Bone Monograph

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					                                 Advances in
                                 Treating Metastatic
                                 Bone Cancer
                                 A Continuing Medical Education Activity sponsored by
                                 InforMEDical Communications, Inc




                                 Robert E. Coleman, MD, FRCP
                                 Professor of Medical Oncology
                                 Cancer Research Centre
                                 Weston Park Hospital
                                 Sheffield, United Kingdom

                                 Theresa A. Guise, MD
                                 Gerald D. Aurbach Professor of Endocrinology
                                 Division of Endocrinology and Medicine
                                 University of Virginia
                                 Charlottesville,Virginia

                                 Allan Lipton, MD
                                 Penn State University
                                 Milton S. Hershey Medical Center
                                 Hershey, Pennsylvania

                                 G. David Roodman, MD, PhD
                                 Director of the Bone Biology Center
                                 Director of the Myeloma Program
                                 VA Pittsburgh Healthcare System
                                 Pittsburgh, Pennsylvania




                                 Supported by educational grants from
                                 Novartis Pharmaceuticals, Amgen, Inc. and Merck & Co., Inc.


For real-time CME Credit complete this activity at www.informedicalcme.com/bone
Advances in Treating Metastatic Bone Cancer                                                            Release Date: September 2008
                                                                                                     Expiration Date: September 2009
Sponsored by Informedical Communications, Inc.
Earn 3.0 Complimentary AMA PRA Category 1 Credits™

                                 CONTINUING MEDICAL EDUCATION INFORMATION

Target Audience                                                        Accreditation and Credit Designation
This educational activity is intended for oncologists, urologists      This CME activity has been planned and implemented in
and other medical professionals who assess, treat and counsel          accordance with the Essential Areas and Policies of the
patients with metastatic bone cancer.                                  Accreditation Council for Continuing Medical Education
                                                                       (ACCME), by InforMEDical Communications, Inc. InforMEDical
How to Obtain Credit                                                   is accredited by the ACCME to provide continuing medical
Participants are expected to review the learning objectives            education for physicians and takes responsibility for the content,
below and read the activity in its entirety before completing the      quality and scientific integrity of this CME activity. InforMEDical
post test and registering for credit. Online: complete the test        designates this educational activity for a maximum of 3.0 AMA
and registration/evaluation at www.informedicalcme.com/bone            PRA Category 1 Credits®. Each physician should claim credit
to receive credit immediately. Fax/Mail: complete the test and         commensurate with the extent of his/her participation in
registration/evaluation and fax/mail as directed. A certificate will   the activity.
be mailed within 30 days.
                                                                       Faculty Disclosure Declarations
Learning Objectives                                                    The program faculty disclosed the following financial relation-
Following successful completion of the activity, participants          ships. Robert Coleman: Speaker: Novartis, Amgen, Roche;
should be able to:                                                     Consultant: Novartis, Amgen; Expert testimony: Novartis.
• Discuss principal mediators of bone metastasis                       Theresa Guise: Leadership: ASBMR, IBMS, Paget Foundation,
     and targets of intervention.                                      ASCI; Consultant: Amgen; Speakers’ Bureau: Amgen, Merck,
• Discuss rationale for using adjuvant bone                            Novartis; Research funding: Scios. Allan Lipton: Consultant:
     targeted therapies in preventing metastasis                       Amgen, Novartis; Speakers’ Bureau: Amgen, Novartis. David
     and bone loss.                                                    Roodman: Consultant: Amgen, Novartis, Merck, Millennium;
• Assess current clinical data (safety and                             Speakers’ Bureau: Novartis; Scientific Advisory Board:
     efficacy) for adjuvant bone targeted agents                       International Myeloma Foundation, Multiple Myeloma
     in preventing metastasis and bone loss.                           Research Foundation.

Educational Need                                                       This CME activity may contain discussion of published and/or
The skeleton is both the most common organ affected by                 investigational uses of agents, devices or diagnostic tools
metastatic cancer and the site that produces the greatest              that have not been approved for use by the US FDA.The
morbidity for patients. Recent advances in our understanding           opinions expressed in the activity are those of the authors,
of bone biology and the pathways by which cancer metastasizes          and do not reflect those of the supporters or CME sponsor.
and spreads to bone have contributed to the development of             Please refer to the official prescribing information for each
several important new drugs targeting these processes, and             product for discussion of approved indications, contraindica-
focused research on further understanding the biology and              tions, contradictions and warnings. Participants/readers should
targets involved in metastasis and bone loss. Oncologists, sur-        appraise the information presented critically and are encour-
geons and other medical professionals need to be able to assess        aged to consult appropriate resources for any product, device
important new data and recommendations related to preventing           or diagnostic tool mentioned in this activity.
bone metastasis, predict who is at risk for skeletal-related events,
and discuss recent advances in clinical research in bone-targeted
therapies so that they can more effectively counsel and treat
their patients.
                                                                        Post Test Answer Key
                                                                             1. d       6. d
                                                                             2. d       7. d
                                                                             3. b       8. d
                                                                             4. d       9. e
                                                                             5. d      10. d



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Advances in Treating Metastatic Bone Cancer                                                               Release Date: September 2008
                                                                                                        Expiration Date: September 2009
Sponsored by Informedical Communications, Inc.
                                                          INSTRUCTIONS
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  bottom of registration form.
                                                         CME POST TEST
Please circle one correct answer for each question. Self-correct using answers on inside front cover.
1.Which of the following is true of               treatment failure or a signal to stop              to intravenous bisphosphonates in
   bisphosphonate therapy?                        treatment.                                         suppressing bone turnover and
a. Bisphosphonate therapy has been             b. Once on therapy, development of a                  reducing SRE risk.
   shown to decrease SREs by up to 50%.           skeletal complication is a signal to stop       d. a and c
b. Despite treatment with bisphospho-             treatment.                                      e. b and c
   nates, approximately 20% of patients        c. Bisphosphonates have been shown to delay
                                                                                                  8.Which of the following is true?
   with bone metastasis still have elevated       second and subsequent complications.
                                                                                                  a. Cathepsin K destroys collagen type I,
   bone resorption markers.                    d. a and c
                                                                                                     which is the main component of the           3
c. Bisphosphonate therapy is associated        e. None of the above
                                                                                                     protein matrix in bone.
   with renal toxicity and osteonecrosis of
                                               5.Which of the following is true of                b. Two novel inhibitors of cathepsin K,
   the jaw.
                                                  bisphosphonate therapy?                            MK-0822 and AAE581, are in Phase II
d. All of the above
                                               a. Adverse events include bone pain,                  clinical testing.
e. a and c
                                                  myalgia, nausea, fatigue, pyrexia and emesis.   c. Inhibitors of cathepsin K effectively
2.Which of the following accurately            b. Both pamidronate and zoledronic acid               suppress bone resorption in animal
   reflects current thinking regarding the        require testing for renal sufficiency              tumor models.
   biology of metastasis?                         before dosing.                                  d. All of the above
a. Micrometastasis to bone is thought to       c. To avoid complications, patients should         e. a and b
   occur early in the malignant process.          have a routine dental exam, complete
                                                                                                  9.Which of the following can identify
b. To treat and prevent bone metastasis           any planned invasive dental procedures,
                                                                                                     patients at risk for bone metastasis?
   tumor stem cells must be eradicated.           and maintain excellent oral hygiene
                                                                                                  a. An increase in estrogen receptor (ER)
c. To treat and prevent bone metastasis           before starting bisphosphonate therapy.
                                                                                                     expression
   factors that facilitate tumor stem cell     d. All of the above
                                                                                                  b. A decrease in ER expression
   reentry into the cell cycle must be         e. b and c
                                                                                                  c. Tissue levels of bone sialoprotein
   blocked.
                                               6.What are NSABP34, AZURE and                      d. All of the above
d. All of the above
                                                  SWOG 0307?                                      e. a and c
e. a and c
                                               a. Phase 3 bone cancer prevention trials
                                                                                                  10.Which of the following is true of
3.What is the “vicious cycle” in bone             of over 3000 patients each.
                                                                                                     treatment-related osteoporosis?
   cancer biology?                             b. Studies comparing standard of care to
                                                                                                  a. Aromatase inhibitor (AI) therapy in
a. The process whereby adjuvant therapy           bisphosphonate therapy plus standard
                                                                                                     breast cancer has been associated with
   for breast cancer increases the risk of        therapy, either in combination or in
                                                                                                     increased risk of bone fractures.
   bone fracture.                                 sequence.
                                                                                                  b. Androgen deprivation therapy (ADT)
b. The process whereby factors released        c. Studies expected to report initial
                                                                                                     in prostate cancer has been associated
   by the bone destructive process amplify        results in 2008/2009.
                                                                                                     with a loss in bone mineral density (BMD).
   the growth of tumor cells in the bone.      d. All of the above
                                                                                                  c. Adjuvant bisphosphonates have been
c. The process whereby tumor stem cells        e. a and c
                                                                                                     shown to prevent bone loss when given
   reenter the cell cycle.
                                               7.Which of the following are true of                  concurrently with AI therapy in breast
d. a and b
                                                  denosumab?                                         cancer patients and to prevent loss in
e a and c
                                               a. It is a monoclonal antibody to RANK                BMD in prostate cancer patients treated
4.Which of the following is true of               ligand.                                            with ADT.
   bisphosphonate therapy?                     b. It is a mediator of Cathepsin K and             d. All of the above
a. Once on therapy, the development of            estrogen.                                       e. a and b
   a skeletal complication is not a sign of    c. Early data suggest it may be similar
    Advances in Treating Metastatic Bone Cancer                                                                                           Release Date: September 2008
    Sponsored by Informedical Communications, Inc.                                                                                      Expiration Date: September 2009

