NCCN Task Force Report: Bone Health in Cancer Care

Authors:
Julie R. Gralow
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,
J. Sybil Biermann
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Azeez Farooki
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Monica N. Fornier
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Robert F. Gagel
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Rashmi Kumar
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 PhD
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Georgia Litsas
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 MSN, ANP-BC, AOCNP
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Rana McKay
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Donald A. Podoloff
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Sandy Srinivas
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Catherine H. Van Poznak
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Volume/Issue:
Volume 11: Issue suppl_3
Online Publication Date:
Aug 2013
DOI:
https://doi.org/10.6004/jnccn.2013.0215
Restricted access

Bone health and maintenance of bone integrity are important components of comprehensive cancer care. Many patients with cancer are at risk for therapy-induced bone loss, with resultant osteoporotic fractures, or skeletal metastases, which may result in pathologic fractures, hypercalcemia, bone pain, and decline in motility and performance status. Effective screening and timely interventions are essential for reducing bone-related morbidity. Management of long-term bone health requires a broad knowledge base. A multidisciplinary health care team may be needed for optimal assessment and treatment of bone-related issues in patients with cancer. Since publication of the previous NCCN Task Force Report: Bone Health in Cancer Care in 2009, new data have emerged on bone health and treatment, prompting NCCN to convene this multidisciplinary task force to discuss the progress made in optimizing bone health in patients with cancer. In December 2012, the panel members provided didactic presentations on various topics, integrating expert judgment with a review of the key literature. This report summarizes issues surrounding bone health in cancer care presented and discussed during this NCCN Bone Health in Cancer Care Task Force meeting.

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Print ISSN:
1540-1405
Online ISSN:
1540-1413
Publisher:
National Comprehensive Cancer Network
Cover Journal of the National Comprehensive Cancer Network
  • 1

    Nordin C. Screening for osteoporosis: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2011;155:276; author reply 276-277.

  • 2

    Johnell O, Kanis JA, Oden A et al.. Predictive value of BMD for hip and other fractures. J Bone Miner Res 2005;20:1185–1194.

  • 3

    Kanis JA, Borgstrom F, De Laet C et al.. Assessment of fracture risk. Osteoporos Int 2005;16:581–589.

  • 4

    Kanis JA, McCloskey EV, Powles T et al.. A high incidence of vertebral fracture in women with breast cancer. Br J Cancer 1999;79:1179–1181.

  • 5

    Chen Z, Maricic M, Bassford TL et al.. Fracture risk among breast cancer survivors: results from the Women's Health Initiative observational study. Arch Intern Med 2005;165:552–558.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Kanis JA, Melton LJ, Christiansen C et al.. The diagnosis of osteoporosis. J Bone Miner Res 1994;9:1137–1141.

  • 7

    Cauley JA, Hochberg MC, Lui LY et al.. Long-term risk of incident vertebral fractures. JAMA 2007;298:2761–2767.

  • 8

    Njeh CF, Fuerst T, Hans D et al.. Radiation exposure in bone mineral density assessment. Appl Radiat Isot 1999;50:215–236.

  • 9

    Screening for osteoporosis: U.S. preventive services task force recommendation statement. Ann Intern Med 2011;154:356–364.

  • 10

    Hillner BE, Ingle JN, Chlebowski RT et al.. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003;21:4042–4057.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Mohler JL, Armstrong AJ, Bahnson RR et al.. NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer. Version 2, 2013. Available at: NCCN.org. Accessed June 18, 2013.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Theriault RL, Carlson RW, Allred C et al.. NCCN Clinical Practice Guidelines in Oncology for Breast Cancer. Version 3, 2013. Available at: NCCN.org. Accessed June 18, 2013.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield. FRAX WHO fracture risk assessment tool. Available at: http://www.shef.ac.uk/FRAX/tool.jsp. Accessed July 17, 2013.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Institute for Clinical Systems Improvement (ICSI). Diagnosis and treatment of osteoporosis. Bloomington (MN): Institute for Clinical Systems Improvement (ICSI); 2011. Available at: http://guideline.gov/content.aspx?id=34270. Accessed July 17, 2013.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Garnero P, Sornay-Rendu E, Claustrat B, Delmas PD. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner Res 2000;15:1526–1536.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Ross PD, Kress BC, Parson RE et al.. Serum bone alkaline phosphatase and calcaneus bone density predict fractures: a prospective study. Osteoporos Int 2000;11:76–82.

  • 17

    Sornay-Rendu E, Munoz F, Garnero P et al.. Identification of osteopenic women at high risk of fracture: the OFELY study. J Bone Miner Res 2005;20:1813–1819.

  • 18

    Riggs BL, Melton LJ III. The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone 1995;17:505S–511S.

  • 19

    Cauley JA, Palermo L, Vogt M et al.. Prevalent vertebral fractures in black women and white women. J Bone Miner Res 2008;23:1458–1467.

  • 20

    Silverman SL. The clinical consequences of vertebral compression fracture. Bone 1992;13(Suppl 2):S27–31.

