1. 19th Annual NOCR Meeting Session I: Breast Cancer
Bone Directed Therapy in Breast Cancer
Christy A Russell, MD
Keck School of Medicine
University of Southern California

2. Indications: Bisphosphonates vs RANK-Ligand inhibitor
•Zoledronic acid is indicated for the treatment of HCM and patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. •Denosumab is indicated for the prevention of skeletal related events in patients with bone metastases from solid tumors.

3. Pathogenesis of Osteolytic Bone Metastases
Tumor Cells in Bone
Tumor-derived osteoclast activating factors
Parathyroid hormone- related protein
Interleukins -6, -8, -11
Tumor necrosis factor
Macrophage colony- stimulating factor
Bone-derived tumor growth factors
Transforming growth factor 
Insulin-like growth factors
Fibroblast growth factors
Platelet-derived growth factor
Bone morphogenic proteins
(+)
(+)
Osteoclast
Bone
Derived from Roodman GD. N Engl J Med. 2004;350:
Reference:
Roodman GD. Mechanisms of bone metastases. N Engl J Med. 2004;350:

4. Pathogenesis of Osteoblastic Bone Metastases
Tumor Cells
Bone-derived growth factors
Osteoblast-derived signals
Tumor-derived osteoclast activating
factors
PTH-RP
IL-6
Tumor-derived osteoblast growth factors
ET-1
TGF-
FGF
BMPs
IGFs
(+)
(+)
Osteoclast
Osteoblasts
Bone
Adapted with permission from Saad F et al. Eur Urol. 2004;45:26-34.
References:
1. Saad F, Schulman CC. Role of bisphosphonates in prostate cancer. Eur Urol. 2004;45:26-34.
2. Mohammad KS, Guise TA. Mechanisms of osteoblastic metastases: role of endothelin-1. Clin Orthop. 2003;415S:S67-S74.
3. Roodman GD. Mechanisms of bone metastases. N Engl J Med. 2004;350:
4. Lipton A. Pathophysiology of bone metastases: how this knowledge may lead to therapeutic intervention. Supportive Oncology. 2004;2:

5. Mechanism of Bisphosphonate Inhibition of Osteoclast Activity
Bisphosphonates may modulate signaling from osteoblasts to osteoclasts
Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis1 X
Increased OPG production2
Decreased RANKL expression3
New bone
Bone
Bisphosphonates are released locally during bone resorption1
Bisphosphonates are concentrated under osteoclasts1
1. Reszka AA, Rodan GA. Curr Rheumatol Rep. 2003;5: Viereck V et al. Biochem Biophys Res Commun. 2002;291: Pan B et al. J Bone Miner Res. 2004;19:
References:
1. Reszka AA, Rodan GA. Bisphosphonate mechanism of action. Curr Rheumatol Rep. 2003;5:65-74.
2. Viereck V, Emons G, Lauck V, et al. Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegrin production by primary human osteoblasts. Biochem Biophys Res Commun. 2002;291:
3. Pan B, Farrugia AN, To LB, et al. The nitrogen-containing bisphosphonate, zoledronic acid, influences RANKL expression in human osteoblast-like cells by activating TNF-alpha converting enzyme (TACE). J Bone Miner Res. 2004;19:

6. Parathyroid hormone/ Parathyroid hormone–related protein
Receptor Activator of Nuclear Factor kB Ligand (RANKL) and Osteoprotegerin (OPG)
Stromal cell/Osteoblast
Parathyroid hormone/ Parathyroid hormone–related protein
1,25D3
RANKL
OPG
PGE2
RANK
Interleukin-11
Osteoclast Precursor
Osteoclast
Derived from Roodman GD. N Engl J Med. 2004;350:
References:
1. Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA. 2004;292:
2. Roodman GD. Mechanisms of bone metastases. N Engl J Med. 2004;350:

7. Breast Cancer

8. The Natural History of Bone Metastases in Breast Cancer
Pathologic fracture is the most common SRE in patients with breast cancer
Median onset is 11 mos from initial diagnosis of bone metastases
~ 20% develop hypercalcemia after a median of 14 mos
~ 10% develop cord compression after a median of 17 mos
Lipton A. Cancer. 2003;97:

9. Untreated Patients Experience Multiple SREs
4.5
Skeletal Morbidity Rate*
4.00
4.0
3.70
3.5
3.0
2.71
2.5
2.0
1.47
1.5
1.0
0.5
SRE
SRE + HCM
Prostate CA[2]
NSCLC + Other Solid Tumors[3]
Breast Cancer[1]
*Mean number of SRE per patient per yr.
1. Lipton A, et al. Cancer. 2000;88: Saad F. Clin Prostate Cancer. 2005;4: Rosen LS, et al. Cancer. 2004;100:

10. FDA-Approved Agents for Prevention of SREs in Metastatic Breast Cancer
Drug Class
Recommended Dose and Schedule
Zoledronic acid
Bisphosphonate
4 mg IV q3-4w
Pamidronate
90 mg IV q3-4w
Denosumab
RANKL-targeted MAb
120 mg SQ q4w
Both ASCO and NCCN recommend all 3 agents[1,2]
No agent recommended over another
1. Van Poznak CH, et al. J Clin Oncol. 2011;29: NCCN. Clinical practice guidelines in oncology: breast cancer. v

11. Proportion of Breast Cancer Patients Having Skeletal-Related Events (SREs) With Pamidronate
12 Months1
24 Months2
P=0.005
P=0.002
P=0.49* P=0.001†
P≤0.001
P<0.001
P=0.002
*P=0.49 for nonvertebral fracture; †P=0.001 for vertebral fracture. 1. Hortobagyi GN et al. N Engl J Med. 1996;335: Lipton A et al. Cancer. 2000;88:
References:
1. Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group.N Engl J Med. 1996;335:
2. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000;88:

12. Bisphosphonates Reduce SREs in Breast Cancer
Study
Treatment Duration, Mos
Patients With SRE, %
P Value
Lipton et al[1]* 24
Placebo 64
< .001
Pamidronate 51
Rosen et al[2] 49 NS
Zoledronic acid 46
Kohno et al[3] 12 50
.003 30
*Includes HCM.
1. Lipton A, et al. Cancer. 2000;88: Rosen LS, et al. Cancer. 2003;98: Kohno N, et al. J Clin Oncol. 2005;23: 12 12

13. Zoledronic Acid Significantly Delays Time to First SRE Compared With Placebo
1.0
0.9
0.8
P = .004
0.7
0.6
Proportion of Patients With Bone Metastases Without an SRE
0.5
0.4
Zoledronic acid 4 mg
0.3
Placebo
0.2
0.1 50
100
150
200
250
300
350
400
Days After Start of Study Drug
Kohno N, et al. SABCS Abstract Kohno N, et al. J Clin Oncol. 2005;23: Reprinted with permission.

14. Zoledronic Acid vs Placebo in Stage IV Breast Cancer With Bone Metastases
100 90
Zoledronic acid 4 mg (n = 114)
Placebo (n = 113) 80 70 60
52.2
Patients (%) 50
38.9 40
30.7 30
25.4
17.7 20
11.5
8.8
8.8 10
2.6
3.5
All SREs
Radiation to
bone
Fractures
Spinal cord
compression
HCM
Events at 12 Mos
Kohno N, et al. J Clin Oncol. 2005;23: 14 14

15. Zoledronic Acid and Pamidronate in Breast Cancer and Multiple Myeloma Patients With Bone Metastases: 13-Month Data
Median time (days)
Zoledronic acid: 373
Pamidronate: 363
SREs=skeletal-related events. Adapted with permission from Rosen LS et al. Cancer J. 2001;7:
Reference:
Rosen LS, Gordon DH, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double blind, comparative trial. Cancer J. 2001;7:

16. Zoledronic Acid vs Pamidronate in Breast Cancer and Multiple Myeloma: 25-Month Data
Zoledronic acid 4 mg
Pamidronate 90 mg
P value
Proportion with skeletal-related event (SRE) (%) 47 51
0.243
Median time to SRE (days)*
376
356
0.151
Mean skeletal morbidity rate*
1.04
1.39
0.084
Multiple event analysis (risk ratio)*
0.841 —
0.030
*Hypercalcemia of malignancy is included as an SRE. Rosen LS et al. Cancer. 2003;98:
Reference:
Rosen LS, Gordon DH, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer. 2003;98:

17. ZOMETA for the Treatment of Bone Metastases
Zoledronic acid is More Effective than Pamidronate
In Reducing the Risk of Skeletal Complications
Multiple Event Analysis: Breast Cancer and Multiple Myeloma
Risk reduction
P value
0.932
Total
Breast cancer
Multiple myeloma 7%
.593
0.799
20%
.025
0.841
16%
.030
0.2
0.4
0.6
0.8 1
1.2
1.4
1.6
1.8 2
Risk ratio (zoledronic acid 4 mg versus pam)
In favor of zoledronic acid
In favor of pamidronate
Rosen LS, et al. Cancer. 2003;98:

18. Renal Profile of Pamidronate and Zoledronic Acid in Patients With Metastatic Breast Cancer or Multiple Myeloma
Zoledronic acid 4 mg Pamidronate 90 mg
*Post–15-minute infusion amendment.
Adapted with permission from Berenson JR. The Oncologist. 2005;10:52-62.
References:
1. Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J. 2001;7:
2. Berenson JR. Recommendations for zoledronic acid treatment of patients with bone metastases. The Oncologist. 2005;10:52-62.

19. Supplemental Calcium and Vitamin D Recommended
3 Identical International, Randomized, Double-Blind, Active-Controlled Trials
Enrollment Criteria
Adults with breast, prostate, or other solid tumors and bone metastases or multiple myeloma
No current or previous IV bisphosphonate administration for treatment of bone metastases
Denosumab 120 mg SC and Placebo IV* q4w (n = 2862)
Supplemental Calcium and Vitamin D Recommended
Zoledronic Acid 4 mg IV* and Placebo SC q4w (n = 2861)
1° Endpoint
Time to first on-study SRE (noninferiority)
2° Endpoints
Time to first on-study SRE (superiority)
Time to first and subsequent on-study SRE (superiority)
*Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine. 19 19

20. Denosumab vs Zoledronic Acid Pivotal Phase III SRE Prevention Trials
In total, > 5700 patients with bone metastases R A N D O M I Z T
Study 136[1]
Breast cancer
(N = 2049)
Denosumab 120 mg SC q4w +
Placebo IV q4w†
Study 103[2]
Prostate cancer
(N = 1904)
Supplemental calcium and vitamin D
Zoledronic Acid 4 mg IV q4w†
+ Placebo SC q4w
Study 244[3]
Other solid tumors/MM
(N = 1779)
1. Stopeck AT, et al. J Clin Oncol. 2010;28: Fizazi K, et al. Lancet. 2011;377: Henry DH, et al. J Clin Oncol. 2011;29: 20

21. SRE Rate: Denosumab vs ZA in Breast Cancer Patients With Bone Metastases
1.2
1.0
0.8
-22% (P = .004)
0.58
SREs per Patient per Yr
0.6
0.45
0.4
0.2 ZA
Denosumab
Stopeck AT, et al. J Clin Oncol. 2010;28:

22. Time to First On-Study SRE: Extended Analysis
1.0
HR: 0.82 (95% CI: ; P = .0096, superiority)
0.8
0.6
Subjects Without SRE (%)
0.4
KM Estimate of Median Mos
0.2
Denosumab
32.7
Zoledronic acid
27.4 3 6 9 12 15 18 21 24 27 30 33
Study Mo
Patients at Risk, n
Zoledronic acid
1020
831
675
584
498
429
356
265
186
111 38 4
Denosumab
1026
834
692
597
510
444
384
280
193
101 9
Stopeck A, et al. SABCS Abstract P

23. Time to First and Subsequent On-Study SRE* (Multiple Event Analysis)
1.5
Rate ratio: 0.77 (95% CI: ;
P = .001†)
1.0
Cumulative Mean Number of SRE
0.5
Total No. of Events
Denosumab
474
Zoledronic acid
608 3 6 9 12 15 18 21 24 27 30
Mos
*Events that occurred at least 21 days apart. †Adjusted for multiplicity.
Stopeck AT, et al. J Clin Oncol. 2010;28: 23

