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

Regulation of Bone Metabolism 1.Roodman GD, NEJM, 350;16,2004

Metastatic Bone Disease Epidemiology Definition: Tumors in bone arising from distant, non- bone source. Vast majority of skeletal cancers are metastatic rather than primary % of the roughly 563,700 people who die annually of cancer have bone metastasis. 1 1.Coleman. Cancer Treatment Reviews. 2001;27:

VCFs in Metastatic Cancer and Multiple Myeloma An estimated 75K-100K cancer induced VCF occur annually in the U.S.  Stage IV Breast 1 and Lung  All Stages of Multiple Myeloma 2,3,4,5,6  Stage III and IV of Prostate 7,8 1.Hortobagy et al, NEJM, Vol. 335, No. 24, ppg Berenson et al, NEJM, Vol. 334, No. 8, ppg Brincker et al, British Journal of Haematology, 1998, V.101, ppg McCloskey et al, 1998, V.100, ppg Melton et al, V.20, No. 3, 2005, ppg Djulbegovic et al, The Cochrane Database of Systematic Reviews, 2002, Issue 4. Art. No.: CD003188, pg Berruti et al, The Journal of Urology, Vol. 164, 0ct. 2000, ppg Diamond et al, Journal of Urology, Volume 172, pg , August 2004

Metastatic Bone Disease Fractures Patients with cancer are at elevated risk for osteoporosis and fractures both because of their disease and its treatment 1 Metastatic cancer in the bone causes skeletal complications every 3 to 4 months – 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 cancer 1 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, Coleman RE. Ann Oncol. 2000;11: Body. Cancer. 2003;97: Hortobagyi GN, Theriault RL, Lipton A, et al. J Clin Oncol. 1998;16:

Metastatic Bone Disease Lesion Types Osteoblastic  Increased bone density  Does not change bone strength but decreases bone stiffness  Common in prostate cancer patients

Metastatic Bone Disease Lesion 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 spine 1  Higher risk for fracture than blastic lesions 2 1. Lieberman, et al. Clinical Orthopaedics and Related Research. 2003;415S:S Patel, B. and DeGroot, H. Orthopedics Journal. 2001;24:612-7.

Metastatic Bone Disease Radiographic Appearance of Skeletal Metastases 1 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: BreastUsually ProstateOccasionallyUsually Urinary BladderUsuallyInfrequently LungUsually Occasionally ThyroidUsually LyticMixedBlastic

Metastatic Bone Disease Prognosis 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: Andre, et al. J of Clinical Oncology. 2004;22: Ryo, et al. Nihon Kokyuki Gakkai Zasshi. 1998;36: Disease Type Median Survival (months) Multiple Myeloma 1 36 – 60 Breast 2 (Years: ) 29* Lung 3 5* * After disease metastasizes to bone

Metastatic Bone Disease Metastasis Sites Most common sites of metastasis 1  Vertebra (69%)  Pelvis (41%)  Femur/Hip (25%)  Skull (14%) Median time from cancer diagnosis to bone metastasis is 30 months 2 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. 4 th ed. Philadelphia: JB Lippincott; 1993: Paterson AGH, et al. J Clinical Oncology. 1993;11:59-65.

Metastatic Bone Disease Diagnostic Tools 1 Imaging  X-ray Will only show bone metastasis if the cancer has destroyed a majority of the bone 1  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

Metastatic Bone Disease Clinical 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

Reduce pain Eradicate or reduce tumor when primary tumors are involved Prevent neurologic complications Treat pathologic fractures and prevent recurrent fracture Metastatic Bone Disease Treatment Goals

Surgery  Open and minimally invasive Radiation Therapy Chemotherapy Bisphosphonates Hormone Therapy Immunotherapy (Active and Passive) Metastatic Bone Disease Available Treatments 1 1.American Cancer Society, 2007

Consequences of Untreated VCF 1.Gold DT, Silverman SL. The Downward Spiral of Vertebral Osteoporosis: Consequences. Designated by Cedar Sinai Medical Center Press, Podichetty, et al. Journal of Musculoskeletal Medicine. 2004;21:  Radiculopathy  Spinal cord compression Neurological Consequences 1,2  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 Consequences 1,2

Consequences …  Chronic pain  Increased dependence  Decreased ability for activities of daily living  Partial to complete immobility Functional Consequences 1,2  Depression or clinical anxiety or both  Sleep disorder Psychological Consequences 1,2 1.Gold DT, Silverman SL. The Downward Spiral of Vertebral Osteoporosis: Consequences. Designated by Cedar Sinai Medical Center Press, Podichetty, et al. Journal of Musculoskeletal Medicine. 2004;21:

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.

