16000417-3 KYPHON ® Balloon Kyphoplasty Minimally Invasive Treatment of Tumor-Related Vertebral Compression Fractures

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KYPHON® Balloon Kyphoplasty

Minimally Invasive Treatment of Tumor-Related Vertebral Compression Fractures

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Regulation of Bone Metabolism

1. Roodman GD, NEJM, 350;16,2004

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Metastatic Bone DiseaseEpidemiology

Definition: Tumors in bone arising from distant, non-bone source.

Vast majority of skeletal cancers are metastatic rather than primary.

30-70% of the roughly 563,700 people who die annually of cancer have bone metastasis.1

1. Coleman. Cancer Treatment Reviews. 2001;27:165-176.

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VCFs in Metastatic Cancer and Multiple Myeloma An estimated 75K-100K

cancer induced VCF occur annually in the U.S. Stage IV Breast1 and

Lung All Stages of Multiple

Myeloma2,3,4,5,6

Stage III and IV of Prostate7,8

1. Hortobagy et al, NEJM, Vol. 335, No. 24, ppg. 1785-17912. Berenson et al, NEJM, Vol. 334, No. 8, ppg. 488-4933. Brincker et al, British Journal of Haematology, 1998, V.101, ppg 280-2864. McCloskey et al, 1998, V.100, ppg 317-3255. Melton et al, V.20, No. 3, 2005, ppg 487-4936. Djulbegovic et al, The Cochrane Database of Systematic Reviews, 2002, Issue 4. Art. No.: CD003188, pg.1-327. Berruti et al, The Journal of Urology, Vol. 164, 0ct. 2000, ppg. 1248-12538. Diamond et al, Journal of Urology, Volume 172, pg. 529-532, August 2004

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Metastatic Bone DiseaseFractures

Patients with cancer are at elevated risk for osteoporosis and fractures both because of their disease and its treatment1

Metastatic cancer in the bone causes skeletal complications every 3 to 4 months.2

17 – 50% of patients with metastatic breast cancer will develop VCFs annually.3

Annual incidence of vertebral fracture is elevated 5-fold among women with newly diagnosed breast cancer1

36-fold among those with a soft-tissue recurrence of breast cancer, relative to women without breast cancer

Median time to first fracture among breast cancer patients (not on bisphosphonate) with at least one lytic lesion is 12.8 months.4

1. Theriault RL, The Oncology Report, 20062. Coleman RE. Ann Oncol. 2000;11:179-184. 3. Body. Cancer. 2003;97:859-865.4. Hortobagyi GN, Theriault RL, Lipton A, et al. J Clin Oncol. 1998;16:2038-2044.

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Metastatic Bone DiseaseLesion Types

Osteoblastic Increased bone density Does not change bone strength but

decreases bone stiffness Common in prostate cancer patients

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Metastatic Bone DiseaseLesion Types

Osteolytic Decreases both bone strength and

density Common in patients with metastatic

cancer and multiple myeloma 70% of multiple myeloma patients present

with osteolytic involvement of the spine1

Higher risk for fracture than blastic lesions2

1. Lieberman, et al. Clinical Orthopaedics and Related Research. 2003;415S:S176-186.2. Patel, B. and DeGroot, H. Orthopedics Journal. 2001;24:612-7.

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Metastatic Bone DiseaseRadiographic Appearance of Skeletal Metastases1

1. Malawer, MM and Delaney, TF. Treatment of Metastatic Cancer to the Bone. Cancer: Principles and Practice of Oncology. 4th ed. Philadelphia: JB Lippincott; 1993:2225-2245

Breast Usually Usually Usually

Prostate Occasionally Usually

Urinary Bladder Usually Infrequently

Lung Usually Usually Occasionally

Thyroid Usually

Lytic Mixed Blastic

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Metastatic Bone DiseasePrognosis

Once bone metastasis occurs, prognosis is generally poor

Patients with longer median survival will require treatment for skeletal complications

1. Attal, et al. NEJM. 1996;335:91-97.2. Andre, et al. J of Clinical Oncology. 2004;22:3302-3308.3. Ryo, et al. Nihon Kokyuki Gakkai Zasshi. 1998;36:317-22.

