Vertebroplasty - 2009 NEJM

Studies Critical Review

• Distinguished Engineering Fellow
DePuy Spine, a Johnson & Johnson Co.

•Prestige Adjunct Professor

•Bioengineering Dept. University of

Toledo

•Co-Founder & Treasurer of the

S.P.I.N.E Society
Hassan Serhan, PhD
www.neareastspine.org

• Contact: hserhan@its.jnj.com
Vertebroplasty
2009 NEJM Studies
Critical Review

Hassan Serhan, Ph.D.

Distinguished Fellow
Employee of DePuy Spine
a J&J company

Prestige Adjunct Professor

The Bioengineering Dept.
University of Toledo, OH
Osteoporosis

Osteoporosis is defined as a skeletal disorder

characterized by compromised bone strength
predisposing to an increased risk of fracture.

Normal Bone Osteoporotic Bone

NIH Consensus Development Conference, March 27-29, 2000

Osteoporosis
A Public Health Problem
 100 Million People Worldwide at Risk
 28 Million People U.S. at Risk
 1.5 Million Fragility Fractures in U.S.
 700,000 spine
 300,000 hip
 250,000 wrist
 250,000 other

National Osteoporosis Foundation

Deformity Progression

16º 25º
kyphosis kyphosis

Aug 31, 2000 Sept 3, 2000

 Deformity Progression
Center of gravity (CG) moves
forward
Axial Loads + Large bending
moment created
Posterior muscles and
ligaments must counterbalance
increased bending
CG
Osteoporotic anterior spine
must resist larger compressive
stresses

White and Panjabi 1990

 Cements Augmentation of VCF
• Indication (product label-FDA)
• Bone cements used in vertebroplasty are indicated for fixation of
pathological fractures of the vertebral body using vertebroplasty or
kyphoplasty procedures.
• Medicare indications:
• Painful osteolytic vertebral body metastatic disease;
• Painful multiple myeloma involving the vertebral body;
• Painful and/or aggressive hemangioma;
• Painful, debilitating, osteoporotic vertebral collapse/ compression
fractures that have not responded to conservative medical
treatment.
• Severe pain and functional debilitation related to activities of daily
living due to chronic vertebral collapse/compression fractures that
require hospitalization for pain control and treatment.
1. Disc-O-Tech Medical Technologies Ltd. Confidence EX High Viscosity Bone Cement Special10(k); K062424. August 2006. Accessed November 18,
2009 at http://www.accessdata.fda.gov/cdrh_docs/pdf6/K062424.pdf.
2. Nationwide Inpatient Sample, 2007; Patients with ICD-9-CM 81.65 as primary diagnosis.
3. Premier Hospital and Drug Database, 2007-2008. Patients with osteoporotic compression fracture (65% inpatient; 35% outpatient). Data on file. DePuy
Spine.
4. Taylor RS, Taylor RJ, Fritzell P. Balloon kyphoplasty for vertebroplasty for vertebral compression fractures: a comparative systematic review of efficacy
and safety. Spine 2006;31:2747–55.
5. Nationwide Inpatient Sample, 2006; Patients with ICD-9-CM 733.13 (pathologic vertebral body fracture) as primary diagnosis.

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2007 - Consensus statement

“These procedures are offered only when traditional

medical therapy has not provided pain relief or pain is
substantially altering the patient’s lifestyle….it is the
position of the Societies that vertebral
augmentation with vertebroplasty or kyphoplasty
is a medically appropriate therapy for the
treatment of painful vertebral compression
fractures refractory to medical therapy when
performed for the medical indications outlined in the
published standards”

M.E. Jensen, J.K. McGraw, J.F. Cardella, and J.A. Hirsch. Position Statement on Percutaneous Vertebral Augmentation: A Consensus Statement
Developed by the American Society of Interventional and Therapeutic Neuroradiology, Society of Interventional Radiology, American Association of
Neurological Surgeons/Congress of Neurological Surgeons, and American Society of Spine Radiology
AJNR Am. J. Neuroradiol., September 1, 2007; 28(8): 1439 - 1443.
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 Literature Reviews -Vertebroplasty Studies

