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What’s New in Osteoporosis
Diagnosis and Treatment?
Neil Binkley, MD
ISCD Official Positions
Published Jan 2004
Diagnosis/Intervention Thresholds Based On
Estimated Absolute Fracture Risk is Coming
For Now, The WHO Criteria Will Continue to be Used
Normal
-1.0
Osteopenia
These Criteria Apply
ONLY to the L-spine
Proximal Femur and
1/3 Radius
-2.5
Osteoporosis
Severe
Osteoporosis
Risk Factors Do Not Allow
Prediction of BMD
IMPACT Trial: ~7000 postmenopausal women had BMD
measurement and risk factor assessment
48% of those with osteoporosis had no risk factors
53% of those with risk factors did not have osteoporosis
Watts, Arth Rheum 2001
Indications for BMD Testing
 All
women aged 65 and older
 Postmenopausal women under age 65 with risk factors
 All men aged 70 and older
 Adults with a fragility fracture
 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
 Any not receiving therapy in whom evidence of bone loss
would lead to treatment
Women discontinuing estrogen should be considered for bone
density testing according to the indications listed
Fractures/100,000
person-years
Fracture Risk Increases With Age
But BMD Measurement Declines
Hip
2500
2000
1500
1000
Vertebral
500
50
Cooper JBMR, 1992
60
70
Age (years)
80
90
Neuner, ASBMR 2003
.
Average Life Expectancy; 2001 US
Female 79.5 years, Male 74.1 years
Ave Remaining Years of Life
20
15
Male
Female
10
5
0
65
70
75
80
85
Current Age (Years)
90
CDC/Natl Center for Health Statistics
www.cdc.gov/nchs/fastats/lifeexpec.htm
Bone Density Measurement Followed
by Clinician Consultation Leads to
Persistent Lifestyle and Safety Changes
Percent of responders
60
Normal BMD
50
2003
40
2004
30
20
10
0
In crea sed
Exercise
In crea sed
Exercise
In crea sed
Exercise
In crea sed
Exercise
Use the L1-L4 Average T-score
Don’t “Cherry-Pick” the Lowest
More vertebral bodies
improves precision
T-score
L1 = -1.6
Criteria for excluding
vertebrae from analysis:
L2 = -0.8
- Focal structural abnormality
- Failure of BMC and area to  from L1-L4
- >1 T-score discrepancy between
adjacent vertebrae
L3 = -0.1
L4 = 0.4
However, It Is Appropriate to
Exclude Abnormal Vertebrae
Exclude L2
Exclude
L2 & L3
What About “Peripheral” BMD
Measurements?
What About “Peripheral” BMD
Measurements?
 Use
of WHO criteria for the diagnosis of normal,
osteopenic or osteoporotic BMD inappropriate
Currently,
if central DXA available; don’t
make dx of osteoporosis based on
peripheral measurement
Cannot be used to monitor osteoporosis
therapy
When Should the Forearm be Measured?
When the Hip and/or Spine Cannot be Accurately
Measured
These Situations Include:
 Extensive
spinal instrumentation
 Severe scoliosis
 Severe degenerative changes
 Multiple compression fractures
 Bilateral hip replacements
 Obesity
Hamdy, JCD 2002
Isn’t the Forearm a
“Peripheral” Site?
“Osteoporosis is defined as a bone
mass more than 2.5 SD below the
young adult reference mean at
the spine, hip or mid-radius.”
WHO Technical Report
Stable BMD on Treatment is a Success
12 mo BMD change in ~3000 ALN treated patients
Hochberg, Arthritis Rheum 1999
This is Due to Anti-resorptive Induced
Reduction in “Stress Risers”
What’s a Real Change on Followup DXA?
