Disclosures

Osteoporosis Diagnosis: BMD, FRAX and Assessment of Secondary Osteoporosis

I have nothing to disclose Steven T Harris MD FACP Clinical Professor of Medicine University of California, San Francisco [email protected]

Pathogenesis of Osteoporosis AGING

MENOPAUSE

BMD: A Continuum of Risk

OTHER RISK FACTORS

RESORPTION > FORMATION

Bone Loss

LOW PEAK BONE MASS

LOW BONE DENSITY

POOR BONE QUALITY

FRACTURES

Relative Risk of Fracture

35

Osteoporosis

30 25

Normal

20 15 10 5 0

-5

-4

-3

FALLS

Modified from Riggs BL and Melton LJ III. Osteoporosis: Etiology, Diagnosis, and Management. New York: Raven Press; 1988.

Low Bone Mass

Meunier PJ, et al. Clin Ther. 1999;21:1025-1044

-2

-1

BMD T-Score

0

1

2

Treatment Threshold Concept WHO Bone Density Criteria Diagnostic criteria*

40

Classification

Current treatment threshold based on T-score

AGE 80

T is above or equal to -1

Normal

T is between -1 and -2.5

Osteopenia (low bone mass)

T is -2.5 or lower

Osteoporosis

T is -2.5 or lower + fragility fracture

Severe, established osteoporosis

10-Year Fracture Probability (%)

30

70

20

60

Treatment threshold concept based on WHO Absolute Fracture Risk

50

10

* Measured in "T-scores;" the T-score indicates the number of standard deviations above or below the average peak bone mass in young adults

0 -3 -2.5 -2 -1.5 -1 -0.5

0

0.5

1

BMD T-score NOF Clinician’s Guide to Prevention and Treatment of Osteoporosis 2008. http://www.nof.org

Adapted from JA Kanis et al, Osteoporos Int. 2001;12:989-995

Risk Factors for Fracture: Beyond Age + T-score Risk Factor

RR

Prior Fracture

1.62 (1.30-2.01)

Parental History of Hip Fracture

2.28 (1.48-3.51)

Current Smoking

1.60 (1.27-2.02)

Systemic Corticosteroids

2.25 (1.60-3.15)

Alcohol Intake ≥ 3 Units Daily

1.70 (1.20-2.42)

Rheumatoid Arthritis

1.74 (0.94-3.20)

Kanis J, et al. Osteoporos Int. 2005;16:581

(95% CI)

Patients With Prior Fracture Have a High Risk of Future Fragility Fractures Prior fracture

Relative risk of future fracture Wrist

Vertebra

Hip

Wrist

3.3

1.7

1.9

Vertebra

1.4

4.4

2.3

Hip

NA

2.5

2.3

Klotzbuecher CM, et al. J Bone Miner Res. 2000;15:721-39

Calculating Absolute Fracture Risk: FRAX

52-Year-Old Woman With T-score -2.0: Effect Of Additional Risk Factors

http://www.shef.ac.uk/FRAX/tool.jsp

Risk of Major Fractures

Risk of Hip Fracture

40 30 10-Year Fracture Risk (%)

20

20 11 10

6.1

5.8 0.8

1.4

1.5

3.0

0 Age & BMD

FRAX Model: Benefits hValidated in large cohort of ~60,000 patients hQuantitative estimation of fracture risk – more comprehensible to patients hApplicability to men and women worldwide hCan be used with economic modeling to determine cost-effective intervention thresholds hCan also be used as a powerful tool to counsel individual patients about the benefits of intervention

Age & BMD Smoking

Age & BMD Age & BMD Smoking Smoking Parental Hip Fx Parental Hip Fx Wrist Fx

FRAX Model: Caveats h The model is based on femoral neck BMD only—not spine BMD h Limited to 4 ethnicities in US (Caucasian, Black, Hispanic, Asian) h Dichotomous input for continuous variables such as previous fracture, steroid use and smoking h It is not clear what margin of error is present in the fracture risk estimates h The model does not fully account for the fracture risk associated with falling h It is not obvious that all risk factors carry equal weight in predicting the response to pharmacologic treatment