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.

Tumor-Related VCFs Non-Surgical Management 1 Bisphosphonates Radiation Therapy Analgesics Bracing Bed rest 1.Yeh & Berenson, Clin Cancer Res. 2006, 10:

Tumor-Related VCFs Effects 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 myeloma 3  Orally administered bisphosphonates have shown little ability to slow the development of skeletal complications in multiple myeloma 3 1.Paterson, et al. J Clin Oncology. 1993;11: Body, J. Supplement to Cancer. 2003;97: McCloskey EV, et al. British J of Haematology. 1998;100: Yeh & Berenson, Clin Cancer Res. 2006, 10:

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 progression 1  Does not correct the anatomic abnormality from fracture 2 1.Tong et al. Cancer. 1982;50: Janjan, N. Seminars in Oncology. 2001;28: Tumor-Related VCFs Effects of Chemotherapy and Radiation Therapy

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 Procedures 1  Balloon Kyphoplasty  Vertebroplasty Tumor-Related VCFs Surgical Management 1.Yeh & Berenson, Clin Cancer Res. 2006, 10:

Multiple Myeloma Epidemiology Estimated 19,970+ new cases in 2007 – about 1% of all new cancer cases 1 Estimated 75,000 – 100,000 living with multiple myeloma in US 2 Typically afflicts the elderly, males, and more African- Americans than Whites by 2:1 3 Estimated 11,000 deaths from multiple myeloma in 2007 – about 2% of all deaths from cancer 1 1.American Cancer Society, Cancer Facts and Figures Durie B, International Myeloma Foundation, Sirohi, et al. The Lancet. 2004;363: Source: SEER , National Cancer Institute

Multiple Myeloma Pathology 1,2 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, Yeh & Berenson, Clin Cancer Res. 2006, 10:

Multiple Myeloma Fractures Over 70% of patients have bone pain at diagnosis and half have back pain % have VCFs or history of vertebral body abnormalities % develop new VCFs annually 3 About half of patients with at least one osteolytic lesion develop pathologic fractures within nine months 4 1.McClosekey, et al. Br J Hematol. 1998;100: Ray et al. J Bone Mineral Research. 1997;12: McCloskey, et al. Drugs. 2001;61: Berenson, et al. NEJM. 1996;334:

Multiple Myeloma Example of VCF T-10 Fracture Due to Multiple Myeloma Courtesy of Steve James, M.D.

Tumor-Related VCFs Vertebroplasty vs. Balloon Kyphoplasty VertebroplastyBalloon Kyphoplasty Fracture Reduction Postural ReductionInflatable Bone Tamp Cavity Creation --Inflatable Bone Tamp Cement Injection High pressure injection into interstices Low pressure fill into cavity created by IBT

Aimed at stabilizing the FractureCorrecting Spinal Deformity Aimed at stabilizing the Fracture and Correcting Spinal Deformity caused by VCFs Tumor-Related VCFs Balloon Kyphoplasty

Aimed at restoring height and stability in fractured vertebral body Treating pain related to vertebral collapse Tumor-Related VCFs Balloon Kyphoplasty Treatment Goals

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 VCFs Balloon Kyphoplasty Procedure

The Inflatable Bone Tamp is inserted into the fractured vertebral body Fracture Reduction & Void Creation Overview of Treatment Steps for VCFs

The balloon is inflated, elevating the endplates and restoring vertebral body height Fracture Reduction & Void Creation Overview of Treatment Steps for VCFs

The balloon is deflated and withdrawn, leaving a cavity within the vertebral body Fracture Reduction & Void Creation Overview of Treatment Steps for VCFs

The void is filled with the surgeon’s choice of material, creating an “internal cast” Fracture Reduction & Void Creation Overview of Treatment Steps for VCFs

KYPHON ® Balloon Kyphoplasty: Clinical Outcomes for Oncology Patients

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.