Disease TypeMedian Survival (months)

Multiple Myeloma1 36 – 60

Breast2

(Years: 1994-2000)29*

Lung3 5*

* After disease metastasizes to bone

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Metastatic Bone DiseaseMetastasis Sites

Most common sites of metastasis1

Vertebra (69%) Pelvis (41%)

Femur/Hip (25%)

Skull (14%)

Median time from cancer

diagnosis to bone metastasis

is 30 months2

1. Malawer, MM and Delaney, TF. Treatment of Metastatic Cancer to the Bone. In: Devita VT, Hellman S, Rosenberg SA (eds). Cancer: Principles and Practice of Oncology. 4th ed. Philadelphia: JB Lippincott; 1993:2225-2245.

2. Paterson AGH, et al. J Clinical Oncology. 1993;11:59-65.

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Metastatic Bone DiseaseDiagnostic Tools1

Imaging X-ray

Will only show bone metastasis if the cancer has destroyed a majority of the bone1

Computed Tomography (CT) Scan Bone Scan Magnetic Resonance Imaging (MRI)

T1, T2 and STIR images are the most useful images to define the extent of spine involvement

Blood Tests Calcium level

Needle Biopsy

1. University of Washington School of Medicine, May 2007

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Metastatic Bone DiseaseClinical Sequelae

Tumor established in bone Bone pain Pathologic fracture

Vertebral compression fractures (VCFs) Long bones

Spinal cord compression Hypercalcemia

1. Roodman GD, NEJM, 350;16,2004

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Reduce pain Eradicate or reduce tumor when primary

tumors are involved Prevent neurologic complications Treat pathologic fractures and prevent

recurrent fracture

Metastatic Bone DiseaseTreatment Goals

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Surgery Open and minimally invasive

Radiation Therapy Chemotherapy Bisphosphonates Hormone Therapy Immunotherapy (Active and Passive)

Metastatic Bone DiseaseAvailable Treatments1

1. American Cancer Society, 2007

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Consequences of Untreated VCF

1. Gold DT, Silverman SL. The Downward Spiral of Vertebral Osteoporosis: Consequences. Designated by Cedar Sinai Medical Center Press, 20032. Podichetty, et al. Journal of Musculoskeletal Medicine. 2004;21:372-378.

Radiculopathy Spinal cord

compression

Neurological Consequences1,2

Compression of the abdominal contents

Early satiety, weight loss Kyphosis Decreased lung function Increased risk of death

from lung disease Spinal instability Risk of more fractures

Biomechanical Consequences1,2

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Consequences …

Chronic pain Increased

dependence Decreased ability for

activities of daily living

Partial to complete immobility

Functional Consequences1,2

Depression or clinical anxiety or both

Sleep disorder

Psychological Consequences1,2

1. Gold DT, Silverman SL. The Downward Spiral of Vertebral Osteoporosis: Consequences. Designated by Cedar Sinai Medical Center Press, 20032. Podichetty, et al. Journal of Musculoskeletal Medicine. 2004;21:372-378.

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Pain Assessment

Establish time course Constant Intermittent Both

Type of intermittent pain Breakthrough Incident End of dose failure

1. LeGrand, S. B., (2007, June). Developing an Index of Suspicion, Presentation at the International Multiple Myeloma meeting, Kos, Greece.

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Incident Pain

The most difficult to control Doses required may be significantly more

than the breakthrough/sustained release dose

May require PCA Often needs an intervention

Disease specific radiation therapy, chemotherapy Surgical stabilization

1. LeGrand, S. B., (2007, June). Developing an Index of Suspicion, Presentation at the International Multiple Myeloma meeting, Kos, Greece.

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Tumor-Related VCFsNon-Surgical Management1

Bisphosphonates Radiation Therapy Analgesics Bracing Bed rest

1. Yeh & Berenson, Clin Cancer Res. 2006, 10: 6279-6284.

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Tumor-Related VCFsEffects of Bisphosphonates

Metastatic bone cancer with lytic lesions Clodronate reduces the risk of VCFs by about 30%1

Multiple Myeloma Clodronate and pamidronate reduce the risk of VCFs by

25 – 45%2

Monthly IV infusions of either pamidronate or zoledronic acid have reduced the skeletal complications among patients with multiple myeloma3

Orally administered bisphosphonates have shown little ability to slow the development of skeletal complications in multiple myeloma3