 Necessary

This is facility, technician and patient population dependent
 UW


to perform an in-vivo precision study
LSC need to see BMD change of:
Ballpark; 3-4% at the L1-4 spine and mean total femur
This varies between facilities
 A “decrease”
from .890 to .875 g/cm2 is no change
2
(grams/cm ),
Use the BMD
Not the T-score When
Performing Follow-up DXA
12/11/02
L1-L4 BMD = .705 g/cm2
T-score = -3.9
1/19/04
L1-L4 BMD = .684 g/cm2
T-score = -4.1
If Huge Change in BMD (>~ 10%)
Look For Technical Problems
Poor Follow-Up Scan
Follow-up
Baseline
L1: .992
L2: 1.103
L3: 1.237
L4: 1.254
L1-L4
BMD = 1.157
T-score = -0.5
L1: 1.003
L2: .930
L3: 1.057
L4: 1.150
L1-L4
BMD = 1.043
T-score = -1.5
WHO Criteria Should Not be Applied
to Healthy Premenopausal Women
 Z-scores
rather than T-scores should be used
 Osteoporosis may be diagnosed if there is low BMD
with secondary causes (glucocorticoid therapy,
hypogonadism, hyperparathyroidism, etc) or with risk
factors for fracture
The
diagnosis of osteoporosis in
premenopausal women should not be made
on densitometric criteria alone
Osteoporosis
A systemic skeletal disease characterized by low bone
mass and microarchitectural deterioration of bone
tissue, with a consequent susceptibility to fracture
How Should Osteoporosis Be Diagnosed In Non-Caucasians?
ISCD Position Regarding Osteoporosis
Diagnosis in Non-Caucasians
Utilize a uniform Caucasian
(universal) normative
database and a T-score of -2.5
for osteoporosis diagnosis
Skeletal Status of AA Women in
Milwaukee
80
60
Percent
150 AA women
Ave age = 54 yrs
BMI = 32 kg/m2
Calcaneal Bone Mass in
AA Wisconsin Women
40
20
0
Normal
Osteopenia Osteoporosis
How Should Osteoporosis Be Diagnosed In Men?
The WHO Criteria Should Not be
Applied in Entirety to Men
Age
65 and older, T-scores should be used and
osteoporosis diagnosed if the T-score is ≤ -2.5
Age 50 to 64, T-scores may be used and osteoporosis
diagnosed if both the T-score is –2.5 or less and other
risk factors for fracture are identified
The
diagnosis of osteoporosis in men less than
age 50 should not be made on densitometric
criteria alone
Densitometric Vertebral Fracture
Assessment (VFA) Will Be Standard
Practice Soon
Only ~25% of Vertebral Fractures are
Clinically Apparent
May be Asymptomatic…….
…… or Unrecognized
Estimated that ~1% of Back Pain
Episodes are Caused by Vertebral
Fracture
Combining BMD With Fracture
Knowledge Identifies Higher Risk
Patients
25.1
14.9
10.2
7.4
4.4
Low BMD Med BMD
1
1 Fx
No Fx
Hi BMD
Ross, 1991
Moderate
and Severe
Fractures
(Grade 2 or
3) are Easy
to Identify
L1 and L3
Grade 2 Fractures
Mild (Grade 1) Fractures are NOT
Don’t Call “Mild” Fractures on VFA
No Fracture
L-spine DJD
Remember
That Not All
Vertebral
Compression
Fractures Are
Due To
Osteoporosis
Calcium Remains the Foundation
of Osteoporosis Treatment
 Insufficiency
extremely common
 Recommended intake


adults; 1000-1500 mg daily
children/adolescents age 9-17; 1300 mg
 These


recommendations are met in only:
~25% of boys and 10% of girls
~50-60% of adults
 Emphasize
calcium fortified foods and dairy products
 Improved calcium supplements
The Planet is Vitamin D Deficient
Vitamin D Status:
Perceived vs. Reality
Toxicity
"Adequate"
Insufficiency
400-600
IU/day
Deficiency
Perceived
Reality
Humans are Designed to Make
Vitamin D When Skin
is Exposed to Sunlight
Vitamin D is Rare in Foods
Food
IU
Cod Liver Oil, 1 Tbs
1360
Salmon, 3.5 oz
360
Mackerel, 3.5 oz
345
Milk, 1 cup
100
Fortified cereal, 3/4 cup
50
Liver, 3.5 oz
30
Egg, one whole
25
Humans Were Not Deficient in
Vitamin D Until the Industrial
Revolution
In the late 1800’s
estimated that ~90% of
children who lived in
industrialized cities of
Europe and North America
had rickets
Signs of rickets include;
growth retardation,
widening of the ends of
the long bones and bowing
and bending of the legs
Vitamin D History
1889; Palm: Children living in 3rd world
countries at lower risk of rickets;
suggested sunbathing
1919; Huldschinsky; exposure of people to
mercury arc lamp cured rickets
1924; Steenbock; food irradiation cured
rickets
Beverages Have Been Vitamin D
Fortified For Years
Vitamin D Fortification;
Current Status
 Many
–
breakfast cereals are fortified with D
Usual fortification level = 40-140 IU’s.