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    Please circle the number that indicates your response to the following questions:
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    • Discuss principal mediators of bone metastasis and targets of intervention . . . . . . . . . . . . . . . . . . . . . . . . .5                   4   3   2   1
    • Discuss rationale for using adjuvant bone-targeted therapies to prevent metastasis and bone loss . . . . .5                                     4   3   2   1
    • Assess data for bone-targeted agents in metastasis prevention and bone loss. . . . . . . . . . . . . . . . . . . . . . . .5                     4   3   2   1

    This CME activity was informative and well presented . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5   4   3   2   1
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    Please indicate any specific areas where you anticipate a possible change from your current practice. (check all that apply)
    K Counsel patients                                 K Assess patients                                  K Seek more information
    K Treat patients                                   K Consult with specialist                          K Seek clinical trials

4   Specific changes?__________________________________________________________________________________________
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    Please mark topics of interest for future program development
    K Metastatic bone cancer                K Bisphosponate therapy             K Lung cancer
    K Assessing/treating bone loss          K Myeloma                           K Renal cancer

    OTHER SUGGESTIONS: _____________________________________________________________________________________

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                                               INTRODUCTION                                Advances in
                                                                                           Treating Metastatic
                                                                                           Bone Cancer

Tumor metastasis to the skeleton affects over 400,000               effects of current therapies. In addition, several novel agents
individuals in the United States annually, more than any other      are being developed to treat bone metastasis. While bisphos-
site of metastasis, including significant proportions of patients   phonates are currently the mainstay for treatment of bone
with breast, prostate, lung and other solid tumors (Table 1).       metastasis, other newer agents directed at cytokines and
An even larger population of patients is at risk for skeletal       other factors responsible for the bone metastatic process are
morbidity. 1, 2, 3 Bone metastases are often associated with        moving forward in the clinic and earlier testing. A humanized
so-called skeletal-related events (SREs) which include severe       antibody to receptor activator of nuclear factor kappa
pain, bone fractures, need for radiation therapy to bone,           B-ligand (RANK L), denosumab (formerly AMG-162, Amgen,
need for surgery to bone, spinal cord compression and bone          Thousand Oaks), is in clinical trials for patients with bone
demineralization. At present, once cancer metastasizes to           metastasis as well as osteoporosis.7 Chemokine receptor
bone, it is incurable and can cause severe morbidity and            antagonists that block the activity of key regulators of the
mortality. Thus, new strategies are focused on the development      metastatic process are in preclinical evaluation and inhibitors
of bone-targeted agents to both prevent the development of          of transforming growth factors-beta (TGF-ß) receptor and
bone metastases, as well as to effectively treat metastases and     src kinase are also being examined.                                 5
their complications when they occur.
                                                                      Table 1
Bisphosphonate therapy, the current standard of care for              Incidence of Bone Metastases in
metastatic bone cancer, has been shown to decrease SREs by            Selected Cancers1,2,3
up to 50% and also to slow the rate of development of SREs.
While this therapeutic advance is significant, bisphosphonate                           2008      Incidence of    Median Survival
                                                                                        New      Bone Metastases Post Diagnosis of
therapy does not completely block the process of bone                                                  (%)
                                                                                       Cases                     Metastasis (years)
metastasis; despite treatment with bisphosphonates, approxi-                                         65 - 75          2-3
                                                                    Prostate           186,320
mately 20% of patients with bone metastasis still have elevated
                                                                    Lung & bronchus    215,020        30 - 40             NA
bone resorption markers.4,5 In addition, bisphosphonate
                                                                    Breast             184,450        65 - 75           1.5 - 2
therapy is associated with renal toxicity and the emerging
                                                                    Bladder             68,810          40                NA
problem of osteonecrosis of the jaw (ONJ), which is causing
                                                                    Renal               54,390        20 - 25             NA
deep concern among patients and dental care professionals
who fear development of ONJ following dental procedures             Thyroid             37,340          60                NA
or even basic dental cleaning.6 Addressing these issues and         Myeloma             19,920        70 - 95            4-5
finding treatments that more effectively prevent and suppress
the bone metastatic process are needed.                             This educational activity has been developed to provide an
                                                                    overview of recent progress and near-term developments in
Several important recent advances in our understanding of           this fast-moving field. It is intended to provide a framework
the pathophysiology underlying the bone metastatic process          for understanding advances in the field with a focus on new
are informing new approaches to assess, treat and potentially       insights into the mediators of bone metastasis and targets
prevent the advance of metastatic disease. In particular, we        for intervention, the rationale for using bone-targeted therapies
have a much better understanding of how tumor cells home            to treat and prevent bone metastasis and bone loss, and
to bone and how they can reside in the bone microenviron-           available data for approved and development-stage bone-
ment, possibly for many years, before they become active in         targeted agents in treating and preventing bone metastasis
bone metastasis. The mechanisms responsible for the process         and bone loss.
of bone destruction induced by metastatic cancer as well as
the underlying factors involved in osteoblastic bone metas-         Please see the inside front cover for information on how
tases are under intense investigation and are providing new         to receive up to 3 AMA PRA Category 1 Credits®‚ for
opportunities to develop novel therapies and address side           particpating in this CME activity.
                                                     BIOLOGY OF BONE METASTASIS
                                                                                  Theresa A. Guise, MD
                                                                                  Gerald D. Aurbach Professor of Endocrinology
                                                                                  Division of Endocrinology and Medicine
                                                                                  University of Virginia Charlottesville, Virginia


