www.uc-osteoporosis.com
SECONDARY CAUSES OF OSTEOPOROSIS
Nelson B. Watts, MD
Bone Health and Osteoporosis CenterMetabolic Bone Diseases and Mineral Disorders
www.uc-osteoporosis.com
• Use of bone densitometry• Secondary causes of bone loss• Laboratory evaluation• Calcium and vitamin D• Bone turnover markers• Lateral spine imaging with DXA
SECONDARY CAUSES OF OSTEOPOROSIS
www.uc-osteoporosis.com
2000 NIH Consensus Development Conference
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.
www.uc-osteoporosis.com
WHO CRITERIA FORPOSTMENOPAUSAL
OSTEOPOROSISThe T-score compares an individual’s BMD with the
mean value for young normal individuals and expressesthe difference as a standard deviation score.
Kanis JA et al, J Bone Miner Res 1994;9:1137-1141
-2.5 and belowOsteoporosis
Between -1.0 to -2.5Low bone mass (osteopenia)
-1.0 and aboveNormal
T-scoreCategory
www.uc-osteoporosis.com
• "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."
WHY THE WHO CHOSE T = -2.5
Kanis JA, et al. J Bone Miner Res 1994; 9:1137-1141
www.uc-osteoporosis.com
BONE DENSITY MEASUREMENTS AT PERIPHERAL SITES
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)
ADVANTAGES• Portable• Less expensive than central DXA• Ultrasound does not involve
radiation
QUS DXA pQCT
www.uc-osteoporosis.com
PREVALENCE OF OSTEOPOROSIS ANDLIFETIME FRACTURE RISK IN WHITE WOMEN
05
1015202530354045
Hip Spine Forearm Any
T -2.5 or below
Lifetime risk of fracture
1. Melton LJ III, et al. J Bone Miner Res 1995;10:1752. Melton LJ III, et al. J Bone Miner Res 1992;7:1005
Percent
1
2
www.uc-osteoporosis.com
0
5
10
15
20
25
30
35
EstimatedSpine+Hip*
Finger DXA ForearmDXA
Heel SXA Heel QUS
PREVALENCE OF OSTEOPOROSIS VARIES BY SITE AND METHOD
Siris E et al, JAMA 2001;286:2815-2822
Percent of subjects 2.5 SD or
more below young
adult mean
NORA Study, 200,160 ambulatory women age 50 and older
*Estimated from NAHNES III
Missed
55% 66% 84% 90%
www.uc-osteoporosis.com
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
30 35 40 45 50 55 60 65 70 75 80 85 90 95
Forearm
PA Spine
Total Hip
Heel
Lat DXA
QCT
AGE DEPENDENCE OF T-SCORES
Age (years)
T-score
Data from manufacturers' data bases
Faulkner KG et al. J Clin Densitom 1999;2:343
www.uc-osteoporosis.com
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.
www.uc-osteoporosis.com
RISK FACTORS FOR OSTEOPOROSIS
FEMALE
OLDER AGE
EARLY MENOPAUSE
FAMILY HISTORY
FAIR SKIN
NULLIPARITY
SLENDER BUILD
LOW CALCIUM INTAKE
SMOKING
INACTIVITY
www.uc-osteoporosis.com
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 haveosteoporosis
67% had no risk factors
33% had one or more risk factors
36% did haveosteoporosis
48% had no risk factors
52% had one or more risk factors
~50% of patients with osteoporosis ..did not have risk factors
~50% of patients with risk factors did ..not have osteoporosis
Watts NB et al, Arthritis Rheum 2001;44:S256
www.uc-osteoporosis.com
WHO SHOULD HAVE ABONE 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
www.uc-osteoporosis.com
WHO SHOULD HAVE ABONE DENSITY TEST?
0
1000
2000
3000
4000
5000
6000
7000
8000
50-54 55-59 60-64 65-69 70-74 75-79
Hip
Vertebra
Nelson HD et al, Ann Intern Med 2002;137;529-541
0
100
200
300
50-54 55-59 60-64 65-69 70-74 75-79
Hip
Vertebra
Number Needed to Screen Number Needed to Treat
Age Age
Fracture Type Fracture Type
www.uc-osteoporosis.com
WHO SHOULD HAVE ABONE DENSITY TEST?