  • 21

    Kuet KP, Charlesworth D, Peel NF. Vertebral fracture assessment scans enhance targeting of investigations and treatment within a fracture risk assessment pathway. Osteoporos Int 2013;24:1007–1014.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Black DM, Arden NK, Palermo L et al.. Prevalent vertebral deformities predict hip fractures and new vertebral deformities but not wrist fractures. Study of Osteoporotic Fractures Research Group. J Bone Miner Res 1999;14:821–828.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Melton LJ, Atkinson EJ, Cooper C et al.. Vertebral fractures predict subsequent fractures. Osteoporos Int 1999;10:214–221.

  • 24

    Lindsay R, Silverman SL, Cooper C et al.. Risk of new vertebral fracture in the year following a fracture. JAMA 2001;285:320–323.

  • 25

    Genant HK, Li J, Wu CY, Shepherd JA. Vertebral fractures in osteoporosis: a new method for clinical assessment. J Clin Densitom 2000;3:281–290.

  • 26

    Lentle BC, Brown JP, Khan A et al.. Recognizing and reporting vertebral fractures: reducing the risk of future osteoporotic fractures. Can Assoc Radiol J 2007;58:27–36.

  • 27

    Vokes T, Bachman D, Baim S et al.. Vertebral fracture assessment: the 2005 ISCD Official Positions. J Clin Densitom 2006;9:37–46.

  • 28

    Robb-Nicholson C. Radiation risk from medical imaging. Harvard Health Publication. Available at: http://www.health.harvard. edu/newsletters/Harvard_Womens_Health_Watch/2010/October/radiation-risk-from-medical-imaging. Accessed July 17, 2013.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    4th ISCD Position Development Conference (Adult). The Inernational Society for Clinical Densitometry Web site. Available at: http://www.iscd.org/official-positions/4th-iscd-position-development-conference-adult/. Accessed July 17, 2013

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Partridge AH, Ruddy KJ. Fertility and adjuvant treatment in young women with breast cancer. Breast 2007;16(Suppl 2):S175–181.

  • 31

    Fornier MN, Modi S, Panageas KS et al.. Incidence of chemotherapy-induced, long-term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane. Cancer 2005;104:1575–1579.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Petrek JA, Naughton MJ, Case LD et al.. Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment: a prospective study. J Clin Oncol 2006;24:1045–1051.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Goodwin PJ, Ennis M, Pritchard KI et al.. Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 1999;17:2365–2370.

  • 34

    Burstein HJ, Winer EP. Primary care for survivors of breast cancer. N Engl J Med 2000;343:1086–1094.

  • 35

    Shapiro CL, Manola J, Leboff M. Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 2001;19:3306–3311.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Bruning PF, Pit MJ, de Jong-Bakker M et al.. Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer. Br J Cancer 1990;61:308–310.

  • 37

    Delmas PD, Balena R, Confravreux E et al.. Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebo-controlled study. J Clin Oncol 1997;15:955–962.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Headley JA, Theriault RL, LeBlanc AD et al.. Pilot study of bone mineral density in breast cancer patients treated with adjuvant chemotherapy. Cancer Invest 1998;16:6–11.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Hershman DL, McMahon DJ, Crew KD et al.. Zoledronic acid prevents bone loss in premenopausal women undergoing adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol 2008;26:4739–4745.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Powles TJ, McCloskey E, Paterson AH et al.. Oral clodronate and reduction in loss of bone mineral density in women with operable primary breast cancer. J Natl Cancer Inst 1998;90:704–708.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Saarto T, Blomqvist C, Valimaki M et al.. Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients. J Clin Oncol 1997;15:1341–1347.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Eastell R, Hannon RA, Cuzick J et al.. Effect of an aromatase inhibitor on bmd and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). J Bone Miner Res 2006;21:1215–1223.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Fogelman I, Blake GM, Blamey R et al.. Bone mineral density in premenopausal women treated for node-positive early breast cancer with 2 years of goserelin or 6 months of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Osteoporos Int 2003;14:1001–1006.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Warming L, Hassager C, Christiansen C. Changes in bone mineral density with age in men and women: a longitudinal study. Osteoporos Int 2002;13:105–112.

  • 45

    Geisler J, King N, Anker G et al.. In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clin Cancer Res 1998;4:2089–2093.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Geisler J, Haynes B, Anker G et al.. Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol 2002;20:751–757.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Cummings SR, Browner WS, Bauer D et al.. Endogenous hormones and the risk of hip and vertebral fractures among older women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1998;339:733–738.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Geisler J, Lonning PE. Impact of aromatase inhibitors on bone health in breast cancer patients. J Steroid Biochem Mol Biol 2010;118:294–299.

  • 49

    Simpson ER, Dowsett M. Aromatase and its inhibitors: significance for breast cancer therapy. Recent Prog Horm Res 2002;57:317–338.

  • 50

    Coates AS, Keshaviah A, Thurlimann B et al.. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 2007;25:486–492.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Coombes RC, Hall E, Gibson LJ et al.. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081–1092.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Forbes JF, Cuzick J, Buzdar A et al.. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008;9:45–53.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53

    Jakesz R, Jonat W, Gnant M et al.. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 2005;366:455–462.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    Eastell R, Adams J, Clack G et al.. Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial. Ann Oncol 2011;22:857–862.

  • 55

    Thurlimann B, Keshaviah A, Coates AS et al.. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353:2747–2757.

