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The Diagnostic Evaluation of Patients with Low Bone Mass
Karen E. Hansen, M.D.
University of Wisconsin School of Medicine & Public HealthUW Rheumatology Section
UW Osteoporosis Clinical & Research Program
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InvestigateInvestigate
Look for underlying diseases causing or contributing to low bone mass
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The Pathogenesis of Idiopathic Postmenopausal Osteoporosis
Before Menopause: “less than optimal peak bone mass”Heredity accounts for 50-70% of peak bone massDietExerciseOther factors
Increasing Age: 1% bone loss per year after age 30-35 years
Following Menopause: estrogen deficiency results in bone resorption and decreased bone formation
Anderson, J Am Coll Nutr 1993;12(4):378-383
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Diagnostic CaveatsT-score -2.5 or less does not always mean
osteoporosis– Example: 65 year old woman with
compression fracture and T-score –2.8
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Diagnostic CaveatsLow T-score does not identify the cause of
osteoporosis– Example: 55 year old woman with itchy rash,
iron deficiency and low vitamin D levels
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Why Evaluate for Secondary Causes?
• Remedial diseases are not missed• Appropriate therapy is chosen based on
the underlying etiology of bone loss
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Laboratory Menu
• CBC• Creatinine• AST• Alkaline phosphatase• Calcium• Phosphorus• Intact PTH• 25(OH)D• TSH• 24 hour urine calcium
Other selected tests:• Celiac sprue panel• Sacroiliac films• Cortisol levels• Markers of bone
turnover• Others
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Primary Hyperparathyroidism• 121 subjects with 1o Hyperparathyroidism,
half undergo surgery and half do not
• Surgical correction of the condition improves bone mass within one year
• In those undergoing surgery,– Lumbar Spine bone mass + 8%– Femoral Neck bone mass + 6%
N Engl J Med 1999;341:1249-55
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Possible Flags Prompting a Work Up for Secondary Osteoporosis in Postmenopausal
Women• Z-score < -1• Z-score < -2• T-score < -3• Cortical > trabecular bone loss• Osteoporosis with > 1 fracture• Failure of antiresorptive therapy to improve bone
mass or prevent a fracture• All women
There is no consensus on the appropriate work up for secondary causes of osteoporosis in older women
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What is in the Literature?
• How often do patients have an identifiable cause of bone loss?
• What is the basic laboratory evaluation for a person with bone loss?
A recent review article states that 20% of women have a secondary cause of osteoporosis
(Fitzpatrick, Mayo Clinic Proceedings)
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Brigham and Women’s• Retrospective study of women referred to the
Brigham and Women’s OP Clinic• 237 women, ~200 postmenopausal• Mean age 56 ( +13.8) years• Mean Lumbar T score –2.35, Z –1.34• Mean Femoral Neck T score –3.25, Z –1.28• Labs: Intact PTH, 25(OH)D, TSH, 24 hour
urine calcium, serum and urine electrophoresis
Haden, Calcif Tissue Int 1999;64:275-279
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By History Alone, 54% Had A Cause of Bone Loss other than Menopause
32%
24%
21%
5%
9%6% 3%
Steroids
Thyroid
PrematureMenopause (<40)Organ Transplant
GI Disorder
RA/AS
Haden, Calcif Tissue Int 1999;64:275-279
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38% with Secondary Cause of Osteoporosis by Laboratory Testing
• 16% had vitamin D Deficiency [25(OH)D < 15 ng]• 15% had high urine calcium• 12% had 1o or 2o Hyperparathyroidism• 4% had hyperthyroidism• one patient with myeloma
Haden, Calcif Tissue Int 1999;64:275-279
