Transcript osteoporosis - Scioto County Medical Society

SECONDARY CAUSES OF
OSTEOPOROSIS
Nelson B. Watts, MD
Bone Health and Osteoporosis Center
Metabolic Bone Diseases and Mineral Disorders
SECONDARY CAUSES OF
OSTEOPOROSIS
•
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Use of bone densitometry
Secondary causes of bone loss
Laboratory evaluation
Calcium and vitamin D
Bone turnover markers
Lateral spine imaging with DXA
DEFINITION OF OSTEOPOROSIS
Normal Bone
Osteoporotic Bone
• A skeletal disorder characterized by
– compromised bone strength
predisposing to
– an increased risk of fracture.
• Bone strength reflects the integration
of two main features:
– bone density and
– bone quality.
2000 NIH Consensus Development Conference
WHO CRITERIA FOR
POSTMENOPAUSAL OSTEOPOROSIS
The T-score compares an individual’s BMD with the
mean value for young normal individuals and expresses
the difference as a standard deviation score.
Category
T-score
Normal
-1.0 and above
Low bone mass
(osteopenia)
Between -1.0 to -2.5
Osteoporosis
-2.5 and below
Kanis JA et al, J Bone Miner Res 1994;9:1137-1141
WHY THE WHO CHOSE T = -2.5
• "When measurements are made at the hip alone, …the
prevalence [of osteoporosis] is about one in five white
women, comparable to the lifetime risk of a single
osteoporotic fracture, such as a hip fracture.“
• "Such a cutoff value identifies approximately 30% of
postmenopausal women as having osteoporosis using
measurements made at the spine, hip, or forearm. This
is approximately equivalent to the lifetime risk of fracture
at these sites."
Kanis JA, et al. J Bone Miner Res 1994; 9:1137-1141
BONE DENSITY MEASUREMENTS AT
PERIPHERAL SITES
QUS
DXA
ADVANTAGES
• Portable
• Less expensive than central DXA
• Ultrasound does not involve
radiation
pQCT
LIMITATIONS
• Less predictive for hip fracture
than hip measurement
• Cannot be used for diagnosis
with WHO criteria
• Cannot be used for monitoring
(sites less likely to change)
PREVALENCE OF OSTEOPOROSIS AND
LIFETIME FRACTURE RISK IN WHITE WOMEN
45
40
35
30
Percent 25
20
15
10
5
0
T -2.5 or below 1
Lifetime risk of fracture
Hip
Spine
2
Forearm
Any
1. Melton LJ III, et al. J Bone Miner Res 1995;10:175
2. Melton LJ III, et al. J Bone Miner Res 1992;7:1005
PREVALENCE OF OSTEOPOROSIS
VARIES BY SITE AND METHOD
NORA Study, 200,160 ambulatory women age 50 and older
35
Missed
30
Percent of
subjects
2.5 SD or
more
below
young
adult mean
25
55%
20
66%
84%
90%
Forearm
DXA
Heel SXA
Heel QUS
15
10
5
0
Estimated Finger DXA
Spine+Hip*
*Estimated from NAHNES III
Siris E et al, JAMA 2001;286:2815-2822
AGE DEPENDENCE OF T-SCORES
Data from manufacturers' data bases
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
-4.0
Forearm
PA Spine
Total Hip
Heel
Lat DXA
QCT
30 35 40 45 50 55 60 65 70 75 80 85 90 95
Age (years)
Faulkner KG et al. J Clin Densitom 1999;2:343
WHO CRITERIA
• Apply only to postmenopausal Caucasian women
– not men, younger women, other ethnic groups
• Apply only PA spine, hip and forearm DXA
– not lateral spine, heel, finger, etc
• Apply only for central DXA
– not peripheral DXA, QCT, QUS, etc.
RISK FACTORS FOR OSTEOPOROSIS
FEMALE
NULLIPARITY
OLDER AGE
SLENDER BUILD
EARLY MENOPAUSE
LOW CALCIUM INTAKE
FAMILY HISTORY
SMOKING
FAIR SKIN
INACTIVITY
RISK FACTORS AND LOW BMD
IMPACT Trial
• ~7,000 women in 21
countries without known
osteoporosis had BMD
testing and risk factor
assessment
64% did not have
osteoporosis
~50% of patients with osteoporosis
..did not have risk factors
~50% of patients with risk factors did
..not have osteoporosis
36% did have
osteoporosis
48% had no
risk factors
67% had no
risk factors
52% had one or
more risk factors
33% had one or
more risk factors
Watts NB et al, Arthritis Rheum 2001;44:S256
WHO SHOULD HAVE A
BONE DENSITY TEST?
U.S. Preventive Services Task Force
• Women 65 years of age and older [should] be screened
routinely for osteoporosis
• Routine screening [should] begin at 60 years of age for
women at increased risk for osteoporotic fractures
– Low body weight (<70 kg)
– Lack of estrogen
– Possibly other risk factors
• No recommendation for or against screening younger
women at high risk
US PSTF, Ann Intern Med 2002;137:526-528
WHO SHOULD HAVE A
BONE DENSITY TEST?
Number Needed to Screen
8000
Number Needed to Treat
300
Fracture Type
7000
Fracture Type
Hip
Hip
6000
Vertebra
5000
Vertebra
200
4000
3000
100
2000
1000
0
0
50-54 55-59 60-64 65-69 70-74 75-79
Age
50-54 55-59 60-64 65-69 70-74 75-79
Age
Nelson HD et al, Ann Intern Med 2002;137;529-541
WHO SHOULD HAVE A
BONE DENSITY TEST?
Society Providing Recommendation
Patient category
US PSTF
NOF
AACE
ISCD
Women  age 65
Yes
Yes
Yes
Yes
Women 60-65 with risk factors
Yes
Yes
Yes
Yes
Women  60 with risk factors
Insufficient
data
Yes
Yes
Yes
Men  age 70
Not
addressed
Yes
Not
addressed
Yes
Younger men with risk factors
Not
addressed
Yes
Not
addressed
Yes
ISCD OsteoFLASH, www.iscd.org
FDA-APPROVED MEDICATIONS
INDICATIONS
Postmenopausal
Osteoporosis
Drug
Estrogen
Prevention
Treatment
Glucocorticoid-induced
Osteoporosis
Prevention
Men
Treatment

