Breast Cancer and Bone Loss. One in seven women will develop breast cancer during a lifetime

Breast Cancer and Bone Loss One in seven women will develop breast cancer during a lifetime

Causes of Bone Loss in Breast Cancer Patients Aromatase inhibitors Bil Oophorectomy Hypogonadism Steroids Chemotherapy Bone Loss Pfeilschifter J and Diel IJ. J Clin Oncol 2000;18:1570-159

Incidence of Cancer Treatment Induced Ovarian Failure Ovarian failure after adjuvant chemotherapy Earlier menopause by an average of 5 to 10 years CMF 63% - 85% of patients FAC 50% overall Age 30-39 yr 33% 40-49 yr 96% 50 yr 100% Samaan NA. Cancer. 1978;41:2084. Tormey DC. NCI Monographs. 1986;1:75. Jordan VC. Cancer Res. 1987;47:624. Bruning P, et al. Br J Cancer. 1990;61:308.

Effect of Premature Menopause in Breast Cancer Patients

Chemotherapy-Induced Menopause Results in Rapid Bone Loss N= 49 * * Total spine * Femoral neck * *P=0.0001 vs baseline. Shapiro CL et al. J Clin Oncol. 2001;19:3306-3311.

Bone Turnover Increases After Chemotherapy-Induced Menopause 59 * Osteocalcin Bone alkaline phosphatase (ALP) *P=0.01 vs baseline; P=0.0001 vs baseline; P=0.05 vs baseline. Shapiro CL et al. J Clin Oncol. 2001;19:3306-3311.

Age Annual Incidence of Vertebral Fractures in Breast Cancer patients Patients followed for 3 years with X-rays every 6 months Controls (%) N=776 Breast Cancer at diagnosis (%) N=352 Breast Cancer at Soft- Tissue relapse (%) N=82 <50 0.45 1.87 15.4 50-59 0.25 2.7 12 60-69 1.06 2.87 14.7 70+ - 5.26 29 All 0.53 2.72 (*4.7) 19.21(*22.7) * age-adjusted risk of vert fx (Odds ratio) Kanis J. Br J Cancer. 1999;79:1179.

Cumulative fracture (%) Cumulative fracture (%) Osteoporotic Fracture Risk Is Increased in 4 3 2 1 0.6 Breast Cancer Survivors Results from the Women s Health Initiative Control 80,848 Breast cancer survivors 5,298 0.6 1.0 * 1.4 2.3 3.2 7.6 9.7 10.5 13.6 14 12 10 8 0 Hip Clinical spine Lower arm/wrist Other Total Results from Cox regression models indicated that breast ca survivors had a 28% increased risk 6 *P=0.049; P=0.001; P<0.001. Chen Z et al. J Bone Miner Res. 2003;18(suppl 2):S22. Abstract 1077.

Effect of Hormonal Therapy on Bone Mass

Premenopausal Effect of Tamoxifen on BMD Lumbar BMD (% change from baseline)/ year 104 102 100 98 96 94 92 Tamoxifen 0 1 2 3 Postmenopausal Powles et al JCO14: 78-84, 1996 104 102 100 98 96 94 92 Tamoxifen 0 1 2 3

Aromatase Inhibitors Cholesterol Pregnenolone Progesterone Aldosterone Androstenedione A Estrone Estradiol X Testosterone X A Cortisol

Prevention and Management of Osteoporosis in Breast Cancer Patients Estrogen therapy is contraindicated Raloxifene therapy would likely be effective but few data regarding its long-term role;not approved either for prevention or treatment of breast cancer Tamoxifen prevents bone loss in post-menopausal women, but is quickly being replaced by aromatase inhibitors Forteo (PTH 1-34) is contraindicated in women who have received breast radiation Safety in those at risk for breast cancer recurrence has not been studied Bisphosphosphonates remain the mainstay of therapy 0.5-1% of patients treated with high dose (monthly) intravenous bisphosphonates will develop osteonecrosis, most commonly of the jaw or maxilla

Chemotherapy-Induced Premature Menopause - Risedronate BMD (% change) 2 0-2 -4-6 Lumbar Spine 0 1 2 3 years Placebo Risedronate Study period BMD (% change) 2 0-2 -4-6 Femoral Neck 0 1 2 3 years Placebo Risedronate Study period Adapted with permission from Delmas PD et al. J Clin Oncol. 1997;15:955-962.