  • 56

    Coleman RE, Banks LM, Girgis SI et al.. Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study. Lancet Oncol 2007;8:119–127.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57

    Goss PE, Ingle JN, Martino S et al.. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793–1802.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    Goss PE, Ingle JN, Pritchard KI et al.. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27—a randomized controlled phase III trial. J Clin Oncol 2013;31:1398–1404.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59

    Hershman DL, Cheung AM, Chapman JW et al.. Effects of adjuvant exemestane versus anastrozole on bone mineral density: two-year results of the NCIC CTG MA.27 bone companion study [abstract]. J Clin Oncol 2011;29:Abstract 518.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60

    Meng MV, Grossfeld GD, Sadetsky N et al.. Contemporary patterns of androgen deprivation therapy use for newly diagnosed prostate cancer. Urology 2002;60:7–11; discussion 11-12.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61

    Nadler M, Alibhai S, Catton P et al.. Osteoporosis knowledge, health beliefs, and healthy bone behaviours in patients on androgen-deprivation therapy (ADT) for prostate cancer. BJU Int 2013;111:1301–1309.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62

    Guise TA, Oefelein MG, Eastham JA et al.. Estrogenic side effects of androgen deprivation therapy. Rev Urol 2007;9:163–180.

  • 63

    Basaria S, Lieb J II, Tang AM et al.. Long-term effects of androgen deprivation therapy in prostate cancer patients. Clin Endocrinol 2002;56:779–786.

  • 64

    Khosla S, Oursler MJ, Monroe DG. Estrogen and the skeleton. Trends Endocrinol Metab 2012;23:576–581.

  • 65

    Mellstrom D, Vandenput L, Mallmin H et al.. Older men with low serum estradiol and high serum SHBG have an increased risk of fractures. J Bone Miner Res 2008;23:1552–1560.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66

    Maillefert JF, Sibilia J, Michel F et al.. Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. J Urol 1999;161:1219–1222.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67

    Mittan D, Lee S, Miller E et al.. Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab 2002;87:3656–3661.

  • 68

    Berruti A, Dogliotti L, Terrone C 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.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69

    Daniell HW, Dunn SR, Ferguson DW et al.. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 2000;163:181–186.

  • 70

    Higano CS. Androgen-deprivation-therapy-induced fractures in men with nonmetastatic prostate cancer: what do we really know? Nat Clin Pract Urol 2008;5:24–34.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71

    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.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72

    Daniell HW, Dunn SR, Ferguson DW et al.. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 2000;163:181–186.

  • 73

    Diamond T, Campbell J, Bryant C, Lynch W. The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma: longitudinal evaluation and response to intermittent cyclic etidronate therapy. Cancer 1998;83:1561–1566.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 74

    Smith MR, Lee WC, Brandman J et al.. 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.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 75

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

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 76

    Kiratli BJ, Srinivas S, Perkash I, Terris MK. Progressive decrease in bone density over 10 years of androgen deprivation therapy in patients with prostate cancer. Urology 2001;57:127–132.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 77

    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.

  • 78

    Smith MR, Boyce SP, Moyneur E et al.. Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer. J Urol 2006;175:136–139; discussion 139.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 79

    Clinician's guide to the prevention and treatment of osteoporosis. National Osteoporosis Foundation Web site. Available at: http://nof.org/files/nof/public/content/resource/913/files/580.pdf. Accessed July 17, 2013.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 80

    Fatalities and injuries from falls among older adults—United States, 1993-2003 and 2001-2005. MMWR Morb Mortal Wkly Rep 2006;55:1221–1224.

  • 81

    Feskanich D, Willett W, Colditz G. Walking and leisure-time activity and risk of hip fracture in postmenopausal women. JAMA 2002;288:2300–2306.

  • 82

    Moyer VA. Prevention of falls in community-dwelling older adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;157:197–204.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 83

    Parker MJ, Gillespie WJ, Gillespie LD. Effectiveness of hip protectors for preventing hip fractures in elderly people: systematic review. BMJ 2006;332:571–574.

  • 84

    Sawka AM, Boulos P, Beattie K et al.. Hip protectors decrease hip fracture risk in elderly nursing home residents: a Bayesian meta-analysis. J Clin Epidemiol 2007;60:336–344.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 85

    Cameron ID, Kurrle SE, Quine S et al.. Improving adherence with the use of hip protectors among older people living in nursing care facilities: a cluster randomized trial. J Am Med Dir Assoc 2011;12:50–57.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 86

    Cameron ID, Kurrle S, Quine S et al.. Increasing adherence with the use of hip protectors for older people living in the community. Osteoporos Int 2011;22:617–626.

  • 87

    Schaafsma FG, Kurrle SE, Quine S et al.. Wearing hip protectors does not reduce health-related quality of life in older people. Age Ageing 2012;41:121–125.

  • 88

    Chapuy MC, Arlot ME, Duboeuf F et al.. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 1992;327:1637–1642.

  • 89

    Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997;337:670–676.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 90

    Murad MH, Elamin KB, Abu Elnour NO et al.. Clinical review: the effect of vitamin D on falls: a systematic review and meta-analysis. J Clin Endocrinol Metab 2011;96:2997–3006.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 91

    Dietary reference intakes for calcium and vitamin D. Institute of Medicine Web site. Available at: http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx. Accessed July, 17, 2013.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 92

    Curhan GC, Willett WC, Speizer FE et al.. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med 1997;126:497–504.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 93

    Bolland MJ, Avenell A, Baron JA et al.. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010;341:c3691.