Studies Pre-op VAS: Post-op VAS:

Study # Patients
Reviewed mean (range) mean (range)

Eck et al
103 7,587 8.36 2.68
(2008)

Hochmuth et 8.1 2.6

30 2,086
al. (2006) (6.4–9.7) (1.7–3.9)

Hulme et al. 8.2 3.0

47 2,958
(2006) (7.8–8.6) (2.4–3.6)

Significant within-group reductions in VAS

from greater than 8/10 base-line pain1

1 . McGirt, MJ, Parker, SL, Wolinsky, JP, Witham, TF, Bydon, A, and Gokaslan, ZL. Vertebroplasty and kyphoplasty for the treatment of
vertebral compression fractures: an evidenced-based review of the literature. Spine J. 2009;9(6):501-508.

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 Kyphoplasty versus Conservative Care
(FREE trial)1

Comparator/Study Results at One Year

Study Patients
Design (Between-group difference)
•Percutaneous
Kyphoplasty (PK) •Fracture edema on •SF-36 PCS score: 3·5 point (1·6–5·4;
(n = 149) MRI p=0·0004) improvement in the kyphoplasty
Wardlaw et al. •Conservative Care •Fractures estimated cohort (p = 0.0004) relative to controls
(2009) (FREE (n = 151) to be less than 3
trial) •Randomized, controlled, months of age •Back pain: 0·9 point (0·3–1·5; p=0·0034)
multi-center (21 sites, 8 •Mean fracture age of improvement in the kyphoplasty improvement
countries) 5.6 weeks relative to controls

Statistically significant improvement in pain and

quality of life at 12 months

1. Wardlaw D, Cummings S, Van Meirhaeghe J, et al. An international multicentered randomized comparison of balloon kyphoplasty
and nonsurgical management in patients with acute vertebral body compression fractures. Lancet 2009; 373: 1016–24.

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 NEJM Blinded RCTs: PV Vs Control

Comparator/
Pain Duration Baseline VAS,
Study Sample size/ Inclusion Criteria Primary Outcome
(weeks) Mean (SD)
Design

• Percutaneous • Primary outcome at one

• Minimum pain at entry of 3.0/10
vertebroplasty month: change on Roland-
• 1 to 3 painful osteoporotic
NEJM (n = 68) Morris Disability Questionnaire
vertebral compression fractures PV: 16 PV: 6.9 (2.0)
Kallmes et (RDQ)
• Fracture less than one-year old Control: 20
al., INVEST • Control • Criteria for success of 3.0
• Fracture confirmed by x-ray Control: 7.2 (1.8)
trial (2009)1 (n = 63) point between-group
• MRI or bone scan only used in
difference
cases with uncertain fracture age
• RCT: 11 sites

1. Kallmes, DF, Comstock, BA, Heagerty, PJ, Turner, JA, Wilson, DJ, Diamond, TH, Edwards, R, Gray, LA, Stout, L, Owen, S,
Hollingworth, W, Ghdoke, B, nnesley-Williams, DJ, Ralston, SH, and Jarvik, JG. A randomized trial of vertebroplasty for osteoporotic
spinal fractures. N Engl J Med. 2009;361(6):569-579.

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 NEJM Blinded RCTs: PV Versus Control
(Cont’d.)
NEJM - Kallmes et al. (2009) (INVEST trial) 1
PV Placebo P-value
N 68 63 NA

Pain intensity (1 mo) 3.9 4.6 0.19

RDQ (1 mo) 12.0 13.0 0.49

Crossover 1 – 3 mos 8 (12%) 27 (43%) < 0.0001

Clinically meaningful reduction in pain* 64% 48% 0.06

“Improvements in pain and pain-related disability

associated with osteoporotic compression fractures in
Authors’ conclusions
patients treated with vertebroplasty were similar to the
improvements in a control group”

