CONTRIBUTION OF PRECLINICAL STUDIES TO EVALUATION OF OSTEOPOROSIS THERAPY

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CONTRIBUTION OF PRECLINICAL STUDIES TO EVALUATION
OF OSTEOPOROSIS THERAPY

• Gideon A Rodan MD PhD
• Merck Research Laboratories
• Bone Biology and Osteoporosis Research

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PRECLINICAL INFORMATION

• Hypothesis Preclinical studies can reduce the
  burden of proof required of clinical trials, by
  providing information on
• Safety (general and bone)
• Efficacy
• Mechanism (pharmacological activity and
  adverse events)

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Historical Perspective and Current Osteoporosis
Guidelines

• Pre 1994 Increased BMD in 2 year PBO-controlled
  trials plus preclinical evidence for bone
  safety/quality
• Reasons for change
• No fracture reduction during third year with
  etidronate treatment, hence three year studies
• No fracture reduction during fluoride treatment,
  in spite of increased BMD, hence fracture
  endpoint

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ETIDRONATE PRECLINICAL STUDIES

• Spontaneous fractures in dogs (Flora et al)
• Impaired fracture healing in dogs (Nunnemaker et
  al)
• Narrow efficacy/safety window (MRL study)

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Schenk Assay
Epiphysis
Growth Cartilage
Metaphysis
Diaphysis
Microradiograph
Control Bisphosphonate
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Dose Response for Inhibition of
Resorption and of Mineralization by
Alendronate in Schenk Assay
25
25
20
20
Bone Volume (
Bone Volume (
Cn
Cn
-
-
BV/TV)
BV/TV)
20
20
Osteoid
Volume
15
15
Osteoid
Volume
(OV/BV)
(OV/BV)
15
15
10
10
-BV/TV ()
-BV/TV ()
Efficacy
Efficacy
10
Safety
OV/BV ()
OV/BV ()
10
Safety
5
5
Cn
Cn
5
5
0
0
0
0
0
0
0.01
0.01
0.1
0.1
1
1
10
10
100
100
0.001
1
Dose mg P/kg/day S.C.
Dose mg P/kg/day S.C.
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Dose Response for Inhibition of
Resorption and Mineralization by
Etidronate in Schenk Assay
Bone Volume (
Cn
-
Bone Volume (
Cn
-
BV/TV)
BV/TV)
Osteoid
Osteoid
Volume
Volume
(OV/BV)
(OV/BV)
-BV/TV ()
-BV/TV ()
Efficacy
Efficacy
OV/TV ()
Safety
Safety
OV/TV ()
Cn
Cn
0
0
0.01
0.01
0.1
0.1
1
1
10
10
100
100
Dose mg P/kg/day S.C.
Dose mg P/kg/day S.C.
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FLUORIDE PRECLINICAL STUDIES

• Bone strength increase is not commensurate with
  bone mass increases (Mosekilde et al. CTI 1987,
  40318-322)
• Abnormal mineralization by x-ray scattering
  (Fratzl et al JBMR 1994, 91541-1549)
• MRL study (Lafage et al, JCI 1995, 952127-2133)