  • 94

    Hennekens CH, Barice EJ. Calcium supplements and risk of myocardial infarction: a hypothesis formulated but not yet adequately tested. Am J Med 2011;124:1097–1098.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 95

    Adams JS, Kantorovich V, Wu C et al.. Resolution of vitamin D insufficiency in osteopenic patients results in rapid recovery of bone mineral density. J Clin Endocrinol Metab 1999;84:2729–2730.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 96

    Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC et al.. Effect of Vitamin D on falls: a meta-analysis. JAMA 2004;291:1999–2006.

  • 97

    Rosen CJ, Gallagher JC. The 2011 IOM report on vitamin D and calcium requirements for north america: clinical implications for providers treating patients with low bone mineral density. J Clin Densitom 2011;14:79–84.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 98

    Camacho PM, Dayal AS, Diaz JL et al.. Prevalence of secondary causes of bone loss among breast cancer patients with osteopenia and osteoporosis. J Clin Oncol 2008;26:5380–5385.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 99

    Crew KD, Shane E, Cremers S et al.. High prevalence of vitamin D deficiency despite supplementation in premenopausal women with breast cancer undergoing adjuvant chemotherapy. J Clin Oncol 2009;27:2151–2156.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 100

    Varsavsky M, Reyes-Garcia R, Cortes-Berdonces M et al.. Serum 25 OH vitamin D concentrations and calcium intake are low in patients with prostate cancer. Endocrinol Nutr 2011;58:487–491.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 101

    Holick MF, Binkley NC, Bischoff-Ferrari HA et al.. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911–1930.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 102

    Cranney A, Horsley T, O'Donnell S et al.. Effectiveness and safety of vitamin D in relation to bone health. Evid Rep Technol Assess (Full Rep) 2007:1–235.

  • 103

    Houghton LA, Vieth R. The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr 2006;84:694–697.

  • 104

    Holick MF, Biancuzzo RM, Chen TC et al.. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab 2008;93:677–681.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 105

    Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–281.

  • 106

    Greenspan SL, Nelson JB, Trump DL, Resnick NM. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial. Ann Intern Med 2007;146:416–424.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 107

    Van Poznak C. Managing bone mineral density with oral bisphosphonate therapy in women with breast cancer receiving adjuvant aromatase inhibition. Breast Cancer Res 2010;12:110.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 108

    Van Poznak C, Hannon RA, Mackey JR et al.. Prevention of aromatase inhibitor-induced bone loss using risedronate: the SABRE trial. J Clin Oncol 2010;28:967–975.

  • 109

    Siris ES, Harris ST, Rosen CJ et al.. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc 2006;81:1013–1022.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 110

    Khan MN, Khan AA. Cancer treatment-related bone loss: a review and synthesis of the literature. Curr Oncol 2008;15:30–40.

  • 111

    Cummings SR, San Martin J, McClung MR et al.. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756–765.

  • 112

    Orwoll E, Teglbjaerg CS, Langdahl BL et al.. A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab 2012;97:3161–3169.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 113

    Smith MR, Saad F, Egerdie B et al.. Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer. J Urol 2009;182:2670–2675.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 114

    Ellis GK, Bone HG, Chlebowski R et al.. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol 2008;26:4875–4882.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 115

    Stopeck AT, Lipton A, Body JJ et al.. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010;28:5132–5139.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 116

    Stopeck A. Denosumab findings in metastatic breast cancer. Clin Adv Hematol Oncol 2010;8:159–160.

  • 117

    Rossouw JE, Anderson GL, Prentice RL et al.. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321–333.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 118

    Questions and answers for estrogen and estrogen with progestin therapies for postmenopausal women (updated). U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm135339.htm. Accessed June 18, 2013.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 119

    Holmberg L, Anderson H. HABITS (hormonal replacement therapy after breast cancer—is it safe?), a randomised comparison: trial stopped. Lancet 2004;363:453–455.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 120

    Christin-Maitre S. The role of hormone replacement therapy in the management of premature ovarian failure. Nat Clin Pract Endocrinol Metab 2008;4:60–61.

  • 121

    Ettinger B, Black DM, Mitlak BH et al.. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) investigators. JAMA 1999;282:637–645.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 122

    Barrett-Connor E, Mosca L, Collins P et al.. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355:125–137.

  • 123

    Martino S, Cauley JA, Barrett-Connor E et al.. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 2004;96:1751–1761.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 124

    Yalcin B, Buyukcelik A, Yalcin S et al.. Re: Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 2005;97:542; author reply 542-543.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 125

    Vogel VG, Costantino JP, Wickerham DL et al.. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295:2727–2741.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 126

    Barrett-Connor E, Mosca L, Collins P et al.. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355:125–137.

  • 127

    Cauley JA, Norton L, Lippman ME et al.. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res Treat 2001;65:125–134.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 128

    O'Regan RM, Gajdos C, Dardes RC et al.. Effects of raloxifene after tamoxifen on breast and endometrial tumor growth in athymic mice. J Natl Cancer Inst 2002;94:274–283.