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Summary of Brigham Experience
• 54 % have historical cause of osteoporosis
• 38 % have laboratory cause of osteoporosis
SteroidsThyroid DiseaseMenopause before Age 40Low Vitamin D Levels
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Mount Sinai Hospital, 1992-1996
• Cross sectional chart review study• 508 women referred to OP Clinic for
evaluation of newly discovered OP
Tannenbaum, J Clin Endocrinol Metab 2002;87:4431-4437
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Women in the StudyStudy Synopsis
Eligible SubjectsComplete labs available
n=173
Ineligible SubjectsIncomplete labs
n=136
No previous known contributorsto osteoporosis based on interview
n=309
A history of diseases and medicationsaffecting bone metabolism
n=335
Perimenopausal or postmenopausal women over age 45BMD T Score < -2.5
n=664
Tannenbaum, J Clin Endocrinol Metab 2002;87:4431-4437
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Cause of Osteoporosis by History: 53%
27%
16%
14%
10%
9%
9%
8%7%
SteroidsEarly MenopauseAlchol/LiverChemo/SeizureMiscellaneousThyroid/ParathyroidMalnutritionImmobility
Tannenbaum, J Clin Endocrinol Metab 2002;87:4431-4437
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173 Subjects Underwent Laboratory Testing
• Subjects with known causes of bone loss by history were excluded
• CBC, chemistry profile, 24 hour urine calcium, 25OHD, PTH
Tannenbaum, J Clin Endocrinol Metab 2002;87:4431-4437
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46% with Metabolic Condition
34%
8%20%
16%
12%
5% 5%
Vitamin DInsufficiencyVitamin DDeficiencyHypercalciuria
Malabsorption
HPT
Hyperthyroidism
Miscellaneous
Tannenbaum, J Clin Endocrinol Metab 2002;87:4431-4437
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Predictors of Metabolic Disease
• No relationship with… – T score– Z score– Age– Weight– History of nephrolithiasis, hypertension,
family and personal fragility fracture
Tannenbaum, J Clin Endocrinol Metab 2002;87:4431-4437
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Evaluation for Secondary Causes of Bone Loss in Kansas
• 180 women with osteoporosis • Detailed interview and examination• Laboratories: CBC, TSH, 25(OH)D,
urinalysis, and 24 hour urine calcium
Johnson, Arch Intern Med 1989;149:1069-1072
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Underlying Cause in 46%
31%
20%12%
8%
11%
18%SteroidsEarly MenopauseLow Vitamin DHyperthyroidGI DiseaseMiscellaneous
Johnson, Arch Intern Med 1989;149:1069-1072
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Osteoporosis is often Multifactorial
• Single cause in 47 of 83 women• Two causes in 29 women• Three causes in 7 women
Johnson, Arch Intern Med 1989;149:1069-1072
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Summary of Studies
Study n % with Cause
Top Causes
Brigham
Boston
237 54% SteroidsHyperthyroid
Premature Ovarian FailureMount Sinai
New York City
664 62% SteroidsPremature ovarian failure
Vitamin DHypercalciuria
Kansas 180 46% SteroidsPremature Menopause
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About 50% of Women Have a Specific Cause of OP
Steroids: 24%
Premature menopause: 21%
Hyperthyroidism: 6%
Inadequate Vitamin D: 9%
Hypercalciuria: 9%
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The Cost Effective StrategyUrine and serum calcium, PTH and
TSH (among women on replacement)
diagnosed
85% of women with secondary causes
Cost
$75 per patient screened
JCEM 2002;87:4431-4437
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Treatment of Common Causes of Osteoporosis in Women
Cause How Many ? Therapy ? BMD Increase?
AlendronateRisedronate
+
+
+
+
+
Bisphosphonates, SERMS, teriparatide
Treat thyroid disease
Vitamin D
HCTZ 25 mg bid
Fracture Decrease
?Steroids ~21 % +
Early Menopause ~21% +
Hyperthyroidism ~6% ?
Vitamin D Deficiency
~9% +
Hypercalciuria 9% ?