Calcitonin
(Miacalcin®, Fortical®)
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Raloxifene
(Evista®)


Ibandronate
(Boniva®)
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Alendronate
(Fosamax®)

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Risedronate
(Actonel®)


Zoledronic acid
(Reclast®)

Teriparatide
(Forteo®)







FDA-APPROVED MEDICATIONS
EVIDENCE FOR FRACTURE REDUCTION
Drug
Vertebral
Fracture
Nonvertebral
Fracture
Hip
Fracture
Calcitonin
(Miacalcin®, Fortical®)

No effect
demonstrated
No effect
demonstrated
Raloxifene
(Evista®)

No effect
demonstrated
No effect
demonstrated
Ibandronate
(Boniva®)

No effect
demonstrated
No effect
demonstrated
Alendronate
(Fosamax®)



Risedronate
(Actonel®)



Zoledronic acid
(Reclast®)



Teriparatide
(Forteo®)


No effect
demonstrated
Evidence for effect but not an FDA-approved indication
NOF TREATMENT GUIDELINES 2008
www.nof.org
NOF GUIDE -- 2008
Postmenopausal women and men age 50 and older
presenting with the following should be treated:
• A hip or vertebral (clinical or morphometric) fracture
• BMD T-score ≤ -2.5 at the femoral neck, total hip or spine
after appropriate evaluation to exclude secondary causes
• Low bone mass (T-score between -1.0 and -2.5 at the
femoral neck, total hip or spine) AND
– 10-year probability of hip fracture ≥3% or
– 10-year probability of any major osteoporosis-related
fracture* ≥20% based on the US-adapted WHO
algorithm
*Hip, humerus, forearm or clinical vertebral fracture
NOF GUIDELINES 2008
After exclusion of secondary cause, treat postmenopausal
women and men age 50 and older who have…
A fracture of the hip
or vertebra (clinical
or morphometric)
T-score -2.5 or below
in the femoral neck,
total hip or spine
T-scores between -1.0 and -2.5
10-year risk ≥3% for hip fracture or
≥20% for major osteoporotic fractures
based on FRAX™ model
www.shef.ac.uk/FRAX
www.shef.ac.uk/FRAX
Mary Smith, 66.8 years old
Wt. 140 lbs., Ht 64 in.
FN T-score -2.4, no risk factors
www.shef.ac.uk/FRAX
EVALUATION OF PATIENTS WITH
OSTEOPOROSIS
• Just because a woman is postmenopausal
and has osteoporosis doesn’t mean that she
has postmenopausal osteoporosis
• Failure to identify underlying disorders may
result in inadequate or inappropriate treatment
SOME CAUSES OF SECONDARY
OSTEOPOROSIS IN ADULTS
Endocrine Disease or
Metabolic Causes
Nutritional Conditions
Hypogonadism
Vitamin D deficiency
Glucocorticoids
Hypercalciuria
Calcium deficiency
Anti-epilepsy drugs
Hyperthyroidism
Vit. B12 deficiency
Hyperparathyroidism
Weight loss
Excess thyroid
hormone
Cushing’s syndrome
Malabsorption
Acromegaly
Gastric surgery
Growth hormone
deficiency
Anorexia nervosa
Chronic liver disease
Alcoholism
Malnutrition
Prolonged TPN
Drugs
Depo-Provera
GnRH agonists
Disorders of
Collagen
Metabolism
Osteogenesis
imperfecta
Homocystinuria
Ehlers-Danlos
syndrome
Marfan
syndrome
Other
Rheumatoid arthritis
Inflammatory bowel
disease
COPD
Organ transplantation
Immobilization
Aromatase inhibitors
Multiple myeloma
Heparin
Some cancers
Renal tubular acidosis
Gaucher’s disease
Mastocytosis
Thalassemia
Adapted from Hodgson SF and Watts NB, AACE Guidelines on Osteoporosis, www.aace.com
ENDOCRINE AND METABOLIC DISEASES
ASSOCIATED WITH OSTEOPOROSIS
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Hypogonadism
Hypercalciuria
Hyperthyroidism
Hyperparathyroidism
Cushing’s syndrome
Acromegaly
Growth hormone deficiency
NUTRITIONAL CONDITIONS
ASSOCIATED WITH OSTEOPOROSIS
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Vitamin D deficiency
Calcium deficiency
Vitamin B12 deficiency
Weight loss
Malabsorption
Gastric surgery
Anorexia nervosa
Chronic liver disease
Alcoholism
Malnutrition
Prolonged TPN
DRUGS ASSOCIATED WITH OSTEOPOROSIS
• Glucocorticoids
• Anti-epilepsy drugs
• Thyroid hormone (supraphysiologic doses)
• Depo-Provera
• GnRH agonists
• Aromatase inhibitors
• TZDs
• SSRIs
• PPIs
DISORDERS OF COLLAGEN METABOLISM
• Osteogenesis imperfecta
• Homocystinuria
• Ehlers-Danlos syndrome
• Marfan syndrome
OSTEOGENESIS IMPERFECTA
Type I
• Autosomal dominant inheritance
• Decreased production of type I
procollagen; substitution for
glycine in triple helix of 1(I)
• Normal stature
• Little or no deformity
• Blue sclerae
• Hearing loss in 50%
• Teeth are usually normal
• Histomorphometry: increased
cortical osteocytes, woven bone,
thin collagen bundles
OSTEOGENESIS IMPERFECTA
Type IV
• Autosomal dominant inheritance
• Point mutation in 2(I) chain
• Normal sclerae
• Mild to moderate deformity
• Variable short stature
• Hearing loss in some
• Dentogenesis imperfecta is common
OTHER CAUSES OF LOW BONE MASS
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Rheumatoid arthritis
Inflammatory bowel disease
COPD
Organ transplantation
Immobilization
Multiple myeloma
Some cancers
Renal tubular acidosis
Gaucher’s disease
Mastocytosis
Thalassemia
How often are secondary causes found?
SECONDARY CAUSES OF OSTEOPOROSIS
Post-menopausal women over age 65
BMD T-score -2.5 or below
(n=664)
No previous known contributors to
osteoporosis based on past medical history
(n=309)
Eligible subjects
Complete battery of
laboratory tests available
(n=173)
History of known medications or diseases
affecting bone and mineral metabolism
(n=355)
Ineligible subjects
Incomplete laboratory testing
(n=136)
Tannenbaum C et al, J Clin Endocrinol Metab 2002;87:4431-4437
SECONDARY CAUSES OF OSTEOPOROSIS
Patients with at least 1 new diagnosis (n=84)
Vitamin D deficiency, <20 ng/mL (n=35)
Hypercalciuria
Renal (n=7)
Idiopathic (n=6)
Undefined (n=4)
Malabsorption
Relative calcium malabsorption (n=11)
Celiac sprue (n=3)
Hyperparathyroidism
Primary (n=1)
Secondary (n=11)
Exogenous hyperthyroidism (n=4)
Cushing’s disease (n=1)
Hypocalciuric hypercalcemia (n=1)
48.6%
20.2%
9.8%
8.1%
6.9%
2.3%
0.6%
0.6%
Tannenbaum C et al, J Clin Endocrinol Metab 2002;87:4431-4437
LABORATORY EVALUATION FOR
OSTEOPOROSIS
24-h urine calcium for all
Serum 25-OH vitamin D for all
Serum calcium for all
Serum TSH for all on replacement
Abnormal
39/173
35/173
3/173
4/25
This strategy finds 98% of cases,
costs $116 per patient screened,
$332 per case found
Tannenbaum C et al, J Clin Endocrinol Metab 2002;87:4431-4437
VITAMIN D STATUS
• Best reflected by serum 25-hydroxyvitamin D
levels
• Lab reference range is 20-100 ng/mL
• Minimum desirable level is 30 ng/mL (80 nmol/L)
• Reasonable range is 30 to 60 ng/mL (80 to 150
nmol/L)
VITAMIN D REDUCES RISK OF FALLING
Meta-Analysis
Bischoff-Ferrari HA et al. JAMA 2004;291:1999-2006
VITAMIN D REDUCES FRACTURES
AND MAY REDUCE MORTALITY
Vitamin D 100,000 IU Q 4 months or placebo
N=2037 men and 649 women ages 65-85
Fractures
Survival
(hip, wrist, forearm, vertebra)
OR 0.78 (0.61,0.99)
OR 0.88 (0.74,1.06))
Trivedi DP et al, BMJ 2003;326-469-475
MOST OF US WILL BENEFIT FROM A
VITAMIN D SUPPLEMENT
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Vitamin D has important skeletal and extra-skeletal effects
Adequate 25-hydroxyvitamin D level is ≥30 ng/dL
Vitamin D deficiency is common
Most patients require 1,000-2,000 IU vitamin D per day to
achieve an adequate level
• “Safe upper limit” is 2,000 IU per day
• Supplements of 1,000 IU tablets are now widely available
(1,000-2,000 IU daily
• Rx 50,000 IU ergocalciferol may be required (weekly, every
other week)
OPTIMAL CALCIUM INTAKE
1200 mg daily for adults age 50 and older
TOTAL FROM ALL SOURCES
Average calcium from diet:
Women 50 and older : ~500 mg daily
Men 50 and older: ~600 mg daily
Most people need a calcium supplement of
700 to 1000 mg daily.
Many people are taking too much.
24-HOUR URINE CALCIUM
• Lab reference range 100-300 mg/day
• Typical is 2-3 mg/kg/day
• Upper limit of “normal” is 4 mg/kg/day
– Wt 100 kg, normal up to 400 mg/day
– Wt 50 kg, normal up to 200 mg/day
• Low urine calcium = low intake or malabsorption
• High urine calcium = high intake or calcium wasting
Must be collected when vitamin D is adequate and
calcium intake is within target of 1200-1500 mg daily
LABORATORY EVALUATION FOR
OSTEOPOROSIS
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CBC
Chemistry panel and phosphorus
25-hydroxyvitamin D
24-hour urine for calcium and creatinine
If patient is male, serum testosterone (total
and free)
• Other studies if indicated by history, physical
findings or initial laboratory results
BIOCHEMICAL MARKERS OF
BONE TURNOVER
• Enzymes (alkaline phosphatase, acid
phosphatase)
• Degradation products (hydroxyproline,
collagen cross links)
• Byproducts (osteocalcin, procollagen I
extension peptides)
COLLAGEN CROSS LINKS
N-TELOPEPTIDE
REGION
HELICAL REGION
C-TELOPEPTIDE
REGION
CTx
NTx
Pyr
Dpd
Watts NB. Clin Chem 1999;45:1359-1368
BMD AND MARKERS PREDICT HIP FRACTURE
THE EPIDOS STUDY
6
CTX
Free DPD
5
4
4.8
4.1
2.7
3
2.2 1.9
2
1
0
Low
Hip BMD
High
Marker
Both
Garnero P et al, J Bone Miner Res 1996;11:1531
NOT EVERYONE WITH OSTEOPOROSIS
HAS ABNORMAL BONE TURNOVER
89 Elderly Women with Osteoporosis
100
80
30
300
25
250
20
200
15
150
10
100
5
50
0
0
60
40
20
0
Pyr
Dpd
NTx
Garnero P et al, J Clin Endocrinol Metab 1994;79:1693
URINE NTX
• Remodeling has diurnal variation: need second