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

Fourney Study Outcomes (15 Patients treated with balloon kyphoplasty alone) Balloon Kyphoplasty provides sustained pain reduction. Results for all time intervals were statistically significant vs baseline. P<0.05

Fourney Study Outcomes 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

Balloon Kyphoplasty Enhances Function and Structural Alignment in Multiple Myeloma Authors: Lane et al Clinical Orthopaedics and Related Research. 2004;426:49-53.

Lane Study Parameters 19 patients with multiple myeloma Total of 46 levels treated with balloon kyphoplasty

Lane Study Outcomes 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

Vertebroplasty and Balloon Kyphoplasty for Osteolytic Vertebral Collapse Authors: Lieberman and Reinhardt Clinical Orthopaedics and Related Research. 2003;415(S):

Lieberman and Reinhardt Study Parameters 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

Lieberman and Reinhardt Study Myeloma Patient Outcomes 0 = no pain p<0.0001

Lower score = better physical function P= Lieberman and Reinhardt Study Myeloma Patient Outcomes

*Balloon Kyphoplasty provides statistically significant improvement in Bodily Pain and Physical Function as measured in SF-36 scores. P<0.0001*P=0.043P=0.0003* P=0.683P=0.043P=0.016P=0.806P=0.008 Lieberman and Reinhardt Study Myeloma Patient Outcomes PhysicalMental General Health

“Less than 5%” asymptomatic leaks in 264 vertebral bodies treated No symptomatic cement leaks Lieberman and Reinhardt Study Myeloma Patient Outcomes

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 Kyphoplasty N = 1947 patients 14 (0.7%) 3 (0.2%) 4 (0.2%) 7 (0.4%) Vertebroplasty N = 6808 patients 199 (2.9%) 132 (1.9%) 28 (0.4%) 39 (0.6%) p-value of difference < 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 )

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 = p = patients 1770 patients 1227 patients 177 patients 1.Kyphon’s meta-analysis: Quantitative Analysis of Perioperative Complication Rates in Balloon Kyphoplasty and Vertebroplasty, completed December 2006 (PN )

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

Taylor Study*: Systematic Literature Review Cement Leakage Results Case series comparison: Balloon Kyphoplasty has a lower rate of cement extravasation than Vertebroplasty p < BK: 90/1111 = 8% VP: 614/1551 = 40% (p-value not reported) BK: 0/1094 = 0% VP: 8/275 = 3% *Includes fracture of all etiologies

Taylor Study: Systematic Literature Review Adverse Events Case 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%

Vertebroplasty and Balloon Kyphoplasty: A Systematic Review of 69 Clinical Studies Authors: Hulme PA, Krebs J, Ferguson SJ, Berlemann U Spine. 2006;31:

Balloon Kyphoplasty has a lower rate of overall complications and total cement leakages than Vertebroplasty Total Cement Leakage (per vertebra) Clinical Complications (per vertebra) Clinical Complications (per patient) Pulmonary Embolism (per vertebra) Neurologic (per vertebra) Balloon Kyphoplasty (n = 1288) 9%1.3%2.2%0.01%0.03% Vertebroplasty (n = 2958) 41%2.6%3.9%0.6% Hulme Study: Systematic Literature Review (Data from Figure 4, Hulme – Spine 2006)

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:

Hadjipavlou Study*: Systematic Literature Review Systematic review of studies published between 1983 and September 2004 BK has lower cement leakage rates than VP *Includes fracture of all etiologies

Summary of Literature Adverse 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

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 30 days 1-year follow-up Note: Post Marketing Study Following Cleared Indications for Use

Indications for Use Not 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.

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.

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.