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Misconceptions about Male Osteoporosis
• Male osteoporosis is uncommon• Men do not require osteoporosis screening
• One in four men aged 50 will experience a fragility fracture in remaining life
• The ISCD recommends a screening bone density study for all men at age 70
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Osteoporosis in MenUniversity of Pennsylvania
• 47 men with low trauma fracture (91%) or radiographic osteopenia (9%)
• All men: interview, radiographs, DXA, bone biopsy, and labs
• Fasting blood for CBC, SPEP, calcium, phosphorus, albumin, creatinine, alk phos, electrolytes, liver and thyroid tests, vitamin D, intact PTH, testosterone
• Fasting urine calcium, phosphorus, creatinine, free cortisol
Ann Intern Med 1995; 123: 452-460
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64% of Men had Specific Cause of Bone Loss
15%17%
36%
15%
17% Steroid Use
Hypogonadism
Alcohol
MiscellaneousCausesPrimaryOsteoporosis
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Miscellaneous Causes
• Osteomalacia (4)• Hyperthyroidism (2)• Anticonvulsants (1)• Multiple Myeloma (1)
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Barcelona, Spain
• 81 men with osteoporosis, defined by low bone mass or low trauma compression fracture
• All patients: interview plus CBC, chemistry profile, 24-hour urine calcium
• Selected patients without obvious cause: testosterone, PTH, cortisol, 25(OH)D, thryroidtests
Brit J Rheumatol 1995;34:936-941
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Spain: 88% had Secondary Osteoporosis
15%
12%
12%
12%
27%
12%
10%
Hypogonadism
Steroids
Alcoholism
Multiple Causes
Miscellaneous
PrimaryOsteoporosisHypercalciuria
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Spain: Miscellaneous Causes
MalabsorptionHemochromatosisHyperparathyroidismHyperthyroidismCushings syndromeAddison’s Disease
Neurologic DisordersPanhypopituitarismAnticonvulsantsAcromegalyOIHematologic Disorder
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Symptoms of Osteoporosis
• 85% of men reported back pain• 69% had vertebral crush fractures• Mean 25(OH)D was 18.2 ng in those
with secondary causes, 13.3 ng in those with “idiopathic” osteoporosis, without an increase in PTH
• Men with hypogonadism did not volunteer symptoms of it
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Men with Osteoporosis
Three Most Likely Causes
Steroid Therapy (12-17%) Hypogonadism (15%) Alcohol Use (12-15%)
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Work Up of Osteoporosis in Men
• Ask men about use of steroids, alcohol• Ask men about symptoms of hypogonadism• If no obvious cause by history, a first morning
testosterone level might be the most appropriate single test
Additional tests if history and serum testosterone are normal
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Questions for Hypgonadism1. Do you have a decrease in libido?2. Do you have a lack of energy?3. Do you have a decrease in strength or endurance?4. Have you lost height?5. Have you noticed a decreased enjoyment of life?6. Are you sad or grumpy?7. Are your erections less strong?8. Have you noted a recent deterioration in your ability to play sports?9. Are you falling asleep after dinner?10. Has there been a recent deterioration in your work performance?
“Yes” to questions 1 or 7, or to three of the above, are highly sensitive and specific for low testosterone levels.
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Summary
• Both women and men often have a specific cause of osteoporosis that can be identified
• If a secondary cause is identified, this can be directly addressed, leading to – More effective increases in bone mass– Different therapeutic options or…– A combination of therapies that best serves the
patient
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Most Common Causes of Osteoporosis
WomenSteroids
Premature menopauseHyperthyroidism
Vitamin D Hypercalciuria
MenSteroids
HypogonadismAlcohol
HypercalciuriaVitamin D
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Chronic Kidney Disease (CKD)
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Intestinal CaAbsorption
Ionized Ca
Renal Function
PhosphorusRetention
Hyperphosphatemia
PTH Secretion
CalcitriolSynthesis
ParathyroidHyperplasia
SecondaryHyperparathyroidism
Renal Bone Disease(Osteitis Fibrosa Cystica)
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Monitoring for Renal Osteodystrophy at Various Stages of CKD
Monitor PTHCheck Vit D StatusPi RestrictionPi Binders
Treat AcidosisAvoid Al(Vit D Sterols)
Consider:Vit D SterolsDialysate Ca Monitor AlBone BxPTXDialysis regimenCalcimimetics?
400
300
200
100
0
PTH
GFR100 0
Target for Intact PTH
Target for PTH 1-84
2
3
4
5
Slide courtesy of Kevin MartinSlide courtesy of Kevin Martin
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K/DOQI Guideline 1Evaluation of Calcium and Phosphorus
Metabolism and Bone DiseaseThe target plasma intact PTH in the various stages of CKD are:
CKDStage
GFR Range (ml/min/1.73 m2) Target “intact” PTH
3 30–59 35-70 pg/ml (OPINION)
4 15–29 70-110 pg/ml (OPINION)
5 <15 or dialysis 150-300 pg/ml (EVIDENCE)
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Renal Osteodystrophy
Low TurnoverOsteomalaciaAluminum related
bone diseaseAdynamic bone
disease
High TurnoverSecondary Hyperparathyroidism (osteitis fibrosa)
Normal boneMild or Mixed Lesion
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Renal Osteodystrophy
Adynamic
Osteomalacia
Normal Mild OsteitisFibrosa
Mixed LesionOsteomalacia + HPT
PTH
Calcium, Vitamin D, Aluminum
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Treatment in CKD
• Oral 1,25(OH)D therapy (e.g. calcitriol) is recommended for– patients with stage 3-4 CKD and– 25(OH)D > 30 ng/ml and– iPTH above goal
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InvestigateInvestigate
Identify major risk factors for fracture
Note- some of these risk factors are well established for postmenopausal
women, but not necessarily for pre-menopausal women or for men
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5 MajorMajor Risk Factors for Osteoporosis and Fracture
1. Adult fracture2. Fragility fracture in 1st degree relative3. Weight <127#4. Current smoking5. Oral steroids > 3 months
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5 MajorMajor Risk Factors for Osteoporosis and Fracture
1. Adult fracture2. Fragility fracture in 1st degree relative3. Weight <127#4. Current smoking5. Oral steroids > 3 months
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Prior Fragility Fracture
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Prevalent Vertebral Fracture PredictsRisk of Future Hip Fracture
Adapted with permission from Melton LJ III, et al. Osteoporos Int. 1999;10:214-221.