1. Paterson, et al. J Clin Oncology. 1993;11:59-65.

2. Body, J. Supplement to Cancer. 2003;97:859-865. McCloskey EV, et al. British J of Haematology. 1998;100:317-325.


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Chemotherapy Some regimens include prednisone, which can lead to

secondary osteoporosis and increase the risk for VCFs Radiation therapy

Conflicting evidence of the link between radiation and incidence of VCFs

Does not prevent fracture progression1

Does not correct the anatomic abnormality from fracture2

1. Tong et al. Cancer. 1982;50:893-899. 2. Janjan, N. Seminars in Oncology. 2001;28:28-34.

Tumor-Related VCFsEffects of Chemotherapy and Radiation Therapy

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Open Surgical Procedures Vertebral column reconstruction Anterior or Posterior decompression with internal

fixation Oncology patients are generally poor candidates for

open surgery due to soft bone/tumor mass and co-morbidities

Minimally Invasive Procedures1

Balloon Kyphoplasty Vertebroplasty

Tumor-Related VCFsSurgical Management


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Multiple MyelomaEpidemiology Estimated 19,970+ new

cases in 2007 – about 1% of all new cancer cases1

Estimated 75,000 – 100,000 living with multiple myeloma in US2

Typically afflicts the elderly, males, and more African-Americans than Whites by 2:13

Estimated 11,000 deaths from multiple myeloma in 2007 – about 2% of all deaths from cancer1

0

10

20

30

40

50

60

Age

Inci

denc

e (C

ases

/ 10

0,00

0)

Men

Women

1. American Cancer Society, Cancer Facts and Figures 20072. Durie B, International Myeloma Foundation, 2006. 3. Sirohi, et al. The Lancet. 2004;363:875-887.

Source: SEER 1975-2001, National Cancer Institute

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Multiple MyelomaPathology1,2

Abnormal plasma cells proliferate in bone marrow Compromises immune function Disrupts bone marrow function Hypergammaglobulinemia end-organ damage (primarily

renal failure) Activation of osteoclasts Decline in osteoblast activity

1. Roodman GD, NEJM, 350;16,20042. Yeh & Berenson, Clin Cancer Res. 2006, 10: 6279-6284.

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Multiple MyelomaFractures

Over 70% of patients have bone pain at diagnosis and half have back pain1

55 - 70% have VCFs or history of vertebral body abnormalities2

15 - 30% develop new VCFs annually3 About half of patients with at least one osteolytic

lesion develop pathologic fractures within nine months4

1. McClosekey, et al. Br J Hematol. 1998;100:317-325.2. Ray et al. J Bone Mineral Research. 1997;12:24-35.3. McCloskey, et al. Drugs. 2001;61:1253-1274.4. Berenson, et al. NEJM. 1996;334:488-493.

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Multiple MyelomaExample of VCF

T-10 Fracture Due to Multiple Myeloma

Courtesy of Steve James, M.D.

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Tumor-Related VCFsVertebroplasty vs. Balloon Kyphoplasty

Vertebroplasty Balloon Kyphoplasty

Fracture Reduction

Postural Reduction Inflatable Bone Tamp

Cavity Creation -- Inflatable Bone Tamp

Cement Injection

High pressure injection into interstices

Low pressure fill into cavity created by IBT

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Aimed at stabilizing the FractureAimed at stabilizing the Fracture and Correcting Correcting Spinal DeformitySpinal Deformity caused by VCFs

Tumor-Related VCFsBalloon Kyphoplasty

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Aimed at restoring height and stability in fractured

vertebral body

Treating pain related to vertebral collapse

Tumor-Related VCFsBalloon Kyphoplasty Treatment Goals

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Minimally invasive Bilateral, 1 cm incisions

Typically one hour per treated fracture General or local anesthesia (supplemented by

conscious sedation) May require an overnight hospital stay

Tumor-Related VCFsBalloon Kyphoplasty Procedure

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The Inflatable Bone Tamp is inserted into the fractured vertebral body

Fracture Reduction & Void CreationOverview of Treatment Steps for VCFs

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The balloon is inflated, elevating the endplates and restoring vertebral body height


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The balloon is deflated and withdrawn, leaving a cavity within the vertebral body


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The void is filled with the surgeon’s choice of material, creating an “internal cast”


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KYPHON® Balloon Kyphoplasty:

Clinical Outcomes for Oncology Patients

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Percutaneous Vertebroplasty and Balloon Kyphoplasty for Painful Vertebral Body Fractures

in Cancer Patients

Authors: Fourney et al J. Neurosurg (Spine 1). 2003;98:21-30.

