The Many

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The Many Faces of Osteoporosis
Paul V. Tomasic, M.D., M.S. Dept Chief for
Endocrinology Southwest Medical Associates Las
Vegas, Nevada November 9, 2006
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Whom to Treat and How Much Calcium Vitamin D
How Treatments Reduce Fracture
Select Best Treatment Future Options
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Definition of Osteoporosis

• A skeletal disorder characterized by
• compromised bone strength predisposing to an
  increased risk of fracture
• Bone strength reflects the integration of two
  main features bone density and bone quality

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Whom to Treat
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Epidemiology
25 million
500,000 vertebral
200,000 wrist
250,000 hip
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In the first year following a hip fracture the
mortality rate is increased by 20
So, Early Diagnosis is crucial
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National Osteoporosis Guidelines for BMD (DXA)

• All women age 65 or older
• Younger postmenopausal women who have one or more
  risk factors
• Postmenopausal women who have had fragility
  fractures

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Bone Density is an important predictor of
fracture risk.
T-score
Compares Bone density to that of peak bone mass
0 to-1 Normal
gt -2.5 Osteoporosis
-1 to 2.5 Osteopenia
1 SD below peak bone mass
10-15 bone loss
1 SD below peak bone mass increases Fracture
risk 2.5 fold higher
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Whom to Treat withPharmacologic Therapy

• Women who have osteoporosis
• fragility fractures
• BMD T score -2.5 and below
• Consider treating women whose BMD is borderline
  low (e.g. -1.5 and below) if they have risk
  factors
• (AACE Osteoporosis Guidelines 2003)

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Risk factors should be considered for risk-
assessment
T-score
Family Hx
age
Fragilty fracture x 4-6 fold
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T score -2.8 Plus 1 risk factor
risk 4 !
T score -1.5 Plus gt5 risk factors
risk 30
T-score
weight
Early Menopause
Race
smoking
Meds Prednisone Thyroxine
T score is only 1 factor in Bone Strength
Fall potential
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The NORA study
The National Osteoporosis Risk Assessment
Trial
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163979 participants! Postmenopausal women
BMD
Fracture rate
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Three observations
40 of the tested women had BMD in the
osteopenic range
7 of the tested women had BMD in the
osteoporosis range
11 of the women gt 45 had one fracture already
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The NORA study
Fracture risk begins to escalate before the the
BMD dips below T Score of 2.5
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Clinical Risk Assessment Fracture Risk Score
Prior fracture BMD Age Weight Family Hx
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A low Z score gt -1.5
Search for secondary cause
Z score is an age matched comparison
Malabsorption
Antigliadin
Hyper parathyroid
Ca, intact PTH
D deficiency
25(OH) D3 level
Hypercortisolism
1 mg Dex Suppression
How does the patient compare with age and race
matched peers?
Hyperthyroidism
Myeloma
TSH
SPEP
Mets to bone
Bone Scan
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Contributors to Bone Strength
Factors of Bone Quality
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How Much Calcium and Vitamin D
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Optimal Calcium Intake

• 1200 mg daily for adults age 50 and older, total
  from all sources
• Average calcium from diet
• women 50 older 500 mg
• men 50 older 600 mg
• Most people need a calcium supplement of 700 to
  1000 mg daily
• Many people are taking too much

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Vitamin D

• Vitamin D deficiency is common
• Adequate vitamin D level is gt 30 ng/dL
• Minimum recommendation 400-800 IU / day
• Many patients need 1,000 - 2,000
• Safe upper limit is 2,000 IU / day

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Treatment Options
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Treatment of Osteoporosis

• Antiresorptive Agents
• Calcitonin
• Raloxifene
• Alendronate
• Risedronate
• Ibandronate
• Zoledronic Acid

• Anabolic Agents
• Teriparatide

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Antiresorptive Agents

• Decrease osteoclastic activity and reduce bone
  resorption
• Change balance of remodeling more in favor of
  bone formation
• Slow the process of remodeling to allow for
  improvement in material properties of bone
• Increase bone density, reduce Fx risk

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Antiresorptive Agents

• Antiresorptive agents reduce fracture risk
• increase in BMD explains less than 20 of
  fracture risk reduction
• decrease in bone resorption explains 50 to 60
• changes in other unmeasured properties must
  account for balance

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How Does One Select an Anti-Resorptive Agent?

