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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
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)
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
ETIDRONATE PRECLINICAL
STUDIES
• Spontaneous fractures in dogs (Flora et al)
• Impaired fracture healing in dogs
(Nunnemaker et al)
• Narrow efficacy/safety window (MRL
study)
Schenk Assay
Epiphysis
Growth Cartilage
Metaphysis
Diaphysis
Microradiograph
Control Bisphosphonate
Schenk Assay Control
Epiphysis
Growth Cartilage
Metaphysis
1° Spongiosa
Metaphysis
2 ° Spongiosa
Diaphysis
Osteoid
Mineralized Bone
Schenk Assay Alendronate
Epiphysis
Growth Cartilage
Metaphysis
1° Spongiosa
Metaphysis
2 ° Spongiosa
Diaphysis
Osteoid
Mineralized Bone
Schenk Assay Etidronate
Epiphysis
Growth Cartilage
Metaphysis
1° Spongiosa
Metaphysis
2 ° Spongiosa
Diaphysis
Osteoid
Mineralized Bone
Dose Response for Inhibition of
Resorption and of Mineralization by
Alendronate in Schenk Assay
25 20
Cn-
Bone Volume ( Cn-
BV/TV)
20
Osteoid Volume 15
(OV/BV)
Cn-BV/TV (%)
15
OV/BV (%)
OV/BV (%)
Efficacy
10
Safety
Safety
10
5
5
0 0
0 0.001 0.01 0.1 1 10 100
1
Dose mg P/kg/day S.C.
Dose Response for Inhibition of
Resorption and Mineralization by
Etidronate in Schenk Assay
35 60
Bone Volume ( Cn-
30 50
BV/TV)
25 Osteoid Volume 40
Cn-BV/TV (%)
(OV/BV)
OV/TV (%)
OV/TV (%)
20
Efficacy
Safety
Safety
30
15
20
10
10
5
0 0
0 0.01 0.1 1 10 100
Dose mg P/kg/day S.C.
FLUORIDE PRECLINICAL
STUDIES
• Bone strength increase is not commensurate
with bone mass increases (Mosekilde et al.
CTI 1987, 40:318-322)
• Abnormal mineralization by x-ray
scattering (Fratzl et al JBMR 1994, 9:1541-
1549)
• MRL study (Lafage et al, JCI 1995,
95:2127-2133)
Correlation of Vertebral Bone Mass and Bone
Strength In Alendronate Treated Animals
Non-OVX Non-OVX
OVX+VEH OVX+VEH
OVX+ALN 0.05 mg/kg IV OVX+ALN 1.8 mg/kg SC
30 OVX+ALN 0.25 mg/kg IV 350 OVX+ALN 18 mg/kg SC
27.5
300
25
Ultimate Strength (MPa)
22.5
Ultimate Load (N)
250
20
17.5 200
15
150
12.5
10
r=0.9 100
7.5 p(x2)=0.0034
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) Baboons 2 Years CTI, 53, 283(1993) Rats 1 Year
Similar Findings in Normal Minipigs (1 Yr), Rats ( 2 Yrs), and Dogs (3 Yrs) Oral Dosing.
Comparison of Alendronate and NaF
Effects on Bone Strength vs. Bone Mass
Alendronate Sodium Fluoride
1600 1600
1400 1400
Failure Load (N)
1200 1200
1000 1000
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)
Bone Strength decreases with
increased NaF content
L4 Core Ultimate Strength (MPa)
1150
1050
950
850
750
1.6 1.8 2.0 2.2
Bone Fluoride Content (mg/g bone ash)
JCI, 95, 2127, (1995)
N.B. In clinical trials NaF increased BMD w/o reducing fractures
PRECLINICAL MODELS FOR BONE
SAFETY
CONCLUSIONS
• 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).
PRECLINICAL MODELS FOR
EFFICACY
• Estrogen-deficiency bone loss
(cancellous>cortical) 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.
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).
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.
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.
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.
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.
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.
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