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Fourney Study Parameters

56 patients 21 with multiple myeloma 35 with bone metastases

97 levels treated 32 with balloon kyphoplasty 65 with vertebroplasty

All patients had intractable pain due to VCFs Median duration of symptoms 3.2 months

Mean follow-up 4.5 months

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Fourney StudyOutcomes (15 Patients treated with balloon kyphoplasty alone)

Balloon Kyphoplasty provides sustained pain reduction.

0

1

2

3

4

5

6

7

8

9

Preop Postop 1 month 3 month 6 month 1 year

Time of Assessment

Me

dia

n S

elf

-Ra

ted

VA

S P

ain

Sc

ore

Results for all time intervals were statistically significant vs baseline. P<0.05

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Fourney StudyOutcomes

Marked or complete pain relief in 49/58 procedures (84%) 2 patients underwent repeat procedures for new

fractures No change in 5 procedures

Cement extravasation 9.2% in vertebroplasty (asymptomatic) 0% in balloon kyphoplasty

42% mean height restoration after balloon kyphoplasty

Reduced analgesic use in follow-up

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Balloon Kyphoplasty Enhances Function and Structural Alignment in Multiple Myeloma

Authors: Lane et al Clinical Orthopaedics and Related Research.

2004;426:49-53.

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Lane StudyParameters

19 patients with multiple myeloma Total of 46 levels treated with balloon

kyphoplasty

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Lane StudyOutcomes

16 of 19 patients showed improvement in Oswestry Disability Index (ODI) scores Mean score improved from 49 to 33 (p <

0.001) Partial restoration of anterior vertebral

body height in 76% of vertebral bodies No complications Results were similar to a comparison

group of patients with osteoporotic VCFs

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Vertebroplasty and Balloon Kyphoplasty for Osteolytic Vertebral Collapse

Authors: Lieberman and Reinhardt Clinical Orthopaedics and Related Research.

2003;415(S):176-186.

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Lieberman and Reinhardt StudyParameters

63 patients with osteolytic collapse 52 with multiple myeloma 11 with osteolytic metastases

264 vertebral bodies treated with balloon kyphoplasty

Mean follow-up 18 weeks in multiple myeloma patients 3 weeks in patients with metastases

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Lieberman and Reinhardt StudyMyeloma Patient Outcomes

Visual Analog Scale

6.18

2.84

0

1

2

3

4

5

6

7

pre-op post-op

Mea

n S

elf-

Rat

ed P

ain

(0

to 1

0)

0 = no pain

p<0.0001

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Oswestry Disability Index

46.7

30.33

0

5

10

15

20

25

30

35

40

45

50

pre-op post-op

Mea

n S

core

Lower score = better physical functionP=0.0001


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SF-36 Scores

0102030405060708090

PF RP BP V SF RE MH GH

Pre-op

Post-op

*Balloon Kyphoplasty provides statistically significant improvement in Bodily Pain and Physical Function as measured in SF-36 scores.

P<0.0001* P=0.043 P=0.0003* P=0.683 P=0.043 P=0.016 P=0.806 P=0.008


Physical Mental General Health

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“Less than 5%” asymptomatic leaks in 264 vertebral bodies treated

No symptomatic cement leaks


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Balloon Kyphoplasty has statistically significant lower overall procedure-related and cement-related complication rates compared to vertebroplasty!

