Osteoporosis Update

1
Osteoporosis Update

• Dana Saffel, Pharm D
• CGP, FASCP
• President, CEO
• PharmaCare Strategies, Inc.

2
Osteoporosis Update

• Objectives
• Describe the medical impact and pathophysiology
  of osteoporosis
• Identify the risk factors for osteoporotic
  fracture
• Evaluate lifestyle modification that can
  potentially reduce the risk for fracture
• Describe pharmacologic and non-pharmacologic
  therapies
• Evaluate the efficacy, safety and tolerability of
  the most frequently prescribed therapies

3
Faculty Disclaimer

• Dr. Saffel provides consulting services to
• Dey, L.P.
• Eli Lilly and Company
• G.S.K.
• Strativa Pharmaceuticals
• Dr. Saffel is on the speakers bureau for
• Forest Pharmaceuticals

4
Overview

• Osteoporosis An Often Silent Risk
• Definition of Osteoporosis
• Impact of Osteoporosis
• 4 Steps to Minimizing Falls and Fractures
• Recognize Residents at Risk
• Assess for Risk
• Implement Appropriate Multidisciplinary Care
  Plans
• Monitor Residents Progress
• Treatment Options

5
Osteoporosis Definition
A skeletal disorder characterized by reduced bone
strength predisposing a person to an increased
risk of fracture. Bone strength primarily
reflects the integration of bone mineral density
and bone quality.1
Normal Bone
Moderate Osteoporosis
Severe Osteoporosis
1. JAMA. 2001285785-795.
6
Osteoporosis Affects the Entire Skeleton

• Osteoporosis is responsible for gt1.5 million
  vertebral and non-vertebral fractures annually
• Spine, hip, and wrist fractures are most common

Other
Vertebral
Hip
Wrist
NIH/ORBD (www.osteo.org), 2000
7
Types of Bone

• Major types of bones
• Cortical
• Trabecular
• Cortical, or compact, bone is the outside of the
  bone, dense and hard comprises 75 to 80 of the
  skeleton
• Trabecular, or cancellous, bone is highly
  vascularized and spongy comprises the inner
  portions of vertebrae and ends of long bones

Femur
Vertebra
TrabecularBone
CorticalBone
8
Osteoporotic Fractures Among Female Senior Care
Residents

• 18-month prospective cohort study
• 1427 Caucasian female residents in 47 senior care
  facilities in Maryland
• 223 osteoporotic fractures occurred in 180 female
  residents

Overall fracture rate 109 per 1000 women per
year
1. JAMA. 2000284972-977.
9
Osteoporosis Prevalence in Senior Care Facilities
21
In the long-term care population, it is
important to deem everyone at risk and consider
appropriate interventions for all residents.
Data for Caucasian men and women in 59 Maryland
nursing homes
Ann of Long-term Care. 20041220-24.
10
Incidence of Osteoporotic Fractures in Women
40 30 20 10
Vertebrae
Annual incidence per 1000 women
Hip
Wrist
50 60 70 80
Age (Years)
Wasnich RD, Osteoporos Int 19977 Suppl 368-72
11
Incidence of Osteoporotic Fractures in Men
4000 2000 0
Vertebrae
Annual incidence per 100,000 men
Hip
Wrist
50 60 70 80
Age (Years)
Wasnich RD, Osteoporos Int 19977 Suppl 368-72
12
All Fractures are Associated with Morbidity
Unable to carry out at least one independent
activity of daily living
80
One year after a hip fracture
Patients ()
Unable to walk independently
40
Permanent disability
Death within one year
30
20
Cooper C, Am J Med, 1997103(2A)12S-17S
13
Vertebral fractures

• Most common fracture type
• Often silent
• Insidious, progressive nature
• Associated with- Deformity, height loss, back
  pain- Impaired breathing - Increased morbidity
  and mortality
• Predict future spine and hip fractures

14
Prior Vertebral Fracture Increases the Risk of
New Fracture
1-year Risk of New Fracture1
30
26.08
25

• Prior vertebral fracture increases fracture risk
• Vertebral 5-fold2
• Hip 2-fold3

17.35
20
Incidence ()
15
10
3.62
3.53
5
1.58
0
Hip Pelvis
Spine
Overall
HumerusLeg
Wrist
Fracture Site
Based on Kaplan-Meier analyses. 1. Osteoporos
Int. 20051678-85. 2. JAMA. 2001285320-323. 3.
J Bone Miner Res. 199914821-828.
15
Osteoporosis Evaluation and Treatment/Intervention
s in SNFs