ISCD OsteoFLASH, www.iscd.org
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 factorsInsufficient
data Yes Yes Yes
Men age 70 Not addressed Yes Not
addressed Yes
Younger men with risk factors Not addressed Yes Not
addressed Yes
www.uc-osteoporosis.com
FDA-APPROVED MEDICATIONSINDICATIONS
Postmenopausal Osteoporosis
Glucocorticoid-induced Osteoporosis
Men
Drug Prevention Treatment Prevention Treatment
Estrogen Calcitonin
(Miacalcin®, Fortical®)
Raloxifene
(Evista®)
Ibandronate
(Boniva®)
Alendronate (Fosamax®)
Risedronate
(Actonel®)
Zoledronic acid
(Reclast®)
Teriparatide
(Forteo®)
www.uc-osteoporosis.com
DrugVertebral 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
FDA-APPROVED MEDICATIONSEVIDENCE FOR FRACTURE REDUCTION
Evidence for effect but not an FDA-approved indication
www.uc-osteoporosis.com
NOF TREATMENT GUIDELINES 2008
www.nof.org
www.uc-osteoporosis.com
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
www.uc-osteoporosis.com
10-year risk ≥3% for hip fracture or ≥20% for major osteoporotic fractures
based on FRAX™ model
T-scores between -1.0 and -2.5
NOF GUIDELINES 2008
After exclusion of secondary cause, treat postmenopausal women and men age 50 and older who have…
T-score -2.5 or below in the femoral neck,
total hip or spine
A fracture of the hip or vertebra (clinical or morphometric)
www.uc-osteoporosis.com www.shef.ac.uk/FRAX
www.uc-osteoporosis.com www.shef.ac.uk/FRAX
www.uc-osteoporosis.com www.shef.ac.uk/FRAX
Mary Smith, 66.8 years oldWt. 140 lbs., Ht 64 in.
FN T-score -2.4, no risk factors
www.uc-osteoporosis.com
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
www.uc-osteoporosis.com
SOME CAUSES OF SECONDARY OSTEOPOROSIS IN ADULTS
Endocrine Disease or Metabolic Causes
Nutritional Conditions DrugsDisorders of
Collagen Metabolism
Other
Hypogonadism
Hypercalciuria
Hyperthyroidism
Hyperparathyroidism
Cushing’s syndrome
Acromegaly
Growth hormone deficiency
Vitamin D deficiency
Calcium deficiency
Vit. B12 deficiency
Weight loss
Malabsorption
Gastric surgery
Anorexia nervosa
Chronic liver disease
Alcoholism
Malnutrition
Prolonged TPN
Glucocorticoids
Anti-epilepsy drugs
Excess thyroid hormone
Depo-Provera
GnRH agonists
Aromatase inhibitors
Heparin
Osteogenesis imperfecta
Homocystinuria
Ehlers-Danlos syndrome
Marfan syndrome
Rheumatoid arthritis
Inflammatory bowel disease
COPD
Organ transplantation
Immobilization
Multiple myeloma
Some cancers
Renal tubular acidosis
Gaucher’s disease
Mastocytosis
Thalassemia
Adapted from Hodgson SF and Watts NB, AACE Guidelines on Osteoporosis, www.aace.com
www.uc-osteoporosis.com
ENDOCRINE AND METABOLIC DISEASES ASSOCIATED WITH OSTEOPOROSIS
• Hypogonadism• Hypercalciuria• Hyperthyroidism• Hyperparathyroidism• Cushing’s syndrome• Acromegaly• Growth hormone deficiency
www.uc-osteoporosis.com
NUTRITIONAL CONDITIONSASSOCIATED WITH OSTEOPOROSIS
• Vitamin D deficiency• Calcium deficiency• Vitamin B12 deficiency• Weight loss• Malabsorption• Gastric surgery• Anorexia nervosa• Chronic liver disease• Alcoholism• Malnutrition• Prolonged TPN
www.uc-osteoporosis.com
DRUGS ASSOCIATED WITH OSTEOPOROSIS
• Glucocorticoids
• Anti-epilepsy drugs
• Thyroid hormone (supraphysiologic doses)
• Depo-Provera
• GnRH agonists
• Aromatase inhibitors
• TZDs
• SSRIs
• PPIs
www.uc-osteoporosis.com
DISORDERS OF COLLAGEN METABOLISM
• Osteogenesis imperfecta
• Homocystinuria
• Ehlers-Danlos syndrome
• Marfan syndrome
www.uc-osteoporosis.com
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
www.uc-osteoporosis.com
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
www.uc-osteoporosis.com
OTHER CAUSES OF LOW BONE MASS
• Rheumatoid arthritis• Inflammatory bowel disease• COPD• Organ transplantation• Immobilization• Multiple myeloma • Some cancers• Renal tubular acidosis• Gaucher’s disease• Mastocytosis• Thalassemia
www.uc-osteoporosis.com
How often are secondary causes found?