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Correlation of Vertebral Bone Mass and Bone
Strength In Alendronate Treated Animals
Non-OVX
Non-OVX
OVXVEH
OVXVEH
OVXALN 1.8 mg/kg SC
OVXALN 0.05 mg/kg IV
OVXALN 18 mg/kg SC
OVXALN 0.25 mg/kg IV
30
350
27.5
300
25
22.5
250
20
200
17.5
Ultimate Strength (MPa)
Ultimate Load (N)
15
150
12.5
10
100
r0.9 p(x2)0.0034
7.5
5
50
0.9
0.95
1.0
1.05
1.1
1.15
1.2
1.25
1.3
1.35
30
35
40
45
50
55
60
65
70
Bone Mineral Density L2-L4 (g/cm2)
Ash Weight (mg)
JCI, 92, 2577 (1993)
CTI, 53, 283(1993)
Baboons 2 Years
Rats 1 Year
Similar Findings in Normal Minipigs (1 Yr), Rats
( 2 Yrs), and Dogs (3 Yrs) Oral Dosing.
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Comparison of Alendronate and NaF Effects on Bone
Strength vs. Bone Mass
Alendronate
Sodium Fluoride
1600
1600
1400
1400
1200
1200
1000
1000
Failure Load (N)
800
800
600
600
400
400
200
200
20
25
30
35
40
45
50
20
25
30
35
40
45
50
Bone Volume/Tissue Volume
Bone Volume/Tissue Volume
JCI, 95, 2127 (1995)
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Bone Strength decreases with increased NaF content
1150
JCI, 95, 2127, (1995)
N.B. In clinical trials NaF increased BMD w/o
reducing fractures
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PRECLINICAL MODELS FOR BONE SAFETYCONCLUSIONS

• Bone measurements (histology and strength) in
  animal models at multiples (5x?) of the
  therapeutic dose detected deleterious effects of
  etidronate and fluoride, and could be sensitive
  enough to evaluate the bone safety of prospective
  OP therapies.
• Recommendation
• Use bones from long term toxicology studies to
  evaluate bone safety (histology and strength).

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PRECLINICAL MODELS FOR EFFICACY

• Estrogen-deficiency bone loss (cancellousgtcortical
  ) occurs in most mammals including humans,
  rodents, primates and other species (in sheep,
  dogs, rabbits, apparently seasonal).
• Agents that increase BMD and bone strength in
  preclinical models reduced fracture risk in
  humans bisphosphonates, estrogens, SERMs, PTH.
  However, quantitative relationships would have to
  be determined in clinical trials.

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Recommended Principles for Preclinical Efficacy
Studies

• Use adult animals - to eliminate confounding
  effect of growth.
• Use any species documented to lose an easily
  quantifiable amount of bone following
  oophorectomy, cancellous or cortical.
• Use several parameters and accepted methodology
  (DXA, histomorphometry, QCT, mechanical testing,
  biochemical markers), look for internal
  consistency.
• Use multiple doses (2-3).

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Recommended Principles for Preclinical Efficacy
Studies (Cont.)

• For prevention registration document the
  prevention of bone loss.
• For treatment registration document the
  restoration of lost bone (treatment of
  osteopenia).
• Follow bone retention after cessation of therapy.

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Mechanism Studies

• Provide important insights for defining the
  necessary safety and efficacy studies.
• Safety
• For agents binding to the mineral, effects on
  mineralization and mineral structure (BPs, F).
• For bone forming agents, woven vs. lamellar bone,
  tumors, ectopic ossification
• Efficacy
• At the tissue level all resorption inhibitors act
  similarly (suppression of bone turnover).
• No known mechanistic difference between
  cancellous and cortical bone resorption.

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INHIBITORS OF RESORPTION vs. FORMATION
STIMULATORS

• Inhibitors of bone resorption retain existing
  normal bone and bone structure and can produce a
  positive bone balance. Unless they alter
  bone/mineral structure (e.g. etidronate) they
  should be totally safe for bone.
• Formation stimulators engender production of new
  bone (e.g. fluoride), which could be woven ,
  normal structure should be confirmed by histology.

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SUMMARY AND CONCLUSIONS

• Preclinical studies
• Can validate the bone safety of osteoporosis
  therapeutic agents and potentially predict if
  increases in bone mass will be associated with
  increases in bone strength.
• Can test the efficacy of prospective therapeutic
  agents in animal models of estrogen-deficiency
  bone loss, and potentially other types of bone
  loss.
• Could, accordingly, help the design of clinical
  trials.

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SUMMARY AND CONCLUSIONS

• Topics in current preclinical guidelines which
  can be revisited
• Multiple species (cortical remodeling) for
  efficacy studies.
• Duration of efficacy studies vs. use of long-term
  toxicology animals for bone safety.
• Different criteria for different resorption
  inhibitors.