• A study of 895 residents with known osteoporosis
  or recent fracture in 67 SNFs

36
1. Osteoporos Int. 200718553-559.
16
The Impact of Untreated Osteoporosis

• For the resident1
• Increased risk of fracture1
• Reduced quality of life1
• Increased dependency1
• Pain and suffering1
• For the caregiver2
• Increased need to provide supervision and
  assistance if a fracture occurs
• For the facility3
• Increased costs
• Legal and regulatory issues

1. JAMWA. 200459295-301. 2. Arch Intern Med.
20021621502-1508. 3. Report of the Surgeon
General. Available at http//www.surgeongeneral.g
ov/library. Accessed December 7, 2007.
17
Osteoporosis Can Impact a Facilitys Quality
Indicator Score

• Osteoporosis may have a devastating impact on
  your residents experience
• and also
• Put Facility Quality Indicators at risk
• New fractures
• Falls
• Becoming bedfast or chairfast
• Declining ADLs
• Declining ROM
• Limited physical activity

1. Centers for Medicare and Medicaid Services.
Facility Guide for Nursing Home Quality
Indicators. Available at http//www.cms.hhs.gov/M
inimumDataSets20/Downloads/CHSRA20QI20Fact20She
et.pdf. Accessed November 5, 2007.
18
An Osteoporosis Plan May Help Regulatory
Compliance

• The revised F 323 requires a facility to
• Provide an environment that is as free as
  possible from environmental hazards over which
  they have control
• Provide supervision and assistive devices to each
  resident to prevent avoidable accidents
• To be in compliance, a facility needs
• A systems approach to identify, evaluate,
  implement, and monitor residents at risk
• Supervision
• Assessments of resident risk and environmental
  hazards

1. Wandering and Elopement Litigation Issues.
Available at http//www.hartfordign.org/resources
/special_topics/wandering-elopement.doc. Accessed
November 5, 2007. 2. Senior Care Facility QIS
News. Available at http//www.nursinghomequality.
com/qis_news.html. Accessed November 5, 2007.
19
Benefits When Senior Care Facilities Provide
Appropriate Osteoporosis Care

• For residents
• An osteoporosis care plan may improve patients
  bone health and quality of life by helping them
  to avoid fractures and their devastating
  aftermath
• For the facility and staff, an osteoporosis care
  plan may lead to
• A better work environment
• Improved quality indicators
• Decreased liability concerns
• Decreased cost and resource utilization

1. J Am Med Dir Assoc. 20067420-425.
20
AMDA Clinical Practice Guidelines Osteoporosis,
Falls and Fractures

• Recognition
• Does the resident have osteoporosis (risk for
  fracture) or evidence of its complications?
• Are there clinical factors such as kyphosis, loss
  of height, or previous bone mineral density
  studies that indicate osteoporosis?
• A history of falls may indicate risk of future
  falls

1. American Medical Directors Association
(AMDA). Tools for Implementation of the Clinical
Practice Guidelines for Falls and Osteoporosis.
Available at www.amda.com. Accessed December 5,
2007.
21
Recognize Residents at Risk of Osteoporosis

• Key osteoporosis risk factors
  for senior care residents
• History of fracture(s) after age 50
• Low bone mass
• Advanced age
• Female gender
• Family history of osteoporosis
• History of smoking
• History of excessive alcohol use
• Low lifetime calcium intake
• Small body frame and low weight
• Vitamin D deficiency

1. Am Fam Physician. 199960194-202. 2. JAMA.
2001285785-795.
22
Dont Overlook Male Residents

• Up to 2 million American men have osteoporosis
• Another 8-13 million are at risk
• 1 in 4 or 5 hip fractures in people aged gt50
  years is in men
• Morbidity and the mortality from hip fractures
  are higher in men than in women
• 20.7 mortality after hip fracture among men
  aged gt75 years
• Men are also at risk for vertebral fractures
• Men fracture 10 years later in life than women
• Some risk factors for osteoporosis in men are
• History of nontraumatic fracture
• Hypogonadism
• Advanced age