2008 NOF Guidelines: Treatment Initiation Post-menopausal Women And Men ≥50

0Secondary causes are not rare

h Idiopathic osteoporosis (disease characterized by low bone density and fractures in young adults without known cause)

T-score between -1.0 and -2.5

Other Fractures after Age 50 (Excluding Fingers, Toes and Face)

10-year Probability of Hip Fracture >3% or Probability of All Major Fractures >20%

h Primary osteoporosis (postmenopausal or age-related)

h Secondary osteoporosis (caused, wholly or in part, by other diseases or medications)

Assess Risk Factors and Measure BMD if Patient Has Risk Factors

Hip or Vertebral Fractures or T-score ≤-2.5 (Spine, FN or Total Hip)

Differential Diagnosis Of Low BMD

Secondary Causes with High Fracture Risk*

h Other bone diseases

0Osteogenesis imperfecta 0Osteomalacia

0Renal osteodystrophy

*such as glucocorticoid use or total immobilization http://www.nof.org

Some Causes Of Secondary Osteoporosis In Adults Endocrine/Metabolic

Nutritional Conditions

Drugs

Collagen Disorders

Most Common Causes Of Secondary Osteoporosis

Other

Diseases Hypogonadism Hyperadrenocorticism

Malabsorption syndromes

Thyrotoxicosis

Malnutrition

Anorexia nervosa

Chronic cholestatic liver disease

Hyperprolactinemia Porphyria Hypophosphatasia, in adults Diabetes mellitus, Type 1 Hyperparathyroidism

Gastric operations Vitamin D deficiency Calcium deficiency Alcoholism Hypercalciuria

Acromegaly

Glucocorticoids Excess thyroid hormone Heparin GnRH agonists Phenytoin Phenobarbital

Osteogenesis imperfecta Homocystinuria Ehlers - Danlos syndrome Marfan syndrome

Conditions

arthritis Myeloma and some cancers Immobilization Renal tubular acidosis

Depo-Provera

COPD

Aromatase inhibitors

Organ transplantation

Hypogonadism Malabsorption COPD Rheumatoid arthritis Myeloma

Vitamin D deficiency Hypercalciuria

Mastocytosis Thalassemia

Some unsuspected Adapted from AACE Guidelines on Osteoporosis

Drugs

Rheumatoid

Steroid therapy Antiepileptics GnRH agonists Depo-Provera Aromatase inhibitors Excess thyroxine

How Often Do Healthy Women With Osteoporosis Have Unsuspected Disorders? Study population: 664 consecutive postmenopausal women with a T-score of -2.5 or below i 54% excluded for a known secondary cause i 173 females (ages 46-87) without known secondary osteoporosis or prior lab abnormalities underwent lab evaluation – CBC, chemistry, 24-hour urine calcium, PTH, 25-OH vitamin D, most also had TSH, SPEP 44% of patients were found to have a secondary cause Data reanalyzed from Tannenbaum C, et al. J Clin Endocrinol Metab. 2002;87(10):4431 using current definition of vitamin D deficiency (personal communication: Luckey MM)

Prevalence of Occult Secondary Osteoporosis h Prevalence in studies that assessed urinary calcium and vitamin D: 0Women and men, varying ages:1-4 37%–63% 0Post-hip fracture patients:5 60%–80% 0Bone loss on pharmacologic therapy:6,7 ≥50% No large, population-based studies; studies from referral centers vary by criteria for inclusion, extent of testing, and definition of vitamin D deficiency 1. Deutschman HA et al. J Intern Med. 2002;252:389 2. Haden ST et al. Calcif Tissue Int. 1999;64:275 3. Ryan CS et al. Presented at: 27th ASBMR Annual Meeting; September 2005; Nashville, TN. Abstract SA380 4. Gabaroi DC et al. Menopause. 2010;17:135 5. Edwards BJ et al. Osteoporos Int. 2008;19:991 6. Lewiecki EM, Rudolph LA. J Bone Miner Res. 2002;17(Suppl 1):S367 7. Geller JL et al. Endocr Pract. 2008;14:293

Osteoporotic Women With New Diagnoses Vitamin D deficiency (25-OH D