Total Procedure-related

Complications

Cement-Related Complications

Access-Related Complications

Non-device Related

Complications

Balloon KyphoplastyN = 1947 patients

14(0.7%)

3(0.2%)

4(0.2%)

7(0.4%)

VertebroplastyN = 6808 patients

199(2.9%)

132(1.9%)

28(0.4%)

39(0.6%)

p-value of difference 0.0002 <0.0001 0.3791 0.8781

Kyphon’s Meta-analysis: Results

1. Kyphon’s meta-analysis: Quantitative Analysis of Perioperative Complication Rates in Balloon Kyphoplasty and Vertebroplasty, completed December 2006 (PN 95000047)

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0.8%

0%

2.8%

3.4%

0%

1%

2%

3%

4%

Osteoporotic Cancer

Ove

rall

Proc

edur

e-Re

late

dCo

mpl

icat

ion

Rate

Balloon Kyphoplasty

Vertebroplasty

Kyphon’s Meta-analysis:Osteoporosis & Cancer Sub-analysis of

VCFs due to osteoporosis or cancer

Procedure-related complications are statistically significantly lower for Balloon Kyphoplasty than Vertebroplasty in both indications

p = 0.0042 p = 0.0072

5581patients

1770patients

1227patients

177patients

1. Kyphon’s meta-analysis: Quantitative Analysis of Perioperative Complication Rates in Balloon Kyphoplasty and Vertebroplasty, completed December 2006 (PN 95000047)

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Balloon Kyphoplasty and Vertebroplasty for Vertebral Compression Fractures: A Comparative Systematic Review of

Efficacy and Safety

Authors: Taylor RS, Taylor RJ, Fritzell P Spine 2006;31:2747–2755

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Cement Leakages per Vertebra(data from Table 6, Taylor - Spine 2006)

8%

0%

40.0%

3%

0%

10%

20%

30%

40%

50%

Overall Symptomatic

Balloon Kyphoplasty

Vertebroplasty

Taylor Study*: Systematic Literature Review Cement Leakage ResultsCase series comparison:Balloon Kyphoplasty has a lower rate of cement extravasation than Vertebroplasty

p < 0.0001BK: 90/1111 = 8%VP: 614/1551 = 40%

(p-value not reported)BK: 0/1094 = 0%VP: 8/275 = 3%

*Includes fracture of all etiologies

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Adverse Events per Patient(data from Table 6, Taylor - Spine 2006)

0.3%0%

0.3%

1.8%

0.5%

2.5%

0.0%

1.0%

2.0%

3.0%

4.0%

Pulmonary embolism Spinal cordcompression

Nerve root pain/radiculopathy

Balloon Kyphoplasty

Vertebroplasty

Taylor Study: Systematic Literature Review Adverse EventsCase series comparison:Balloon Kyphoplasty has a lower complication rate than Vertebroplasty

BK: 1/291 = 0.3%VP: 15/803 = 1.8%

BK: 0/195 = 0%VP: 3/631 = 0.5%

BK: 1/322 = 0.3%VP: 32/1100 = 2.5%

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Vertebroplasty and Balloon Kyphoplasty: A Systematic Review of 69 Clinical Studies

Authors: Hulme PA, Krebs J, Ferguson SJ, Berlemann U

Spine. 2006;31:1983-2001

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Balloon Kyphoplasty has a lower rate of overall complications and total cement leakages than Vertebroplasty

Total Cement Leakage

(per vertebra)

Clinical Complications(per vertebra)

ClinicalComplications

(per patient)

Pulmonary Embolism

(per vertebra)

Neurologic(per vertebra)

BalloonKyphoplasty

(n = 1288)9% 1.3% 2.2% 0.01% 0.03%

Vertebroplasty(n = 2958) 41% 2.6% 3.9% 0.6% 0.6%

Hulme Study: Systematic Literature Review

(Data from Figure 4, Hulme – Spine 2006)

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Percutaneous vertebroplasty and balloon kyphoplasty for the treatment of osteoporotic vertebral

compression fractures and osteolytic tumours

Authors: Hadjipavlou AG, Tzermiadianos MN, Katonis PG, Szpalski M

J. Bone Joint Surg Br. 2005;87:1595-1604

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Hadjipavlou Study*: Systematic Literature Review

Location of Cement Extravasation

8.4%

1.2%4.0% 4.6%

29.0%

10.7%8.4%

5.0%

0%0%

6.0%

0.6%

0%

5%

10%

15%

20%

25%

30%

35%

TOTAL

Epidur

al

Foram

inal

Intra

disca

l

Paras

pinal

Intra

veno

us

Pe

rce

nta

ge

Balloon Kyphoplasty (n = 1279 vertebral bodies)

Vertebroplasty (n = 2729 vertebral bodies)