1. Endocrinol Metab Clin N Am. 200736399419.
23
AMDA Clinical Practice Guidelines Osteoporosis,
Falls and Fractures

• 2. Assessment
• Assess the residents function and
  osteoporosis-associated disabilities
• Perform individualized fall assessments for new
  admissions and after any fall
• Is osteoporosis treatment indicated?
• If BMD tests or results are not available,
  determine probable osteoporosis by
• Age
• Previous fracture

1. American Medical Directors Association
(AMDA). Tools for Implementation of the Clinical
Practice Guidelines for Falls and Osteoporosis.
Available at www.amda.com. Accessed December 5,
2007.
24
Step 2 Assess Osteoporosis Risk
1. American Medical Directors Association (AMDA).
Osteoporosis Guideline. Columbia (MD) American
Medical Directors Association (AMDA) 2003.
25
AMDA Clinical Practice Guidelines Osteoporosis,
Falls and Fractures

• Treatment
• Select and provide appropriate interventions
• Provide nonpharmacologic interventions such as
  adequate nutrition, vitamin D and calcium
  supplementation, and exercise training to prevent
  falls
• Determine if pharmacologic treatment is indicated
  to
• Prevent further bone loss
• Improve bone mineral density
• Rebuild bone

1. American Medical Directors Association (AMDA).
Osteoporosis Guideline. Columbia (MD) American
Medical Directors Association (AMDA) 2003.
26
Normal Bone Remodeling A Balance of Bone
Resorption and Formation
Osteoclast precursors
Resorption
Formation
Osteoclasts
Osteoblasts
Lining cells
Lining cells
Bone remodeling unit
Resting Stage
Secondary mineralization
Remodeling Completed
Formation
Activation
Resorption
24 weeks
34 months
1. Adapted from Rosen CJ. Available at
http//www.endotext.org/parathyroid/index.htm.
Accessed December 7, 2007.
27
Osteoporosis Resorption Exceeds Formation
Pits develop that weaken bone
Osteoclast precursors
Resorption
Formation
Lining cells
Osteoclasts
Osteoblasts
Lining cells
Bone remodeling unit
Resting Stage
Secondary Mineralization
Remodeling Completed
Formation
Activation
Resorption
24 weeks
34 months
1. Adapted from Rosen CJ. Available at
http//www.endotext.org/parathyroid/index.htm.
Accessed December 7,2007.
28
Treatment Goals For Osteoporosis Care
Preserve Existing Bone or Rebuild Bone?

• Preserve Existing Bone
• Osteopenic T-score (-1.0 to -2.4)
• Osteoporotic T-score (-2.5 or
  worse), no fractures or signs/symptoms of
  fracture
• Success with antiresorptive therapy

• Rebuild Bone
• One or more fractures due to osteoporosis
• OR
• Signs/symptoms and risk factors for fracture
  including
• Low T-score (-3.0 or worse)
• Back Pain
• Height loss
• Kyphosis
• Intolerance to antiresorptive therapy
• Significant bone loss on antiresorptive therapy

29
Estrogens Mechanism of Action in Bone
Precursor (Osteoblast)
Precursor (Osteoclast)
Cytokines IL-1, TNF-a IL-6, TGF-b,....
Estrogens
apoptosis TGF-ß
?
?
Cytokines RANK-L
osteoblast
osteoclast
30
Bisphosphonates Block Osteoclasts Reduce
Resorption
New bone formation by osteoblasts renders
bisphosphonate inert, inaccessible
Bisphosphonate attaches to exposed bone mineral
surfaces
Osteoclast takes up bisphosphonate ? loss of
ruffled border, inactivation, detachment
Secondary Mineralization
Remodeling Completed
Resting Stage
Formation
Activation
Resorption
Inactivated osteoclast
Osteoclast precursors
Lining cells
Osteoclast
Bisphosphonate
Osteoblast
1. Adapted from Osteoporosis Int. 1999Suppl
2S66-S80.
31
Teriparatide rDNA origin injection) Rebuilds
Bone
3. Stimulates osteoblast activity
1. Stimulates formation of new bone independent
of bone remodeling cycle
2. Increases bone turnover
Osteoclasts
Osteoblasts
Lining cells
Lining cells
Bone remodeling unit
Resting Stage
Secondary mineralization
Remodeling Completed
Formation
Activation
Resorption
24 weeks
34 months
Information regarding mechanisms of action does
not provide evidence of comparative fracture
protection.
Adapted from Rosen CJ. Available at
http//www.endotext.org/parathyroid/index.htm.
Accessed December 7, 2007.
32
Osteoporosis Treatments Have Different Effects on
the Bone Remodeling Cycle
Information regarding mechanisms of action does
not provide evidence of comparative fracture
protection.
1. FORTEO Package insert. Indianapolis, IN Eli
Lilly and Company 2004. 2. Osteoporosis Int.
1999Suppl 2S66-S80.
33
Osteoporosis Treatments Have Different
Administration Safety Concerns
1. FORTEO prescribing information.
Indianapolis, IN Eli Lilly and Company 2007. 2.
National Osteoporosis Foundation. Physician's
Guide to Prevention and Treatment of
Osteoporosis. Washington, DC National
Osteoporosis Foundation 200322.
34
Non-Pharmacological Approaches