    The development of micrometastasis to bone probably occurs                    marrow via receptors such as CXCR-4, they home to areas
    early in the malignant process. Vessella and co-workers have                  that have high levels of stromal cell derived factor 1 (SDF-1)
    reported that 71% of patients have detectable prostate cancer                 which are present in hematopoietic niches. Osteoblasts appear
    cells in their peripheral blood prior to undergoing radical                   to play an important role in these niches.To treat and prevent
    prostatectomy.8 Thus early dissemination of tumor cells appears               bone metastasis, it will be necessary to eradicate tumor stem
    to occur in the majority of patients with prostate cancer.                    cells that reside in this osteoblast niche and to block the
    Similarly, many patients with breast cancer that have apparent                expression or activity of factors that determine or trigger
    isolated disease clinically have micrometastasis at the time of               reentry into the cell cycle. Expanding our understanding of
    diagnosis.9 To effectively treat and prevent bone metastasis and              cancer stem cell dormancy and how these cancer stem cells
    related complications, including bone loss, it is necessary to                reenter the cell cycle is an important area of investigation.
    elucidate and target pathways by which cancer cells establish
    themselves and proliferate in the bone microenvironment.                      How cancer cells home to bone is another area of investiga-
                                                                                  tion that has made important strides. In addition to the
6   Cancer Stem Cells                                                             CXCR-4/SDF-1 axis mentioned above, recently the RANK
    Like self-renewing adult tissues, tumors appear to be main-                   receptor has been found to be expressed on cancer cells and
    tained by stem cells, which provide a mechanism for cancer                    play a role in tumor cell homing.11 RANK ligand (RANK L) is
    cell dormancy and the development of heterogeneity within a                   expressed in the bone marrow microenvironment by marrow
    specific tumor.10 When tumor stem cells home to the bone                      stromal cells and immature osteoblasts, and recent studies


      Figure 1
      The “Vicious Cycle” of Osteolytic Metastases

               Metastatic Cancer Cells
                                                                                       Mediators of Bone Resorption, Formation
                                                                                       and Pain

                                                                                       Bone-derived Growth Factors            TGF-ß
                                       Osteoblastic Factors      Growth Factors        Osteolytic Factors                     PTHrP, IL-11, IL-6,
     Bone-derived        Osteolytic
    Growth Factors        Factors                Osteoblast Maturation                                                        IL-8,TNF-α, IL-1
                                                                                       Osteoblastic Factors                   ET-1, AM, PDGF,
                                                                                                                              CCNs,VEGF
                                                                 New Bone
                                                                                       Growth Factors                         IL-6, CCNs, RANK L
                                      Osteoblasts
               Osteoclasts
                                             Mineralized Bone Matrix

         Once cancer cells arrive in bone, the 4 major players in this cycle are metastatic cancer cells, osteoblasts, osteoclasts and
         mineralized bone matrix. Cancer cells secrete both osteoblastic factors, which contribute to bone formation, and osteolytic
         factors, which contribute to bone destruction. Most of the osteolytic factors increase osteoclast formation and bone resorption.
         The increased bone resorption releases growth factors from the bone matrix that increase tumor growth, establishing a “vicious
         cycle” between tumor stimulation of bone destruction and tumor growth.


         Source for data: Guise,TA, Mohammed KS and Clines, G. et al. Basic mechanisms responsible for osteolytic and osteoblastic bone
         metastases. Clin Can Res 2006. 12(20):6214s.
have shown that breast cancer cells and other tumor cells can        tumor growth. Bisphosphonates are hypothesized to interrupt
also express RANK and utilize this receptor to home to bone.         this vicious cycle by inhibiting osteoclast-mediated bone
                                                                     resorption and inhibiting the effects of bone-derived growth
Bone Microenvironment “Vicious Cycles”                               factors. Inhibitors of RANK L are hypothesized to block
Another advance in our understanding of the bone metastatic          osteoclast formation.
process over the last several years has been the realization
and documentation of the importance of the bone micro-               One of the principal identified osteolytic factors, parathyroid
environment in regulating both normal bone formation and             hormone related protein (PTHrP) has been shown to play
the progression of bone metastasis. Identification of the roles      an important role in bone metastasis in breast cancer and
that cytokines, chemokines and hormones made by tumor                prostate cancer through its induction of RANK L.12 In
cells play in bone destruction, and recognition that the bone        addition, tumor cells produce other factors, which can enhance
destructive process results in the release of growth factors         osteoclast activity including Interleukins 6, 11, 8 and 1 (IL-6,
from the bone microenvironment to increase tumor growth,             IL-11, IL-8 and IL-1), tumor necrosis factor alpha (TNF-α),
have resulted in the concept of the “vicious cycle,” that            granulocyte macrophage colony stimulating factor (GM-CSF),
theorizes how tumor cells metastasize to bone, and the               macrophage inflammatory protein-1 alpha (MIP-1α), and
bone destructive process amplifies the growth of the tumor.          MCP-1. All these factors can expand the pool of osteoclast
                                                                     precursors, and either alone or in combination can enhance
As illustrated in Figure 1, the four major players in this vicious   osteoclast formation and bone destruction.
cycle include metastatic cancer cells, osteoblasts, osteoclasts
and mineralized bone matrix, a major source of immobilized           In addition, the pathophysiology underlying osteoblastic bone      7
growth factors. Cancer cells secrete both osteoblastic factors       metastasis has also begun to be clarified. Factors have been
and osteolytic factors. Osteoblastic factors (ET-1, AM,VEGF,         identified such as endothelin-1, which stimulates osteoblast
PDGF, CCNs) stimulate osteoblast proliferation, differentiation      activity by suppression of the Wnt pathway inhibitor, dickopf 1
and the secretion of more growth factors, which are deposited        protein (DKK1), appear to play important roles in the expres-
into the bone matrix, and also enrich the local tumor cell           sion of the osteoblastic phenotype in bone metastasis.13,14
microenvironment. Most of the osteolytic factors secreted by         Although the phenotype of these metastases is osteoblastic,
the tumor act via the osteoclast differentiation factor, RANK L.     there is ongoing bone destruction. Patients with prostate
RANK L, in turn, increases osteoclast formation and bone             cancer have the highest bone resorption markers of all the
resorption.                                                          cancers studied in a recent trial.15 Thus, identification of
                                                                     osteoblastic factors produced by tumors as well as the relative
Increased bone resorption releases growth factors from the           importance of bone resorption in osteoblastic metastasis is a
bone matrix that increase tumor growth, establishing a “vicious      topic of active investigation.
cycle” between tumor stimulation of bone destruction and



  Table 2
  Osteoclast Inhibitors and Other Cellular Targets for Bone Metastasis Therapy:
  2008 and Beyond

      Osteoclast Inhibitors                                             Other Cellular Targets
      Bisphosphonates                                                   Platelets: LPA
      RANK L antibody                                                   Endothelial cells: PDGFR, PlGF
      Cathepsin K inhibitor                                             Anti CTGF
      Src inhibitor                                                     CXCR4 antagonists
      PTHrP antibody                                                    LPA antagonist
                                                                        HDAC inhibitors
                                                                        Anti-integrin
                                                                        TGF-β inhibitors
                                                                        ETRA
                                                                        Wnt inhibitors
                                        CURRENT TREATMENT FOR METASTATIC DISEASE
                                                                       G. David Roodman, MD, PhD
                                                                       Director of the Bone Biology Center
                                                                       Director of the Myeloma Program
                                                                       VA Pittsburgh Healthcare System Pittsburgh, Pennsylvania