BMD in Premenopausal Breast Cancer Patients Receiving Adjuvant Hormonal Therapy (ABCSG-012) Premenopausal patients Stages I and II ER+ and/or PR+ Planned enrollment = 1,250 (3 BMD measurements available for 172 patients) Surgery (+XRT) Goserelin 3.6 mg/28days R A N D O M I Z E Tamoxifen + Zoledronic acid (4 mg)* q 6 mo Tamoxifen + placebo Anastrozole + Zoledronic acid (4 mg)* q 6 mo Anastrozole + placebo Baseline BMD 6-month BMD 3 years Final BMD *8 mg reduced to 4 mg. Gnant M, et al. San Antonio Breast Cancer Symposium. 2002. Abstract 12.

Lumbar Spine BMD (g/cm 2 ) Zoledronic Acid Protects Against 1.04 0.99 0.94 0.89 0.84 Anastrozole-Induced Bone Loss Preliminary Analysis p<0.0001 0 6 12 18 Tamoxifen + Zoledronic Acid p=0.43 Anastrozole + Zoledronic Acid Tamoxifen Anastrozole 172 of 667 women had 3 BMDs, mean age 44.8 years Gnant M, et al. San Antonio Breast Cancer Symposium. 2002. Abstract 12.

Clinical Guidelines Diamond et al. Cancer 2004;100:892-899. Clinical presentation Investigation Management Any fracture (minimal trauma) Spine X-rays Fracture on T/LS spine x-ray T- Score Suspected vertebral FX BMD < -2.5 (osteoporosis) Bisphosphonate Therapy Risk for FX ADT Previous FX DEXA or QCT -1 to -2.5 (osteopenia) >-1 (normal) Repeat BMD after 6-12 mos Repeat BMD after 2 yrs Modified from Diamond et al. cancer 2004;100:892-899

The Challenges of Management of Breast Cancer-related Bone Loss Current 59 yr-old female first evaluated at age 32 yrs for pregnancy-related osteoporosis Vertebral fractures at T9 and T12 Only potential cause was thyroiditis leading to subsequent hypothyroidism Treated with calcium/vitamin D, subcutaneous calcitonin; started on alendronate in 1996 1999 (42y) developed ER+/PR+ left breast cancer Surgery, FAC Chemotherapy, Radiation Chemotherapy-induced cessation of periods for 9 month before restarting Tamoxifen 2001 at age 44 y develop permanent menopause 2000-2005 Tamoxifen

BMD (gm/cm2) Management of a 59 Year Old with Breast Cancer and Past History of Pregnancy-related Osteoporotic Fractures 0.85 Pregnancy-related fractures in mid-1980s 0.8 1999 Left breast cancer with lymph node metastasis & Surgery 0.75 1999 FAC Chemotherapy induced menopause 0.7 2000 Radiotherapy 2001- Menopause 0.65 2000-2005 Tamoxifen 0.6 2005-2006 Letrozole 2006-2009 Raloxifene 0.55 2009 Rising CA 27.29 Feb, 2010-present 0.5 exemustane 0.9 Lumbar Spine Total Hip Femoral Neck 7-8% Decline at hip sites with initiation of aromatase inhibitor Date

The Challenges of Management of Breast Cancer-related Bone Loss 2005-2006 Letrozole Discontinued because of side-effects Continued alendronate Would you do anything more?

Rising CA 27.29

The Challenges of Management of Breast Cancer-related Bone Loss Presumed recurrence of breast cancer, although no metastatic disease identified Raloxifene discontinued Feb 2010 started exemustane What would you do?

Rising CA 27.29

Bone Turnover Markers 1000 Serum Osteocalcin (ng/ml) Serum CTX (pg/ml) Serum Osteocalcin and CTX 100 10 1 12/6/99 4/19/01 9/1/02 1/14/04 5/28/05 10/10/06 2/22/08 7/6/09 11/18/10 4/1/12

What Would You Do?