• Hard to compare intermediate endpoints such as
  BMD
• Ideally head-to-head trials with fracture
  endpoints
• Must look at proven anti-fracture efficacy

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ERT is no longer considered as a choice for
prevention or treatment of osteoporosis
WHY?
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HERS trial
WHI trial
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Womens Health Initiative (WHI)
What are the protective effects of HRT in healthy
women with no obvious disease?
What are the adverse effects of HRT in healthy
women with no obvious disease?
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Summary
Results
Useof HRT ( PremPro) in healthy women for
prevention.
CAD 29 Stroke 41 VTE 111 Breast ca 26
Colo- Rectal ca 37 Hip Fracture 34 Vert
fracture 34
WHI data the bone protection is NOT worth the
other risks
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When ERT is stopped. The bones go through a
second menopause
So What?
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ERT
1 2 3 4 Years
1 2 3 4 5
Years
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ERT
1 2 3 4 Years
1 2 3 4 5
Years
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Selective Estrogen Receptor Modulator (SERM)
Therapy (The MORE Trial)
Number of Patients 7705 (2641
with prior VFX,
5064 with hip/spine T-score gt 2.5) Mean Age 67
(postmenopausal) Study Design 3 year,
randomized, double-blind, placebo-controlled Drug
60 mg (marketed dose) or 120 mg raloxifene
Calcium Intake 1000 mg daily with Prevalent
VFx 34
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Do we switch these women who were on ERT to
SERMs? (Raloxifene)
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Raloxifene
Effect on hip BMD
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Conclusions
Raloxifene increased BMD in the spine and reduced
Vertebral fracture by 34
Hip fracture reduction NO significant reduction
The MORE Study
Risk of VTE
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Choice of Bisphosphonates
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Bisphosphonates
O
O
O
P
P
P
HO
OH
OH
OH
HO
HO
O
O
C
OH
O
O
C
C
OH
OH
CH
CH
CH
2
OH
2
P
P
HO
HO
OH
N
P
P
P
OH
HO
HO
HO
OH
OH
P
P
HO
HO
OH
OH
CH
CH
C
C
3
3
N
N
N
N
CH
CH
OH
OH
HO
O
C
C
CH
CH
HO
N
N
O
O
2
2
2
(CH
(CH
)
)
CH
CH
P
P
OH
OH
HO
HO
RISEDRONATE
2
2
4
4
3
3
P
HO
OH
OH
P
HO
O
O
IBANDRONATE
O
O
O
O
IBANDRONATE
ZOLEDRONATE
ZOLEDRONATE
P
P
HO
HO
OH
OH
ALENDRONATE
C
C
H
S
S
Cl
Cl
H
HO
P
HO
P
OH
OH
O
O
O
O
P
P
OH
HO
HO
OH
TILUDRONATE
TILUDRONATE
HO
C
C
CH
CH
HO
CH
CH
CH
CH
NH
NH
2
2
2
2
2
2
2
2
P
P
OH
OH
HO
HO
O
O
PAMIDRONATE
PAMIDRONATE
CLODRONATE
CLODRONATE
O
O
O
O
P
P
HO
OH
OH
HO
ETIDRONATE
P
P
HO
OH
OH
ETIDRONATE
HO
C
CH
HO
HO
CH
NH
C
CH
CH
NH
2
2
2
2
2
2
O
O
C
Cl
OH
OH
HO
HO
C
Cl
Cl
Cl
P
P
P
P
HO
HO
OH
OH
HO
P
OH
OH
HO
P
O
O
C
OH
CH
CH
C
OH
O
O
3
3
P
P
OH
HO
HO
OH
O
O
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General comparisons
Effect on vertebral fractures in women with PMO
(post menopausal osteoporosis)
Pivotal trial FIT trial
VERT trial HIP trial
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Both bisphosphonates significantly
reduce incidence of vertebral as well as hip
fractures
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Pivotal trial 960 women with PMO BMD less than
-2.5 T score Alendronate vs placebo 3 years
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Risedronate The VERT Study
Multi National Study 2 vertebral North
American Study 1 Vertebral plus Lumbar T lt-2.5
4000 ambulatory Post Menopausal women under 85
years
At least one vertebral fracture at entry
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Risedronate Reduces Vertebral FractureRisk in
the First Year of Treatment

• 1-year vertebral fracture reduction regardless
  of disease severity

Placebo
Risedronate 5 mg
20
65
61
15
74
of Patients
10
65
5
0
North American
Multinational
North American
Multinational
(AR 4.0)
(AR 7.4)
(AR 7.1)
(AR 8.9)
All Patients
High-Risk Patients
AR absolute risk reduction plt0.001 gt2
prevalent vertebral fractures. Harris ST, et al.
JAMA. 19992821344-1352. Reginster J-Y, et al.
Osteoporos Int. 20001183-91. Watts N, et al. J
Bone Miner Res. 199914(suppl 1)S136. Please see
Actonel package insert for full prescribing
information.
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Risedronate Reduces Vertebral FractureRisk in
the First Year of Treatment