ObservedExpected
Cum
ulat
ive
inci
denc
e (%
) of h
ip
fract
ure
in m
en a
nd w
omen
Years after vertebral fracture
0
5
10
15
20
25
0 1 2 3 4 5 6 7 8 9 10
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Physical Exam Findings Suggesting Compression Fracture
• Rib-pelvis distance < 2-3 finger breadths
• Tooth count < 20 • Wall-occiput distance: inability to touch
occiput to wall when standing with back and heels against the wall
• Height Loss
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0
5
10
15
20
25
30
Overall 0 1 2+
Risk of Another Vertebral Fracture is Higher in the Year Following a New
Fracture
* p<0.05, vs. patients with no prevalent vertebral fractures (12-Fold Increased Risk)
Perc
ent (
%) o
f Pat
ient
s
Number of Baseline Vertebral Fractures
**
Lindsay, et. al., JAMA 2001; 285: 320-23
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Identifying Patients with Prior Spine Fractures
• Vertebral compression fractures are the most common form of osteoporotic fracture
• Two in three vertebral fractures are painless
• If my patient experiences a painless vertebral fracture, how can I tell?
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Signs of Silent Osteoporotic Compression Fractures
• Height Loss: each complete compression fracture causes ~1 cm loss in height
• Dorsal kyphosis • Ribs rest on pelvis• Abdominal distention
Dequeker, Rheumatology 1st edition, Chapter 32: Osteoporosis. St. Louis: Mosby: 1994.
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Height Loss and Odds Ratio for Compression Fracture
Height loss, cm Odds Ratio 95% CI
none 1
0-1 1.8 1.1-3.1
1-2 5.1 3.0-8.7
2-3 13.5 6.9-26.3
3-4 19.1 8.1-45.0
>4 20.6 9.3-45.8
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Height Loss
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L4 Compression Fracture
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5 MajorMajor Risk Factors for Osteoporosis and Fracture
1. Adult fracture2. Fragility fracture in 1st degree relative3. Weight <127#4. Current smoking5. Oral steroids > 3 months
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Family History of Fracture• Family history of wrist fracture increased a
woman’s risk of wrist fracture– Maternal wrist fracture = 1.52 fold risk– Paternal wrist fracture = 2.41 fold risk
• Family history of hip fracture increased a woman’s risk of hip fracture – Maternal hip fracture = 1.48 fold risk – Sister’s hip fracture = 1.83 fold risk– Brother’s hip fracture = 2.26 fold risk
Fox, Osteoporosis Int 1998;8:557-562
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Family History of Fracture
• Family history of osteoporotic fracture at the wrist, hip or spine was associated with a 2-fold higher risk of osteoporotic fracture among 1,003 Caucasian women aged 45-64 years
• A positive family history of wrist fracture increased a woman’s own risk of wrist fracture by over 4-foldKeen, Osteoporosis Int 1999;10:161-166.
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Family History of FractureSummary of Two Studies
• The higher risk of fracture based on family history remained true and unchanged, after controlling for bone density
• A site-specific risk of fracture was noted• A male relative with fragility fracture also
increased a woman’s risk of fragility fracture• The overall risk of fracture was about two fold
higher when a family member had experienced fragility fracture
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Family History of Fragility Fracture
• Did any person in your family break a hip or wrist ?
• Did any of your relatives have a “widow’s hump” or break a spine bone ?
