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OSTEOPOROSIS
A systemic skeletal disease characterized by low bone mass and microarchitectural
deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk.
CASE
•
A 42 year old woman asks for advice about osteoporosis therapy. A DXA scan done at her request after a screening study at a health fair showed low BMD, confirmed low BMD with a T score of -2.5 at the femoral neck.
Medical History
•
Normal menses.•
Weight stable, BMI 22
•
Mother and maternal grandmother both have severe osteoporosis
•
No renal or hepatic disease.•
No exogenous glucocorticoids
•
Normal PTH, TSH and vitamin D
QUESTIONS
•
DOES SHE HAVE OSTEOPOROSIS?
•
WHAT FURTHER STUDIES SHOULD BE DONE?
•
IS THERAPY APPROPRIATE?
•
WHAT THERAPY?
Osteoporosis Prevalence•
Affects 200 million women worldwide1
_ 1/3 of women aged 60 to 70 -
2/3 of women aged 80 or older
•
Approximately 30% of women over the age of 50 have one or more vertebral fractures2
•
Approximately one in five men over the age of 50 will have an osteoporosis-related fracture in their remaining lifetime1
1.
IOF, 2005 (www.osteofound.org)2.
Dennison E & Cooper C, Horm
Res, 2000;54 suppl
1:58-63
All
fractures
are associated
with morbidity
Cooper
C, Am
J Med, 1997;103(2A):12S-17S
40%
Unable to walk independently
30%
Permanentdisability
20%
Death within one year
80%
One year after an
hip fracture:
Patie
nts
(%)
Unable to carry out at least one independent activity of daily living
OSTEOPOROSIS
Densitometric
Definition:Bone density 2.5 SD or more below the mean for young adult women (T score less than or equal to -2.5)
Karis, JA et al,J
Bone Miner. Res., 1994
DXA
•
Dual energy x-ray absorptiometry
Measure of x-ray energy using 2 energy levels.
Assumes a 2 compartment model.
DXA TERMS
•
T-score:
(BMD of patient –
BMD of young-normal)__________________________________
SD of young normal
DXA TERMS
•
Z-score:
(BMD of patient –
BMD of age matched normals)
___________________________________SD of age matched normals
Interpretation of bone mineral density (BMD)
Z score: -1.0 (age-dependent)T score: -2.5 (age-independent)
BMD of patient A is 0.72 g/cm
0.72
T Z
+ 1SD
- 1SD
Age (yr)
A
BMDg/cm2
59
Raisz L. N Engl J Med 2005;353:164-171
Dual-Energy X-Ray Absorptiometry of the Spine and Hip of a 66-Year-Old Postmenopausal Woman
DXA –
Sources of Error
•
Osteoarthritis•
Laminectomy
•
Previous Fracture•
Osteomalacia
•
Overlying Metal Hardware
•
Soft Tissue Calcifications
•
Severe Scoliosis•
Extreme obesity or ascites
•
Vertebral deformities•
Inadequate reference population ranges
•
Poor operating procedures
Adapted from Kanis, Lancet:359:1929, 2002 and Becker, The Endocrine Society, 2005
Diagnosis in Postmenopausal Women
WHO criteria should be used
Normal = T-score -1 or greaterOsteopenia = T-score between -1 and - 2.5Osteoporosis = T-score -2.5 or less
Diagnosis in Premenopausal Women
•
WHO criteria should not apply to healthy pre-menopausal women.
•
Z-scores should be used.•
Osteoporosis may be diagnosed if there is low BMD with risk factors.
•
The diagnosis of osteoporosis should not be made on densitometric
criteria alone.