  • 129

    Stewart HJ, Forrest AP, Everington D et al.. Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. The Scottish Cancer Trials Breast Group. Br J Cancer 1996;74:297–299.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 130

    Eng-Wong J, Reynolds JC, Venzon D et al.. Effect of raloxifene on bone mineral density in premenopausal women at increased risk of breast cancer. J Clin Endocrinol Metab 2006;91:3941–3946.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 131

    Baum M, Buzdar A, Cuzick J et al.. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003;98:1802–1810.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 132

    Farooki A, Fornier M, Girotra M. Anabolic therapies for osteoporosis. N Engl J Med 2007;357:2410–2411.

  • 133

    MacLean C, Newberry S, Maglione M et al.. Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 2008;148:197–213.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 134

    Cranney A, Tugwell P, Zytaruk N et al.. Meta-analyses of therapies for postmenopausal osteoporosis. VI. Meta-analysis of calcitonin for the treatment of postmenopausal osteoporosis. Endocr Rev 2002;23:540–551.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 135

    Background document for meeting of advisory committee for reproductive health drugs and drug safety and risk management advisory committee. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM341779.pdf. Accessed July 17, 2013.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 136

    Bundred NJ, Campbell ID, Davidson N et al.. Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST study results. Cancer 2008;112:1001–1010.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 137

    Gnant M, Mlineritsch B, Schippinger W et al.. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009;360:679–691.

  • 138

    Shapiro CL, Halabi S, Hars V et al.. Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: final results from CALGB trial 79809. Eur J Cancer 2011;47:683–689.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 139

    Smith MR, Eastham J, Gleason DM et al.. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 2003;169:2008–2012.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 140

    Smith MR, Morton RA, Barnette KG et al.. Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer. J Urol 2010;184:1316–1321.

  • 141

    Smith MR, Egerdie B, Hernandez Toriz N et al.. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009;361:745–755.

  • 142

    Grigg AP, Shuttleworth P, Reynolds J et al.. Pamidronate reduces bone loss after allogeneic stem cell transplantation. J Clin Endocrinol Metab 2006;91:3835–3843.

  • 143

    Tauchmanovà L, Colao A, Lombardi G et al.. Bone loss and its management in long-term survivors from allogeneic stem cell transplantation. J Clin Endocrinol Metab 2007;92:4536–4545.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 144

    Tauchmanova L, De Simone G, Musella T et al.. Effects of various antireabsorptive treatments on bone mineral density in hypogonadal young women after allogeneic stem cell transplantation. Bone Marrow Transplant 2006;37:81–88.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 145

    Brown JE, Ellis SP, Lester JE et al.. Prolonged efficacy of a single dose of the bisphosphonate zoledronic acid. Clin Cancer Res 2007;13:5406–5410.

  • 146

    Grey A, Bolland MJ, Wattie D et al.. The antiresorptive effects of a single dose of zoledronate persist for two years: a randomized, placebo-controlled trial in osteopenic postmenopausal women. J Clin Endocrinol Metab 2009;94:538–544.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 147

    Hershman DL, McMahon DJ, Crew KD et al.. Prevention of bone loss by zoledronic acid in premenopausal women undergoing adjuvant chemotherapy persist up to one year following discontinuing treatment. J Clin Endocrinol Metab 2010;95:559–566.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 148

    Lester JE, Dodwell D, Purohit OP et al.. Prevention of anastrozole-induced bone loss with monthly oral ibandronate during adjuvant aromatase inhibitor therapy for breast cancer. Clin Cancer Res 2008;14:6336–6342.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 149

    Brufsky AM, Harker WG, Beck JT et al.. Final 5-year results of Z-FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole. Cancer 2012;118:1192–1201.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 150

    Llombart A, Frassoldati A, Paija O et al.. Immediate administration of zoledronic acid reduces aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer: 12-month analysis of the E-ZO-FAST trial. Clin Breast Cancer 2012;12:40–48.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 151

    Coleman R, de Boer R, Eidtmann H et al.. Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol 2013;24:398–405.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 152

    Fuleihan Gel H, Salamoun M, Mourad YA et al.. Pamidronate in the prevention of chemotherapy-induced bone loss in premenopausal women with breast cancer: a randomized controlled trial. J Clin Endocrinol Metab 2005;90:3209–3214.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 153

    Hines SL, Mincey BA, Sloan JA et al.. Phase III randomized, placebo-controlled, double-blind trial of risedronate for the prevention of bone loss in premenopausal women undergoing chemotherapy for primary breast cancer. J Clin Oncol 2009;27:1047–1053.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 154

    Ripps BA, VanGilder K, Minhas B et al.. Alendronate for the prevention of bone mineral loss during gonadotropin-releasing hormone agonist therapy. J Reprod Med 2003;48:761–766.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 155

    Gnant M, Mlineritsch B, Luschin-Ebengreuth G et al.. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol 2008;9:840–849.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 156

    Brown JE, Sherriff JM, James ND. Osteoporosis in patients with prostate cancer on long-term androgen deprivation therapy: an increasing, but under-recognized problem. BJU Int 2010;105:1042–1043.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 157

    Lee CE, Leslie WD, Czaykowski P et al.. A comprehensive bone-health management approach for men with prostate cancer receiving androgen deprivation therapy. Curr Oncol 2011;18:e163–172.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 158

    Michaelson MD, Kaufman DS, Lee H et al.. Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol 2007;25:1038–1042.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 159

    Smith MR, McGovern FJ, Zietman AL et al.. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001;345:948–955.

