1. SECONDARY CAUSES OF OSTEOPOROSIS
Nelson B. Watts, MD
Bone Health and Osteoporosis Center
Metabolic Bone Diseases and Mineral Disorders

2. 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

3. 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
The “old” definition distinguished osteoporosis (in which the makeup of bone was normal) from osteomalacia (in which mineralization was clearly abnormal).
The “modern” definition introduces the importance of bone quality (micro-architecture). Although this definition dates back to 1991, there is still no clinical test of bone quality. Thus, the clinically-relevant parts of the definition are bone mass and fractures.
2000 NIH Consensus Development Conference
Osteoporotic Bone

4. 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.
Kanis JA et al, J Bone Miner Res 1994;9:
-2.5 and below
Osteoporosis
Between -1.0 to -2.5
Low bone mass (osteopenia)
-1.0 and above
Normal
T-score
Category

5. 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."
In developing the WHO criteria it was appealing to identify the same number of individuals with osteoporosis as would eventually have an osteoporotic fracture (realize that these would not necessarily be the same individuals).
Using the T=-2.5 threshold, the prevalence of osteoporosis in postmenopausal women approximately equals the lifetime fracture risk for a a 50-year-old Caucasian women.
See next slide.
Kanis JA, et al. J Bone Miner Res 1994; 9:

6. BONE DENSITY MEASUREMENTS AT PERIPHERAL SITES
QUS
DXA
pQCT
ADVANTAGES
Portable
Less expensive than central DXA
Ultrasound does not involve radiation
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)

7. PREVALENCE OF OSTEOPOROSIS AND LIFETIME FRACTURE RISK IN WHITE WOMEN1 2
Percent
Note that at a T-score = -2.5
Lifetime fracture risk is close to the prevalence at each site and combination of all three.
For example, 16% of postmenopausal Caucasian women have osteoporosis at the femoral neck which is similar to the 17.5% lifetime risk of hip fracture for a 50-year-old Caucasian woman.
This methodology has implications for the future approach for other groups: men, younger women, other racial groups to be discussed later in this lecture.
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

8. PREVALENCE OF OSTEOPOROSIS VARIES BY SITE AND METHOD
NORA Study, 200,160 ambulatory women age 50 and older
Missed
55%
Percent of subjects
2.5 SD or more below young adult mean
66%
84%
90%
*Estimated from NAHNES III
Siris E et al, JAMA 2001;286:

9. AGE DEPENDENCE OF T-SCORES
Data from manufacturers' data bases
T-score
Age (years)
Faulkner KG et al. J Clin Densitom 1999;2:343

10. 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.
Points out the limitation of the WHO criteria.
Limited by patient population, site and technology.

11. RISK FACTORS FOR OSTEOPOROSIS
FEMALE
OLDER AGE
EARLY MENOPAUSE
FAMILY HISTORY
FAIR SKIN
NULLIPARITY
SLENDER BUILD
LOW CALCIUM INTAKE
SMOKING
INACTIVITY

12. RISK FACTORS AND LOW BMD
IMPACT Trial
~7,000 women in 21 countries without known osteoporosis had BMD testing and risk factor assessment
36% did have
osteoporosis
48% had no risk factors
52% had one or more risk factors
64% did not have
osteoporosis
67% had no risk factors
33% 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

13. 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:

14. WHO SHOULD HAVE A BONE DENSITY TEST?
Number Needed to Screen
Number Needed to Treat
Fracture Type
Fracture Type
Age
Age
Nelson HD et al, Ann Intern Med 2002;137;

15. WHO SHOULD HAVE A BONE DENSITY TEST?
Society Providing Recommendation
Patient category
US PSTF
NOF
AACE
ISCD
Women  age 65
Yes
Women with risk factors
Women  60 with risk factors
Insufficient data
Men  age 70
Not addressed
Younger men with risk factors
ISCD OsteoFLASH,

16. FDA-APPROVED MEDICATIONS INDICATIONS
Postmenopausal Osteoporosis
Glucocorticoid-induced Osteoporosis
Men
Drug
Prevention
Treatment
Estrogen 
Calcitonin
(Miacalcin®, Fortical®)
Raloxifene
(Evista®)
Ibandronate
(Boniva®)
Alendronate (Fosamax®)
Risedronate
(Actonel®)
Zoledronic acid
(Reclast®)
Teriparatide
(Forteo®)
Paget’s dose: Fosamax 40 mg/day x 6 mo., Actonel 30 mg/day x 2 mo.