    Diagnosis                                                                    Consensus Guidelines recommend that all patients with
    Bone metastases are often found in multiple sites at the time                multiple myeloma and radiologically confirmed bone metas-
    of diagnosis. Principal sites include the vertebrae, pelvis,                 tases from breast cancer should start on bisphosphonates
    femur, ribs, humerus and skull. Several procedures may be                    from the time of diagnosis and continue for at least two
    used to detect bone metastases. In patients with a diagnosed                 years.16, 17 Once on therapy, the development of a skeletal
    primary cancer, bone pain is highly indicative of bone metasta-              complication is not a sign of treatment failure or a signal to
    sis, though not all patients report pain. A bone fracture in a               stop treatment, and evidence is now available to confirm that
    patient with primary disease should also be investigated for                 bisphosphonates delay second and subsequent complications,
    possible metastasis. A radionuclide bone scan is usually the                 not just the first event.
    first method of checking for bone metastasis, as it is the most
    cost-effective and available whole-body screening test. Bone                 Switching to a more potent agent like zoledronic acid may
    scans are not appropriate for patients with myeloma, since                   be an appropriate option for patients in whom a less potent
    they underestimate the extent of disease.15 Radiography is                   agent like pamidronate or clodronate therapy proves unsatis-
8   the standard for characterizing lesions once they have been                  factory. Bisphosphonate treatment, specifically zoledronic acid,
    identified. Combined analysis improves diagnosis and assess-                 is also appropriate for patients with endocrine-resistant
    ment of response to therapy. The use of magnetic resonance                   metastatic bone disease from prostate cancer and a broad
    imaging (MRI) or position emission tomography (PET) scans,                   range of other solid tumors. Patients with symptomatic
    which have improved diagnostic sensitivity, depends on their                 metastasis to bone should be considered for treatment with
    availability, patient throughput and cost. MRI commonly costs 2-             zoledronic acid, especially if bone is the dominant site of
    3 times more than a bone scan, and PET often 8 times as much.                metastasis and/or the prognosis is more than three to six
                                                                                 months. Patients with renal cell cancer particularly appear
    Bisphosphonate Therapy                                                       to benefit from treatment.18
    Bisphosphonates are the principal therapeutic option
    currently available to treat skeletal-related events associated              Pamidronate
    with bone metastasis. Over the past decade, successive                       Pamidronate (90 mg infused over 2-4 hours) was demon-
    generations of ever more potent nitrogen-containing                          strated to significantly reduce the incidence and delay the
    bisphosphonates with higher therapeutic indices have been                    onset of skeletal complications in patients with osteolytic
    developed. In the late 1990's, the second-generation bisphos-                lesions from multiple myeloma or metastatic breast cancer in
    phonate pamidronate (Aredia®, Novartis Oncology, East                        three randomized, placebo-controlled trials. In patients with
    Hanover) received international regulatory approval and                      multiple myeloma, pamidronate significantly decreased the
    became a standard treatment for preventing SREs in patients                  percentage of patients who experienced a skeletal complica-
    with breast cancer or multiple myeloma. In 2002 zoledronic                   tion and significantly reduced the mean annual incidence of
    acid (Zometa®, Novartis Oncology, East Hanover) was                          skeletal complications.19 In patients with breast cancer,
    approved to treat skeletal morbidity associated with bone                    pamidronate significantly reduced the percentage of patients
    metastasis from breast cancer and multiple myeloma, as well                  who experienced a skeletal complication and extended the
    as bone metastasis secondary to any solid tumor, including                   median time to the onset of skeletal complications by almost
    prostate, lung and renal cell cancers. It is now considered the              6 months.18
    standard of care for the SREs associated with bone metasta-
    sis. Three other bisphosphonates have now received regula-                   Zoledronic Acid
    tory approval for use in the oncology setting outside the US,                Zoledronic acid is the most potent bisphosphonate currently
    including ibandronic acid (Boniva®, GlaxoSmithKline and                      available. It was first demonstrated to be superior to
    Roche Laboratories), risedronate (Actonel®, Proctor and                      pamidronate in the treatment of hypercalcemia of malignancy.20
    Gamble Pharmaceuticals, Cincinnati) and clodronate                           The phase III testing program of zoledronic acid was conducted
    (Bonefos®, Schering AG, Berlin).                                             in over 3,000 patients with bone lesions from multiple myeloma
or bone metastases secondary to breast, prostate, lung cancer                                 Patients were treated with zoledronic acid every 3-4 weeks
and a variety of other solid tumors. Zoledronic acid (4 mg                                    for up to 2 years. In the final 25-month analysis of these
via 15-minute infusion) is currently the only bisphosphonate                                  patients, zoledronic acid was equivalent to pamidronate and
approved around the world for use in treating bone lesions                                    reduced the overall risk of developing skeletal complications
from all malignancies.                                                                        (including hypercalcemia of malignancy) by an additional 16%
                                                                                              relative to pamidronate as assessed by multiple event
In the largest single trial of bisphosphonates (n=1,648), zole-                               analysis.22 In patients with breast cancer, zoledronic acid
dronic acid was compared with pamidronate in patients with                                    reduced the risk of SREs by an additional 20% compared
bone lesions from breast cancer or multiple myeloma.21                                        with pamidronate.


  Figure 2
  Zoledronic Acid vs Placebo in Prostate Cancer

              2A: Efficacy


                             60%   Zoledronic acid 4 mg (n=214)                                  Zoledronic acid 4 mg (n=74)
                                   Placebo (n=208)                                               Placebo (n=58)
                                                                                                       49%                     Percentage of prostate cancer
                             50%
                                                                                  44%                                          patients with ≤ 1 SRE who
                                                                                                                                                                    9
    Patients with ≥ 1 SRE




                                                                                                 38%                           have cancer progression
                             40%
                                                                           33%                                                 after treatment with at least
                                                              31%                                                              one hormonal therapy.
                             30%
                                          23%
                                                        21%
                             20%                                                                                               Saad F. Clinical benefit of zole-

                                   12%                                                                                         dronic acid for the prevention
                             10%                                                                                               of skeletal complications in
                                                                                                                               advanced prostate cancer.
                              0%                                                                                               Clin Prostate Cancer. 2005
                                   P=.003                P=.025             P=.021                P=.028                       Jun; 4(1):31-7.
                                   Month 3               Month 6           Month 15              Month 24
                                                         Patients without SREs


     2B: Median Time to First Skeletal-Related Event

                  100%                                                             Zoledronic acid 4 mg
                                                                         P=.009
                                                                                   Placebo