  • 160

    Bhoopalam N, Campbell SC, Moritz T et al.. Intravenous zoledronic acid to prevent osteoporosis in a veteran population with multiple risk factors for bone loss on androgen deprivation therapy. J Urol 2009;182:2257–2264.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 161

    Greenspan SL, Nelson JB, Trump DL et al.. Skeletal health after continuation, withdrawal, or delay of alendronate in men with prostate cancer undergoing androgen-deprivation therapy. J Clin Oncol 2008;26:4426–4434.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 162

    Klotz LH, McNeill IY, Kebabdjian M et al.. A phase 3, double-blind, randomised, parallel-group, placebo-controlled study of oral weekly alendronate for the prevention of androgen deprivation bone loss in nonmetastatic prostate cancer: the Cancer and Osteoporosis Research with Alendronate and Leuprolide (CORAL) study. Eur Urol 2012;63:927–935.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 163

    Serpa Neto A, Tobias-Machado M, Esteves MA et al.. Bisphosphonate therapy in patients under androgen deprivation therapy for prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 2012;15:36–44.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 164

    Smith MR, Fallon MA, Lee H, Finkelstein JS. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab 2004;89:3841–3846.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 165

    Smith MR, Malkowicz SB, Chu F et al.. Toremifene increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer: interim analysis of a multicenter phase 3 clinical study. J Urol 2008;179:152–155.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 166

    Eidtmann H, de Boer R, Bundred N et al.. Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST Study. Ann Oncol 2010;21:2188–2194.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 167

    Gnant M, Mlineritsch B, Luschin-Ebengreuth G et al.. Long-term follow-up in ABCSG-12: significantly improved overall survival with adjuvant zoledronic acid in premenopausal patients with endocrine-receptor-positive early breast cancer [abstract]. Cancer Res 2011;71(24 Suppl):Abstract S1-2.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 168

    Davies C, Pan H, Godwin J et al.. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381:805–816.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 169

    Powles TJ, Hickish T, Kanis JA et al.. Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 1996;14:78–84.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 170

    Vehmanen L, Elomaa I, Blomqvist C, Saarto T. Tamoxifen treatment after adjuvant chemotherapy has opposite effects on bone mineral density in premenopausal patients depending on menstrual status. J Clin Oncol 2006;24:675–680.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 171

    Lester JE, Dodwell D, Purohit OP et al.. Prevention of anastrozole-induced bone loss with monthly oral ibandronate during adjuvant aromatase inhibitor therapy for breast cancer. Clin Cancer Res 2008;14:6336–6342.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 172

    Rabenda V, Hiligsmann M, Reginster JY. Poor adherence to oral bisphosphonate treatment and its consequences: a review of the evidence. Expert Opin Pharmacother 2009;10:2303–2315.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 173

    Sheehy O, Kindundu C, Barbeau M, LeLorier J. Adherence to weekly oral bisphosphonate therapy: cost of wasted drugs and fractures. Osteoporos Int 2009;20:1583–1594.

  • 174

    Weycker D, Lamerato L, Schooley S et al.. Adherence with bisphosphonate therapy and change in bone mineral density among women with osteoporosis or osteopenia in clinical practice. Osteoporos Int 2013;24:1483–1489.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 175

    Wade SW, Curtis JR, Yu J et al.. Medication adherence and fracture risk among patients on bisphosphonate therapy in a large United States health plan. Bone 2012;50:870–875.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 176

    Gallo M, De Luca A, Lamura L, Normanno N. Zoledronic acid blocks the interaction between mesenchymal stem cells and breast cancer cells: implications for adjuvant therapy of breast cancer. Ann Oncol 2012;23:597–604.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 177

    Boissier S, Ferreras M, Peyruchaud O et al.. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 2000;60:2949–2954.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 178

    Senaratne SG, Pirianov G, Mansi JL et al.. Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer 2000;82:1459–1468.

  • 179

    Teronen O, Konttinen YT, Salo T et al.. Bisphosphonates inhibit matrix metalloproteinases—a new possible mechanism of action. Duodecim 1999;115:13–15.

  • 180

    van der Pluijm G, Vloedgraven H, van Beek E et al.. Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J Clin Invest 1996;98:698–705.

  • 181

    Daubine F, Le Gall C, Gasser J et al.. Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst 2007;99:322–330.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 182

    Fournier P, Boissier S, Filleur S et al.. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002;62:6538–6544.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 183

    Sasaki A, Boyce BF, Story B et al.. Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res 1995;55:3551–3557.

  • 184

    Powles T, Paterson S, Kanis JA et al.. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 2002;20:3219–3224.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 185

    Powles T, Paterson A, McCloskey E et al.. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 2006;8:R13.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 186

    Diel IJ, Solomayer EF, Costa SD et al.. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357–363.

  • 187

    Diel IJ, Jaschke A, Solomayer EF et al.. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann Oncol 2008;19:2007–2011.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 188

    Saarto T, Blomqvist C, Virkkunen P, Elomaa I. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 2001;19:10–17.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 189

    Ha TC, Li H. Meta-analysis of clodronate and breast cancer survival. Br J Cancer 2007;96:1796–1801.