 Enriched
rice and cornmeal; not fortified
 Enriched noodle products; rarely fortified
 Margarine; none fortified in a limited market review
 Most yogurts target to adults DO NOT contain D
 Cheese, cottage cheese, butter, ice cream do not contain D
 Fruit juice can’t contain > 100 IU D per serving
Vitamin D Supplementation
Reduces Falls
50% had 25OHD
< 12 ng/ml
Probability
Double blind 12 wk trial
122 LTC women
Mean age 85 yrs
Rx calcium 1200 mg
vs Ca + D 800 IU
.8
Cal + D
Calcium
.6
.4
.2
0
0
1
2
3
Number of Falls
4
•
Improved muscle function
Reduced falls risk by 49%
Bischoff, JBMR 2003
.
2686 people randomly
Assigned to placebo or
Vitamin D3 100,000 IU
q three months by mail
Self-reported fractures
Cumulative Probability of Fracture
Vitamin D Supplementation
Reduces Fracture Risk
0.14
0.12
Placebo
0.10
0.08
0.06
Vitamin D
0.04
0.02
0
0
1
2
3
4
5
Years
33% reduction in risk of osteoporotic
fracture (hip, spine, wrist)
Trivedi, BMJ 2003
Options to Correct
Hypovitaminosis D
QuickTime™ and a
Photo - JPEG decompressor
are needed to see this picture.
.
Nichols
80
25OHD (ng/ml)
Be a Little
Cautious
With High
Dose D2
Therapy
100
DiaSorin
60
58
47
40
29
20
16
18
13
50,000 IU 3x/wk
50K/d
0
1/7
2/11 2/18
3/24
.
Vitamin D Supplementation,
25OHD Concentration and Safety
800
Toxicity cases all
Involve intake
>40,000 IU/day
Published Toxicity
Circulating 25OHD (ng/ml)
Assembled data from
many D supplementation
studies & published
cases of toxicity
Supplementation Study
600
400
200
0
100
1,000
10,000
100,000
1,000,000
Vitamin D Intake (units/day)
“…the currently accepted no observed adverse effect
level of 2000 IU/day is too low by at least 5-fold.”