                            80%                                     >5 months

                                                                                                                               Saad F, Gleason DM, Murray R
                            60%
                                                                                   Median: 488 days          11% absolute      et al. Zoledronic Acid Prostate
                                          Median: 321 days                                                   reduction in      Cancer Study Group. Long-term
                            40%                                                                              patients with     efficacy of zoledronic acid
                                                                                                             ≥1 SRE
                                                                                                             (P=.028)          for the prevention of skeletal
                            20%                                                                                                complications in patients with
                                                                                                                               metastatic hormone-refractory
                                                                                                                               prostate cancer. J Natl Cancer
                            0%
                                    120           240         360          480          600            720                     Inst. 2004 June 2; 96(11): 879-82.
                                                Time after start of therapy (days)
     Zoledronic acid is the only bisphosphonate to demonstrate            bisphosphonate experience an infusion reaction.27 Acute-
     long-term efficacy in men with advanced prostate cancer. In a        phase reactions are typically self-limiting, resolve within 24-48
     24-month randomized trial in men with hormone refractory             hours, and occur less frequently after subsequent infusions.
     metastatic prostate cancer, zoledronic acid significantly            Supportive care, such as nonsteroidal anti-inflammatory drugs,
     reduced the percentage of patients with a skeletal complica-         acetaminophen, and adequate hydration, are often sufficient
     tion by 25% compared with placebo, reduced the percentage            management of the acute-phase reaction.
     of patients who experienced each type of skeletal complica-
     tion and reduced the mean skeletal morbidity (0.77 vs. 1.47          Intravenous bisphosphonates are excreted primarily by the
     SREs/year) compared with placebo. In addition, zoledronic            kidneys and may cause an increase in serum creatinine levels.
     acid delayed the median time to the first SRE by more than 5         Intravenous bisphosphonates are associated with dose and
     months. Patients treated with zoledronic acid had a 36%              infusion rate dependent effects on renal function. In the
     lower risk of developing an SRE by multiple event analysis and       clinical trials evaluating zoledronic acid, 8 mg treatment arms
     pain scores were reduced relative to the placebo group at            were discontinued due to renal toxicity. The infusion of 4 mg
     every time point.23                                                  was increased from 5 to 15 minutes because of renal toxicity.
                                                                          Based on these observations, the modifications in package
     Zoledronic acid has also demonstrated significant benefits in        inserts for both pamidronate and zoledronic acid require
     patients with bone metastases from solid tumors other than           testing of patients for renal sufficiency before dosing.
     breast or prostate cancer. Zoledronic acid significantly
     delayed the median time to the first skeletal complication by        Osteonecrosis of the jaw (ONJ) is the presence of exposed
10   more than 2 months and significantly delayed the median time         bone in the mandible or maxilla for a period of 8 weeks or
     to the first pathologic fracture. Multiple event analysis revealed   longer with proper dental care in the absence of infection
     a 27% reduction in the overall risk of developing a skeletal         or tumor in the jaw. Osteonecrosis has been reported in
     complication among patients treated with 4 mg zoledronic             patients receiving bisphosphonate therapy, both oral and IV.
     acid.The benefits to the overall population are especially           The frequency of ONJ has previously been reported in
     profound given the poor prognosis of the overall patient             patients receiving cytotoxic chemotherapy, corticosteroids,
     population (median survival was only 6 months).24 In a               and stem cell transplant. The frequency of ONJ has been
     retrospective subset analysis of patients with renal cell cancer,    estimated in a number of retrospective studies. An MD
     zoledronic acid reduced the risk of developing an SRE by 61%         Anderson chart review of 3,994 patients with metastatic
     and significantly prolonged the time to first SRE and time until     bone disease receiving cancer therapies, which included
     bone lesion progression.25                                           bisphosphonate treatment, estimated the overall frequency
                                                                          at 0.73%.28 The incidence appears to be higher in patients
     For patients in whom a less potent bisphosphonate, such as           with multiple myeloma ranging from 2-10%.29 The frequency
     pamidronate or clodronate, proves unsatisfactory, switching          of ONJ is difficult to estimate, and relies extensively on retro-
     to a more potent agent like zoledronic acid may be an appro-         spective review. The variation in the reported frequency of
     priate option. Clemons et al. conducted a phase II clinical trial    ONJ may be, in part, because until recently there was no
     involving 31 patients with breast cancer who had experienced         consensus definition for ONJ.
     progression in bone or a skeletal complication while on
     pamidronate or clodronate therapy.Thirteen of 31 (42%)               Practice guidelines for the prevention, diagnosis and manage-
     subjects who were switched to monthly zoledronic acid                ment of ONJ in cancer patients were recently published.30
     reported a reduction in pain (P<.001) and showed significant         Before starting bisphosphonate therapy, patients should be
     reductions in urinary markers of bone turnover (P=.008).26           encouraged to have a routine dental examination. If the
                                                                          patient requires a surgical dental procedure, then it is recom-
     Bisphosphonate Safety                                                mended that it be completed before initiation of bisphospho-
     The safety profile of zoledronic acid is well defined from the       nate therapy when possible. While on therapy, patients
     large database of phase III clinical trials. The most common         should maintain excellent oral hygiene and avoid invasive den-
     adverse events include bone pain, myalgia, nausea, fatigue,          tal procedures, if possible. A conservative approach is recom-
     pyrexia and emesis. These events are among those that                mended to treat ONJ. This includes antibiotics, oral rinses,
     characterize an initial infusion (acute-phase) reaction.             pain control and limited debridement.
     Approximately 33% of patients receiving an intravenous
  Table 3
  Ongoing Trials of Bisphosphonates to Prevent Bone Metastasis
                                                                                                                    Primary
  Trial                   Phase       Design                            Patient No.          Population             Endpoint

  NSABP34                    III     Randomized; standard therapy      3000- enrollment      Women, stage I-III     Disease-free
                                     with clodronate or placebo        completed             breast cancer          survival

                                     Randomized, open label,           3,360-                Women,
                                     neoadjuvant or adjuvant           enrollment            stage II or III        Disease-free
  AZURE35                    III     chemotherapy and/or               completed             breast cancer at       survival
                                     hormonal therapy with                                   high risk
                                     vs without zoledronate                                  of relapse

                                     Randomized, open label:           950 out of            Women,
                                     standard therapy plus either      4,500 planned         stage I-III            Disease-free
  SWOG S0307      37
                             III     zoledronic acid, oral             enrollment            breast cancer          survival
                                     ibandronate or oral clodronate

Trials represented: National Surgical Adjuvant Breast and Bowel Project (NSABP), Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE),
South Western Oncology Group (SWOG)
                                                                                                                                           11

Bisphosphonates in Preventing Bone Metastasis                           metastasis, but also through direct effects on tumor cells in
Because bisphosphonates are potent inhibitors of bone                   the bone marrow and possible synergy with adjuvant
osteolysis, their use in early cancer could be an adjuvant              chemotherapy.The AZURE study will assess disease-free sur-
therapeutic strategy of potential importance.31 Bisphos-                vival and time to bone and distant metastasis in patients treat-
phonates may also have direct effects on tumor cells in the             ed with standard anticancer therapy alone, compared to
bone marrow microenvironment.32 Although clinical trial                 those treated with standard therapy plus zoledronic acid (4
results with the early bisphosphonate clodronate have proved            mg) administered initially monthly for 6 doses, and then every
inconclusive in metastasis prevention,33 several large phase III        3-6 months to complete 5 years of treatment. Recruitment
clinical trials with clodronate and zoledronic acid now under-          was completed in early 2006. Initial results indicate that zole-
way to assess the ability of bisphosphonates to prevent bone            dronic acid given with neoadjuvant chemotherapy caused a
metastasis: NSABP, AZURE and S0307, with results expected               significant proportion of women with no detectable DTC at
in 2008/2009 (Table 3). Results of these studies are eagerly            baseline to continue to be DTC-free at 3 months. Reports of
awaited.                                                                the first full efficacy data are expected in 2008/2009.36


The National Surgical Adjuvant Breast and Bowel Project                 A third trial, the South Western Oncology Group study
(NSABP) B-34 trial of adjuvant clodronate has randomized                S0307, is ongoing and is planned to recruit 4500 women
over 3000 women with stage I-III breast cancer to daily oral            with stage I-III breast cancer. Following completion of adjuvant
clodronate or placebo in addition to standard adjuvant treat-           chemotherapy, patients are randomized to zoledronic acid
ment(s).34 Accrual was completed more than 3 years ago but,             4 mg monthly for 6 months then 3 monthly, oral ibandronate
due to the low event rate, efficacy results are not anticipated         50mg daily or oral clodronate 1600mg daily.37
until 2008/2009.