Systematic review of studies published between 1983 and September 2004 BK has lower cement leakage rates than VP

*Includes fracture of all etiologies

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Summary of LiteratureAdverse Events

No reported complications related to balloon kyphoplasty for tumor-related VCFs

Complications during balloon kyphoplasty for osteoporotic VCFs have been reported

Complication rate < vertebroplasty

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Kyphon CAFE Study

Cancer Fracture Evaluation Objective: Determine benefit of

balloon kyphoplasty vs. non-surgical treatment in tumor-related VCFs with respect to function and pain

Multicenter randomized clinical trial N=200 Primary endpoint: Roland Morris

Disability Questionnaire score @ 30 days

1-year follow-up

Note: Post Marketing Study Following Cleared Indications for Use

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Indications for UseNot Investigational – Indicated for Cancer-Related Fractures KYPHON® HV-R™ Bone Cement was originally cleared for

marketing in the United States in 2004 for treatment of pathologic VCFs using a balloon kyphoplasty procedure Indicated for the treatment of pathological fractures of the

vertebral body due to osteoporosis, cancer, or benign lesions using a balloon kyphoplasty procedure. Cancer includes multiple myeloma and metastatic lesions, including those arising from breast or lung cancer, or lymphoma. Benign lesions include hemangioma and giant cell tumor.

KYPHON® Inflatable Bone Tamps were originally cleared for marketing in the United States in 1998 Intended to be used as conventional bone tamps for the

reduction of fractures and/or creation of a void in cancellous bone in the spine (including use during balloon kyphoplasty with KYPHON® HV-R™ Bone Cement), hand, tibia, radius and calcaneus.

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Adverse Events

Any type of surgery involves risk. Although the complication rate for balloon kyphoplasty is low, serious adverse events, some of which can be fatal, can occur, including myocardial infarction (heart attack), cerebrovascular accident (stroke), pulmonary embolism (blood, fat or cement clot that migrates to the lungs), and cardiac arrest (heart stops beating).

Other risks (relevant to the anatomy being treated) include deep or superficial wound infection, leakage of bone cement into the muscle and tissue surrounding the spinal cord and nerve injury that can, in rare instances, cause paralysis. Patients are encouraged to discuss these and other risks with their physician.

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Disclosure

• The physicians referenced may be paid consultants of, and research cited may have been funded partially or in whole by, Kyphon Inc.

• Although the complication rate with Balloon Kyphoplasty has been demonstrated to be low, as with most surgical procedures, there are risks associated with Balloon Kyphoplasty, including serious complications. For complete information regarding indications for use, warnings, precautions, adverse events and methods of use, please reference the devices’ Instructions for Use.

• Kyphon and KyphX are registered trademarks, and HV-R and Ahead of the Curve are trademarks of Kyphon Inc.

• © 2007 Kyphon Inc. All rights reserved.

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References1. American Cancer Society, Cancer Facts and Figures, 20072. American Cancer Society, Types of Treatment, 20073. Andre F, et al. (2004) Breast Cancer with Synchronous Metastases: Trends in Survival during a 14-Year Period. J of Clin Oncology 22:3302-33084. Attal M, et al. (1996) A Prospective, Randomized Trial of Autologous Bone Marrow Transplantation and Chemotherapy in Multiple Myeloma.

NEJM 335:91-975. Berenson, et al. (1996) Efficacy of Pamidronate in Reducing Skeletal Events in Patients with Advanced Multiple Myeloma. NEJM 334:488-4936. Berruti et al, "Incidence of Skeletal Complications in Patients with Bone Metastatic Prostate Cancer and Hormone Refractory Disease", The

Journal of Urology, Vol. 164, 0ct. 2000, ppg. 1248-12537. Brincker et al, "Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: a double-blind placebo controlled trial", British

Journal of Haematology, 1998, V.101, ppg 280-2868. Body, Jean-Jacques (2003) Effectiveness and Cost of Bisphosphonate Therapy in Tumor Bone Disease. Cancer Supplement 97:859-8659. Coleman, R.E. (2001) Metastatic Bone Disease: Clinical Features, Pathophysiology and Treatment Strategies. Cancer Treatment Reviews