References 1.American Cancer Society, Cancer Facts and Figures, American Cancer Society, Types of Treatment, Andre F, et al. (2004) Breast Cancer with Synchronous Metastases: Trends in Survival during a 14-Year Period. J of Clin Oncology 22: Attal M, et al. (1996) A Prospective, Randomized Trial of Autologous Bone Marrow Transplantation and Chemotherapy in Multiple Myeloma. NEJM 335: Berenson, et al. (1996) Efficacy of Pamidronate in Reducing Skeletal Events in Patients with Advanced Multiple Myeloma. NEJM 334: 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 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 Body, Jean-Jacques (2003) Effectiveness and Cost of Bisphosphonate Therapy in Tumor Bone Disease. Cancer Supplement 97: Coleman, R.E. (2001) Metastatic Bone Disease: Clinical Features, Pathophysiology and Treatment Strategies. Cancer Treatment Reviews 27: Coleman, R.E. (2000) Uses and Abuses of Bisphosphonates. Ann Oncol. 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 , August Djulbegovic et al, "Bisphosphonates in multiple myeloma (Review)", The Cochrane Database of Systematic Reviews, 2002, Issue 4. Art. No.: CD003188, pg Durie B, “Understanding Balloon Kyphoplasty and Myeloma-Induced Vertebral Compression Fractures”, International Myeloma Foundation, June 2006, P Fourney D., et al. (2003) Percutaneous Vertebroplasty and Kyphoplasty for Painful Vertebral Body Fractures in Cancer Patients. J Neurosurg (Spine 1) 98: Gold DT, Silverman SL. The Downward Spiral of Vertebral Osteoporosis: Consequences. Designated by Cedar Sinai Medical Center Press, 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: Hortobagyi GH, et al. (1996) Efficacy of Pamidronate in Reducing Skeletal Complications in Patients wit Breast Cancer and Lytic Bone Metastases. NEJM 335: 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: Hulme et al, “Vertebroplasty and Kyphoplasty: A Systematic Review of 69 Clinical Studies”, Spine. 2006;31: Janjan N. (2001) Bone Metastases: Approaches to Management. Seminars in Oncology 28: Kyphon Data on File. Literature review conducted as of July, 2004, Kyphon Prospective Study.

References Continued 22.Lane J, et al. (2004) Kyphoplasty Enhances Function and Structural Alignment in Multiple Myeloma. Clinical Orthopaedics and Related Research Sep(426): 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-S 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: 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: McCloskey, et al. (1998) A Randomized Trial of the Effect of Clodronate on Skeletal Morbidity in Multiple Myeloma. British J. Hemtaol. 100: Melton et al, "Fracture Risk with Multiple Myeloma: A Population-based Study", V.20, No. 3, 2005, ppg Patel, B. and DeGroot, H.(2001) Evaluation of the Risk of Pathologic Fractures Secondary to Metastatic Bone Disease.Orthopedics Journal. 24: Paterson AGH, et al. (1993) Double-Blind Controlled Trial of Oral Clodronate in Patients with Bone Metastases from Breast Cancer. J Clinical Oncology;11: Podichetty V., et al. (2004) Managing Vertebral Compression Fractures and Multiple Myeloma in Older Patients. J of Musculoskeletal Medicine 21: Ray et al. (1997) Medical Expenditures for the Treatment of Osteoporotic Fractures in the U.S. in 1995: Report from the National Osteoporosis Foundation. J Bone Mineral Research;12: Roodman et al, “Mechanisms of Bone Metastases”, NEMJ, 2004;350: Ryo, et al. (1998) Bone Metastasis of Primary Lung Cancer. Nihon Kokyuki Gakkai Zasshi 36: Sirohi, B. and Powles, R. (2004) Seminar: Multiple Myeloma. The Lancet 363: Taylor et al, “Balloon Kyphoplasty and Vertebroplasty for Vertebral Compression Fractures: A Comparative Systematic Review of Efficacy and Safety”, Spine 2006;31:2747– Theriault et al, “Task Force Reports on Bone Health in Patients with Cancer”, The Oncology Report, Tong D., et al. (1982) The Palliation of Symptomatic Osseous Metastases: Final Results of the Study by the Radiation Therapy Oncology Group. Cancer 50: University of Washington School of Medicine, “When Cancer Spreads to the Bone: Surgery for Metastatic Bone Disease”, 2007, 40.Yeh & Berenson. Treatment of Myeloma Bone Disease. Clinical Cancer Res (2006). 10: