Transcript Conflict of Interest Jonathan D. Adachi

Introduction: Pathways and Targets
Leading to the Prevention and Treatment
of Osteoporosis and Fractures
Jonathan D. Adachi, MD, FRCPC
Professor, Department of Medicine
St. Joseph’s Healthcare
McMaster University
Hamilton, Ontario
Canada
Prevalence of Vertebral Deformity
The Canadian Multicentre Osteoporosis Study
Jackson SA, et al. Osteoporos Int. 2000;11:680-687.
Mortality from The Canadian Multicentre
Osteoporosis Study

Hip fracture: 1 in 4 die within 5 years of
fracture

Vertebral fracture: 1 in 6 die within 5
years of fracture

No fracture: 1 in 12 die within 5 years of
follow-up
Ioannidis G, et al. CMAJ. 2009;181:265-271.
CaMos HUI3 Scores—Baseline
Differences Between Diseases
0
-0.02
-.02
-0.04
-.05
-0.06
-.06
-.07
-0.08
-0.1
-.08
-.1
-0.12
Abbreviations: CaMos, Canadian Multicentre Osteoporosis Study;
COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus.
Sawka AM, et al. Osteoporos Int. 2005;16:1836-1840.
Arthritis
Osteoporosis
COPD
He art Disease
DM
Hype rtension
Percentage of Participants on Therapya
Clinical Vertebral Fracture
Women
Men
80%
71.60
70.00
66.67
64.55
61.84
60%
45.61
44.44
40%
25
20%
0%
14.28
12.50
11.11
0.00
Ye ar 0
Ye ar 1
Ye ar 2
Ye ar 3
Ye ar 4
Difference in % treated (baseline to year 5):
 Women:
+26%
 Men:
+25%
aHormone
replacement therapy, bisphosphonate, raloxifene, or calcitonin/fluoride.
Adachi JD, et al. CaMos Annual Meeting 2008.
Ye ar 5
Percentage of Participants on Therapya
Hip Fracture
Women
Men
57.74
60%
45.56
43.75
43.20
41.89
40%
37.50
28.94
28.57
25
20%
8.33
5.88
6.25
0%
Ye ar 0
Ye ar 1
Ye ar 2
Ye ar 3
Ye ar 4
Difference in % treated (baseline to year 5):
 Women:
+29%
 Men:
+29%
aHormone
replacement therapy, bisphosphonate, raloxifene, or calcitonin/fluoride.
Adachi JD, et al. CaMos Annual Meeting 2008.
Ye ar 5
Corticosteroid-Induced Osteoporosis
Relative Risk for Fracture by Steroid Dose
6
5.2
5
4
3
2.6
2.3
1.8
2
1
1
1
0
Hip
Spine
van Staa TP, et al. J Bone Miner Res. 2000;15:993-1000.
Control
2.5–7.5 mg/d
>7.5 mg/d
Corticosteroid-Induced Osteoporosis
Relative Risk for Fracture by Time on Steroids
Nonvertebral Fracture Rate
(Per 1000 PYR)
40
37
35
31
30
25
20
20
15
10
5
0
<5 Years
Graphic courtesy of Dr. Jonathan Adachi.
5–10 Years
>10 Years
Corticosteroid-Induced Osteoporosis
Corticosteroid-Associated Adverse Events—
What Are Patients Concerned About?
Adverse Event
Preference Value (0–1)
Hip fracture requiring nursing home stay
0.55
Vertebral fracture – chronic pain
0.58
Hip fracture – uncomplicated
0.61
Septic arthritis
0.63
Vertebral fracture – acute
0.65
Ulcer requiring hospitalization
0.68
New onset diabetes
0.69
Rib fracture
0.77
Preference value anchors are 1 = “current health”; 0 = “death”.
Graphic courtesy of Dr. J. D. Adachi.
Corticosteroid-Induced Osteoporosis
Corticosteroid-Associated Adverse Events and
Matched Historical Cohort
Adverse Event
User (112)
Nonuser (112)
21
8
Cataract
17
5
Serious infection
14
4
GI bleed or ulcer
11
4
Diabetic complication
8
3
Herpes zoster
8
1
Myocardial infarction
4
4
Stroke
6
1
Glaucoma
1
1
Death
2
0
Fracture
Saag KG, et al. Am J Med. 1994;96:115-123.
Pathways and Targets Leading to
the Prevention and Treatment of
Osteoporosis and Fractures
The RANK/RANKL/OPG Concept
RANK
RANKL
OPG
Ligand binding
activates cellular
signaling
• Expressed by osteoclasts and their precursors
• Activated by RANKL binding
• Signaling protein expressed by osteoblasts/bone lining cells
• Binds to RANK and promotes osteoclast formation, function,
and survival
• Protein secreted by osteoblasts/bone lining cells
• Natural inhibitor of RANKL
• Blocks RANKL signaling to balance bone remodeling
Ligand bound to
decoy receptor
cannot activate
cellular signaling
Abbreviations: OPG, osteoprotegerin; RANKL, RANK ligand. Boyle WJ, et al. Nature. 2003;423:337-342.
Many Factors Stimulate Osteoblast
Expression of RANKL
Prefusion Osteoclast
Glucocorticoids PTH
Vitamin D
IL-11
RANKL
RANK
Multinucleated
Osteoclast
PGE2
IL-6
IL-1
PTHrP
Activated
Osteoclast
TNF-
Estrogen
Osteoblast
Boyle WJ, et al. Nature. 2003;423:337-342.
Hofbauer LC, Schoppet M. JAMA. 2004;292:490-495.
Abbreviations: IL, interleukin; PGE2, prostaglandin E2;
PTH, parathyroid hormone; PTHrP, parathyroid-related hormone;
TNF, tumor necrosis factor.
OPG
Decoy Receptor Prevents RANKL Binding to RANK:
Inhibits Osteoclast Formation, Function, and Survival
Prefusion
Osteoclast
CFU-M
RANKL
RANK
OPG
Hormones
Growth factors
Cytokines
Osteoclast Formation, Function,
and Survival Inhibited
Osteoblasts
Bone Formation
Bone Resorption Inhibited
In the presence of M-CSF
Abbreviations: CFU-M, colony-forming unit macrophage; M-CSF, macrophage colony-stimulating factor.
Boyle WJ, et al. Nature. 2003;423:337-342.
Sites of Action for Currently Available
Pharmacologic Agents
RANK ligand
Precursors
Prefusion
Osteoclast
RANK
Multinucleated
Osteoclast
Hormones
Cytokines
Growth Factors
Calcitonin
BPs
PTH
SERMs
HRT
Activated
Osteoclast
Osteoblasts
Bone Formation
Abbreviations: BPs, bisphosphonates;
HRT, hormone replacement therapy;
PTH, parathyroid hormone;
SERMs, selective estrogen receptor modulators.
.Boyle
WJ, et al. Nature. 2003;423:337-342.
Bone Resorption
Resorbing Osteoclast
Signals Determining Differentiation
Toward Osteoblasts and Acting on Mature
Osteoblasts to Enhance Bone Formation
Wnt and BMP
Preosteoblast
PTH
Osteoblast
Bone Formation
Growth
Hormone
Insulin-Like
Growth
Factor
Under the influence of Wnt
and BMP, undifferentiated
mesenchymal cells
differentiate toward cells of
the osteoblast lineage.
PTH enhances cell
replication, and PTH and
growth hormone induce the
synthesis of insulin-like
growth factor I, which
enhances osteoblastic bone
formation.
New Bone
Abbreviations: BMP, bone morphogenic protein; PTH, parathyroid hormone.
Signaling Pathways Used by BMPs in
Osteoblasts
Bone
Morphogenic
Protein
R1 R2
Extracellular
Antagonists
R2
R1 R2
Cell Membrane
pSmad
1 and 5
Smad 4
MAPK
(ERK)
Intracellular
Antagonists
Cytoplasm
Transcription
Nucleus
Gene Expression
After BMP binds to its predimerized types I and II receptors (RI and RII), Smad 1 and 5 proteins are
phosphorylated (pSmad), associate with Smad 4, and translocate to the nucleus to regulate transcription.
Another pathway used by BMP involves binding to its type II receptor, an intrinsic kinase that activates
the type I receptor; the newly dimerized receptor complex activates the mitogen-activated protein kinase (MAPK)
extracellular regulated kinase (ERK) pathway to regulate transcription.
Extracellular antagonists bind BMP and prevent signal transduction.
Basal Conditions
LRP5 and
LRP6
Frizzled
Cell Membrane
Axin
APC GSK3ß
ß-Catenin
Proteosome
Cytoplasm
Nucleus
Under basal conditions β-catenin is phosphorylated by glycogen synthase
kinase 3β (GSK-3β), axin, and adenomatous polyposis coli (APC) tumor
suppressor protein and degraded in the proteasome.
Wnt Signal
LRP5 and
LRP6
Wnt
Frizzled
Cell Membrane
Disheveled
APC
Axin
ß-Catenin
Cytoplasm
ß-Catenin
GSK3ß
ß-Catenin
ß-Catenin
Nucleus
Proteosome
TCF-4
LEF-1
Transcription
After Wnt binding to its receptor (frizzled) and coreceptors (low density lipoprotein
receptor-related proteins 5 and 6 [LPR5 and LPR6]), disheveled, an intracellular protein is induced
to degrade GSK-3β. In addition, the cytoplasmic tails of LRP5 and LRP6 bind and anchor axin.
These 2 events lead to the stabilization of β-catenin and its translocation to the nucleus,
where it binds to T-cell factor 4 (TCF-4) or lymphoid enhancer binding factor1 (LEF-1)
to regulate transcription.
Wnt Antagonists
LRP5 and
LRP6
Kremen
Frizzled
Wnt
Sclerostin
sFRP-1
DKK-1
Cell Membrane
Axin
ß-Catenin
APC GSK3ß
Proteosome
Cytoplasm
Nucleus
The extracellular Wnt antagonists prevent Wnt signaling. Dikkopf-1 (Dkk-1) in
association with Kremen and sclerostin bind LRP5 and LRP6. Soluble frizzledrelated protein (sFRP-1) binds Wnt and prevents its interaction with frizzled.
Summary

Osteoporosis is common and is
relevant to the rheumatologist

It results in significant morbidity and
mortality

It is a major concern to our patients
Summary



Advances in our understanding of bone
biology have led to the discovery and use of
a wide variety of therapies
Recent discovery of the RANK/RANKL/OPG
pathway has resulted in a new therapy
Future therapies may arise from our
understanding of signaling pathways that
inhibit the osteoclast and stimulate the
osteoblast
Who Is At Risk for Osteoporosis and
Fractures?
Michael J. Maricic, MD
Clinical Associate Professor of Medicine
University of Arizona School of Medicine
Co-director of Catalina Pointe Clinical Research
Tucson, Arizona
Osteoporosis and Fractures in
Rheumatoid Arthritis
Osteoporosis and fractures significantly
increase the morbidity of patients with
rheumatoid arthritis
Kvien TK. Pharmacoeconomics. 2004;22(suppl 1):1-12.
Types of Bone Loss in
Rheumatoid Arthritis

Erosions–at joint margins in areas of direct pannus
invasion

Periarticular osteopenia–adjacent to inflamed joints

Generalized osteoporosis–of the axial and
appendicular skeleton
Erosion
Periarticular
osteopenia
Schett G, et al. Nat Clin Prac Rheumatol. 2005;1:47-54.
Goldring SR, Crotti TN. In: Bone Disease in Rheumatology.
Lippincott Williams & Wilkins;2005:8-14.
Generalized skeletal osteoporosis
Cumulative % of
Patients with Erosions
Most Rheumatoid Arthritis Patients
Develop Bone Erosions During First
2 Years of Disease
100
90
80
70
60
50
Hands
40
Feet
30
Hands or Feet
20
Hands and Feet
10
0
Baseline
1
2
3
4
5
Years of Follow-Up
Patients with rheumatoid arthritis <1 year underwent annual radiologic assessment of hands and feet.
Hulsmans HM, et al. Arthritis Rheum. 2000;43:1927-1940.
Graphic courtesy of Dr. Michael Maricic.
Early Generalized Bone Loss In
Rheumatoid Arthritis



Bone mineral density (BMD) measured
over first 2 years, before glucocorticoids
or disease-modifying anti-rheumatic drug
therapy
No difference in BMD at baseline between
patients and controls
Difference in BMD at 12 months
– Spine
– Trochanter
Gough AK, et al. Lancet. 1994;344:23-27.
-2.4 vs -0.6%
-4.3 vs -0.4 %
Factors Associated with Systemic Bone
Loss in Rheumatoid Arthritis

Systemic and local inflammation due to
inflammatory cytokines

Glucocorticoids and other medications

Age

Gonadal deficiency

Immobility (functional status)
Cytokine Regulation of Bone
Resorption in RA
Stimulatory
Inhibitory

RANKL

OPG

M-CSF

IL-4

TNF

IL-12

IL-1 and -

IL-18

IL-6, -7, -15, and -17

GM-CSF

PGE2

IFN

PTH

PTHrP

Vitamin D
Goldring S, and Crotti T. In: Bone Disease in Rheumatology. Lippincott Williams & Wilkins;2005:8-14.
Osteoclasts Are Present at Sites of
Bone Cartilage Interface in RA
Unmineralized
cartilage
Osteoclasts
Mineralized
cartilage
Cortical bone-cartilage
interface
Osteoclasts in affected joints of patients with RA
With permission from Schett G, et al. Nat Clin Prac Rheumatol. 2005;1:47-54.
Essential Role of RANKL in RA—Link
Between Chronic Inflammation and
Bone Loss

Through RANKL, T-cells and fibroblast-like
synoviocytes (FLS) drive osteoclast
differentiation and bone erosion in the joint

T-cells and FLS are major cell types
expressing RANKL in RA synovial tissue

RANKL expression is supported by other
proinflammatory cytokines
– Including TNF, IL-1, IL-6, IL-17, PGE2
Schett G, et al. Nat Clin Prac Rheumatol. 2005;1:47-54.
Fracture Risk Among a Very Large Cohort
of RA: Age- and Gender-Specific Results


Compared incidence rates of fracture in Blue Cross
Blue Shield participants
–
47,036 patients with RA
–
826,606 controls
Incidence rate ratios of fracture were increased in
patients with RA compared to controls
–
Hip
2.07 [95%CI (1.84-2.33)]
–
Pelvis
2.64 [95%CI (2.33-2.97)]
–
Humerus
1.80 [95%CI (1.52-2.15)]
–
Wrist
1.19 [95%CI (1.04-1.35)]
–
All fractures
1.13 [95%CI (1.04-1.22)]
Solomon D, et al. Abstract 595. ACR Scientific meeting 2009
Risk Factors of Osteoporosis in
Systemic Lupus Erythematosus

Traditional
–
–
–
–
–
–
–

Glucocorticoids
Anticonvulsants
GNRH antagonists
Immunosuppressants ?
Lane NE. Nat Clin Prac Rheum.2006;2:562-569.
Inflammation
–
–
–
–
–
Age
Weight
Smoking
Alcohol
Peak bone mass
History of fracture
Family history of fracture
Medications
–
–
–
–


CRP
TNF
Il-6
Oxidized LDL
RANKL
Metabolic
–
–
–
Low vitamin D
Low thyroid activity
High homocysteine
level
Bone Loss in Systemic Lupus

The prevalence of low bone mass in systemic lupus
erythematosus varies from 15%–46% (osteopenia) to
6%–15% (osteoporosis) in different studies

This prevalence varies according to the site of
measurement (lumbosacral spine, total hip, femoral
neck), gender, and age of the patient studied

Decreases in both cortical and trabecular bone have
been reported

Low bone mineral density is evidenced in both early
and late disease
Gluck O, Maricic M. In: Systemic Lupus Erythematosus. 2007.
Fractures in Systemic Lupus

In a retrospective study of 702 women with
lupus with a total of 5951 person-years, the
risk of fracture was increased (OR = 4.7) in
the lupus cohort compared with controls
– Older age at lupus diagnosis and longer duration
of glucocorticoid use seemed to be independent
determinates of fractures

In another study of 242 patients with
systemic lupus erythematosus, age and
reduced BMD, but not glucocorticoid use,
predicted fracture risk
Ramsey-Goldman R, et al. Arthritis Rheum.1999;42:882-890.
Yee CS, et al. Ann Rheum Dis. 2005;64:111-113.
Osteoporosis in Ankylosing Spondylitis

Technically challenging to detect

Predominantly confined to the axial
skeleton

Vertebral osteoporosis is a common
complication of ankylosing spondylitis,
with a prevalence between 18.7% and
62% in various series
Fractures in Ankylosing Spondylitis




Cumulative prevalence 10%–20% in
ankylosing spondylitis
Mainly thoracic spine involved
Peripheral bony fractures not increased
Reported vertebral fracture prevalence in AS
Mean Age
34 y
38 y
41 y

Prevalence
9.5% vs 3.4% (Cooper 1994)
16.7% vs 2.6% (Mitra 2000)
18% (Ralston 1990)
Relative risk for vertebral fractures increased
6- to 8-fold
Mitra D, et al. Rheumatology. 2000;39:85-89.
Osteoarthritis and Fractures

Patients with radiographic hip and/or knee
OA have higher adjusted levels of BMD, but
have no difference in the rate of fractures

Among older women in the Study of
Osteoporotic Fractures with radiographic hip
OA, there was no difference in the risk of hip
or vertebral fractures, over a mean follow-up
of 7.4 years
Arden NK, et al. Arthritis Rheum.1999;42:1378-1385.
Glucocorticoid-Induced Osteoporosis
(GIOP)

GIOP is the 2nd most common form of
osteoporosis in the world, and the most
common iatrogenic form

0.2% of adults receive prednisone on a longterm basis (>500,000 adults in United States)

Most common reasons are rheumatoid
arthritis and chronic obstructive pulmonary
disease
Pathophysiology of GIOP—Bone
Formation and Resorption
Glucocorticoids
 Apoptosis
 Life span
 Function
 Osteoblasts and
Osteocytes
 GI calcium absorption
 Urinary calcium excretion
 Estrogen
 Testosterone
 Adrenal androgens
 Calcium
 OPG
 RANKL
 Osteoclast bone
resorption
Osteoporosis
Rapid BMD Decline Due to
Glucocorticoids in Rheumatoid Arthritis
4
Placebo
(n = 17)
% Change Lumbar BMD
2
0
-2
-4
-6
Prednisone
(n = 13)
-8
-10
0
20
Weeks
With permission from Laan RF, et al. Ann Intern Med. 1993;119:963-968.
44
Dose Relationship of Fracture Risk
with Glucocorticoids



Chart review from General Practice Database in
United Kingdom
Steroid users matched by age, gender, and clinical
practice
~60% female, mean age 57 years
Relative Risk
6
5
Control
4
Prednisolone
2.5–7.5 mg
3
Prednisolone
>7.5 mg
2
1
0
Hip
van Staa TP, et al. J Bone Miner Res. 2000;15:993-1000.
Graphic courtesy of Dr. Michael Maricic.
Spine
6
Compared with Control
Relative Risk of Fracture
Fracture Risk Is Increased Even at
Doses <2.5 mg Prednisolone
5
4
All nonvertebral
Forearm
Hip
Vertebral
3
2.59
2
1.55
1.17 1.1 0.99
5.18
Statistically significant
1.77
1.36
1.04
2.27
1.64
1.19
1
0
n=
2192 531 236 191
Low Dose
(<2.5 mg/d)
2486 526 494 440
1665 273 328 400
Medium Dose
(2.5–7.5 mg/d)
High Dose
(>7.5 mg/d)
van Staa TP, et al. J Bone Miner Res. 2000;15:993-1000.
Graphic courtesy of Dr. Michael Maricic.
Effect of Daily Glucocorticoid Dose on
Nonvertebral Fractures
2.8
2.7
2.6
2.5
2.4
2.3
2.2
2.1
2.0
1.9
1.8
1.7
1.6
1.5
1.4
1.3
1.2
1.1
Adjusted Relative Rate
of Fracture (and 95% CIs)
0
5
10
15
20
Average Daily Corticosteroid Dosage (mg)
With permission from van Staa TP. Rheumatology. 2000;39:1383-1389.
25
Fracture Risk
Fracture Risk in GIOP Increases on
Treatment, Then Quickly Reverts When
GCs Are Discontinued
3 months
3 months
Time on steroids
Abbreviations: GCs, glucocorticoids; GIOP, glucocorticoid-induced osteoporosis.
van Staa TP, et al. J Bone Miner Res. 2000;15;993-1000.
Incidence of Vertebral Fracture in
Postmenopausal Patients Receiving GCs
Compared with Nonusers of GCs
40
Receiving GCs
Percent
35
Nonusers of GCs
30
25
20
15
10
5
0
-4.5
-4 -3.5
-3 -2.5
-2 -1.5
-1 -0.5 0
0.5
Lumbar Spine BMD
The individual data points correspond to the incidence in subgroups of the GC user and nonuser populations, as based on
quintiles of baseline BMD. The solid line is a curve representing smoothing of these individual estimates.
Abbreviations: BMD, bone mineral density; GCs, glucocorticoids.
With permission from van Staa TP, et al. Arthritis Rheum. 2003;48:3224-3229.
Incidence of Vertebral Fracture in
Postmenopausal Patients Receiving GCs
Compared with Nonusers of GCs
40
Receiving GCs
Percent
35
Nonusers of GCs
30
25
20
15
10
5
0
-4.5
-4 -3.5
-3 -2.5 -2 -1.5 -1 -0.5
Femoral Neck BMD
0
0.5
The individual data points correspond to the incidence in subgroups of the GC user and nonuser
populations, as based on quintiles of baseline BMD. The solid line is a curve representing smoothing of
these individual estimates.
With permission from van Staa TP, et al. Arthritis Rheum. 2003;48:3224-3229.
Predictors of Vertebral Fracture in
Postmenopausal Patients Receiving
Oral Glucocorticoid Therapy—Results

Compared with nonusers of GCs, patients
receiving GCs were younger, had a higher
BMD at baseline, and had fewer prevalent
fractures

Nevertheless, the risk of fracture was higher
in the GC users compared with nonusers
(adjusted RR 5.67, 95% CI 2.57–12.54)
van Staa TP, et al. Arthritis Rheum. 2003;48:3224-3229.
Risk Factors for Hip Fracture in Men
and Women
RR
3.0
2.0
1.0
0.0
Prior
fracture
FH
(hip)
Smoking
current
Without BMD
Kanis J, et al. Osteoporos Int. 2005;16:581-589.
Graphic courtesy of Dr. Michael Maricic.
Steroids
ever
Alcohol
>2u
With BMD
RA
FRAX—Factors That Independently Increase
the Risk of Hip Fractures in Addition to Age
and Femoral Neck T-Score
Risk Factor
RR
(95% CI)
Prior fracture after 50 years
1.62
(1.30–2.01)
Parental history of hip fracture
2.28
(1.48–3.51)
Current smoking
1.60
(1.27–2.02)
Ever systemic corticosteroids
2.25
(1.60–3.15)
Alcohol intake >2 drinks daily
1.70
Rheumatoid arthritis
1.73
(1.20–2.42)
(0.94–3.20)
With permission from Kanis J, et al. Osteoporos Int. 2005;16:581-589.
Conclusions

Patients with inflammatory arthritis,
especially rheumatoid arthritis, are at
increased risk for osteoporosis and
fractures

These risks are significantly increased
in those patients taking glucocorticoids
Strategies for Reducing
Fracture Risk
E. Michael Lewiecki, MD, FACP, FACE
Osteoporosis Director
New Mexico Clinical Research
& Osteoporosis Center
Clinical Assistant Professor of Medicine
University of New Mexico School of Medicine
Albuquerque, New Mexico
Maura’s
Aunt
Edna
In her 50s
Graphics courtesy of Dr. E. M. Lewiecki.
In her 70s
Fracture Risk Assessment
Intervention Threshold
Treatment Decisions
Follow-Up
Fracture Risk Assessment
(BMD, VFA, FRAX)
Intervention Threshold
Treatment Decisions
Follow-Up
Fracture Risk Assessment
Intervention Threshold
(fracture probability at which
treatment is cost-effective)
Treatment Decisions
Follow-Up
National Osteoporosis Foundation
Treatment Guidelines
Graphics with permission from National Osteoporosis Foundation.
Universal Recommendations

Regular weight-bearing exercise

Fall prevention

Avoid tobacco use and excess alcohol

Identification and treatment of risk
factors for fracture

Elemental calcium at least 1200 mg/day

Vitamin D3 800–1000 IU/day
National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2008.
Available at: http://www.nof.org/professionals/NOF_Clinicians_Guide.pdf
Vitamin D

Serum 25-OH-D levels should be measured
in patients at risk for vitamin D deficiency

Serum 25-OH-D level should be at least
30 ng/mL

Many patients need more than 800–1000 IU
per day to achieve a desirable level

Many elderly patients are at high risk for
vitamin D deficiency

Intake >2000 IU per day is safe and necessary
for some patients
National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2008.
Available at: http://www.nof.org/professionals/NOF_Clinicians_Guide.pdf
NOF Treatment Guidelines
Postmenopausal women and men age 50 and older with
the following should be considered for treatment:
Osteoporosis


T-score ≤-2.5 at femoral
neck (FN) or lumbar
spine (LS) after
evaluation for
secondary causes, or
Hip or vertebral (clinical
or morphometric)
fracture
Osteopenia

T-score between -1.0
and -2.5 at FN or LS,
and

Fracture Risk
Assessment (FRAX)
10-year probability of
hip fracture ≥3% or
major osteoporotic
fracture ≥20%
National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2008.
Available at: http://www.nof.org/professionals/NOF_Clinicians_Guide.pdf
ACR Guidelines for GIO
Beginning treatment with prednisone ≥5 mg/day
for ≥3 months.

Baseline bone mineral density and repeat
every 6–12 months

Modify risk factors (smoking, alcohol)

Weight-bearing exercise

Calcium & vitamin D

Bisphosphonate
– Use with caution in premenopausal women
ACR Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum. 2001;44:1496-1503.
ACR Guidelines for GIO
Established treatment with prednisone ≥5 mg/day
for ≥3 months.






Modify risk factors (smoking, alcohol)
Weight-bearing exercise
Calcium & vitamin D
Hormone replacement therapy, if deficient
If T-score <-1.0, start bisphosphonate
(use calcitonin as second-line agent)
If T-score normal, repeat bone mineral
density every 1–2 years.
ACR Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum. 2001;44:1496-1503.
Using FRAX and NOF Guide

FRAX is validated in
–
–

NOF guide uses FRAX for treatment decisions in
–

Untreated women and men between the age of 40
and 90 years
White, black, Hispanic, Asian in United States
Untreated postmenopausal women and men age 50 and
older with osteopenia who do not qualify for treatment
based on other treatment indications
Do NOT use FRAX with the NOF guide in
–
–
–
–
Patients who meet other treatment indications
Treated patients
T-score normal or osteoporosis
Premenopausal women, men younger than age 50, children
Abbreviations: FRAX, Fracture Risk Assessment; NOF, National Osteoporosis Foundation.
Old Guide vs New Guide
Case
Old Guide
New Guide
55-year-old White
woman (120 lbs, 5’2”)
with T-score = -2.1
Treat
(T-score <-2.0)
Don’t treat
(10-year risk of major
fracture 10%, hip 1.5%)
80-year-old White
woman (120 lbs, 5’2”)
with T-score = -1.1
Don’t treat
(T-score ≥-1.5)
Treat
(10-year risk of major
fracture 24%, hip 2.4%)
Graphic courtesy of Dr. E. M. Lewiecki.
Benefits of NOF Guide

Improved selection of patients most likely
to benefit from therapy
– Fewer “young” patients with slightly low BMD
and low risk treated
– More “old” patients with slightly low BMD and
high risk treated

Better use of limited healthcare resources

Application beyond postmenopausal
White women
Limitations of NOF Guide

Cost-effectiveness modeling may be
irrelevant if drug cost is extremely low

May be used inappropriately to restrict
pharmacy benefits

Conflicting recommendations for treatment
if FRAX is used when BMD is normal or
osteoporosis

May identify patients for treatment with little
or no evidence of benefit (T-score >-1.5)
Fracture Risk Assessment
Intervention Threshold
Treatment Decisions
(whom to treat and how to treat)
Follow-Up
Decision to Treat

Public health factors
– Fracture probability (FRAX)
– Cost-effectiveness (NOF Guide)

Patient factors
– Efficacy and safety for individual patient
– Nonskeletal risks and benefits
– Comorbidities
– Expected adherence to therapy
– Patient beliefs and preferences
– Insurance coverage/affordability
Laboratory Evaluation

Complete blood count

Celiac antibodies

Blood chemistries

Testosterone


–
Creatinine

Follicle-stimulating hormone
–
Calcium

Urinalysis
–
Phosphorus
–

Albumin
–
Alkaline phosphatase
Serum protein
electrophoresis,
immunofixation, light chains
–
Liver enzymes

Parathyroid hormone

25-OH-vitamin D

Urinary free cortisol

Dexamethasone
suppression
24-hour urine for calcium,
sodium, and creatinine
Thyroid-stimulating
hormone
FDA Indications for Osteoporosis
Drug
PMO
Prevention
GIO (Women, Men)
Treatment
Estrogen

Alendronate PO


Risedronate PO


Ibandronate PO



Teriparatide SC
Graphic courtesy of Dr. E. M. Lewiecki.












Calcitonin IN
Raloxifene PO
Treatment

Ibandronate IV
Zoledronate IV
Prevention
Men



Bone Mineral Density Response
to Therapy
Medication
Spine
Hip
Estrogen


Alendronate


Risedronate


Ibandronate


Zoledronate


Salmon Calcitonin
~
-
Raloxifene


Teriparatide


Graphic courtesy of Dr. E. M. Lewiecki.
Fracture Risk Reduction in Randomized
Controlled Trials
Medication
Spine
Nonvertebral
Hip
Estrogen



Alendronate



Risedronate



Ibandronate

(meta-analysis)
Zoledronate


Calcitonin

Raloxifene

Teriparatide

Graphic courtesy of Dr. E. M. Lewiecki.


Fracture Risk Assessment
Intervention Threshold
Treatment Decisions
Follow-Up
(Monitoring, Compliance,
Persistence)
Clinical Challenges After Starting
Treatment





Motivating the patient to fill the prescription,
take medication correctly, regularly, and for a
sufficient amount of time to benefit
Determining how (or if) to follow and monitor
the patient to assure that benefit is achieved
Deciding when (if ever) to stop or change
therapy
Knowing when (if ever) to restart, if treatment
is stopped
Managing side effects, perceived side effects,
and fear of side effects
Improving Adherence to Therapy

Longer dosing intervals

Less complex administration

Injectable therapy?

Patient education

Ongoing communication

Nurse monitoring
FLEX—Incidence of Fractures
% Fracture Incidence
25
ALN/PLB (n = 437)
RR = 1.0
CI (0.8, 1.3)
20
15
ALN/ALN (n = 662)
ARR = 2.9%
P = 0.013
RR = 0.9
CI (0.6, 1.2)
10
5
0
RR = 0.45
CI (0.2, 0.8)
5%
2%
Clinical Vertebral
RR = 1.0
CI (0.5, 2.1)
11%
10%
Vertebral
Morphometric
Abbreviations: ALN, alendronate; PLB, placebo.
Black DM, et al. JAMA. 2006;296:2927-2938.
19%
19%
Nonvertebral
3%
3%
Hip
FLEX—Continuing Alendronate for
Years 5–10 Reduces NVFs in Women
with Osteoporotic T-Scores
1.6
1.41
1.4
1.2
1
0.8
0.79
0.5
0.6
0.4
0.2
0
≤-2.5
>-2.0
-2.0 to -2.4
Femoral Neck T-Score After 5 Years of Alendronate
Abbreviations: NVFs, nonvertebral fractures.
Schwartz AV, et al. J Bone Miner Res. 2007;22(suppl 1):S16.
When to Consider an Alendronate
Holiday

When patient never needed treatment in the
first place
– Retrospective application of NOF guide

After good response (bone mineral
density/bone turnover marker) to at least
5 years treatment and fracture risk no longer
high
– No fracture, T-score >-2.5, “young”

Continue treatment in high-risk patients
– Previous fractures, T-score -2.5 and below
When to End a Bisphosphonate Holiday

Not clear

Possible approaches
– Arbitrarily restart treatment after 1–2
years
– Monitor BMD/BTM every 6–12 months and
restart treatment when significant
decrease in BMD or increase in BTM

Reconsider treatment plan if fracture or
change in clinical status
Emerging Therapy

Antiresorptive
(anti-catabolic)

Osteo-anabolic
(bone-forming)
–
Denosumab
–
Sclerostin inhibitor
–
Lasofoxifene
–
–
Bazedoxifene
Variations of parathyroid
hormone
–
CE/bazedoxifene
–
–
Odanacatib
–
Calcium-sensing
receptor antagonist
(calcilytic)
New delivery systems
–
New delivery systems
–
Combinations of
antiresorptive and
anabolic
Denosumab for Postmenopausal
Osteoporosis

BMD
–
–

BTMs
–

Lumbar spine ↑ 9.2% (P <.0001)
Total hip ↑ 6.0% (P <.0001)
CTX ↓ 72% (P <.001)
Fracture risk
–
–
–
Vertebral ↓ 68% (7.2% placebo vs 2.3% denosumab,
P <.0001)
Hip ↓ 40% (1.2% placebo vs 0.7% denosumab, P = .036)
Nonvertebral ↓ 20% (8.0% placebo vs 6.5% denosumab,
P = .011)
Cummings SR, et al. N Engl J Med. 2009;361:756-765.
FREEDOM Safety—Adverse Events
Adverse Events
Denosumab
Placebo
All
92.8%
93.1%
Infections
52.9%
54.4%
Cancer
4.8%
4.3%
Hypocalcemia
0%
0.1%
ONJ
0%
0%
Denosumab
Placebo
Falling
4.5%
5.7%
Eczema
3.0%
1.7%
Flatulence
2.2%
1.4%
Adverse Events in at
least 2% of subjects
with P <.05
With permission from Cummings SR, et al. N Engl J Med. 2009;361:756-765.
FREEDOM Safety—Serious Adverse
Events
SAEs
Denosumab
Placebo
All
25.8%
25.1%
Infections
4.1%
3.4%
Cancer
3.7%
3.2%
Atrial fibrillation
0.7%
0.7%
Deaths
1.8%
2.3%
Cardiovascular events
4.8%
4.6%
Denosumab
Placebo
Concussion
<0.1%
0.3%
Cellulitis
0.3%
<0.1%
SAEs in at least 0.1% of
subjects with P <.01
Abbreviation: SAEs, serious adverse events.
With permission from Cummings SR, et al. N Engl J Med. 2009;361:756-765.
Denosumab for Rheumatoid Arthritis




12-month randomized controlled trial of
denosumab 60 or 180 mg q6mo vs placebo
in rheumatoid arthritis patients on methotrexate
Primary endpoint: MRI erosion score at
6 months
Secondary endpoint: modified Sharp erosion
score at 12 months
Results: decreased erosion scores with
denosumab; no effect on joint space narrowing;
comparable adverse events
Cohen SB, et al. Arthritis Rheum. 2008;58:1299-1309.
Lasofoxifene for Postmenopausal
Osteoporosis

Efficacy
– Increases BMD, reduces BTMs, decreases
risk of vertebral and nonvertebral fractures
– Decreases risk of ER+ breast cancer
– Improves signs and symptoms of
vulvovaginal atrophy

Safety
– Increases risk of VTEs, hot flushes, muscle
spasm, and vaginal bleeding
Cummings SR, et al. J Bone Miner Res. 2008;23:S81.
Eastell R, et al. J Bone Miner Res. 2008;23:S81.
Bazedoxifene for Postmenopausal
Osteoporosis

Efficacy
– Increases BMD, reduces BTMs, and
decreases risk of vertebral fractures

Safety
– Increases risk of VTEs, hot flushes,
muscle cramps
Silverman SL, et al. J Bone Miner Res. 2008;23:1923-1934.
Summary

BMD + clinical risk factors (CRFs) predict
fracture risk better than BMD or CRFs alone

NOF guide better identifies patients for costeffective intervention to reduce fracture risk

Optimal use of these tools requires full
understanding of their benefits and
limitations

Treatment decisions must consider all known
clinical factors using good judgment
Challenges and Controversies in
Managing Your Osteoporosis
Patients
Nancy E. Lane, MD
Director and Endowed Professor
Aging Center, Medicine and Rheumatology
UC Davis Medical Center
Sacramento, California
Case 1
Bone Loss in 80-Year-Old Female on
Chronic Alendronate Treatment
Mrs. W

80-year-old woman was diagnosed with
postmenopausal osteoporosis on 6/2/98 with L1L4
T-score = -2.5 at age 72

Baseline evaluation showed normal physical
examination and normal CBC, comprehensive
metabolic panel, CRP, urinalysis

Started on alendronate 6/98 and continued ever since

Patient says she is taking alendronate regularly and
correctly, with daily calcium and multivitamin
BMD Response to Therapy



Lumbar spine bone mineral density (BMD)
increase of 6.8% after 4 years of therapy
2 years later (6 years after beginning
alendronate) BMD decreased by 4.8%
(>least significant concentration): evaluation
showed normal CBC, and low serum 25-OH-D
(25 ng/mL) – treated and corrected
BMD continued to decline at annual rate of
2%–3%
Evaluation for Secondary Osteoporosis
After 11 Years of Bisphosphonate
Treatment









No cardiac, pulmonary, GI, or renal symptoms
Normal physical examination
Normal CMP, CRP, urinalysis
CBC normal except high mean corpuscular volume of
105 (normal folate and B12 level)
25-OH-D=25 ng/mL, despite adequate vitamin D3
supplementation
Fasting serum NTX=15.0 nM BCE
Serum protein electrophoresis–increase
in polyclonal gamma fraction
Endomysial Ab IgA high at 1:1280 (normal <1:10)
A procedure was performed
Endoscopy with Small Bowel Biopsy
5/21/09

“Duodenal mucosa with moderate to
severe villous atrophy and marked
intraepithelial lymphocytosis consistent
with gluten-induced enteropathy”

Started on gluten-free diet

Additional vitamin D3 1000 IU/day

Alendronate continued
Biopsy of Celiac Disease
With permission from Virginia Commonwealth University Department of Pathology. Available
at: www.pathology.vcu.edu/_education/gi/CeliacDiseaseHistology3.jpg
Case 2
Patient with Prostate Cancer
Receiving Androgen Deprivation
Therapy
Mr. H

A 69-year-old white male is discovered
to have metastatic (stage IV) prostate
cancer and chooses to undergo
androgen deprivation therapy (ADT)
rather than orchiectomy

Does ADT have an impact on his bone
health?
Bone Loss During Initial Therapy
for Prostate Cancer
% Change in BMD at 1 Year
0
Orchiectomy
Orchiectomy or
GnRH Agonist
GnRH Agonist
-0.6%
-2
-2.4%
1.8% -
-2.1%
-2.3%
2.8% -
3.3% -
-4
-3.7%
-3.9%
4.6% -
-6
-8
-10
9.6% -
Hip (low-high range)
-12
Spine
Abbreviations: BMD, bone mineral density; GnRH, gonadotropin-releasing hormone.
Adapted from Smith MR. Nat Clin Pract Urol. 2005;2:608-615.
Fracture-Free Survival Diminishes with
Time and Cumulative Use of GnRH
100
Unadjusted Fracture-Free
Survival (%)
90
80
70
60
50
40
No androgen deprivation (n = 32,931)
GnRH agonist, 1–4 doses (n = 3763)
GnRH agonist, 5–8 doses (n = 2171)
GnRH agonist, ≥9 doses (n = 5061)
Orchiectomy (n = 3399)
30
20
10
0
1
2
3
4
5
6
7
8
9
10
Years after Diagnosis
Shahinian VB, et al. N Engl J Med. 2005;352:154-164. Copyright ©[2005]. Massachusetts Medical
Society. All Rights Reserved.
2008 NOF Synopsis of Major
Recommendations
When to Perform BMD Testing
A. In women age 65 years and older, and men
age 70 years and older, recommend BMD
testing
B. In postmenopausal women and men age
50–70 years, recommend BMD testing
when you have concern based on their risk
factor profile
2008 ISCD Indications for BMD Testing





Adults with a disease or condition associated
with low bone mass or bone loss
Adults taking medications associated with
low bone mass or bone loss
Anyone being considered for pharmacologic
therapy
Anyone being treated, to monitor treatment
effect
Anyone not receiving therapy in whom
evidence of bone loss would lead to
treatment
Treatment of Low Bone Density in Men
with Prostate Cancer About to Undergo
Androgen Deprivation Therapy

At what bone density value should
treatment with a bone active agent begin?

What bone active agent should he be
treated with?
Treatment of Bone Loss in Men Treated
with Androgen Deprivation Therapy

Oral bisphosphonates
– Alendronate 70 mg weekly
– Risedronate 35 mg weekly or 150 mg monthly

Zoledronic Acid 4 mg IV q3mo

Denosumab 60 mg SQ q6mo (In the future?)

Teriparatide contraindicated?
Mean Percentage Change in BMD from
Baseline to 6 and 12 Months
Posterior-Anterior Spine
6
4
4
2
2
0
0
-2
-2
0
Change in Bone Mineral Density (%)
Latteral Spine
6
6
Months
12
Total Hip
2
0
1
0
0
12
Femoral Neck
2
1
6
Months
-1
-1
0
6
Months
12
One-Third Distal Radius
1
0
0
-1
-1
-2
-2
-3
12
Ultra Distal Radius
1
0
6
Months
-3
0
6
Months
12
Alendronate
0
6
Months
Placebo
With permission from Greenspan SL, et al. Ann Intern Med. 2007;146:416-424.
12
Treatment of Bone Loss Due to ADT
with Zoledronic Acid
8
P <.001
Zoledronic acid 4 mg IV q3mo
Placebo
5.6%
Mean % Change
from Baseline
6
4
P <.001
1.1%
2
0
-2
-4
-2.2%
-2.8%
Lumbar Spine
Total Hip
Abbreviation: ADT, androgen deprivation therapy.
With permission from Smith MR, et al. J Urol. 2003;169:2008-2012.
Zoledronic Acid Increased Lumbar Spine
BMD from Baseline over 24 Months
14
Mean % Change
from Baseline in
Lumbar Spine BMD
12
10
8
Alendronate
Zoledronic Acid
P = NS
6
4
2
0
24 Months
Month 24 results are reported with last observation carried forward. Error bars represent standard error.
NS = not significant. P-value obtained from ANCOVA on % change from baseline of BMD with treatment,
center and baseline lumbar spine BMD as explanatory variables.
Reclast® (zoledronic acid) Injection [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals
Corporation; May 2009.
Phase III Trial—Denosumab in the Treatment
of Bone Loss in Patients Undergoing ADT for
Nonmetastatic Prostate Cancer
Patientsa with
nonmetastatic
prostate cancer

R
A
N
D
O
M
I
Z
E
Denosumab
60 mg SC,
q6mo
Placebo
SC, q6mo
Primary endpoint
– Change in BMD at 24 months

Secondary endpoint
– Fractures (both vertebral and nonvertebral)
a
Current or prior IV bisphosphonates administration was not allowed.
Smith MR, et al. N Engl J Med. 2009:361:756-765.
A
S
S
E
S
S
Denosumab in Patients Undergoing
Androgen Deprivation Therapy
Denosumab Placebo
(n = 734)
(n = 734)
P value
Lumbar spine
BMD at 24 mo
+5.6%
-1.0%
<.001
New vertebral
fractures
at 36 mo
1.5%
3.9%
.006
Smith MR, et al. N Engl J Med. 2009:361:756-765.
What Are the Key Clinical
Pearls/Take-Aways from this Case?



Low bone density and osteoporosis are
common in men undergoing androgen
deprivation therapy (ADT) for prostate cancer,
even before ADT
ADT accelerates bone loss and increases
fracture risk
The bisphosphonates are effective treatments
for preventing bone loss in men treated with
ADT, and may reduce the heightened risk
of fractures
Case 3
Rheumatoid Arthritis Patient
Receiving Glucocorticoids
Mrs. L

28-year-old premenopausal woman

Rheumatoid arthritis, age of onset,
21 years

Complications of her RA include
– Osteonecrosis of hip from prednisone
– Pulmonary involvement
– Vasculitis
Investigations




Positive rheumatoid arthritis factor >1:640
CRP 7
Anti-cyclic citrullinated peptide antibody -50
X-ray of hands and feet show erosion,
osteopenia, and deformities
Further History of Bone Health

No family history of osteoporosis

≤1 serving of dairy products per day

Adequate outdoor sun exposure

Menarche age 12/regular cycles prior
to prednisone dose >30 mg/day

Appetite and weight stable
Current Treatment

Prednisone 10–30 mg daily (x 6 months)
– Currently 15 mg daily

Hydroxychloroquine 400 mg daily

Methotrexate 20 mg/wk

Folic acid 1 mg/daily

Etanercept
Laboratory Data

Vitamin D
–









20 ng/mL
Calcium normal
PTH normal
TFTs normal
Estradiol <40 pmol/L
Progesterone <1 nmol/L
Follicle-stimulating hormone 3U/L
Luteinizing hormone <1 U/L
Creatinine and blood urea nitrogen normal
Bone mineral density
–
–
Spine -2.0 T-score
Hip -2.5 T-score
Osteoporotic Therapies in Women of
Childbearing Age

Are there any issues with osteoporotic
therapies in women of childbearing
age?
Bisphosphonates in Premenopausal
Females—Issues




Animal studies with bisphosphonates have
identified skeletal abnormalities in the fetus
FDA Category C pregnancy risk – contraindicated
during pregnancy
Preconception exposure bisphosphonate case
reports have not identified any developmental or
bone density abnormalities
Lower birth weight, lower gestational age at birth,
and higher rates of spontaneous abortion have
been reported (but confounding factors affect
interpretation)
McNicholl DM, Heaney LG. Curr Drug Safety. 2010. Apr 1. [Epub ahead of print].
Osteoporosis Management in Mrs. L

Combination of calcium carbonate
and vitamin D

Risedronate 35 mg weekly

Consider denosumab when it is
approved, since it is given every 6
months and does not accumulate
in the bone
Alternatives to BPs—BMD Changes with
Denosumab in RA Patients with and Without GCs
Bone Mineral Density and Bone Turnover: Glucocorticoids vs. No Glucocorticoids
No Glucocorticoids
Glucocorticoids
Placebo
Placebo
Denosumab 60 mg q6mo
Denosumab 60 mg q6mo
6
5
Percentage Change from Baseline
(mean, SE)
Percentage Change from Baseline
(mean, SE)
BMD: Lumbar Spine
No Glucocorticoids
4
3
2
1
0
-1
-2
Baseline Month 1
Month 6
Month 12
6
5
Glucocorticoids
4
3
2
1
0
-1
-2
Baseline Month 1
Month 6
Month 12
6
5
No Glucocorticoids
4
3
2
1
0
-1
-2
Baseline Month 1
Month 6
Month 12
Percentage Change from Baseline
(mean, SE)
Percentage Change from Baseline
(mean, SE)
BMD: Total Hip
6
5
Glucocorticoids
4
3
2
1
0
-1
-2
Baseline Month 1
Month 6
Month 12
Abbreviations: BMD, bone mineral density; BPs, bisphosphonates; GCs, glucocorticoids; RA, rheumatoid arthritis.
With permission from Dore RK, et al. Ann Rheum Dis. 2009. Sep 6. [Epub ahead of print].
Denosumab—Changes in Bone Turnover
Markers in Rheumatoid Arthritis Patients
Treated with GCs and No GCs
.6
sCTx-1, ng/mL, median (Q1, Q3)
sCTx-1, ng/mL, median (Q1, Q3)
Bone Turnover: sCTx-1
No Glucocorticoids
.4
.2
0
Baseline
Month 3
Month 6
.6
Glucocorticoids
.4
.2
0
Month 12
Baseline
Month 3
Month 6
Month 12
60
P1NP, ng/mL, median (Q1, Q3)
P1NP, ng/mL, median (Q1, Q3)
Bone Turnover: P1NP
No Glucocorticoids
40
20
0
Baseline
Month 3
Month 6
Month 12
60
Glucocorticoids
40
20
0
Baseline
Month 3
Month 6
Month 12
With permission from Dore RK, et al. Ann Rheum Dis. 2009. Sep 6.[Epub ahead of print].
Conclusions/Summary

Secondary causes of osteoporosis is a
rapidly growing entity

Bone loss in individuals undergoing
hormone ablation therapy for cancer, on
glucocorticoids, and with celiac disease
can be identified and prevented