Veith, AJCN 1999
“Currently recommended vitamin
D intakes hover somewhere
between inadequate and
irrelevant.” Heaney, 2003
Pharmacologic Rx; Agents That  Fractures
Could be Anti-resorptive, Anabolic, Alter
Bone Quality or Have Extra-skeletal Effects
When to Initiate Pharmacologic Therapy
Without With
Risk
Risk
Factors Factors
NOF
AACE
-2
-3
-2.5
-2
-1.5
-1.5 -1
T-score
-.5
0
Estrogen? WHI Bone Conclusion
Estrogen Prevents Osteoporotic Fracture
Discontinuation Increases
Osteoporotic Fracture Risk If
Nothing Else is Done
Estrogen Discontinuation is Associated
with Increased Hip Fracture Risk
2.0
1.5
Odds Ratio
NORA Study
1-year follow-up; 140,295
postmenopausal women
269 confirmed hip fractures
Odds Ratio for Hip Fracture
Compared to Never Users
1.0
0.5
0.0
Current
Use
Quit
Š 5 yrs
Ago
Quit
> 5yrs
Ago
Yates, Obstet Gynecol 2004
Selective Estrogen Receptor
Modulators (SERMs)
 Raloxifene,
lasofoxifene, bazedoxifene, etc
 Raloxifene (Evista) approved for osteoporosis
treatment and prevention, dose = 60 mg/day
 Phytoestrogens may be thought of as SERMS
Bisphosphonates
Alendronate
(Fosamax)
Risedronate (Actonel)
Ibandronate (Boniva)
Etidronate (Didronel)
Zoledronate (Zometa)
Pamidronate (Aredia)
.
ALN 10
mg/day
15
Percent of New Vert Fx
Alendronate; BMD and
Fracture Effects
16
12
RR .53
p < 0.001
8
4
145
78
Placebo
n = 965
Alendronate
n = 981
0
10
ALN 5
mg/day
5
0
0
2
4
6
8
10
Years
Percent of New Hip Fx
2
RR .49
p = 0.047
1
22
11
Placebo
n = 965
Alendronate
n = 981
0
Bone, JBMR, 2002
Black, Lancet, 1996
Oral Alendronate Buffered Solution
Received FDA Approval Feb 2004
Same
dosing requirements as tablets (30
minutes before breakfast, don’t lay down,
follow with H20
No possibility of pill-induced esophagitis
Potentially useful for those with swallowing
dysfunction, e.g., dementia, parkinsons, etc
Zoledronic Acid
is a very potent
bisphosphonate.
Equal BMD
effectg whether
given every three
mo or 1X per yr
% change LSBMD
Intravenous Bisphosphonates;
Not Yet FDA-Approved
6
4 mg 1x/year
4
1 mg q 3 months
2
0
Placebo
0
6
Months
NO Fracture Data Yet
12
Reid, NEJM 2002
Once Per Month Oral
Ibandronate is Coming
144 postmenopausal
women with low Lspine BMD
50, 100 or 150
mg/month
% Change from Baseline
0
Serum CTX
Urine CTX
-10
-20
-30
-40
-50
-60
Placebo
150 mg/month
Not Yet Available
Reginster, JBMR 2003
.
Percent of New Vert Fx
12
8
RR .35
p < 0.0001
4
0
64
22
Placebo
(n = 448)
PTH 20
(n = 444)
6
Percent of New Non-Vert Fx
PTH 1-34 BMD and
Fracture Effects
4
RR .47
p = 0.02
2
30
14
0
Placebo
(n = 544)
PTH 20
(n = 541)
Neer, NEJM, 2001
In male and female rats, teriparatide caused an increase in the
incidence of osteosarcoma (a malignant bone tumor), that was
dependent on dose and treatment duration. The effect was
observed at systemic exposures to teriparatide ranging from 3 to
60 times the exposure in humans given a 20-mcg dose. Because
of the uncertain relevance of the rat osteosarcoma finding to
humans, teriparatide should be prescribed only to patients for
whom the potential benefits are considered to outweigh the
potential risk. Teriparatide should not be prescribed for patients
who are at increased baseline risk for osteosarcoma (including
those with PagetÕs disease of bone or unexplained elevations of
alkaline phosphatase, open epiphyses, or prior radiation therapy
involving the skeleton) (see WARNINGS and PRECAUTIONS,
Carcinogenesis).