Hip
frac
ture
risk
(% p
er 1
0 Ye
ars)
-3
60
70
80
0
5
10
15
20
50
BMD T-score-2.5 -2 -1.5 -1 -0.5 0 0.5 1
10-Year Fracture Risk: age and BMD
For a given BMD,
For a given BMD,
risk increases with
risk increases with ageage
Kanis
JA et al, Osteoporos
Int, 2001;12:989-995
Vertebrae
Hip
Wrist
50
60
70
80
40
30
20
10
Age (Years)
Ann
ual i
ncid
ence
pe
r 100
0 w
omen
Incidence of osteoporotic fractures in women
Wasnich
RD, Osteoporos
Int
1997;7 Suppl
3:68-72
Rationale for Diagnosis Position in Premenopausal Woman
•
Premenopausal women do not have same relationship between BMD and fracture risk as postmenopausal women, therefore WHO classification does not apply
•
Major risk factors in premenopausal women elevate fracture risk sufficiently so that osteoporosis may be diagnosed if low BMD is also present
Pathogenesis of osteoporosis
Resorbed
cavity too large
Newly formed packet of bone too small
Formation does not
match resorptionIncreased numbers of
remodeling
units
INCREASED BONE LOSS
Determinants of Peak Bone Mass
Genetics
Lifestyle
PEAK BONE MASS 20-22 years of age HormonesNutrition
Candidates
genes
involved
in the genetics
of peak bone
mass and/or
osteoporosisReceptors•
Vitamine D Receptor
(VDR)•
Estrogen
receptors•
Calcitonin
receptor•
Calcium
sensing
receptor•
PTH•
Androgen•
Osteoprotegerin•
Glucocorticoids•
Tumor
necrosis
factor
Bone-associated
proteins•
Collagen
type
1•
Osteocalcin
Growth
factor
and cytokines•
Interleukin
6•
TGF-
Beta•
IGF-I•
Bone
morphogenetic
protein
2 •
Interleukin-1 receptor
antagonist•
Tumor
necrosis
factor
alpha
Enzymes•
Aromatase•
Methylenetetrahydrofolate
reductase
Miscellaneous•
Apolipoprotein
E•
Heparin
sulfate
glycoprotein
Changes in BMD in response to calcium fortified foods in prepubertal
girls
distributed according
their spontaneous calcium intake
PlaceboCalcium supplemented
Yearly
BMD increase
0
10
20
30
mg/
cm2
x yr
low highCalcium intake
Bonjour JP et al, J Clin
Invest 1997;99:1287-1294
P≤0.01
Effect of physical exercise on PBM
Peak total body BMC(g/year)
Peak femoral neck BMC(g/year)
Peak lumbar spine BMC(g/year)
Bailey
DA et al, J Bone
Miner Res, 1999;14:1672-1679
100
200
300
400
500
0Girls Boys
10121416
2468
0Girls Boys
0.50.60.70.8
0.20.30.4
0Girls Boys
1
0.1
0.9
Inactive Average Active
**
**
** ** **
Significantly greater than inactive,*P≤0.005, **P≤0.001
Disorders Causing Bone Loss
•
Estrogen deficiency•
Premature menopause <45 y.
•
Long-term secondary amenorrhea >1y.
•
Primary hypogonadism•
Other disorder associated with
•
Osteoporosis•
Maternal/ family history of hip
fracture•
Prolonged immobilization
•
Anorexia nervosa•
Malabsorption
syndromes•
Primary Hyperparathyroidism
•
Hyperthyroidism•
Corticosteroid therapy
•
Cushing’s syndrome•
Post-transplantation
•
Chronic renal failure•
Drugs
Kanis
JA, Lancet, 2002;359:1929-1936
Secondary osteoporosis
Endocrine Nutritional Drug-induced Immobilization Others
HyperthyroidismHypogonadism
Cushing Syndrome
GlucocorticoidsImmunosuppressly
Anticonvulsants
Rheumatoid A.DiabetesTumors
(Myeloma, etc.)
BMD and risk of fracture
1
For a cumulative dose of 13.9 g of prednisone (Van Staa
et al, 2002)2
General Practice Research Database 3 From Marshall D et al, BMJ, 1996;312:1254-1259
Estimated
BMD Decreases1
Spine
-
0.5 SD
3.0
1.5
Hip
-
0.4 SD
2.2
1.4
Relative Risk of FractureGIOP2 Postmen. OP3
For the same change in BMD, glucocorticoid-treated patients
may be at higher risk of fracture
Van Staa
TP et al, Osteoporos
Int, 2002;13:777-787
Management of glucocorticoid-induced osteoporosis
Guidelines
ACR, 2001
UK, 1998
a.
Patients about to start a long term (>3 months) GC treatment General measures
Yes
Yes (smoking cessation-alcohol reduction)
(exercise)Initiate calcium plus vitamin D
Yes
YesDXA evaluation to consider BP
Yes
YesT-score Cut-off to start BP -
-1.5GC dose
≥5 mg /d
Not specified
b. Patients already taking GC treatmentGeneral measures
Yes
Yes(smoking cessation-alcohol reduction)(exercise) Initiate calcium plus vitamin D
Yes
YesDXA evaluation to consider BP
Yes
YesT-score Cut-off to start BP -1
-1.5GC dose
≥5mg/d
Not specified
ACR: American
College
of
Rheumatology, UK: National Osteoporosis
Society
Further Studies
•
PTH, Calcium, phosphate, 25-hydroxy- vitamin D
•
CBC•
Serum creatinine
•
Alkaline phosphatase, aminotransferases•
TSH
Non Pharmacological
Approaches to
the Prevention
of
Postmenopausal
Osteoporosis
•
Adequate intake of dietary calcium & protein
•
Regular physical activity
•
Avoid tobacco
•
Minimize risk of falls
•
Recommend hip protectors in those prone to falls
Surgeon General Report 2004
•
“…Calcium has been singled out as a major
public health concern today not only because it
is a critical nutrient for bone but also because of
national surveys that suggest that the average
calcium intake of individuals is far below the
levels recommended for optimal bone health”
U.S. Department of Health and Human Services. Bone Health and Osteoporosis: A report of the Surgeon General. 2004;115
The Majority of Americans Are Not Receiving Adequate Levels of Vitamin D
*Percent consuming adequate intake or above from diet + supplements significantly different from diet alone; P<0.05.