morning fasting urine or fasting blood
• Urine sample may be preferred for logistical reasons
Reference range
Ostex
Mayo
Quest
Premenopausal women
5-65
0-64
10-110
Men
3-51
0-64
11-103
NA
0-130
NA
Postmenopausal women
Target: at or below the median value for premenopausal women
(30 nmol BCE/mmol creatinine)*
*de Papp AE et al, Bone 2007;40:1222-1230
CLINICAL USES FOR BONE
TURNOVER MARKERS
• Patient with borderline low BMD who is not a
treatment candidate: when to test again
• Patient with low BMD who has no other risk
factors: when to treat
• Patient on antiresorptive treatment who has
bone loss or fracture: is the medication being
absorbed and is it working?
• Patient on anabolic therapy: is medication
working?
REMINDER
Osteoporosis can be
diagnosed based on the
presence or history of an
osteoporotic fracture;
however, a fracture is not
required for diagnosis
LATERAL SPINE IMAGING WITH DXA
• Done with current DXA
equipment at time of DXA
visit (convenient)
• Small amount of radiation
• Good at visualizing T4-L4
and identifying moderate and
severe fractures
• Not good at visualizing upper
thoracic vertebrae or mild
compression fractures
IMPORTANCE OF RECOGNIZING
VERTEBRAL DEFORMITIES
482 women being screened
for osteoporosis studies.
All had BMD and lateral
spine imaging.
57% T above –2.5
No vertebral deformity
32% T –2.5 or below
Osteoporosis was defined
as either T-2.5 or below OR
a vertebral deformity.
26% of those with “osteoporosis”
had T-scores above –2.5 but had
one or more vertebral deformities
11% T above
-2.5 but
vertebral
deformity
Greenspan SL et al, J Clin Densitom 2001;4:373-380
USING DXA EQUIPMENT FOR
VERTEBRAL FRACTURE ASSESSMENT
• CPT code 77082, reimbursement ~$30
• Vertebral fracture assessment (VFA) with DXA
equipment is useful for screening patients with
– “osteopenia” (to decide when to treat) or
– osteoporosis (for selection of therapeutic agent)
• Utility for monitoring not clear
• If vertebral fractures are strongly suspected, get xrays
FOR PATIENTS WITH FRACTURE
Remember: not all fractures are
due to osteoporosis.
• Consider bone scan if there is
equivocal fracture or if fracture
might be remote
• Consider MRI or biopsy if
fracture might be due to
metastatic carcinoma
• Consider MRI if there is
question of lateral or posterior
displacement
ILIAC CREST BONE BIOPSY
• Patients with unusual features of
osteoporosis
– men
– young women
– patients with very low bone mass
– patients who have fragility fractures but
normal bone mass
• Patients failing conventional therapy
EVALUATION OF PATIENTS WITH
OSTEOPOROSIS
• Use central DXA for testing, women 65 and older
without risk factors and younger postmenopausal
women with risk factors
• All patients with osteoporosis should have lab workup
for secondary causes
• Give the right amount of calcium and plenty of
vitamin D
• Bone turnover markers have a limited role
• Lateral spine imaging with DXA should be done in
selected patients
SECONDARY CAUSES OF
OSTEOPOROSIS
Questions
or
comments?
WILL YOUR BONES LAST AS LONG AS YOU DO?