Osteoporosis and Its Consequences

1
Osteoporosis and Its Consequences

• Systemic skeletal disorder characterized by
• low bone mass
• microarchitectural deterioration of bone tissue
• increased bone fragility and susceptibility to
  fracture
• Risk of fracture increases with age
• Postmenopausal osteoporosis (PMO) results
  primarily from decline in estrogen levels after
  menopause

2
Number of Vertebral Deformities at Baseline
Increases Risk of Future Fracture
Data from Black DM, et al. J Bone Miner Res.
199914821-828.
3
Prevalent Vertebral Fracture PredictsRisk of
Future Hip Fracture
Adapted with permission from Melton LJ III, et
al. Osteoporos Int. 199910214-221.
4
Women With Osteoporotic Fractures Often Go
Undiagnosed and Untreated
Data from Hajcsar EE, et al. CMAJ.
2000163819-822.
5
Relevance of BMD Changesto Fracture Risk
Reduction

• Strengths
• BMD measurement is the most accurate and
  precise means of assessing skeletal fragility
• BMD is the strongest available predictor of
  initial fracture risk
• BMD increases correlate with fracture risk
  reduction

• Weaknesses
• Impact of changes in BMD on fracture risk is
  not bidirectional
• Lack of uniformity exists among current BMD
  testing standards
• Many factors other than BMD also have an impact
  on fracture risk

6
Effect of Low-Dose Estrogen Therapyon BMD in
Postmenopausal Women

• 406 postmenopausal women were randomly assigned
  unopposed ERT (estrogen 0.3 mg/d, 0.625 mg/d, or
  1.25 mg/d) or placebo1
• all ERT doses significantly increased lumbar
  spine BMD vs. baseline and placebo at 6, 12, 18,
  and 24 months
• occurrence of endometrial hyperplasia was
  clinically relevant only at ERT doses of 0.625
  mg/d and 1.25 mg/d
• 128 Caucasian women gt65 yrs. with BMD of 0.90
  g/cm2 or less were randomized to low-dose HRT
  (estrogen 0.3 mg/d and medroxyprogesterone 2.5
  mg/d) or placebo2
• spine BMD increased 3.23 vs. placebo (P lt
  0.001)
• HRT-related symptoms were mild and short-lived

1. Genant HK, et al. Arch Intern Med.
19971572609-2615.2. Recker RR, et al. Ann
Intern Med. 1999130897-904.
7
Effect of PTH on Fracture Riskin Postmenopausal
Women
69?
54?
RR0.35, 95 CI0.22-0.55. RR0.31, 95
CI0.19-0.50.
RR0.47, 95 CI0.25-0.88. RR0.46, 95
CI0.25-0.86.
Data from Neer RM, et al. N Engl J Med.
20013441434-1441.
8
Effect of Raloxifene on Incident Vertebral
Fracturesin Postmenopausal Women With
Osteoporosis
RR0.5, 95 CI0.3-0.7. RR0.6, 95
CI0.4-0.9.
RR, 0.7, 95 CI0.6-0.9. RR, 0.5, 95
CI0.4-0.6.
Adapted with permission from Ettinger B, et al.
JAMA. 1999282637-645.
9
Intranasal Salmon Calcitonin 5-YearResults of
the PROOF Trial
Reprinted with permission from Chesnut CH III, et
al. Am J Med. 2000109267-276.
10
Long-Term Effect of Alendronate on BMD in
Postmenopausal Women With Osteoporosis
Adapted with permission from Tonino RP, et al. J
Clin Endocrinol Metab. 2000853109-3115.
11
Effect of Once -Weekly Alendronate in
Postmenopausal Women With Osteoporosis
Data from Schnitzer T, et al. Aging (Milano).
2000121-12.
12
Effect of Risedronate on Fracture Risk in
Postmenopausal Women With Osteoporosis
1. Reginster J-Y, et al. Osteoporos Int.
20001183-91.2. Harris ST, et al. JAMA.
19992821344-1352.
13
Effect of Risedronate on Hip Fracture Risk in
Women 70-79 Yrs. of Age With PMO
Data from McClung MR, et al. N Engl J Med.
2001344333-340.
14
Effect of Risedronate on Hip FractureRisk in
Elderly Women
Reprinted with permission from McClung MR, et al.
N Engl J Med. 2001344333-340.
15
GI Tolerability of Bisphosphonates

• Clinical trials of bisphosphonates reveal rates
  of upper GI events comparable to placebo and
  lower than NSAIDs1
• Risedronate 30 mg/d or alendronate 40 mg/d caused
  significantly fewer gastric erosions than aspirin
  650 mg qid (P lt 0.001)1
• Risedronate 5 mg/d caused significantly fewer
  endoscopic gastric ulcers than alendronate 10
  mg/d (P lt 0.001)2
• Endoscopic erosions do not always correlate with
  clinical symptoms1,2

1. Lanza F, et al. Am J Gastroenterol.
2000953112-3117. 2. Lanza FL, et al.
Gastroenterology. 2000119631-638.
16
Postmenopausal OsteoporosisConclusions

• PMO is a serious health risk for older women
• BMD loss associated with reduction in estrogen
  production starting at menopause
• increased risk of fractures with increasing age
• Bone densitometry is indicated for all
  postmenopausal women 65 yrs. and older and prior
  to initiating therapy
• Bone densitometry is indicated for all
  postmenopausal women younger than 65 yrs. who
  have one or more risk factors

These National Osteoporosis Foundation (NOF)
recommendations apply primarily to Caucasian
women because of a lack of data in women of
other races or ethnicities.
17
Postmenopausal OsteoporosisConclusions (contd)

• Each SD decrease in BMD is associated with a
  twofold increase in fracture risk
• Primary treatment goals prevent first fragility
  fracture stabilize/increase bone mass
• According to NOF guidelines, therapy should be
  considered in
• women with T score lower than 2 with no risk
  factors
• women with T score lower than 1.5 with at least
  one risk factor
• women gt 70 yrs. of age with more than one risk
  factor or prior fractures even without
  densitometry

18
Prevention and Treatment of PMO Summary

• ERT/HRT For prevention only increases BMD
  reduces vertebral fracture risk treats
  menopausal symptoms increases risk of DVT may
  increase breast cancer risk for bone benefit,
  initiate within 5 years of menopause and continue
  indefinitely low doses may improve BMD with
  fewer AEs
• Salmon calcitonin Antiresorptive agent
  maintains BMD decreases vertebral fracture risk
  occasional nasal irritation from spray
• Raloxifene Maintains/increases bone density
  decreases vertebral fracture risk no treatment
  of menopausal symptoms, but no estrogen AEs
  except increased risk of DVT reduces risk of
  breast cancer in women with PMO
• Bisphosphonates Inhibit bone resorption
  maintain or increase BMD alendronate and
  risedronate decrease risk of vertebral fracture
  and hip fracture oral nitrogen-containing
  bisphosphonates may cause esophageal irritation
  in some patients