• 1-year vertebral fracture reduction regardless of
  disease severity

Placebo
Risedronate 5 mg
20
65
61
15
74
of Patients
10
65
5
0
North American
Multinational
North American
Multinational
(AR 4.0)
(AR 7.4)
(AR 7.1)
(AR 8.9)
All Patients
High-Risk Patients
AR absolute risk reduction plt0.001 gt2
prevalent vertebral fractures. Harris ST, et al.
JAMA. 19992821344-1352. Reginster J-Y, et al.
Osteoporos Int. 20001183-91. Watts N, et al. J
Bone Miner Res. 199914(suppl 1)S136. Please see
Actonel package insert for full prescribing
information.
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Effect of Risedronate on Clinical Vertebral
Fractures at 1 Year

• A significant risk reduction was observed as
  early as 6 months

2.0
Control
Risedronate
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Cumulative of Patients
1.0



0.0
0
3
6
9
12
Months
plt0.01 vs control absolute risk reduction
1.1 at 1 year. Combined analysis of VERT-NA and
VERT-MN in 2442 postmenopausal women. All
patients received 1000 mg/d calcium and, if
baseline levels were low, 500 IU/d vitamin D.
Clinical vertebral fractures were reported as
adverse events and all were confirmed
radiographically. Watts N, et al. J Bone Miner
Res. 200116(suppl 1)S407. Please see Actonel
package insert for full prescribing information.
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How about hip fracture reduction?
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Literature Review of Studies with Hip Fracture
Analyses
MORE Raloxifene
HIP-CRF
PROOF Calcitonin
FIT I Alendronate
FIT II Alendronate
HIP-LBD
Risedronate
Inclusion Criteria
Age /or PM yr
Data not comparable since extracted from
independent studies.
MORE Multiple Outcomes of Raloxifene Evaluation,
Ettinger, JAMA, 1999 PROOF Prevent Recurrence of
Osteoporotic Fracture Chesnut, Am J Med, 2000
FIT I Fracture Intervention Trial Fx Arm
Black, Lancet, 1996 FIT II Fracture
Intervention Trial Cummings, JAMA, 1998 HIP I
II McClung, NEJM, 2001
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Published HIP Fracture Incidence in Prospective
Trials Over 3-5 Years
P lt 0.003
5.7
6
5
P 0.02
P 0.009
3.9
P NS
4
3.2
3.0
P 0.047
2.8
of Patients with Hip Fracture
P 0.044
3
P NS
2.3
2.2
2.2
2.0
1.9
2
P NS
1.1
1.1
1.0
0.9
0.8
0.7
1
0
FIT I, LBD,
FIT II
FIT II-LBD
MORE
PROOF
HIP
HIP, LBD
HIP, LBD,
VFX
VFX
Placebo
Active
Data not comparable since extracted from
independent studies.
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Published HIP Fracture Incidence in Prospective
Trials Over 3-5 Years
P lt 0.003
5.7
6
Alendronate
Risedronate
5
P 0.02
P 0.009
3.9
P NS
4
3.2
3.0
P 0.047
2.8
of Patients with Hip Fracture
P 0.044
3
P NS
2.3
2.2
2.2
2.0
1.9
2
P NS
1.1
1.1
1.0
0.9
0.8
0.7
1
0
FIT I, LBD,
FIT II
FIT II-LBD
MORE
PROOF
HIP
HIP, LBD
HIP, LBD,
VFX
VFX
Placebo
Active
Data not comparable since extracted from
independent studies.
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Apparently, the best risk reductions are seen
in patients with...
Prior Vertebral fracture
Low BMD
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General comparisons
Effect on hip fracture reduction in women with
vertebral fracture and low BMD
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60
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Alendronate
Risedronate
Compliance
Proper instructions
Is the patient on adequate Ca and Vit D?
Is the patient taking the calcium with
bisphosphonate?
Can you tell if it is working?
Urine test
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Urine N-Telopeptide
Urine N-Telopeptide is a marker
of bone resorption
After start of bisphosphonate Rx 20-30
reduction in urine N telopetide noted
Test needs to be done as baseline (morning
collection) and 3-6months later
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When to repeat the BMD to determine if the drug
is working?
18 months -2 years
What is drug failure?
Fracture
Decreasing BMD
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Safety Concern

• Oversuppression of bone turnover
• 9 patients with spontaneous fracture of pelvis,
  femur, rib, metatarsal
• delayed or absent healing 3 - 24 months
• suppressed bone turnover on bone bx
• 3 received alendronate estrogen 3-5 yrs, 2
  received alendronate steroids 3-4 yrs, 4
  received alendronate alone 5-8 years
• Odvina, et al, JCEM 2005901294