• Adequate intake of dietary calcium vitamin D
• Regular physical activity
• Minimize alcohol intake
• Minimize risk of fall
• Recommend hip protectors in those prone to falls

35
Risk Factors for Falling

• Age
• Impaired gait or balance lower body muscle
  weakness
• Poor vision cataracts
• Malnutrition excessive alcohol intake
• Certain medical conditions, e.g. arthritis,
  diabetes, postural hypotension, cognitive
  impairment, peripheral neuropathy
• Polypharmacy certain medications, e.g.
  psychoactive medications, antihypertensives
• Footwear with slippery soles, high heels
• Factors in the home, e.g. poor lighting, loose
  rugs, loose cabling, uneven or wet surfaces,
  bathtubs without handrails or bath mat, clutter
  at floor level, stepping over pets
• Environmental factors, e.g. wet or cracked paving
  or steps, ice or snow

36
Vit D3 and Calcium in Prevention of Fractures in
Elderly Women
1200mg/d calcium, 20µg/d vitamin D
Chapuy MC et al, N Engl J Med, 19923271637-1642
37
Physical Activity and Prevention of Loss of Bone
Mass

• Meta-analysis of clinical intervention trials
• 18 studies out of 217 extracted
• In Women older than 50
• Efficacy demonstrated only at spine L2-L4
• (Effect size 0.875)
• No effects on hip and forearm

Berard A et al, Osteoporos Int, 19977331-337
38
Treatment Objectives
39
Drugs Used in Osteoporosis Treatment

• HRT
• SERM/Raloxifene
• Calcitonin
• Bisphosphonates- Alendronate- Risedronate-
  Ibandronate
• -Zoledronic acid

• Teriparatide

• Strontium ranelate

40
Effect of Hormone Replacement Therapy on BMD the
PEPI Trial
Hip
Spine
6
4
4




2
2
change from baseline n875
0
0
-2
-2
-4
-4
12
36
24
0
months
months
CEE conjugated equine estrogen
MPA medroxyprogesterone acetate MP micronized
progesterone cyc cyclical cont continuous
PEPI Trial, JAMA, 19962761389-1396
41
Effect of Hormone Replacement Therapy on
Fractures


Time (years)
Cauley JA et al, JAMA, 20032901729-1738
42
Womens Health Initiative - First Randomized,
Controlled Trial in Women (50-79 years) Treated
with HRT
6700 women with 5.2 years of follow-up
Disadvantages
160
112
120
Intestinal cancer
Vertebral fracture
Hip fracture
80
41
29
26
40
Difference vs. placebo
0
-40
-34
-34
Stroke
-37
Cardiovascular diseases
-80
Breast cancer
Tromb. venous
Advantages
Manson JE at al, N Engl J Med, 2003349523-534
43
Effect of Raloxifene in Women with
Postmenopausal Osteoporosis
O
N
O
OH
S
HO
Mean change from baseline
Ettinger B et al, JAMA, 1999282637-645
44
Effects of Raloxifene on Vertebral Fractures
(MORE study)
O
N
O
OH
S
HO
Vertebral Fractures
Group 2 (n2,304) BMD -2.5 prevalent fractures
20
Group 1 (n4,524) BMD -2.5 no prevalent fractures
15
- 30
of patients with incident Vertebral Fractures
10
5
- 50
0
Placebo
Raloxifene 60 mg/d
Placebo
Raloxifene 60 mg/d
Ettinger B et al, JAMA, 1999282637-645
45
Calcitonin Nasal Spray Effects on Spine and
HipPROOF Study Analysis at 5 Years
Chesnut CH 3rd et al, Am J Med, 2000109267-276
46
Effect of Alendronate on BMD
Mean Change in BMD ()
Posterior-anterior spine
Femoral neck
Time (months)
Black DM et al, Lancet, 19963481535-1541
47
Effects of Alendronate on Cumulative Incidence of
Symptomatic Vertebral and Hip Fractures (FIT-1
2)
3
5
- 59
- 63