What We Did Discontinued alendronate Initiated denosumab 60 mg every 6 months

Bone Turnover Markers 1000 Serum Osteocalcin (ng/ml) Serum CTX (pg/ml) Serum Osteocalcin and CTX 100 10 1 12/6/99 4/19/01 9/1/02 1/14/04 5/28/05 10/10/06 2/22/08 7/6/09 11/18/10 4/1/12

BMD (gm/cm2) Management of a 59 Year Old with Breast Cancer and Past History of Pregnancy-related Osteoporotic Fractures 0.85 Pregnancy-related fractures in mid-1980s 0.8 1999 Left breast cancer with lymph node metastasis & Surgery 0.75 1999 FAC Chemotherapy induced menopause 0.7 2000 Radiotherapy 2001- Menopause 0.65 2000-2005 Tamoxifen 0.6 2005-2006 Letrozole 2006-2009 Raloxifene 0.55 2009 Rising CA 27.29 Feb, 2010-present 0.5 exemustane 0.9 Lumbar Spine Total Hip 7-8% Decline at hip sites with initiation of aromatase inhibitor Femoral Neck Date

Current T-Scores Lumbar Spine -1.7 Total Hip -1.6 Femoral Neck -1.8

Is This Patient a Candidate for Treatment with Teriparatide? Current bone density not in osteoporotic range and no recent history of fracture Prior history of radiation therapy Even if she had not been treated with XRT, concern about treatment with teriparatide in patient with breast cancer that is active or undetermined

What would you do if she developed a vertebral fracture without history of trauma?

Prostate Cancer and Bone Loss

Causes of Bone Loss in Prostate Cancer patients Bilateral Orchiectomy Androgen Deprivation RX Chemotherapy Steroids Hypogonadism XRT Bone Loss Pfeilschifter J and Diel IJ. J Clin Oncol 2000;18:1570-159

Androgen Deprivation Therapy Decreases Bone Mineral Density Change from Study N Treatment Baseline BMD at 12 months Eriksson et al 1 11 Orchiectomy Hip: -9.6% Radius: -4.5% Maillefert et al 2 12 GnRH agonist Hip: -3.9% L spine: -4.6% Daniell et al 3 26 Orchiectomy or Hip: -2.4% GnRH agonist Berrutti et al 4 35 GnRH agonist Hip: -0.6% L spine: -2.3% Higano 5 16 LHRH agonist plus AA Hip: -2.5% L spine: -4.5% 1. Eriksson S, et al. Calcif Tissue Int. 1995;57:97-99. 2. Maillefert JF, et al. J Urol. 1999;161:1219-1222. 3. Daniell HW, et al. J Urol. 2000;163:181-186. 4. Berruti A, et al. J Urol. 2002;167:2361-2367. 5. Higano, Proc Am Soc Clin Oncol 1999;18:314a.

Androgen Deprivation Therapy (GNRH) Decreases Bone Mineral Density 12-month analysis P <.001 Lumbar spine Total hip Mittan D, et al. J Clin Endocrinol Metab. 2002;87:3656-3661.

Bone Turnover Increases During Androgen Deprivation Therapy Urine N-telopeptide (NTX) P<0.05 P<0.05 Bone ALP 6 months 12 months 6 months 12 months Control Gonadotropin-releasing hormone agonist (GnRHa) Adapted with permission from Mittan D et al. J Clin Endocrinol Metab. 2002;87:3656-3661.

Bone Density Decreases Rapidly After Orchiectomy * 1 year observations *P<0.05. Eriksson S et al. Calcif Tissue Int. 1995;57:97-99.

Androgen Deprivation Therapy 50 Increases Fracture Risk Cumulative incidence (%) 40 30 20 10 0 Postorchiectomy No orchiectomy 1 2 3 4 5 6 7 8 9 Years Adapted with permission from Daniell HW. J Urol. 1997;157:439-444.

What should be done?

Pamidronate to Prevent ADT-induced Bone Loss in 47 Prostate Cancer Pts Recurrent or locally advanced CaP; negative bone scan (N = 47) Randomize ADT + pamidronate (60 mg q 3 months) ADT Primary endpoint = bone mineral density Smith MR, et al. N Engl J Med. 2001;345:948-955. ADT = Androgen Deprivation Therapy

Mean percent change from baseline 12-month data Pamidronate Prevents ADT-induced Bone Loss 2 1 0 0.42 0.21 P<0.005 for each comparison -1-2 No pamidronate Pamidronate -3-4 -5-3.34 Lumbar spine -1.82 Total hip Smith MR, et al. N Engl J Med. 2001;345:948-955.

Thank You! Questions?