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Osteonecrosis of the Jaw

• Nonhealing extraction socket or exposed necrotic
  bone refractory to conservative debridement and
  anitbiotic therapy
• About 750 cases reported to FDA
• Predominantly patients with malignancy treated
  with IV pamidronate or zoledronate or both

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Long-term Use of Bisphosphonates

• Alendronate 10 years (original phase III study)
• Alendronate 10 years (FLEX)
• Risendronate 7 years (VERT-MN)
• Risendronate 4 years (VERT-NA)

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Long-term Use of Bisphosphonates

• Appears to be safe for most patients (5-10 years)
• Safety issues occur but appear to be rare in
  osteoporosis doses
• After 3-5 years, a drug holiday can be
  considered for 1 - 2 years without major loss of
  efficacy

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Combination Therapy of two anti-resorptive agents

• Combining two antiresorptive agents yields
  slightly additive effects on BMD
• alendronate and estrogen
• alendronate and raloxifene
• risendronate and estrogen
• Use of two antiresorptive agents hard to justify
• effects on fractures not documented, increased
  cost, potential side effects

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Teriparatide
How does it work?
How effective is it?
Who are the candidates for Forteo?
Drawbacks?
Bisphosphonates- Before, During or After Forteo?
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1
Teriparatide
How does it work?
Anabolic effect on Osteoblast
Intermittent
Stimulates osteoblast
Continuous
Stimulates osteoclast
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2
Teriparatide
How effective
On BMD
On fractures
Spine
Hip
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Effect of parathyroid hormone on fractures and
BMD in postmenopausal women with osteoporosis
Neer et al, N Engl J Med 2001344 1434
1637 post menopausal women with prior vertebral
fractures
Randomized to
21 mo follow up
Primary end points Vertebral radiographs for
fracture BMD
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14
5
4
9
13
3
6
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No significant reduction in hip fracture
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Effect of parathyroid hormone on fractures and
BMD in postmenopausal women with osteoporosis
Neer et al, N Engl J Med 2001344 1434
Conclusions
1. PTH decreases the risk of vertebral and non
vertebral fractures
2. PTH increases vertebral, femoral and total
body BMD
Does not have an FDA approval for hip fracture
prevention
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3
Teriparatide
Who are the candidates?
Severe disease Refractory disease
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4
Teriparatide
Drawbacks
Daily injections Pen use Cost Duration of
therapy- ( osteosarcoma)
Catch up loss that is expected to occur after
discontinuation of PTH
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5
Teriparatide
Bisphosphonates During,or after?
Enhancement of bone mass in osteoporotic women
with PTHfollowed by alendronate Rittmaster
et al, J Clin Endocrinol Metab 200085 2129
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Enhancement of bone mass in osteoporotic women
with PTHfollowed by alendronate Rittmaster
et al, J Clin Endocrinol Metab 200085 2129
66 postmenopausal osteoporotic women Treated for
1 year with 50, 75, or 100 mcg PTH then
stopped and started on Alendronate 10 for one year
BMD in Lumbar spine Femoral Neck Whole Body
Markers Skeletal AP Osteocalcin N telopeptide
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66 postmenopausal osteoporotic women Treated for
1 year with 50, 75, or 100 mcg PTH then
stopped and started on Alendronate 10 for one year
BMD LS
BMD Femoral Neck
0.3
7.1 5.6
During first year on PTH
13.4 6.4
4.4 7.2
After addition of ALN
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Enhancement of bone mass in osteoporotic women
with PTHfollowed by alendronate Rittmaster
et al, J Clin Endocrinol Metab 200085 2129
Conclusions
1. Sequential treatment of osteoporosis with PTH
and alendronate results in a better increase in
vertebral bone density
2. And may prevent catch up loss that is
expected after discontinuation of PTH
No fracture data
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How about combining Alendronate with PTH
concurrently?
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Combination Therapy anabolic and antiresorptive
Conclusions
1. Combination of PTH with estrogen or raloxifene
similar to anabolic alone Combination with
alendronate may blunt anabolic effect effects
on bone strength and fracture unknown use
monotherapy until more is known
2. Follow 2 year of anabolic treatment with
bisphosphonate
No fracture data
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Future

• New anabolic (1-84 PTH)
• New bisphosphonates (zoledronic acid)
• New SERMs
• SERM combined with estrogen
• Osteoprotegerin analog
• Cathepsin K inhibitors
• Strontium ranelate

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Whom to Treat and How Much Calcium Vitamin D
How Treatments Reduce Fracture
Select Best Treatment Future Options