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5 MajorMajor Risk Factors for Osteoporosis and Fracture
1. Adult fracture2. Fragility fracture in 1st degree relative3. Weight <127#4. Current smoking5. Oral steroids > 3 months
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Low Body Weight
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Low Body WeightLow body weight is one of the best single predictors of
low bone mass and future fracture
The full mechanism by which low body weight increases risk of osteoporosis and fracture is unknown
The cut off for “low” body weight differs among published guidelinesWeight < 154 pounds Weight < 127 pounds
USPTFNOF
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Low Body Weight as a Risk Factor for Hip Fracture in Women
• Women aged > 50 with hip fracture were identified among six centers in Europe
• Two control women of the same age were selected for each woman with hip fracture
• A structured interview recorded various risk factors for osteoporosis and fracture
• The study identified ≅ 2,000 with hip fracture and 3500 controls
Johnell, J Bone Miner Res 1995;10:1802-1815
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Relative Risk of Hip Fracture According to Weight
00.10.20.30.40.50.60.70.80.9
1
Rel
ativ
e R
isk
of H
ip
Frac
ture
< 50 51-58 59-64 65-70 >71Weight, kg
It doesn’t help to weigh more than ~155#
Risk plateaus beyond 155#
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5 MajorMajor Risk Factors for Osteoporosis and Fracture
1. Adult fracture2. Fragility fracture in 1st degree relative3. Weight <127#4. Current smoking5. Oral steroids > 3 months
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Tobacco and Bone Density• Meta-analysis of 29 studies on smoking• Smoking has no material effect on bone
density in pre-menopausal women• Bone density was lower in postmenopausal
women who smoked, compared to nonsmokers
• For every 10 years increase in age, bone density of smokers fell by about 2%
Law, BMJ 1997;315:841-846
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Tobacco and Fracture
• A meta-analysis of 19 studies reporting fracture showed a higher risk of hip fracture in smokers compared to nonsmokers that was– 17 % higher at age 60– 41 % higher at age 70– 71 % higher at age 80– 108 % higher at age 90
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Tobacco and Fracture• The higher risk of fracture in smokers was
independent of – body mass index– exercise– use of estrogens
• There was a dose-response relationship with higher risk of fracture in heavier smokers
• One in 8 hip fractures could be directly attributed to smoking, after control for other risk factors
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5 MajorMajor Risk Factors for Osteoporosis and Fracture
1. Adult fracture2. Fragility fracture in 1st degree relative3. Weight <127#4. Current smoking5. Oral steroids > 3 months
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Fracture Risk with Steroids
• Retrospective cohort study using UK General Practice Research Database
• Controls matched to steroid users for age, gender
• 244,235 steroid users and 244,235 controls• Mean age 57 years, 59% female• Most frequent indication for steroids:
respiratory disease (40%)
Van Staa TP, JBMR 2000;15:993-1000
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Fracture Risk During Steroid Therapy
0.99
1.77 2.271.55
2.59
5.18
0
1
2
3
4
5
6
Relative Risk
Hip Vertebral Fractures
< 2.5 mg2.5-7.5 mg> 7.5 mg
Van Staa TP, JBMR 2000;15:993-1000
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Relative Risk of Fracture after Cessation of Steroids
020406080
100120140160180
Year 1 Year 2
Non
vert
ebra
l Fra
ctur
es
> 10 grams> 6 months
Suggests osteoblast recovery
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Fractures Occur at Lower T-scores when Taking Steroids
05
10152025303540
-4 -3.5 -3 -2.5 -2 -1.5 -1
T-score
Perc
ent w
ith F
ract
ure
ControlsSteroid Users
Van Staa, Arthritis Rheum 2003;48(11):3224-3229
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Correct Causes of Bone Loss and Fracture Risk Factors
• Stop steroids or minimize dose• Stop use of tobacco products• Minimize falls• Correct any underlying conditions
– Hyperparathyroidism– Vitamin D deficiency– Hypercalciuria
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5 MajorMajor Risk Factors for Osteoporosis/Fracture:Women
1. Adult fracture2. Fragility fracture in 1st degree relative3. Weight <127#4. Current smoking5. Oral steroids > 3 months
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5 MajorMajor Risk Factors for Osteoporosis/Fracture in Men1. Adult fracture2. Fragility fracture in 1st degree relative3. Weight <127#4. Current smoking5. Oral steroids > 3 months
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Thank you for your attention
Questions?