The Adjuvant Zoledronic Acid to Reduce Recurrence
(AZURE) trial has finished accrual of 3,360 relatively high-risk
patients with stage II or III breast cancer.35 The trial tested the
hypothesis that zoledronic acid may have beneficial effects, not
only through the inhibition of bone resorption and reduction
in growth factors and cytokines in the bone marrow micro-
environment that appear to promote the development of a
                                                            NOVEL BONE-TARGETED THERAPIES
                                                                                  Allan Lipton, MD
                                                                                  Penn State University
                                                                                  Milton S. Hershey Medical Center
                                                                                  Hershey, Pennsylvania


     Although management of tumor-induced bone loss can                           Denosumab (AMG-162) is an investigational, fully human mon-
     potentially include therapies to inhibit bone resorption or                  oclonal antibody that specifically binds RANK L, thereby inhibit-
     stimulate bone formation, the most advanced approaches                       ing osteoclast-mediated bone destruction and blocking the
     currently are focused on blocking bone resorption. Table 4, on               vicious cycle typical of cancer-mediated bone disease. As a
     the next page, lists novel bone-targeted agents in development.              human immunoglobulin G2 molecule, it has a long circulatory
                                                                                  residence time and results in a rapid and sustained decrease of
     Inhibiting Osteoclast Differentiation: Denosumab                             bone resorption in both healthy postmenopausal women and
     As discussed above, activated osteoclasts are found in proximi-              patients with bone metastases. Denosumab does not cause
     ty to tumor cells and play a key role in patients with multiple              renal toxicity and results in fewer acute phase reactions than
     myeloma and solid tumor-related bone metastases. A triad of                  bisphosphonates. Denosumab is in phase IIl trials in patients
     molecules has been shown to regulate the maturation, differ-                 with postmenopausal osteoporosis and metastatic cancer.40,41
     entiation, and survival of osteoclasts: RANK, RANK Ligand
     (RANK L) and osteoprotegerin. RANK L, a member of the                        Two phase II randomized trials are now being conducted to
12   tumor necrosis family, binds to RANK on preosteoclasts and                   assess the safety and efficacy of denosumab as compared to
     mature osteoclasts and mediates the differentiation, function                intravenous (IV) bisphosphonates (BP) in reducing urinary
     and survival of osteoclasts. Osteoprotegerin, a natural soluble              markers of bone resorption in metastatic bone cancer.
     decoy receptor of RANK L, modulates the effect of RANK L                     Interim analysis from one of these trials was reported by
     and is able to prevent excessive bone resorption.38,39 An                    Lipton et al. in bisphosphonate-naïve breast cancer patients
     excessive production of RANK L by osteoblasts plays                          with bone metastases showed that denosumab suppressed
     a key role in the pathogenesis of tumor-induced osteolysis.                  levels of bone turnover markers to an extent similar to that
     Inhibition of RANK L in animal models prevents tumor-                        seen with intravenous bisphosphonates.41 This study enrolled
     induced bone destruction.                                                    255 women who were stratified by type of antineoplastic
                                                                                  therapy received and randomly assigned to one of six
                                                                                  cohorts: five denosumab and one open-label IV BP. The


       Figure 3
       Denosumab Effects on Bone Turnover in Breast Cancer
       20%                                          IV BP                             Denosumab 180 mg Q4W
                                                    Denosumab 30 mg Q4W               Denosumab 60 mg Q12W
                                                    Denosumab 120 mg Q4W              Denosumab 180 mg Q12W
        0%
                                                                                      All Denosumab

      -20%

      -40%

      -60%

      -80%

     -100%
             0        2             5                   9                  13                 17                 21 Study Week 25

     Source for data: Lipton A, et al. J Clin Oncol. 2006; 24(18S):6S abstract #512


     Median (Q1, Q3) percentage reduction in urine N-telopeptide (uNTx) corrected for urine creatine level (INTx/Cr) from baseline through
     study week 25. All denosumab (subcutaneous) versus intravenous bisphosphnate (IV BP) and denosumab dose groups versus IV BP. Study
     week 1= baseline. Q4W= every 4 weeks; Q12W= every 12 weeks.
primary endpoint for the study was median percent change                     selective cathepsin K inhibitor. In a recently completed phase II
in the bone turnover marker urine N-telopeptide corrected                    trial in women with breast cancer and bone metastasis,
for urine creatinine (uNTx/Cr) from baseline to study week                   odanacatib suppressed markers of bone resorption uNTx and
13. Secondary endpoints included percentage of patients                      UDPD after 4 weeks of treatment. 45 Another novel cathepsin
achieving >65% uNTx/Cr reduction, time to >65% uNTx/Cr                       K inhibitor, Balicatib (formerly AAE581, Novartis Oncology,
reduction, patients experiencing one or more on-study skeletal               East Hanover), has been shown to reduce breast cancer
related events (SRE), and safety. Suppression of uNTx/Cr was                 induced osteolysis and skeletal tumor burden
seen in all treatment groups. In the denosumab groups this                   in an animal model. Several Phase II studies have recently
reduction was seen at the first study visit after initial dosing             completed accrual in postmenopausal women with osteope-
and through week 13 (Figure 3).                                              nia/osteoporosis. The primary endpoints of these trials are
                                                                             changes in bone mineral density.46
At 13 weeks on study the median percent reduction in
uNTx/Cr was 71% for the pooled denosumab treatment                           Src is a tyrosine kinase that is required for the formation of the
groups and 79% for the IV BP group. Greater than 65%                         ruffled border in osteoclasts. The importance of Src in osteo-
reduction in uNTx/Cr occurred in 74% of the denosumab-                       clast activity is revealed by Src null mice that develop osteopet-
treated patients and 63% in the IV BP-treated patients (91%                  rosis because of the lack of bone resorption. Inhibition of Src
received zoledronic acid). The median time to >65% reduc-                    activity decreases skeletal destruction in animal tumor model
tion in uNTx/Cr reduction was 13 and 29 days for all deno-                   systems.47,48 Dasatinib (BMS-354825, Bristol-Myers Squibb,
sumab and IV BP treatment groups respectively.The time to                    New York), an inhibitor of multiple tyrosine kinases, is currently
the first on-study SRE appeared to be similar for patients in                on the market place for the treatment of adults with resistant        13
the denosumab and IV BP cohorts. On study SREs were                          CML and Philadelphia chromosome positive ALL. Two phase II
experienced by 9% (20 of 211) and 16% of the denosumab                       trials are now ongoing to assess the efficacy of dasatinib alone
and IV BP cohorts, respectively. The incidences of adverse                   or in combination with zoledronic acid in patients with breast
events (AEs) were similar among the denosumab and IV BP                      cancer and bone metastasis. In these trials changes in bone
cohorts and the pattern of the AEs were consistent with                      turnover markers, tumor response, progression free survival
advanced cancer patients receiving systemic therapy. These                   and overall survival will be evaluated.49,50 AZD0530
early data suggest that denosumab may be similar to IV BPs                   (AstraZeneca, Wilmington), a dual inhibitor of Src/Abl kinase
in suppressing bone turnover and reducing SRE risk.                          inhibitor, is also being evaluated in metastatic bone cancer. 51

Three phase III trials are now ongoing, comparing the safety                 Chemokine Antagonists
and efficacy of denosumab to zoledronic acid for the treat-                  Stromal cell derived factor 1 (SDF-1) is a chemokine that
ment of bone metastases in breast cancer, hormone-refractory                 regulates stem cell activity, and its action on cancer cells is
prostate cancer, advanced cancer (excluding breast and                       thought to promote their migration to SDF-1-rich areas such
prostate) and myeloma patients. A fourth phase III study being               as the bone marrow, liver, and lungs, with subsequent angio-
conducted is a randomized, double-blind, placebo-controlled                  genesis and metastasis. CTCE-9908, an analog of SDF-1 now
study of denosumab on prolonging bone metastasis-free                        in Phase I/II clinical testing, acts as a competitive antagonist at
survival in men with hormone refractory prostate cancer.42                   CXCR4 receptors commonly found on the surfaces of stem
There are also two phase III clinical trials in patients with non-           cells and various common cancers.
metastatic cancer. The purpose of these studies is to evaluate
denosumab for the treatment of bone loss in subjects under-
going aromatase inhibitor therapy for breast cancer and              Table 4
androgen deprivation therapy for prostate cancer.                    Novel Agents Targeting Bone in Development
                                                                     Agent                   Target               Clinical Development Phase
Inhibiting Osteoclast Signaling:
                                                                     Denosumab                RANK L                    Phase III
Inhibitors of Cathepsin K and Src
Cathepsin K is a lysosomal protease that is highly expressed         CTCE-9908                Stem cells                Phase I/II
in osteoclasts and plays a key role in the degradation of bone       MK-0822                  Cathepsin K               Phase II
collagen. Inhibitors of cathepsin K effectively suppress bone        AAE581                   Cathepsin K               Phase II
resorption in animal tumor models.43,44 Odanacatib (former-          Dasatinib                Tyrosine kinases          Phase II
ly MK-0822, Merck & Co, Whitehouse Station) is a highly
                                                                     AZD0530                  Src/Able kinases          Phase II
                                                 PRESERVING NORMAL BONE HEALTH
                                                                          Robert E. Coleman, MD, FRCP
                                                                          Professor of Medical Oncology
                                                                          Cancer Research Centre
                                                                          Weston Park Hospital Sheffield, United Kingdom