17. FDA-APPROVED MEDICATIONS EVIDENCE FOR FRACTURE REDUCTION
Drug
Vertebral Fracture
Nonvertebral Fracture
Hip
Fracture
Calcitonin
(Miacalcin®, Fortical®) 
No effect demonstrated
Raloxifene
(Evista®)
Ibandronate
(Boniva®)
Alendronate
(Fosamax®) 
Risedronate
(Actonel®)
Zoledronic acid
(Reclast®)
Teriparatide
(Forteo®)
Evidence for effect but not an FDA-approved indication

18. NOF TREATMENT GUIDELINES 2008

19. NOF GUIDE
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

20. NOF GUIDELINES 2008
After exclusion of secondary cause, treat postmenopausal women and men age 50 and older who have…
T-scores between -1.0 and -2.5
A fracture of the hip or vertebra (clinical or morphometric)
T-score -2.5 or below in the femoral neck, total hip or spine
10-year risk ≥3% for hip fracture or ≥20% for major osteoporotic fractures
based on FRAX™ model

23. FN T-score -2.4, no risk factors
Mary Smith, 66.8 years old
Wt. 140 lbs., Ht 64 in.
FN T-score -2.4, no risk factors

24. 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

25. SOME CAUSES OF SECONDARY OSTEOPOROSIS IN ADULTS
Endocrine Disease or Metabolic Causes
Nutritional Conditions
Drugs
Disorders 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
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,

26. ENDOCRINE AND METABOLIC DISEASES ASSOCIATED WITH OSTEOPOROSIS
Hypogonadism
Hypercalciuria
Hyperthyroidism
Hyperparathyroidism
Cushing’s syndrome
Acromegaly
Growth hormone deficiency

27. NUTRITIONAL CONDITIONS ASSOCIATED WITH OSTEOPOROSIS
Vitamin D deficiency
Calcium deficiency
Vitamin B12 deficiency
Weight loss
Malabsorption
Gastric surgery
Anorexia nervosa
Chronic liver disease
Alcoholism
Malnutrition
Prolonged TPN

28. DRUGS ASSOCIATED WITH OSTEOPOROSIS
Glucocorticoids
Anti-epilepsy drugs
Thyroid hormone (supraphysiologic doses)
Depo-Provera
GnRH agonists
Aromatase inhibitors
TZDs
SSRIs
PPIs

29. DISORDERS OF COLLAGEN METABOLISM
Osteogenesis imperfecta
Homocystinuria
Ehlers-Danlos syndrome
Marfan syndrome

30. 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

31. 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

32. 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

33. How often are secondary causes found?

34. SECONDARY CAUSES OF OSTEOPOROSIS
Post-menopausal women over age 65
BMD T-score -2.5 or below
(n=664)
History of known medications or diseases
affecting bone and mineral metabolism
(n=355)
No previous known contributors to
osteoporosis based on past medical history
(n=309)
Ineligible subjects
Incomplete laboratory testing
(n=136)
Eligible subjects
Complete battery of
laboratory tests available
(n=173)
Tannenbaum C et al, J Clin Endocrinol Metab 2002;87:

35. 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) 2.3%
Cushing’s disease (n=1) %
Hypocalciuric hypercalcemia (n=1) 0.6%
Tannenbaum C et al, J Clin Endocrinol Metab 2002;87:

36. LABORATORY EVALUATION FOR OSTEOPOROSIS
Abnormal
24-h urine calcium for all /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 2002;87:

37. VITAMIN D STATUS Best reflected by serum 25-hydroxyvitamin D levels
Lab reference range is 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)

38. VITAMIN D REDUCES RISK OF FALLING
Meta-Analysis
Bischoff-Ferrari HA et al. JAMA 2004;291:

39. 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
(hip, wrist, forearm, vertebra)
Survival
OR 0.78 (0.61,0.99)
OR 0.88 (0.74,1.06))
Trivedi DP et al, BMJ 2003;

40. 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)

42. 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.

43. 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 mg daily

44. 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

45. BIOCHEMICAL MARKERS OF BONE TURNOVER
Enzymes (alkaline phosphatase, acid phosphatase)
Degradation products (hydroxyproline, collagen cross links)
Byproducts (osteocalcin, procollagen I extension peptides)

46. COLLAGEN CROSS LINKS N-TELOPEPTIDE C-TELOPEPTIDE HELICAL REGION REGION
CTx
Pyr
NTx
Dpd
Watts NB. Clin Chem 1999;45:

47. BMD AND MARKERS PREDICT HIP FRACTURE THE EPIDOS STUDY6
CTX
Free DPD
High
Marker
4.8
4.1
Both 5 4
Odds
Ratio
2.7 3 2 1
Low
Hip BMD
Garnero P et al, J Bone Miner Res 1996;11:1531

48. 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

49. 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
11-103
Postmenopausal women NA
0-130
Target: at or below the median value for premenopausal women
(30 nmol BCE/mmol creatinine)*
*de Papp AE et al, Bone 2007;40:

50. 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?

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

52. 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

53. IMPORTANCE OF RECOGNIZING 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 –2.5
No vertebral deformity
11% T above -2.5 but 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 2001;4:

54. 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 x-rays

55. 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

56. 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

57. 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

58. SECONDARY CAUSES OF OSTEOPOROSIS
Questions or
comments?
WILL YOUR BONES LAST AS LONG AS YOU DO?