  • 190

    Paterson AH, Anderson SJ, Lembersky BC et al.. Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol 2012;13:734–742.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 191

    Möbus V, Diel I, Harbeck N et al.. GAIN study: a phase III trial to compare ETC vs. EC-TX and iIbandronate vs. observation in patients with node-positive primary breast cancer—1st interim efficacy analysis [abstract]. Cancer Res 2011;71(24 Suppl):Abstract S2-4.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 192

    Coleman RE, Marshall H, Cameron D et al.. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 2011;365:1396–1405.

  • 193

    Gregory W, Marshall H, Bell R et al.. Adjuvant zoledronic acid (ZOL) in postmenopausal women with breast cancer and those rendered postmenopausal: results of a meta-analysis [abstract]. J Clin Oncol 2012;30(Suppl):Abstract 513.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 194

    Goss PE, Barrios CH, Bell R et al.. Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer who are at high risk of disease recurrence (D-CARE): an international, randomized, double-blind, placebo-controlled phase III clinical trial [abstract]. J Clin Oncol 2012;30(Suppl):Abstract TPS670.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 195

    Smith MR, Kabbinavar F, Saad F et al.. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol 2005;23:2918–2925.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 196

    Mason MD, Sydes MR, Glaholm J et al.. Oral sodium clodronate for nonmetastatic prostate cancer--results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J Natl Cancer Inst 2007;99:765–776.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 197

    Smith MR, Saad F, Coleman R et al.. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012;379:39–46.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 198

    Saad F, Smith MR, Shore ND et al.. Effect of denosumab on prolonging bone-metastasis free survival (BMFS) in men with non-metastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics [abstract]. J Clin Oncol 2012;30:Abstract 4510.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 199

    ZEUS study yields no survival benefits and positive results. European Association of Urology Web site. http://www.uroweb.org/eau-news/?no_cache=1&aid=648. Accessed July 17, 2013

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 200

    Li S, Peng Y, Weinhandl ED et al.. Estimated number of prevalent cases of metastatic bone disease in the US adult population. Clin Epidemiol 2012;4:87–93.

  • 201

    Msaouel P, Pissimissis N, Halapas A, Koutsilieris M. Mechanisms of bone metastasis in prostate cancer: clinical implications. Best Pract Res Clin Endocrinol Metab 2008;22:341–355.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 202

    Koutsilieris M. Skeletal metastases in advanced prostate cancer: cell biology and therapy. Crit Rev Oncol Hematol 1995;18:51–64.

  • 203

    Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat Rev Cancer 2011;11:411–425.

  • 204

    Papachristou DJ, Basdra EK, Papavassiliou AG. Bone metastases: molecular mechanisms and novel therapeutic interventions. Med Res Rev 2012;32:611–636.

  • 205

    Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584–593.

  • 206

    Guise TA, Mohammad KS, Clines G et al.. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res 2006;12:6213s–6216s.

  • 207

    Kingsley LA, Fournier PG, Chirgwin JM, Guise TA. Molecular biology of bone metastasis. Mol Cancer Ther 2007;6:2609–2617.

  • 208

    Braun S, Pantel K, Muller P et al.. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 2000;342:525–533.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 209

    Giuliano AE, Hawes D, Ballman KV et al.. Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. JAMA 2011;306:385–393.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 210

    Lucci A, Hall CS, Lodhi AK et al.. Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol 2012;13:688–695.

  • 211

    Braun S, Vogl FD, Naume B et al.. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 2005;353:793–802.

  • 212

    Janni W, Vogl FD, Wiedswang G et al.. Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse—a European pooled analysis. Clin Cancer Res 2011;17:2967–2976.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 213

    Wiedswang G, Borgen E, Karesen R et al.. Isolated tumor cells in bone marrow three years after diagnosis in disease-free breast cancer patients predict unfavorable clinical outcome. Clin Cancer Res 2004;10:5342–5348.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 214

    Meng S, Tripathy D, Shete S et al.. HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci U S A 2004;101:9393–9398.

  • 215

    Roudier MP, Vesselle H, True LD et al.. Bone histology at autopsy and matched bone scintigraphy findings in patients with hormone refractory prostate cancer: the effect of bisphosphonate therapy on bone scintigraphy results. Clin Exp Metastasis 2003;20:171–180.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 216

    Hsu H, Lacey DL, Dunstan CR et al.. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A 1999;96:3540–3545.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 217

    Logothetis CJ, Lin SH. Osteoblasts in prostate cancer metastasis to bone. Nat Rev Cancer 2005;5:21–28.

  • 218

    Street J, Bao M, deGuzman L et al.. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A 2002;99:9656–9661.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 219

    Dai J, Kitagawa Y, Zhang J et al.. Vascular endothelial growth factor contributes to the prostate cancer-induced osteoblast differentiation mediated by bone morphogenetic protein. Cancer Res 2004;64:994–999.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 220

    Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350:1655–1664.

  • 221

    Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 2001;27:165–176.