     Predicting Who Will Develop Bone Metastases                            Table 5
     There is increased interest in personalized medicine whereby
                                                                            Predictors of Bone Metastisis
     biological factors are utilized to predict the probability or
                                                                            From Breast Cancer
     distribution of recurrence following treatment of early cancer.
     In breast cancer, gene expression profiling has identified genetic      Established Clinico-pathological Characteristics
     signatures that are strongly associated with prognosis52,53
                                                                             Tumor size
     possibly outperforming conventional panels of clinical and
     pathological criteria. However the risk of metastasis per se            Axillary lymph node involvement
     does not necessarily predict for metastasis to specific sites.          Histological grade
     Recently a 69 gene signature was described that predicted               Estrogen and progesterone receptor status
     specifically for metastasis to bone as opposed to metastasis in         Epidermal Growth Factor (EGFR) -1 and -2 (HER 2) status
     other sites.54 The set of genes expressed suggested involve-
                                                                             Circulating (CTC) or Disseminated (DTC) tumor cells
     ment of the fibroblast growth factor receptor (FGFR) pathway
14   in the process of metastasis to bone. Subsequently, a classifier
                                                                             Potential Predictive Biomarkers
     of 31 genes was constructed which was able to predict all
     tumors relapsing in bone with a specificity of 50%. Much more           Proliferation markers (Ki-67 and Cyclin D1)
     work is required to confirm the utility of genetic profiling in         Collagen breakdown products
     clinical management but this approach holds much promise.               Bone sialyl protein (BSP)
                                                                             Osteopontin (SPARC)
     There are also an increasing number of individual tissue-based
                                                                             Parathyroid Hormone Related Protein (PTHrP)
     markers that predict for metastasis to bone.The association
     between estrogen receptor (ER) expression and bone metastasis           Dickopf 1 protein (DKK-1)
     has been appreciated for over 20 years.55 More recently other           Wingless-related MMTV integration site (Wnt) proteins
     markers, especially the non-collagenous bone proteins, have             Bone Morphogenic Proteins (BMPs)
     been suggested as predictors of bone recurrence (Table 5).              Receptor activator of nuclear factor kappa B (RANK)
     These have included bone sialoprotein (BSP), which in addi-
                                                                             RANK-ligand (RANKL)
     tion to appearing to predict for bone metastasis in breast
                                                                             Macrophage Colony Stimulating factor (M-CSF)
     cancer,56 may be relevant in other tumors with a propensity
     to metastasize to bone.57 Again, further study is required but,         Macrophage In ammatory Protein (MIP-1α)
     assuming bone specific therapies do have an impact on the               Chemokine-ligand-receptors (CXC 12 and 4)
     development of metastases, identification of patients at high           Transforming Growth Factors (TGF) α and β
     risk of bone metastasis, especially by simple tissue based              Fibroblast Growth Factors (FGFs)
     assays such as BSP, would be very valuable for patient
                                                                             Insulin-like Growth Factors (IGFs)
     selection over and above the traditional clinico-pathological
                                                                             Interleukin-6 (IL-6)
     characteristics.
                                                                             Interleukin-8 (IL-8)

     Prioritizing Bisphosphonate Use in Advanced Cancer                      Endothelin-1
     Despite the obvious clinical benefits of bisphosphonates, data           Cathepsin K
     from recent studies suggest that only a proportion of SREs              Matrix metalloproteinases (MMP 2 and 9)
     are prevented. In addition, because some patients do not                A Disintegrin and Metalloprotease with Thrombospondin
     experience a SRE despite the presence of metastatic bone                Motifs (ADAMTS) family
     disease, it is often not possible to predict accurately whether an      Plasminogen activators (uPA and tPA)
     individual patient needs or will benefit from bisphosphonate
                                                                             Gene Pro le of Primary Tumor
treatment. Bisphosphonates are a relatively costly additional                   zoledronic acid (4 mg) on a marker-directed schedule based
intervention in cancer care that is now potentially applicable                  on changes from baseline Ntx.The primary endpoint is the
to a very large proportion of patients with advanced malig-                     frequency and timing of SREs. Secondary endpoints include
nancy.The cost effectiveness of routine long-term treatment                     the evaluation of pain, quality of life, incidence of new bone
has been questioned, and prioritization of bisphosphonate use                   metastases and overall survival.
is needed. 58,59
                                                                                Uncertainty remains as to the appropriate duration and
A report on the use of the bone resorption marker                               schedule of treatment. Bone marker-directed therapy is
n-telopeptide of type I collagen (Ntx) suggested that bio-                      under evaluation in randomized clinical trials and the value
chemical monitoring could be useful to identify patients at                     of maintenance therapy after one to two years of treatment
increased risk of bone complications.58 In this study of 121                    may become clear from the Optimize trial ongoing in the
patients, all skeletal complications, hospital admissions for                   United States.
control of bone pain, and deaths during the period of
observation were recorded. Ntx was strongly correlated                          Treatment-Induced Bone Loss
with the number of skeletal events and/or deaths (p<0.001).                     Breast Cancer
Patients with Ntx values above 100 nmol/mmol creatinine                         Tamoxifen has been the cornerstone of adjuvant endocrine
were many times more likely to experience an SRE or death                       therapy for breast cancer for several decades. Recent research
than those with Ntx below this level (p<0.01).Thus, a more                      indicates, however, that the use of aromatase inhibitors (AIs),
cost-effective use of bisphosphonates, particularly in patients                 anastrozole, letrozole and exemestane, may further reduce
with additional extensive visceral metastases or solid tumors                   the risk of recurrence after a diagnosis of estrogen receptor-    15
associated with a short life expectancy, might be to prioritize                 positive breast cancer when given either in place of tamoxifen
them in patients with raised Ntx levels.                                        or after a few years of tamoxifen therapy.63-67 Overall,
                                                                                Als have a favorable side-effect profile but, due to the known
Further clinical evidence of correlations between bone mark-                    relationships between residual estrogen levels and fracture
er levels and patient outcomes has come from retrospective                      risk,68 the associated marked reduction in estradiol would be
analyses of large randomized trials with zoledronic acid.60,61                  expected to have significant effects on bone physiology.This
Elevated on-study bone marker levels correlated with nega-                      has been confirmed in a range of studies and the use of Als is
tive clinical outcomes in patients with metastatic breast                       indeed associated with increased bone turnover leading to a
cancer, prostate cancer, lung cancer, or other solid tumors.52                  loss of bone mineral density (BMD) and an increased rate of
Specifically, patients with elevated urinary Ntx levels either                  fracture (Table 6) .
at baseline or at their most recent assessment
had an approximate 2-fold increase in their risk of            Table 6
disease progression and an approximate 2- to 3-fold            Effects          of Aromatase Inhibitors on Fracture Risk
increase in their relative risk of skeletal-related events                                Fracture Incidence    Fracture Incidence
(SREs) compared with patients with low Ntx                                                in Aromatase          in Tamoxifen/
levels.60,61 Elevated Ntx levels clearly have negative                                    Inhibitor Treated     Placebo Treated    Increase
prognostic implications, and there is a continuum              Study                      Patients              Patients           (%)
of risk among all patients with bone lesions.62                ATAC 63
                                                                                          340 (11%)             237 (7.7%)            43
                                                                  (Anastrozole)
It has been proposed that the aim of bisphosphonate               BIG1-98 64
                                                                                          211 (8.6%)            237 (7.7%)            50
treatment should be to adjust the dose and schedule               (Letrozole)
to maintain a normal rate of bone resorption.                     IES 65
                                                                  (Exemestane)            162 (7.0%)            115 (4.9%)            41
Randomized trials to assess this approach are in
progress, including the BISMARK trial (cost-effective             ABCSG 66
                                                                  (Anastrozole)           34 (2.0%)              16 (1.0%)            113
use of BISphosphonates in metastatic bone disease: a
comparison of bone MARKer-directed zoledronic acid                MA17 67
                                                                  (Letrozole)             137 (5.3%)            119 (4.6%)            15
therapy to a standard schedule). This study is planned
to enroll 1,500 patients with bone metastases from          Trials represented: Arimidex,Tamoxifen, Alone or in Combination (ATAC), Breast
breast cancer. Patients will be randomized to receive       International Group (BIG 1-98), Intergroup Exemestane Study (IES), and the
either zoledronic acid (4 mg) every 3 to 4 weeks or         Austrian Breast Cancer and Colorectal Cancer Study Group (ABCSG)
     In comparison to naturally occurring bone loss, Al-associated                  The bisphosphonates are the preferred treatment for Al-
     bone loss is more marked with particularly rapid rates of loss                 induced bone loss.The results of several intervention studies
     in the immediate postmenopausal period.69-71 However the                       with zoledronic acid have been recently published,69-73 and
     risk for fractures is more complex than changes in BMD alone,                  preliminary data are also available from smaller studies using
     and, as in postmenopausal osteoporosis, other factors including                oral bisphosphonates at standard osteoporosis doses, such
     family history, lifestyle, concomitant medication, and nutrition,              as ibandronate in the ARIBON trial74 and risedronate in the
     all influence the risk for bone loss and may interfere with                    SABRE trial (Table 7).75 The data from these studies demon-
     assessing the effect of therapy-induced bone loss.72                           strate the ability of bisphosphonates to prevent bone loss
                                                                                    when given concurrently with Als.