www.uc-osteoporosis.com
SECONDARY CAUSES OF OSTEOPOROSIS
Eligible subjectsComplete battery of
laboratory tests available(n=173)
Ineligible subjectsIncomplete laboratory testing
(n=136)
No previous known contributors toosteoporosis based on past medical history
(n=309)
History of known medications or diseasesaffecting bone and mineral metabolism
(n=355)
Post-menopausal women over age 65BMD T-score -2.5 or below
(n=664)
Tannenbaum C et al, J Clin Endocrinol Metab 2002;87:4431-4437
www.uc-osteoporosis.com
SECONDARY CAUSES OF OSTEOPOROSIS
Tannenbaum C et al, J Clin Endocrinol Metab 2002;87:4431-4437
Patients with at least 1 new diagnosis (n=84) 48.6%Vitamin D deficiency, <20 ng/mL (n=35) 20.2%Hypercalciuria 9.8% Renal (n=7) Idiopathic (n=6) Undefined (n=4)Malabsorption 8.1% Relative calcium malabsorption (n=11) Celiac sprue (n=3)Hyperparathyroidism 6.9% Primary (n=1) Secondary (n=11)Exogenous hyperthyroidism (n=4) 2.3%Cushing’s disease (n=1) 0.6%Hypocalciuric hypercalcemia (n=1) 0.6%
www.uc-osteoporosis.com
LABORATORY EVALUATION FOR OSTEOPOROSIS
Abnormal
24-h urine calcium for all 39/173
Serum 25-OH vitamin D for all 35/173
Serum calcium for all 3/173
Serum TSH for all on replacement 4/25
Tannenbaum C et al, J Clin Endocrinol Metab 2002;87:4431-4437
This strategy finds 98% of cases, costs $116 per patient screened,
$332 per case found
www.uc-osteoporosis.com
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)
www.uc-osteoporosis.com
VITAMIN D REDUCES RISK OF FALLING
Bischoff-Ferrari HA et al. JAMA 2004;291:1999-2006
Meta-Analysis
www.uc-osteoporosis.com
VITAMIN D REDUCES FRACTURESAND MAY REDUCE MORTALITY
Trivedi DP et al, BMJ 2003;326-469-475
Fractures (hip, wrist, forearm, vertebra)
Survival
Vitamin D 100,000 IU Q 4 months or placeboN=2037 men and 649 women ages 65-85
OR 0.78 (0.61,0.99) OR 0.88 (0.74,1.06))
www.uc-osteoporosis.com
MOST OF US WILL BENEFIT FROM A VITAMIN D SUPPLEMENT
• 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)
www.uc-osteoporosis.com
www.uc-osteoporosis.com
OPTIMAL CALCIUM INTAKE
1200 mg daily for adults age 50 and olderTOTAL 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.
www.uc-osteoporosis.com
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
www.uc-osteoporosis.com
LABORATORY EVALUATION FOR OSTEOPOROSIS
• 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
www.uc-osteoporosis.com
BIOCHEMICAL MARKERS OF BONE TURNOVER
• Enzymes (alkaline phosphatase, acid phosphatase)
• Degradation products (hydroxyproline, collagen cross links)
• Byproducts (osteocalcin, procollagen I extension peptides)
www.uc-osteoporosis.com
COLLAGEN CROSS LINKS
CTxNTx
N-TELOPEPTIDEREGION
HELICAL REGION C-TELOPEPTIDEREGION
PyrDpd
Watts NB. Clin Chem 1999;45:1359-1368
www.uc-osteoporosis.com
BMD AND MARKERS PREDICT HIP FRACTURETHE EPIDOS STUDY
0
1
2
3
4
5
6
OddsRatio
LowHip BMD
Garnero P et al, J Bone Miner Res 1996;11:1531
2.7
CTX
Free DPD
2.2 1.9
HighMarker
4.84.1
Both
www.uc-osteoporosis.com
0
20
40
60
80
100
0
5
10
15
20
25
30
0
50
100
150
200
250
300
NOT EVERYONE WITH OSTEOPOROSIS HAS ABNORMAL BONE TURNOVER
89 Elderly Women with Osteoporosis
Pyr Dpd NTx
Garnero P et al, J Clin Endocrinol Metab 1994;79:1693
www.uc-osteoporosis.com
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
Postmenopausal women NA 0-130 NA
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
www.uc-osteoporosis.com
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?
www.uc-osteoporosis.com
Osteoporosis can be diagnosed based on the presence or history of an osteoporotic fracture; however, a fracture is not required for diagnosis
REMINDER
www.uc-osteoporosis.com
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
www.uc-osteoporosis.com
IMPORTANCE OF RECOGNIZINGVERTEBRAL DEFORMITIES
Greenspan SL et al, J Clin Densitom 2001;4:373-380
26% of those with “osteoporosis” had T-scores above –2.5 but had one or more vertebral deformities
482 women being screened for osteoporosis studies.
All had BMD and lateral spine imaging.
Osteoporosis was defined as either T-2.5 or below OR a vertebral deformity.
32% T –2.5 or below
57% T above –2.5No vertebral deformity
11% T above -2.5 but
vertebral deformity
www.uc-osteoporosis.com
USING DXA EQUIPMENT FORVERTEBRAL 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 x-
rays
www.uc-osteoporosis.com
FOR PATIENTS WITH FRACTURE
Remember: not all fractures aredue 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
www.uc-osteoporosis.com
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
www.uc-osteoporosis.com
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
www.uc-osteoporosis.com
WILL YOUR BONES LAST AS LONG AS YOU DO?
Questionsor
comments?
SECONDARY CAUSES OF OSTEOPOROSIS
Top Related