  • 222

    Sathiakumar N, Delzell E, Morrisey MA et al.. Mortality following bone metastasis and skeletal-related events among women with breast cancer: a population-based analysis of U.S. Medicare beneficiaries, 1999-2006. Breast Cancer Res Treat 2012;131:231–238.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 223

    Sathiakumar N, Delzell E, Morrisey MA et al.. Mortality following bone metastasis and skeletal-related events among men with prostate cancer: a population-based analysis of US Medicare beneficiaries, 1999-2006. Prostate Cancer Prostatic Dis 2011;14:177–183.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 224

    Lage MJ, Barber BL, Harrison DJ, Jun S. The cost of treating skeletal-related events in patients with prostate cancer. Am J Manag Care 2008;14:317–322.

  • 225

    Pockett RD, Castellano D, McEwan P et al.. The hospital burden of disease associated with bone metastases and skeletal-related events in patients with breast cancer, lung cancer, or prostate cancer in Spain. Eur J Cancer Care (Engl) 2010;19:755–760.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 226

    Roberts CC, Daffner RH, Weissman BN et al.. ACR appropriateness criteria on metastatic bone disease. J Am Coll Radiol 2010;7:400–409.

  • 227

    Hamaoka T, Madewell JE, Podoloff DA et al.. Bone imaging in metastatic breast cancer. J Clin Oncol 2004;22:2942–2953.

  • 228

    Durning P, Best JJ, Sellwood RA. Recognition of metastatic bone disease in cancer of the breast by computed tomography. Clin Oncol 1983;9:343–346.

  • 229

    Muindi J, Coombes RC, Golding S et al.. The role of computed tomography in the detection of bone metastases in breast cancer patients. Br J Radiol 1983;56:233–236.

  • 230

    Hanna SL, Fletcher BD, Fairclough DL et al.. Magnetic resonance imaging of disseminated bone marrow disease in patients treated for malignancy. Skeletal Radiol 1991;20:79–84.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 231

    Avrahami E, Tadmor R, Dally O, Hadar H. Early MR demonstration of spinal metastases in patients with normal radiographs and CT and radionuclide bone scans. J Comput Assist Tomogr 1989;13:598–602.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 232

    Frank JA, Ling A, Patronas NJ et al.. Detection of malignant bone tumors: MR imaging vs scintigraphy. AJR Am J Roentgenol 1990;155:1043–1048.

  • 233

    Ma J, Costelloe CM, Madewell JE et al.. Fast dixon-based multisequence and multiplanar MRI for whole-body detection of cancer metastases. J Magn Reson Imaging 2009;29:1154–1162.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 234

    Steinborn MM, Heuck AF, Tiling R et al.. Whole-body bone marrow MRI in patients with metastatic disease to the skeletal system. J Comput Assist Tomogr 1999;23:123–129.

  • 235

    Schmidt GP, Baur-Melnyk A, Haug A et al.. Comprehensive imaging of tumor recurrence in breast cancer patients using whole-body MRI at 1.5 and 3 T compared to FDG-PET-CT. Eur J Radiol 2008;65:47–58.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 236

    Krishnamurthy GT, Tubis M, Hiss J, Blahd WH. Distribution pattern of metastatic bone disease. A need for total body skeletal image. JAMA 1977;237:2504–2506.

  • 237

    Zelinka T, Timmers HJ, Kozupa A et al.. Role of positron emission tomography and bone scintigraphy in the evaluation of bone involvement in metastatic pheochromocytoma and paraganglioma: specific implications for succinate dehydrogenase enzyme subunit B gene mutations. Endocr Relat Cancer 2008;15:311–323.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 238

    Daldrup-Link HE, Franzius C, Link TM et al.. Whole-body MR imaging for detection of bone metastases in children and young adults: comparison with skeletal scintigraphy and FDG PET. AJR Am J Roentgenol 2001;177:229–236.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 239

    Ohta M, Tokuda Y, Suzuki Y et al.. Whole body PET for the evaluation of bony metastases in patients with breast cancer: comparison with 99Tcm-MDP bone scintigraphy. Nucl Med Commun 2001;22:875–879.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 240

    Kao CH, Hsieh JF, Tsai SC et al.. Comparison and discrepancy of 18F-2-deoxyglucose positron emission tomography and Tc-99m MDP bone scan to detect bone metastases. Anticancer Res 2000;20:2189–2192.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 241

    Dehdashti F, Flanagan FL, Mortimer JE et al.. Positron emission tomographic assessment of “metabolic flare” to predict response of metastatic breast cancer to antiestrogen therapy. Eur J Nucl Med 1999;26:51–56.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 242

    Mortimer JE, Dehdashti F, Siegel BA et al.. Metabolic flare: indicator of hormone responsiveness in advanced breast cancer. J Clin Oncol 2001;19:2797–2803.

  • 243

    Costelloe CM, Rohren EM, Madewell JE et al.. Imaging bone metastases in breast cancer: techniques and recommendations for diagnosis. Lancet Oncol 2009;10:606–614.

  • 244

    Han LJ, Au-Yong TK, Tong WC et al.. Comparison of bone single-photon emission tomography and planar imaging in the detection of vertebral metastases in patients with back pain. Eur J Nucl Med 1998;25:635–638.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 245

    Romer W, Nomayr A, Uder M et al.. SPECT-guided CT for evaluating foci of increased bone metabolism classified as indeterminate on SPECT in cancer patients. J Nucl Med 2006;47:1102–1106.