27:165-17610. Coleman, R.E. (2000) Uses and Abuses of Bisphosphonates. Ann Oncol. 11:179-184. 11. Diamond et al, "Osteoporosis and Spinal Fractures in Men with Prostate Cancer: Risk Factors and Effects of Androgen Deprivation Therapy",

Journal of Urology, Volume 172, pg. 529-532, August 200412. Djulbegovic et al, "Bisphosphonates in multiple myeloma (Review)", The Cochrane Database of Systematic Reviews, 2002, Issue 4. Art. No.:

CD003188, pg.1-3213. Durie B, “Understanding Balloon Kyphoplasty and Myeloma-Induced Vertebral Compression Fractures”, International Myeloma Foundation, June

2006, P 1614. Fourney D., et al. (2003) Percutaneous Vertebroplasty and Kyphoplasty for Painful Vertebral Body Fractures in Cancer Patients. J Neurosurg

(Spine 1) 98:21-3015. Gold DT, Silverman SL. The Downward Spiral of Vertebral Osteoporosis: Consequences. Designated by Cedar Sinai Medical Center Press, 200316. Hadjipavlou et al, “Percutaneous vertebroplasty and balloon kyphoplasty for the treatment of osteoporotic vertebral compression fractures and

osteolytic tumours, J. Bone Joint Surg Br. 2005;87:1595-160417. Hortobagyi GH, et al. (1996) Efficacy of Pamidronate in Reducing Skeletal Complications in Patients wit Breast Cancer and Lytic Bone

Metastases. NEJM 335:1785-179118. Hortobagyi GN, Theriault RL, Lipton A, et al. (1998) Long-term Prevention of Skeletal Complications of Metastatic Breast Cancer with

Pamidronate. J Clin Oncol.16:2038-204419. Hulme et al, “Vertebroplasty and Kyphoplasty: A Systematic Review of 69 Clinical Studies”, Spine. 2006;31:1983-200120. Janjan N. (2001) Bone Metastases: Approaches to Management. Seminars in Oncology 28:28-3421. Kyphon Data on File. Literature review conducted as of July, 2004, Kyphon Prospective Study.

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References Continued22. Lane J, et al. (2004) Kyphoplasty Enhances Function and Structural Alignment in Multiple Myeloma. Clinical Orthopaedics and Related

Research Sep(426):49-5323. LeGrand, S. B., (2007, June). Developing an Index of Suspicion. Presentation presented at the meeting of the International Multiple

Myeloma, Kos, Greece.24. Lieberman I. and Reinhardt M.K. (2003) Vertebroplasty and Kyphoplasty for Osteolytic Vertebral Collapse. Clinical Orthopaedics and

Related Research (415S):S176-S18625. Malawer, MM and Delaney, TF. Treatment of Metastatic Cancer to the Bone. In: Devita VT, Hellman S, Rosenberg SA (eds). Cancer:

Principles and Practice of Oncology. 4th ed. Philadelphia: JB Lippincott; 1993:2225-224526. McCloskey, et al. (2001) The Clinical and Cost Considerations of Bisphosphonates in Preventing Bone Complications in Patients with

Metastatic Breast Cancer or Multiple Myeloma. 61:1253-127427. McCloskey, et al. (1998) A Randomized Trial of the Effect of Clodronate on Skeletal Morbidity in Multiple Myeloma. British J. Hemtaol.

100:317-325.28. Melton et al, "Fracture Risk with Multiple Myeloma: A Population-based Study", V.20, No. 3, 2005, ppg 487-49329. Patel, B. and DeGroot, H.(2001) Evaluation of the Risk of Pathologic Fractures Secondary to Metastatic Bone Disease.Orthopedics Journal.

24:612-7.30. Paterson AGH, et al. (1993) Double-Blind Controlled Trial of Oral Clodronate in Patients with Bone Metastases from Breast Cancer. J

Clinical Oncology;11:59-6531. Podichetty V., et al. (2004) Managing Vertebral Compression Fractures and Multiple Myeloma in Older Patients. J of Musculoskeletal

Medicine 21:372-37832. Ray et al. (1997) Medical Expenditures for the Treatment of Osteoporotic Fractures in the U.S. in 1995: Report from the National

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16000417-3 KYPHON ® Balloon Kyphoplasty Minimally Invasive Treatment of Tumor-Related Vertebral Compression Fractures