*% with 30% decrease from baseline VAS

RDQ = Roland Morris Disability questionnaire
NR = Not reported

1. Kallmes, DF, Comstock, BA, Heagerty, PJ, Turner, JA, Wilson, DJ, Diamond, TH, Edwards, R, Gray, LA, Stout, L, Owen, S,
Hollingworth, W, Ghdoke, B, nnesley-Williams, DJ, Ralston, SH, and Jarvik, JG. A randomized trial of vertebroplasty for osteoporotic
spinal fractures. N Engl J Med. 2009;361(6):569-579. 12
 North American Spine Society (NASS)
Study Limitations1
Fracture Acuity
• Imaging (MRI or bone scan) not required to verify fracture age
• Fracture age <1 yr not generally classified as “acute” (generally 4-
6 wks of pain)
• Patients most willing to be randomized to “sham” may have resolving,
less severe VCF pain
Enrollment
• Kallmes et al.
131 enrolled out of 1,812 screened patients
(93% screen failure rate, decline of consent most common reason)
• Outcomes of patients who refused enrollment were not assessed

1. North American Spine Society: Newly Released Vertebroplasty RCTs: A Tale of Two Trials. Accessed November 16,
2009 at http://www.spine.org/Documents/NASSComment_on_Vertebroplasty.pdf.

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 NASS
Study Limitations1 (cont)

Control Group
• Kallmes et al.
An alternative intervention rather than a “sham”
Anesthetic injection into facet capsule or periosteum (Kallmes et
al.) may have resulted in pain relief (though not fracture pain
relief)
Outcomes
• Kallmes et al.
Did not seek to verify source of back pain (e.g., no
palpation/percussion to verify source of pain)
Crossover at one month suggests superiority of vertebroplasty:
43% control versus 12% for vertebroplasty (p < 0.0001)

1. North American Spine Society: Newly Released Vertebroplasty RCTs: A Tale of Two Trials. Accessed November 16, 2009 at
http://www.spine.org/Documents/NASSComment_on_Vertebroplasty.pdf.

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 NASS’s Recommendations1

“…future PRCTs might benefit from a more strict mechanism by

which patients with truly acute pain relatable to an osteoporotic
VCF are enrolled”

“…it is time for cooler heads to prevail…the conclusions drawn by

the authors, however, may not be as decisive as they appear.
More practical conclusions should be made based on a
thorough and systematic review of all the literature in order to
better define the subgroup of patients for which
vertebroplasty might be most appropriate.”

1. North American Spine Society: Newly Released Vertebroplasty RCTs: A Tale of Two Trials. Accessed November 16, 2009 at
http://www.spine.org/Documents/NASSComment_on_Vertebroplasty.pdf.

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Additional Study Limitations

Mid-trial adjustments
Inclusion criteria
• Relaxation of inclusion criteria to include patients with 3.0/10 VAS
scores

Statistical power and sample size

• Enrollment targets were adjusted at mid-trial
• Kallmes et al
Reduced from 250 (pre-specified) to 130 patients

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Additional Study Limitations (cont)

Mid-trial adjustments
Outcomes
Success criteria were adjusted at mid-trial
• Kallmes et al. - Roland Morris Disability Questionnaire
(RDQ) adjusted from 2.5 (pre-specified) to 3.0
VAS improvement adjusted from 1.0 to 1.5
• “There was a trend toward a higher rate of clinically meaningful
improvement in pain in the vertebroplasty group, than in the
control group (64% vs. 48% P=0.06)”

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 Conclusions
• Data from thousands of patients demonstrate pain reduction with
vertebroplasty.
• The multicenter, randomized controlled trial of kyphoplasty versus
conservative care reveals statistically significant and clinically meaningful
improvement in pain and quality of life.
• The recent NEJM articles have multiple limitations that preclude definitive
conclusion about the value of vertebroplasty, including
• Selection bias;
• Inadequate sample size and statistical power;
• No confirmation of fracture age;
• Mid-trial adjustment to sample size targets and improvement
thresholds; and
• Flaws in the measurement of pain; and
• Use of an active control that is not standard of care for patients with
VCF.
• Ongoing and planned studies will enhance the evidence base for
treatment of VCFs

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