24. Pooled Analysis: Time to First On-Study SRE by Previous SRE History
With Previous SRE
Without Previous SRE
Overall
Zoledronic acid (n = 819) Denosumab (n = 818)
Zoledronic acid (n = 1091) Denosumab (n = 1094)
Zoledronic acid (n = 1910) Denosumab (n = 1912)
1.0
0.8
0.6
Proportion of Patients Without On-Study SRE
0.4
0.2
HR: 0.82 (95% CI: ; P = .015)
HR: 0.83 (95% CI: ; P = .021)
HR: 0.83 (95% CI: ; P < .001) 6 12 18 24 30 6 12 18 24 30 6 12 18 24 30
Study Mo
Risk Set, n
ZA Dmab
0 1
36 48
4 3
78 79
4 4
n = number of patients randomized
Lipton A, et al. ASCO Abstract 9015.

25. Skeletal Complication Risk: Incremental Benefits in Breast Cancer
No bisphosphonate 64% risk at 2 yrs
Pamidronate ~ 20% risk reduction
Zoledronic acid
Additional ~ 20% risk reduction
Denosumab
Additional 18% risk reduction
64%
51%
34%
27%
Lipton A, et al. Cancer. 2000;88: Rosen LS, et al. Cancer. 2003;100: Stopeck A, et al. ECCO/ESMO Abstract 2LBA. Stopeck AT, et al. J Clin Oncol. 2010;28:

26. Between-Group Differences in AEs With Unadjusted P < .05
Denosumab,
Zoledronic Acid,
n (%) (n = 1020)
n (%) (n = 1013)
Hypocalcemia
Toothache
Renal failure acute
Blood urea increased
Bronchospasm
Hyperthermia
Skin hyperpigmentation
Metastases to spine
Hypercalcemia
Edema
Alanine aminotransferase increased
Lumbar vertebral fracture
Dyspepsia
Renal failure
Pain
Chills
Anemia
Arthralgia
Bone pain
Pyrexia
247
(24.4)
170
(16.7)
238
(23.5)
186
(18.2)
291
(28.7)
250
(24.5)
232
(22.9)
192
(18.8) 58
(5.7) 29
(2.8) 97
(9.6) 72
(7.1) 25
(2.5) 2
(0.2) 74
(7.3) 52
(5.1) 56
(5.5) 35
(3.4) 47
(4.6) 28
(2.7) 40
(3.9) 22
(2.2)
(3.5) 17
(1.7) 21
(2.1) 9
(0.9) 19
(1.9) 7
(0.7) 15
(1.5) 4
(0.4) 10
(1.0) 8
(0.8)
(0.0) 1
(0.1) 37
(3.7) 57
(5.6) 34
-10 -5 5 10
Risk Difference
Favors denosumab
Favors zoledronic acid
Stopeck AT, et al. J Clin Oncol. 2010;28:

27. Adverse Events: From Extended Analysis
Event, n (%)
Zoledronic Acid (n = 1013)
Denosumab (n = 1020)
All adverse events
987 (97.4)
961 (96.2)
Serious adverse events
509 (50.2)
489 (47.9)
Adverse events related to renal toxicity
95 (9.4)
55 (5.4)
Osteonecrosis of the jaw*
18 (1.8)
26 (2.5)
Hypocalcemia (any)
37 (3.7)
62 (6.1)
Hypocalcemia of grade 3 or 4†
12 (1.2)
Acute-phase reactions‡
286 (28.2)
109 (10.7)
*P = †No cases of hypocalcemia were grade 5 (fatal). ‡In the first 3 days after initial treatment.
Stopeck A, et al. SABCS Abstract P

28. ONJ Associated With Bone-Targeted Therapy in Patients With Bone Metastases
All patients (N = 5723)
Potential ONJ (n = 276)
Positively adjudicated for ONJ (n = 89)
Integrated analysis of pivotal denosumab SRE prevention trials
Zoledronic acid
(n = 37)
1.3%
Denosumab
(n = 52)
1.8%
No significant difference between groups (P = .13)
Saad F, et al. Ann Oncol. 2012;23:

