although there are currently no published randomized trials using an annual dose of ZA (5 mg) for women on AIs, this is also a reasonable dosing option.

39. In September 2011, denosumab (Prolia) gained FDA approval to increase bone mass in women at high risk for fracture who are receiving adjuvant AI therapy for breast cancer. A fully human monoclonal antibody that targets the receptor activator of the nuclear factor-kappa-B ligand (RANKL) protein, which acts as the primary signal to promote bone removal.

40. Mechanism of Action of Denosumab RANKL Osteoclast Formation, Function,and SurvivalInhibitedby Denosumab Y CFU-M Denosumab OPG Y Prefusion osteoclast RANKL RANK Y Multinucleated osteoclast Growth factors HormonesCytokines Y Mature osteoclast Osteoblast Bone Adapted from Boyle WJ, et al. Nature. 2003;423:337-342.

41. By inhibiting the development and activity of osteoclasts, denosumab decreases bone resorption and increases bone density. A dose of 60 mg SC is administered once every 6 months. FDA approval was based on a 2-year, double-blind, placebo-controlled study of 252 postmenopausal women with breast cancer receiving aromatase inhibitor therapy.

42. Bone mineral density (BMD) was higher at 1 year in the lumbar spine in those treated with denosumab (+4.8%) compared with placebo (-0.7%). The treatment difference was 5.5% (95% confidence interval [CI], 4.8-6.3%; P < .0001).

43. After 2 years, differences in BMD favoring denosumab were 7.6% in the lumbar spine, 4.7% in the (total) hip, and 3.6% in the femoral neck.[13] Current American Society of Clinical Oncology (ASCO) guidelines recommend denosumab (Xgeva) at 120 mg SC every 4 weeks as an option for patients with breast cancer and evidence of bone metastases.

44. The FRAX Index: Assessing Fracture Risk Available at: http://www.shef.ac.uk/FRAX.

45. Practical Guidance for Prevention of CTIBL T-score < -2.0 Bisphosphonate therapy+ calcium and vitamin D supplements (Zoledronic acid 4 mg/6 mos ) Monitor BMD every 2 yrs T-score ≥ -2.0, no risk factors • Any 2 of the following risk factors: • T-score < -1.5 • Older than 65 yrs of age • Low BMI (< 20) • Family history of hip fracture • Personal history of fragility fracture after 50 yrs of age • Oral corticosteroid use of > 6 mos • Smoking (current or history of) Calcium and vitamin D supplements Monitor risk status and BMD every 1-2 yrs* *≥ 5% drop in BMD should trigger zoledronic acid treatment (4 mg / 6 mos). Use lowest T-score from 3 sites. Data for oral bisphosphonates are emerging Evidence from 4 clinical trials indicates that zoledronic acid prevents AI-associated bone loss Hadji P, et al. Ann Oncol. 2008;19:1407-1416 by permission of Oxford University Press.

46. Thank you