SECONDARY CAUSES OF OSTEOPOROSIS

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SECONDARY CAUSES OF OSTEOPOROSIS

• Nelson B. Watts, MD

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SECONDARY CAUSES OF OSTEOPOROSIS

• Use of bone densitometry
• Secondary causes of bone loss
• Laboratory evaluation
• Calcium and vitamin D
• Bone turnover markers
• Lateral spine imaging with DXA

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DEFINITION OF OSTEOPOROSIS

• 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.

Normal Bone
2000 NIH Consensus Development Conference
Osteoporotic Bone
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WHO CRITERIA FORPOSTMENOPAUSAL OSTEOPOROSIS
The T-score compares an individuals BMD with
the mean value for young normal individuals and
expresses the difference as a standard deviation
score.
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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
91137-1141
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BONE DENSITY MEASUREMENTS AT PERIPHERAL SITES
QUS
DXA
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)

• ADVANTAGES
• Portable
• Less expensive than central DXA
• Ultrasound does not involve radiation

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PREVALENCE OF OSTEOPOROSIS ANDLIFETIME FRACTURE
RISK IN WHITE WOMEN
1
2
Percent
1. Melton LJ III, et al. J Bone Miner Res
199510175 2. Melton LJ III, et al. J Bone Miner
Res 199271005
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PREVALENCE OF OSTEOPOROSIS VARIES BY SITE AND
METHOD
NORA Study, 200,160 ambulatory women age 50 and
older
Percent of subjects 2.5 SD or more below young
adult mean
Estimated from NAHNES III
Siris E et al, JAMA 20012862815-2822
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AGE DEPENDENCE OF T-SCORES
Data from manufacturers' data bases
T-score
Age (years)
Faulkner KG et al. J Clin Densitom 19992343
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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.

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RISK FACTORS FOR OSTEOPOROSIS

• FEMALE
• OLDER AGE
• EARLY MENOPAUSE
• FAMILY HISTORY
• FAIR SKIN

• NULLIPARITY
• SLENDER BUILD
• LOW CALCIUM INTAKE
• SMOKING
• INACTIVITY

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RISK FACTORS AND LOW BMD

• IMPACT Trial
• 7,000 women in 21 countries without known
  osteoporosis had BMD testing and risk factor
  assessment

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 200144S256
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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 (lt70 kg)
• Lack of estrogen
• Possibly other risk factors
• No recommendation for or against screening
  younger women at high risk

US PSTF, Ann Intern Med 2002137526-528
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WHO SHOULD HAVE ABONE DENSITY TEST?
Number Needed to Screen
Number Needed to Treat
Fracture Type
Fracture Type
Age
Age
Nelson HD et al, Ann Intern Med 2002137529-541
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WHO SHOULD HAVE ABONE DENSITY TEST?
ISCD OsteoFLASH, www.iscd.org
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FDA-APPROVED MEDICATIONSINDICATIONS
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FDA-APPROVED MEDICATIONSEVIDENCE FOR FRACTURE
REDUCTION
?Evidence for effect but not an FDA-approved
indication
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NOF TREATMENT GUIDELINES 2008
www.nof.org
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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
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NOF GUIDELINES 2008
After exclusion of secondary cause, treat
postmenopausal women and men age 50 and older who
have
21
www.shef.ac.uk/FRAX
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www.shef.ac.uk/FRAX
23
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
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EVALUATION OF PATIENTS WITH OSTEOPOROSIS

• Just because a woman is postmenopausal and has
  osteoporosis doesnt mean that she has
  postmenopausal osteoporosis
• Failure to identify underlying disorders may
  result in inadequate or inappropriate treatment

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SOME CAUSES OF SECONDARY OSTEOPOROSIS IN ADULTS
Adapted from Hodgson SF and Watts NB, AACE
Guidelines on Osteoporosis, www.aace.com
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ENDOCRINE AND METABOLIC DISEASES ASSOCIATED WITH
OSTEOPOROSIS

• Hypogonadism
• Hypercalciuria
• Hyperthyroidism
• Hyperparathyroidism
• Cushings syndrome
• Acromegaly
• Growth hormone deficiency

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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

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DRUGS ASSOCIATED WITH OSTEOPOROSIS