29. Associated Oral Events
Zoledronic Acid
(n = 37)
Denosumab
(n = 52)
All
(N = 89)
Tooth extraction
24 (65)
30 (58)
54 (61)
Jaw pain
25 (68)
46 (88)
71 (80)
Local infection
17 (46)
26 (50)
43 (48)
Location of ONJ
n (%)
Zoledronic Acid
(n = 37)
Denosumab
(n = 52)
All
(N = 89)
Mandible
31 (84)
34 (65)
65 (73)
Maxilla
5 (14)
15 (29)
20 (22)
Both
1 (3)
3 (6)
4 (4)
Saad F, et al. Ann Oncol. 2012;23:

30. Systemic Risk Factors Subjects With ONJ Subjects Without ONJ n (%) ZA
Denosumab
(n = 52)
All
(N = 89)
(n = 2824)
(n = 2810)
(N = 5634)
Diabetes
11 (30)
9 (17)
20 (22)
431 (15)
443 (16)
874 (16)
Anemia (Hb <10)
17 (46)
23 (44)
40 (45)
1185 (42)
1119 (40)
2304 (41)
Chemotherapy agents
27 (73)
36 (69)
63 (71)
1950 (69)
1921 (68)
3871 (69)
Antiangiogenics
8 (22)
6 (12)
14 (16)
236 (8)
214 (8)
450 (8)
Corticosteroids
28 (76)
39 (75)
67 (75)
1786 (63)
1762 (63)
3548 (63)
Saad F, et al. Ann Oncol. 2012;23:

31. Preventing and Managing ONJ
Risk factors
Invasive dental procedures
Poor oral hygiene or pre-existing dental disease
Advanced malignancies, infections, concomitant therapies
Before bone-targeted treatment
Consider dental examination and preventive dentistry in patients with active dental/jaw conditions
During treatment
Avoid invasive dental procedures
Maintain good oral hygiene
Suspected cases
Refer to dentist or oral surgeon
Extensive dental surgery may exacerbate
Denosumab. EPAR and summary of product characteristics; Amgen. Zoledronic acid. Summary of product characteristics; Novartis.

32. Incidence of Hypocalcemia in the 3 Pivotal Phase III Trials
Hypocalcemia Events, n (%)
Denosumab
(n = 2841)
Zoledronic Acid
(n = 2836)
Hypocalcemia
273 (9.6)
141 (5.0)
IV calcium Rx
104 (3.7)
47 (1.7)
SAE of hypocalcemia
41 (1.4)
18 (0.6)
Grade 3*
72 (2.5)
33 (1.2)
Grade 4*
16 (0.6)
5 (0.2)
*CTCAE grading, grade 3 < 7 mg/dL, grade 4 < 6 mg/dL;
No fatal events of hypocalcemia were reported
Body JJ, et al. Presentation from the 12th International Conference on Cancer-Induced Bone Disease, November 15-17, 2012, Lyon, France.

33. Incidence of Hypocalcemia,* n (%)
Hypocalcemia in Relation to Calcium/Vit D Supplementation With Denosumab
Patients, n
Incidence of Hypocalcemia,* n (%)
Reported supplements
2461
213 (8.7)
Did not report supplements
380
60 (15.8)
*All AEs of hypocalcemia.
Median time to hypocalcemia was 2.8 mos
Most common in the first 6 mos of initiation of denosumab therapy
Body JJ, et al. Presentation from the 12th International Conference on Cancer-Induced Bone Disease, November 15-17, 2012, Lyon, France.

34. Hypocalcemia in Relation to Tumor Type With Denosumab Treatment
Primary Tumor Type, n (%)
Patients With Hypocalcemia
Multiple myeloma (N = 86)
(14.0)
Prostate (N = 943)
121 (12.8)
Other solid tumors (N = 386)
48 (12.4)
Lung (N = 406)
35 (8.6)
Breast (N = 1020)
57 (5.6)
Body JJ, et al. Presentation from the 12th International Conference on Cancer-Induced Bone Disease, November 15-17, 2012, Lyon, France.

35. Preventing and Managing Hypocalcaemia
Situation
Action
Pre-existing hypocalcemia or vitamin D deficiency
Correct before starting bone-targeted therapy
Start of bone-targeted therapy
Start daily oral supplements of ≥ 500 mg calcium and 400 IU vitamin D
Severe renal impairment (creatinine clearance < 30 mL/min) or dialysis
Monitor calcium levels more frequently
Hypocalcemia on therapy
Additional short-term calcium supplementation may be necessary
Denosumab. Summary of product characteristics; Amgen. Zoledronic acid. Summary of product characteristics; Novartis. Block G, et al. Poster presentation at the National Kidney Foundation spring clinical meeting 2010.

