Bone Turnover Suppression

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• Bone Turnover Suppression
• Based on an ASBMR/ECTS Clincal Debate
• Too Much Suppression of Turnover Is Bad for
  Bone
• Co-Chairs Socrates Papapoulos, Douglas C. Bauer
• Debaters Richard Eastell, Ian R. Reid
• Friday, October 15, 2010
• ASBMR 2010
• Toronto, Ontario

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• In support of the statement that too much
  suppression of bone turnover is bad for bone
• Patients
• Treated with high-dose bisphosphonates (BPs)
• With adynamic bone disease
• Treated with glucocorticoids
• Patients undergoing radiotherapy for cancer
  therapy can have zero bone turnover at the site
  of irradiation and are at risk for fracture

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Glucocorticosteroid Effects on Vertebral Fracture

• Patients on glucocorticoid therapy have a
  fivefold increase in vertebral fracture risk over
  controls within months of initiating treatment
• Dialysis patients with adynamic bone disease have
  6x higher hip fracture risk, more 2x the
  vertebral fracture risk than dialysis patients
  without low bone turnover

4
Fractures in the ADOPT Study

• Plt0.01 Plt0.05 for the comparison with
  rosiglitazone (unadjusted, contingency chi-square
  test).
• Over 9 of women developed a fracture over 4
  years compared with 5 of those on metformin and
  about 3 on glyburide
• Rosiglitazone decreases bone formation and can
  lead to a rapid and significant decrease in bone
  density
• Adapted from Kahn et al. N Engl J Med
  20063552427-43.

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Bone Suppression/Low Bone Turnover

• Too much suppression should be defined as bone
  turnover markers below levels found in healthy
  people
• Bone markers in clinical use remain
  controversial but P1NP may be the most useful
• Various clinical trials indicate that many
  patients who receive standard treatment for
  osteoporosis have low bone turnover
• Atypical subtrochanteric fractures may be
  associated with long-term BP use although they
  can occur in treatment-naive patients as well
• Severe sustained suppression of bone turnover
  can lead to osteonecrosis of the jaw regardless
  of how bone turnover is suppressed
• Glycosylation of the bone matrix can impair the
  mechanical properties of bone

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PINP levels showing density distribution of
patients treated with alendronate 10 mg/day or
raloxifene 60 mg/day for 12 months

• After treatment, most women had P1NP
  concentrations within the lower half of the
  premenopausal reference interval (3 below
  lower limit)
• After treatment, 60 of women had P1NP
  concentrations below the lower limit of the
  premenopausal reference interval
• 1.2, 1.9 on scale represent the lower and upper
  limits and 1.5 the geometric mean.
• Prior to treatment, P1NP concentrations were in
  the upper half of the reference interval.
• P1NP procollagen type I N-terminal propeptide
• FACTForteo-Alendronate Comparator Trial
  AAAAnabolic After Antiresorptive MOREMultiple
  Outcomes of Raloxifene Evaluations GHAHA
  Randomized Double-Blind Trial to Compare the
  Efficacy of Teriparatide with Alendronate in
  Postmenopausal Women with Osteoporosis
• Adapted from Eastell et al. Osteoporos Int
  2010Epub ahead of print.

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• The majority of patients in the FREEDOM trial
  had P1NP levels below reference intervals for
  healthy young individuals
• Despite this, the incidence of vertebral
  fracture, hip and non-vertebral fracture risk in
  denosumab recipients was lower than in controls
  and there was no signal of bone harm

8
Summary

• Evidence linking BP use with osteonecrosis of
  the jaw is extremely weak
• Even in the setting of atypical fractures of
  the femur, research indicates there is
  considerable cellular activity near the femur
• There is no clear link between low bone
  turnover and AFFs
• The ASBMR Task Force recently stated that a
  causal association between BPs and AFFs has not
  been established