Forteo package insert
Tashhjian, JBMR, 2002
Appropriate PTH Candidates Include
Declining
BMD on Rx without apparent reason for
bone loss; “osteoporosis treatment failures”
Low BMD and multiple prior low-trauma fractures
Extremely low BMD
Unique low-trauma fractures, e.g., sacral
insufficiency fractures
What About Combination PTH +
Bisphosphonate?
238 women T < -2.5
PTH 1-84 (100 ug) n = 119
ALN 10 mg/day n = 60
PTH + ALN n = 59
Mean age ~70
~10% prior BP use
Follow-up at 12 months
“Concurrent use of alendronate
may reduce the anabolic effects
of parathyroid hormone.”
Median % change PINP
.
200
PTH
100
Both
0
ALN
-100
0 1
3
Month
Black, NEJM 2003
12
Sequential Therapy Looks Promising
66 women treated
With PTH (1-84)
50, 75 or 100 ug or
PBO for 1 year
Then Rx with ALN
10 mg/day for 1 year
“….. repeated cycles of PTH treatment ... offers
hope that it may be possible to normalize bone
density in osteoporotic patients.” Rittmaster, JCEM 2000
Treatment of Osteoporosis After
Hip Fracture
Though more women
than men receive
osteoporosis therapy
upon hospital discharge,
less than 1/4 are treated
Kiebzak, Arch Int Med 2002
Insufficient Diagnosis and Treatment
Post Procedure Isn’t Limited to Hip Fx
Retrospective review of
156 patients who had
vertebroplasty 1999-2001
< 8% of patients
received osteoporosis
treatment after
vertebroplasty
Recknor, ASBMR, 2003
Osteoporosis Screening
Time to Take Responsibility
“The responsibility to ensure appropriate
osteoporosis screening and treatment begins
with any internist or specialist… The status
quo of “missed opportunities” is
unacceptable.
The buck stops with us.”
Mazanec, Arch Intern Med May, 2004
72 Year-old Female; T-score -1.9 and
Prior Vertebral Fracture.
Rx With Ca/D and an Oral
Bisphosphonate
Follow-up BMD is Stable, but She Now
Has a T-score of -2.5
How Did This Happen?
Derived T-score is Dependent on
the Young-normal Population
T-score = Patients BMD- Young Normal Mean BMD
SD of Young Normal
GE Lunar Upgraded their Database
(Fall 2002) to Include NHANES Data
This
is the recommendation of the International
Committee for Standards in Bone Measurement
NHANES III used Hologic Densitometers
Recent equations allow NHANES III use at the
femoral neck and trochanteric regions
GE Lunar incorporated these data into their software
releases beginning ~November 2002
NHANES Mean Young-Adult BMD
2
(g/cm ) & StDev
Site
Neck
Troch
Total
Lunar
Pre v7.x
.980
(.12)
.790
(.11)
1.000
(.12)
Lunar
v7.x+
1.038
(.12)
.851
(.099)
1.0077
(.122)
The Bar is Set Higher
Same BMD but Different
Diagnostic Classification
OLD DATABASE
NEW DATABASE
T-score = 0
T-score = 0
T-score = -1
T-score = -1
T-score = -2
T-score = -2
T-score = -3
T-score = -3
With this Database, More Women Are
Diagnosed as “Low”
115 postmenopausal
women; femur scans
analyzed with “old” and
“new” software
Mean T-score 
0.5 at femur neck
0.7 at trochanter
Binkley, ISCD 2004
The Solution is to Recalculate the
NHANES SD
The FN SD
increases from
0.120 g/cm2
to 0.138 g/cm2
SD Recalculation Resolves
Diagnostic Discrepancy
20
15
G E Pre U pdate
G E Post Update
G E Recalculated
H ologic
10
5
0
G E/H ologic Com parison
n = 89
How Does This Affect You/Your
Patients?
This
is not a problem at UW, we have not
upgraded past software version 6.8
A GE Lunar software upgrade is coming and
will correct this problem
There have been an unknown number of
women inappropriately diagnosed as “low”
with this software problem and will be
confused when you see them