                  Table 7
                  Trials of Bisphosphonates in Bone Loss Prevention
                  Secondary to Breast Cancer Treatment
                                                                         No.                                    Primary
                  Trial            Phase        Design                   Patients     Population                Endpoint           Results

16               ABCCSG 69          III     Randomized, OL                401         Premenopausal,            Percent change     Zoledronic acid
                                            lgoserelin & tamoxifen                    early breast cancer,      BMD at             prevented
                                              with or without                         receiving adjuvant        36 months          bone loss
                                              zoledronic acid                         endocrine therapy
                                            lgoserelin & anastrozole                  for hormone
                                              with or without                         responsive
                                              zoledronic acid                         breast cancer

                 Z-FAST 70          III     Randomized, OL                602         Postmenopausal,           Percent change     Immediate
                                            lImmediate zoledronic                     breast cancer,            LS BMD at          zoledronic acid
                                              acid                                    receiving adjuvant        12 months          therapy prevents
                                            lDelayed zoledronic                       letrozole therapy                            bone loss
                                              acid

                 ZO-FAST 71         III     Randomized, OL                1,065       Postmenopausal,           Percent change     Immediate
                                            lImmediate zoledronic                     stage I, II, or IIIa,     BMD                zoledronic acid
                                              acid                                    ER and/or PR                                 therapy prevents
                                            lDelayed zoledronic                       positive breast cancer                       bone loss
                                              acid

                 ARIBON 72          IV      Randomized, DB                 50         Postmenopausal,           Percent change     Ibandronate
                                            lIbandronate                              breast cancer,            LS BMD             prevented
                                            lplacebo                                  osteopenic,               at 12 months       bone loss
                                                                                      receiving anastrole
                                                                                      adjuvant therapy

                 SABRE 73           III     Randomized                    154         Postmenopausal,           Percent change     Risedronate
                                            lrisedronate                              hormone receptor          LS BMD             prevented
                                            lplacebo                                  responsive breast         at 12 months       bone loss
                                                                                      cancer, low risk of
                                                                                      fracture, adjuvant
                                                                                      anastrozle

                Trials represented: Austrian Breast and Colorectal Cancer Study Group (ABCCSG), Zometa-Femara Adjuvant Synergy Trial (ZO-
                FAST), Effect of oral ibandronate on anastrole induced bone loss (ARIBON), Study of Anastrozole with the Bisphosphonate
                Risedronate (SABRE), open label (OL), double blind (BD), estrogen receptor (ER), progesterone receptor (PR), lumbar spine (LS),
                bone mineral density (BMD).
Prostate Cancer
Many men with prostate cancer are at risk of developing                                            CONCLUSION
osteoporosis, largely because of the androgen deprivation
therapy (ADT) they receive for their cancer. ADT is being
introduced earlier and earlier in the course of the disease
with the result that men may experience many years of
androgen suppression. ADT results in substantially reduced         Issues and Opportunities for the Treating Physician
serum concentrations of testosterone (to less than 5%              As the U.S. population ages, both the number of patients with
normal level) and estrogen (to less than 20% of normal level).     cancer and the number presenting with bone metastases are
                                                                   expected to increase, challenging practicing physicians and our
It might be expected that androgen deprivation would lead to       approaches to treatment. Recent advances in our under-
increased bone loss and increased fracture rate. As yet there      standing of the process of bone metastasis and treatment
appear to have been no large prospective studies of the rela-      have provided treating physicians with greater opportunity to
tionship between fracture rate and androgen deprivation            counsel their patients about the risk of developing bone
therapy but retrospective studies indicate a significantly         metastases, and new therapies to possibly prevent their
increased fracture rate with an estimated 10 year fracture         occurrence and to treat the disease. Clinical trials are ongoing
free survival of only 60%.76 As the potential scale of the prob-   to test new therapies to prevent and treat bone metastases,
lem is being realized, management guidelines to assess those       and information from these trials is being rapidly disseminated
at risk are in development and therapeutic options such as         in clinical meetings as well as online and in the lay press.
bisphosphonates to prevent or treat therapy related bone                                                                                 17
loss in prostate cancer are under investigation. Pamidronate       Patients are more aware than they have ever been of these
given on a three monthly schedule has been shown to pre-           trials and will need informed physicians to help them navigate
vent loss in BMD in patients with locally advanced prostate        the wealth of information that will be available. More fre-
cancer.77 A multi-centre prospective study has evaluated zole-     quently, clinical trials are now utilizing physicians not based at
dronate in locally advanced or recurrent prostate cancer.78 At     academic centers to participate in trials and make these novel
1 year, in the zoledronic acid arm, BMD increased by 5.3% at       agents available to their patients. Thus, physicians need to be
the lumbar spine and 1.1% in the total hip. In the placebo         aware of new treatments for bone metastasis, be able to dis-
arm, the BMD decreased by 2% in the lumbar spine and 2.8%          cuss the prevention and treatment of side effects of current
in the total hip.                                                  and new therapies and their potential benefits and risks with
                                                                   their patients and, if possible, have their patients participate in
A number of other phase II, III, and IV trials are ongoing to      clinical trials.
evaluate the safety and efficacy of zoledronic acid to prevent
bone loss caused by cancer treatment induced bone loss and
to prevent further bone loss in osteoporotic patients with
prostate cancer.
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Advances in Treating Metastatic Bone Cancer
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