• Glucocorticoids
• Anti-epilepsy drugs
• Thyroid hormone (supraphysiologic doses)
• Depo-Provera
• GnRH agonists
• Aromatase inhibitors
• TZDs
• SSRIs
• PPIs

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DISORDERS OF COLLAGEN METABOLISM

• Osteogenesis imperfecta
• Homocystinuria
• Ehlers-Danlos syndrome
• Marfan syndrome

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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

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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

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OTHER CAUSES OF LOW BONE MASS

• Rheumatoid arthritis
• Inflammatory bowel disease
• COPD
• Organ transplantation
• Immobilization
• Multiple myeloma
• Some cancers
• Renal tubular acidosis
• Gauchers disease
• Mastocytosis
• Thalassemia

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• How often are secondary causes found?

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SECONDARY CAUSES OF OSTEOPOROSIS
Eligible subjects
Complete battery of
laboratory tests available
(n173)
Tannenbaum C et al, J Clin Endocrinol Metab
2002874431-4437
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SECONDARY CAUSES OF OSTEOPOROSIS
Patients with at least 1 new diagnosis (n84)
48.6 Vitamin D deficiency, lt20 ng/mL (n35)
20.2 Hypercalciuria 9.8 Renal
(n7) Idiopathic (n6) Undefined
(n4) Malabsorption 8.1 Relative calcium
malabsorption (n11) Celiac sprue
(n3) Hyperparathyroidism 6.9 Primary
(n1) Secondary (n11) Exogenous
hyperthyroidism (n4) 2.3 Cushings disease
(n1) 0.6 Hypocalciuric hypercalcemia
(n1) 0.6
Tannenbaum C et al, J Clin Endocrinol Metab
2002874431-4437
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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

This strategy finds 98 of cases, costs 116 per
patient screened, 332 per case found
Tannenbaum C et al, J Clin Endocrinol Metab
2002874431-4437
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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)

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VITAMIN D REDUCES RISK OF FALLING
Meta-Analysis
Bischoff-Ferrari HA et al. JAMA 20042911999-2006
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VITAMIN D REDUCES FRACTURESAND MAY REDUCE
MORTALITY
Vitamin D 100,000 IU Q 4 months or placebo N2037
men and 649 women ages 65-85
Fractures (hip, wrist, forearm, vertebra)
Survival
OR 0.78 (0.61,0.99)
OR 0.88 (0.74,1.06))
Trivedi DP et al, BMJ 2003326-469-475
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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)

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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.
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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
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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

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BIOCHEMICAL MARKERS OF BONE TURNOVER

• Enzymes (alkaline phosphatase, acid phosphatase)
• Degradation products (hydroxyproline, collagen
  cross links)
• Byproducts (osteocalcin, procollagen I extension
  peptides)

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COLLAGEN CROSS LINKS
Watts NB. Clin Chem 1999451359-1368
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BMD AND MARKERS PREDICT HIP FRACTURETHE EPIDOS
STUDY
6
5
4
Odds Ratio
2.7
3
2
1
0
Low Hip BMD
Garnero P et al, J Bone Miner Res 1996111531
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NOT EVERYONE WITH OSTEOPOROSIS HAS ABNORMAL BONE
TURNOVER
89 Elderly Women with Osteoporosis
Pyr Dpd NTx
Garnero P et al, J Clin Endocrinol Metab
1994791693
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URINE NTX

• Remodeling has diurnal variation need second
  morning fasting urine or fasting blood
• Urine sample may be preferred for logistical
  reasons

Target at or below the median value for
premenopausal women (30 nmol BCE/mmol
creatinine)
de Papp AE et al, Bone 2007401222-1230
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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?

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REMINDER
Osteoporosis can be diagnosed based on the
presence or history of an osteoporotic fracture
however, a fracture is not required for diagnosis
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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

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IMPORTANCE OF RECOGNIZINGVERTEBRAL 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.
26 of those with osteoporosis had T-scores
above 2.5 but had one or more vertebral
deformities
Greenspan SL et al, J Clin Densitom 20014373-380
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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

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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

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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

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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

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SECONDARY CAUSES OF OSTEOPOROSIS
Questions or comments?
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