36. Question: What is the Maximum Time You Provide Bone-Modifying Therapy

37. Guidelines and Duration of Bone-Targeted Therapy
ESMO[1]
“The timing and optimal duration of bisphosphonate treatment are unknown; benefit of duration beyond 2 yrs has not been demonstrated Long-term treatment seems wise due to ongoing risk of skeletal events”
NCCN[2]
“Optimal schedule and duration are unknown Limited long-term safety data indicating bisphosphonate treatment can continue beyond 2 yrs”
ASCO[3]
“Until evidence of substantial decline (clinical judgment) in general performance status”
1. Cardoso F, et al. Ann Oncol. 2011;22(suppl 6) vi NCCN. Clinical practice guidelines in oncology: breast cancer. v Van Poznak CH, et al. J Clin Oncol. 2011;29:

38. 2-Yr Open-Label Extension Phase
Dmab 120 mg SC q4w 2 yrs
(n = 652)
Dmab 120 mg SC + Placebo IV q4w
(n = 1026) A n a l y s i
Superiority of Dmab over ZA
positive risk:benefit profile
Yes (89%) † P r i m a y
Adults with advanced breast cancer and confirmed bone metastases
Patient choice for open-label Dmab
(n = 752)
ZA 4 mg IV + Placebo SC q4w
(n = 1020))
2-yr survival follow-up q12w
Among patients previously receiving denosumab or zoledronic acid, 89% in each treatment group chose to receive open-label denosumab
Cumulative median exposure to denosumab for the entire study (including blinded and open-label treatment phases) was 19.1 mos (range: mos, ie, ~ 5 yrs)
216 patients received denosumab for ≥ 3 yrs
76 patients received denosumab for ≥ 4 yrs
Stopeck AT, et al. SABCS Abstract P

39. AEs During Open-Label Treatment Phase
Event, n (%)
Dmab/Dmab
(n = 318)
ZA/Dmab
(n = 334)
All AEs
283 (89)
303 (91)
Serious AEs
126 (40)
133 (40)
ONJ
20 (6)
18 (5)
Hypocalcemia
12 (4)
9 (3)
Hypocalcemia, grade 3 or 4
4 (1)
3 (1)
No new safety signals were observed with up to ~ 5 yrs of monthly denosumab therapy
Incidence and pattern of AEs in patients who switched from zoledronic acid to denosumab were similar to those observed in pts who continued with denosumab
Cumulative incidence of positively adjudicated ONJ was 4.7% for denosumab/ denosumab pts when administered for up to ~ 5 yrs and 3.5% for pts who switched from zoledronic acid to denosumab
No neutralizing anti-denosumab antibodies were detected in either group
Stopeck AT, et al. SABCS Abstract P

40. BMA Optimal Interval

41. [TITLE]

42. [TITLE]

43. [TITLE]

44. [TITLE]

45. Management Summary
Patients with bone metastases from breast cancer should be offered therapy with a bone modifying agent in the absence of contraindications
BMA should be used as an adjunct to systemic therapy for the underlying malignancy
Appropriate bone modifying agents include subcutaneous denosumab, IV pamidronate, and IV zoledronic acid
For patients receiving a bisphosphonate, creatinine clearance must be monitored and dose adjustments should be made as necessary
The use of calcium and vitamin D supplements should be explored in patients receiving bone modifying agents particularly with denosumab use
Routine dental care should be performed prior to initiation of a bone modifying agent
Continuation of the bone modifying agent for up to 2 years is certainly acceptable though the optimal duration of therapy remains unclear

46. Conclusions Bisphosphonates and denosumab are both effective at
Preventing SREs and HCM
Palliating pain from bone mets
Preventing the development of pain
2 distinct choices
Different toxicity profiles
Zoledronic acid: flulike symptoms, fevers, bone pains, renal toxicity
Denosumab: hypocalcemia
Subcutaneous vs intravenous administration