Effect of OnceWeekly Oral Alendronate on Bone Loss in men Receiving Androgen Deprivation Therapy for

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Effect of Once-Weekly Oral Alendronate on Bone
Loss in men Receiving Androgen Deprivation
Therapy for Prostate Cancer

• Ann Intern Med. 2007146416-424.

Hong Nguyen, DO Georgetown University
Hospital April 24th, 2007
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Background

• Prostate Cancer is the second leading cause of
  death due to cancer in men in the United States
• Most prostate carcinomas are hormone dependent
  (mainly testosterone)
• Androgen deprivation therapy (ADT) has been used
  to treat advanced prostate cancer, and is now
  frequently used for patients with non-metastatic
  disease in combination with XRT

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Background

• Men with prostate cancer who are initiating ADT
  have a 5- to 10-fold increased loss of bone
  density at multiple skeletal sites, placing them
  at increased risk of fracture
• Bone loss is maximal in the first year after
  initiation of ADT, suggesting initiation of early
  preventive therapy.

Greenspan, SL., Coates, P., J Clin Endocrinol
Metab. 2005 Dec90(12)6410-7. 2005 Sep 27
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Background- Use of IV Bisphosphonate

• Previous studies have demonstrated that
  intravenous bisphosphonate therapy, such as
  zoledronic acid and pamidronate, maintains or
  improves bone mass in men with prostate cancer
  who receive ADT

Smith, MR, et al. J Urol. 2003 1692008-12
Diamond, TH, et al. Cancer. 2001 921444-50
Smith, MR, et. al. N Eng J Med. 2001345948-55
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Objectives

• Primary To examine whether once-weekly oral
  bisphosphonate can maintain or improve bone mass
  and reduce bone bone turnover in men with
  non-metastatic prostate cancer who receive ADT
• Secondary To determine whether a second year of
  alendronate therapy provided additional benefit
  to patients compared with only 1 year of
  treatment

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Methods- Patient Characteristics

• Screened men 85 yrs of age or younger who were
  receiving ADT for non-metastatic prostate cancer
• Recruited from urologists, geriatricians,
  internists in the Pittsburgh, PA area
• ADT included gonadotropin-releasing hormone
  agonists, anti-androgens, or a combination
• Included pts who had just initiated ADT (within
  previous 6 months) or who were receiving
  long-term ADT

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Patient Characteristics cont

• Exclusion criteria
• men with radiographic evidence of metastatic
  prostate cancer
• Men dx with non-prostate cancers
• Men if they had an elevated PSA level, a
  testosterone level out of castrate range, or any
  illness that would affect bone and mineral
  metabolism
• Men who were taking medication that would affect
  bone and mineral metabolism
• Had previously received or currently receiving tx
  with bisphosphonate therapy

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Clinical Protocol and Study Design

• Design Randomized, double-blinded,
  placebo-controlled, partial crossover trial (for
  secondary aim)
• Participant encounters at screening, at
  randomization (baseline), and at 6- and 12-
  months, where they were evaluated and data were
  collected
• Setting University Medical Center (U Pitt)

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• Study Flow Diagram

Greenspan, SL., Ann Intern Med. 2007146416-424
Greenspan, SL., Ann Intern Med. 2007146416-424
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Clinical Characteristics, Bone Mineral
Metabolism, and Gonadal Status

• At baseline, the following were measured
• - serum 25-hydroxyvitamin D levels by
  radioimmunoassay,
• -intact parathyroid hormone levels,
• -gonadal status (by serum testosterone and free
  testosterone)

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Outcome Variables

• Bone Mineral Density
• - primary outcome was the percentage change in
  anterior-posterior spine (lumbar spine) BMD at 12
  months
• - secondary outcome included percentage changes
  at the total hip and femoral neck at 12 months

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Outcome Variables

• Markers of Bone Turnover
• - for bone resorption (specifically increased in
  men receiving ADT), serum C-telopeptide
  crosslinks of type I collagen levels, and morning
  urine specimen for creatinine and N-telopeptide
  crosslinks of type I collagen levels were
  measured
• -for bone formation, serum intact N-terminal
  propeptide of type I procollagen, bone-specific
  alkaline phosphatase, and intact osteocalcin
  levels were measured

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Sample Size

• A 2-sided test at a 5 alpha-level
• Allowed for a 10 dropout rate during the year
• However, to determine the effect of an additional
  year of alendronate treatment in men who were
  originally assigned to alendronate, the sample
  size was increased to 112 (56 per group) to
  provide 80 power to assess this secondary
  objective

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Statistical Analyses

• Intention-to-treat approach for primary analyses
• Used t-tests to assess percentage change of BMD
  at 6 and 12 months
• Compared the actual values at 1 year by using
  analysis of covariance (ANCOVA) model, covarying
  for baseline value
• Also used ANCOVA to compare groups adjusted for
  baseline PSA levels, duration of therapy, and
  vitamin D intake

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Results

• Most baseline characteristics did not differ
  significantly between groups
• 96 were white, similar intake of daily calcium
  and vitamin D
• Men had been receiving ADT for a median of 14
  months
• Baseline levels of serum calcium, albumin,
  hematocrit, 25-hydroxyvitamin D, and parathyroid
  hormone were within normal range levels of
  total testosterone were in the castrate range
  PSA levels and T-scores at spine level were also
  similar

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Greenspan, SL., Ann Intern Med. 2007146416-424
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Mean Percentage Change in Markers of Bone
Turnover from Baseline to 6 and 12 months
Greenspan, SL., Ann Intern Med. 2007146416-424
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Adverse Events

• 2 groups did not statistically differ in adverse
  events, serious adverse events, or
  hospitalizations
• The study was not powered to examine the
  statistically significant differences in
  individual events
• Rate of gastric symptoms (5), arthralgias
  (20-30), myalgias (4-14) were similar in both
  groups
• One fragility fracture occurred in each group

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Conclusions- Primary Aims

• Once-weekly oral alendronate statistically
  significantly increases BMD of the spine and hip
  in men with prostate cancer receiving ADT
  compared with those receiving calcium and vitamin
  D alone
• All measures of bone turnover markers
  statistically significantly decreased in pts in
  txed with alendronate
• In the placebo group, measures of bone turnover
  markers showed a mixed response

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Conclusions- Secondary Aims

• Not Yet Available
• Awaiting data from the 2-group, parallel study,
  to determine at the end of year 2 whether a
  second year of oral alendronate provides
  additional benefit over that provided by a single
  year of treatment

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Study Strengths

• Single center
• Enrolled pts who had just initiated ADT within
  the previous 6 months and those who were
  receiving long-term therapy
• Oral once-weekly bisphosphonates are widely
  available
• Provides additional information for treating men
  with low bone mass or osteoporosis

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Study Limitations

• Not powered to examine fracture reduction as an
  outcome (surrogate- bone turnover markers)
• Not powered to examine for differences in those
  pts who received at most 6 months of ADT vs.
  longer treatment with ADT (long-term tx)
• Did not use BMD as an inclusion or exclusion
  criteria (only 9 of sample had a normal bone
  mass)
• Poor external validity due to homogenous
  demographics of the sample (geographic,
  racial/ethnic, SES, insurance status)

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What Do We Tell Our Patients?

• Bone density increased in men who received
  alendronate, and decreased in men who received
  placebo men with prostate cancer taking
  hormone-lowering treatments should have their
  bone density measured.
• However, the study was not designed to show
  whether alendronate reduces fractures.