4
PBO
PBO
2
3
Cumulative Incidence
Cumulative Incidence
2
ALN
ALN
1




1





0
0
0
6
12
18
24
30
36
0
6
12
18
24
30
36
Months
Months
P lt 0.05
Black DM et al, J Clin Endocrinol Metab,
2000854118-4124
48
Change in NTX Excretion
O
O
P
P
H
O
O
H
O
H
H
O
H
O
C
C
C
H
C
H
H
O
C
H
C
H
C
H
C
H
N
H
N
H
2
2
2
2
2
2
2
2
P
H
O
P
O
H
O
H
H
O
O
O
75

50
Urine NTX
25
0
months
0
3
6
9
12
15
18
21
24
At 24 months Alendronate 59 decrease from
baseline (plt0.001) Placebo 9 decrease from
baseline
Braga de Castro Machado et al, J Bone Miner Res,
199914602-608
49
Risedronate Vertebral Fracture Studies (patients
with prevalent vertebral fractures)
Radiological vertebral fractures
Year 0-1
Years 0-3
-49 P lt 0.001
-41 P lt 0.003
-61 P lt 0.001
-65 P lt 0.001
of patients with fractures
PBO 660
RIS 669
PBO 334
RIS 333
PBO 678
RIS 696
PBO 346
RIS 344
n
MN
NA
MN
NA
MNMultinational NANorth American
Harris ST et al, JAMA,19992821344-1352 Reginster
JY et al, Osteoporos Int, 20001183-91
50
Risedronate Reduction of Hip Fracture Risk
McClung MR et al, N Engl J Med, 2001344333-340
51
Risedronate Reduces Vertebral Fracture Risk in
High-risk Subjects in One Year
Watts NB et al, J Clin Endocrinol Metab,
200388542-549
52
Bisphosphonate Adverse Events

• Acute phase response
• Upper GI
• Rash
• Iritis
• Renal impairment
• Jaw osteonecrosis

53
Effect of Teriparatide on BMD over 18 Months
1637 Postmenopausal women with prior vertebral
fracture
Neer RM et al, N Engl J Med, 20013441434-1441
54
Teriparatide Effects on Risk of New Vertebral
Fractures Over 18 Months
Placebo PTH 20 µg
Neer RM et al, N Engl J Med, 20013441434-1441
55
Effect of Teriparatide on Incidence of New Non
Vertebral Fractures and Fragility Fractures over
18 Months
60
50

40
Number of women with new fractures
30
20
10
0
Total fractures
Fragility fractures
Placebo PTH 20 µg
Neer RM et al, N Engl J Med, 20013441434-1441
56
Treatment with Teriparatide(woman 69 years)
Before CtTh 0.32 mm CD 2.9 mm3
Dempster DW et al, J Bone Miner Res,
2001161846-1853
57
Risk for Vertebral Fracture
Ann Intern Med. 2008148197-213.
58
Risk for Nonvertebral Fracture
Ann Intern Med. 2008148197-213.
59
Anti-Fracture Efficacy of the Most Frequently
Used Treatments for Postmenopausal
OsteoporosisAs derived from placebo controlled
randomized trials
Adapted from Delmas PD, Lancet, 20023592018-2026
60
Not Head to Head Comparisons
F femoral neck L lumbar spine H total hip
FRR Fracture Risk Reduction FRR reported as
Relative Risk Reduction/Actual Risk Reduction w/o
no pre-existing fractures p/e pre-existing
fractures
61
Investigational Agents

• Ospemifene
• Lasofoxifene
• Bazedoxifene
• Arzoxifene
• Stontium ranelate
• Increases collagen noncollagen protein
  systhesis, enhances preosteoblast
  differentiation, reduces osteoclast function
• Denosumab
• Human mAb, inhibits RANKL which inhibits
  osteoclast activation and survival
• PTH (1-84) injection

SERMs