51–70 yFemales
Perc
ent N
ot C
onsu
min
g A
dequ
ate
Inta
ke (A
I) Vi
tam
in D
Moore C et al. J Am Diet Assoc. 2004;104:980–983.
010203040
Females
*
*
Vitamin D Intake (Diet + Supplement)
NHANES III•
According to an NHANES III survey of 3,444 women 51 years and older, over 70% of women 51 to 70 years of age were estimated not to meet adequate intake guidelines for vitamin D based on daily intake from diet and supplements (400 IU).
•
Nearly 90% of women older than 70 years were estimated not to meet guidelines (600 IU).
5060708090
100
>70 yNHANES = National Health and Nutrition Examination Survey.
Consequences of Vitamin D Insufficiency
1.
Holick MF. Curr Opin Endocrinol Diabetes. 2002;9:87–98.2.
Lips P. Endocr Rev. 2001;22:477–501.
Calcium absorption1
—When vitamin D status is sufficient, absorption of dietary calcium is approximately 30% to 40%.
—As vitamin D status declines, absorption of dietary calcium declines to about 10% to 15%.
PTH—Low levels of vitamin D lead to increased release
of PTH,2
which increases bone resorption and decreases bone mass.
Sources of Vitamin D•
Sunlight exposure— Major source of vitamin D.1,2
— Vitamin D production is affected by season, duration of exposure, sunscreen use, and skin pigmentation.2
•
Endogenous production—
Skin and kidneys form and process vitamin D4; this may decrease with age.2
•
Dietary intake—
Minor source of vitamin D.2
—
Vitamin D is rare in foods other than fatty fish and fortified food products, such as milk and breakfast cereals.3,4
1.
Holick MF. J Cell Biochem. 2003;88:296–303.2.
Holick MF. Osteoporos Int. 1998;8(suppl 2):S24–S29.3.
Lips P. Adv in Nutr Res. 1994:151–165..
Defining the Upper Limit of Vitamin D Intake:
There is limited information regarding doses of vitamin D associated with acute toxicity, although intermittent (yearly or twice yearly) single doses of vitamin D as high as 600,000 IU have been given without reports of toxicity.
What is the Optimal Intake of Vitamin D?
Important contribution of Calcium (Osteoporosis Studies)
All studies that formed the basis of
osteoporosis indications for risedronate,
alendronate, ibandronate, teriparatide,
raloxifene and calcitonin required calcium
supplementation in the study design
Sunyecz
JA et al. Journal of Womens
Health 2005;14(2):180-192
DXA for Monitoring Therapy
•
Slow response time.•
Increased signal to noise ratio.
GarneroGarnero
P & P & DelmasDelmas
PD, PD, Curr
Opin
Rheumatol, 2004;16:428-434
DXA for Monitoring Therapy
•
Decreases in BMD while on therapy do not always indicate treatment failure.
•
Some who lose BMD the first year, gain during the second year –
“regression to
the mean”.•
Even when BMD declines during therapy, fracture risk may decrease.
Biochemical markers of bone turnover
Formation
markers
•
Osteocalcin•
Bone
specific
alkaline
phosphatase
•
Procollagen
type-1 N-propeptide
•
Procollagen
type-1 C-propeptide
Resorption
markers•
Hydroxyproline
•
Hydroxylysine•
Pyridinoline•
Deoxypyridinoline•
Bone
sialoprotein•
Acid phosphatase•
Tartrate-resistant
acid phosphatase
•
Type-1 collagen
telopeptides
(CTX, NTX)
Association between BMD, resorption
markers and fracture risk
0
1
2
3
4
5
low hip BMD high CTX low
hip BMD+ high CTX
2.72.2
4.8R
isk
ofhi
p fr
actu
re(o
dds
ratio
)
Garnero
P et al, J Bone
Miner Res, 1996;11:1531-1538
2 Years later
•
Her T-score is -2.9.•
She is oligomenorrheic
and having hot
flashes.•
Her FSH on day 3 of the menstrual cycle is 42.
Drugs used in osteoporosis treatment
• HRT
• SERM/Raloxifene
• Calcitonin
• Bisphosphonates -
Alendronate
-
Risedronate
-
Ibandronate
-
Zoledronic
Acid
•
Parathyroid hormone (PTH)
Anti-fracture Efficacy of Therapeutic Agents
Drug Vertebral fractures
Non-vertebral fractures (hip)
Alendronate, Risedronate + + + + +
Ibandronate +++ -
Zoledronic
Acid +++ -HRT + + +PTH + + + + +Raloxifene + + + 0Calcitonin +
Adapted
from
Delmas
PD, Lancet, 2002;359:2018-2026
Conclusions
•
In premenopausal women, low bone mass alone is not adequate to establish a diagnosis of osteoporosis.
•
Low BMD in premenopausal women may result from low peak bone mass or accelerated bone loss.
•
Premenopausal women with low BMD deserve careful follow up.
Conclusions
•
Bone density testing is appropriate in premenopausal women with history of a fragility fracture or known secondary cause of osteoporosis
•
Adequate calcium and vitamin D intake are fundamental components of osteoporosis therapy.
Recommended