OSTEOPOROSIS

A systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk.

CASE
A 42 year old woman asks for advice about osteoporosis therapy. A DXA scan done at her request after a screening study at a health fair showed low BMD, confirmed low BMD with a T score of -2.5 at the femoral neck.

Medical History
Normal menses. Weight stable, BMI 22 Mother and maternal grandmother both have severe osteoporosis No renal or hepatic disease. No exogenous glucocorticoids Normal PTH, TSH and vitamin D

QUESTIONS
DOES SHE HAVE OSTEOPOROSIS? WHAT FURTHER STUDIES SHOULD BE DONE? IS THERAPY APPROPRIATE? WHAT THERAPY?

Osteoporosis Prevalence
Affects 200 million women worldwide1 _ 1/3 of women aged 60 to 70 - 2/3 of women aged 80 or older Approximately 30% of women over the age of 50 have one or more vertebral fractures2 Approximately one in five men over the age of 50 will have an osteoporosis-related fracture in their remaining lifetime1
1. IOF, 2005 (www.osteofound.org) 2. Dennison E & Cooper C, Horm Res, 2000;54 suppl 1:58-63

All fractures are associated with morbidity

Patients (%)
n a r te f a r a : e e y r u One p fract hi Unable to walk
independently Death within one year Permanent disability Unable to carry out at least one independent activity of daily living

80%

40%

30%

20%
Cooper C, Am J Med, 1997;103(2A):12S-17S

OSTEOPOROSIS
Densitometric Definition:
Bone density 2.5 SD or more below the mean for young adult women (T score less than or equal to -2.5)

Karis, JA et al,J Bone Miner. Res., 1994

Bone Mineral Density Measurement

DXA
Dual energy x-ray absorptiometry Measure of x-ray energy using 2 energy levels. Assumes a 2 compartment model.

DXA TERMS
T-score: (BMD of patient BMD of young-normal)
__________________________________ SD of young normal

DXA TERMS
Z-score: (BMD of patient BMD of age matched normals)
___________________________________ SD of age matched normals

Interpretation of bone mineral density (BMD)

BMD
g/cm2
Z

BMD of patient A is 0.72 g/cm Z score: -1.0 (age-dependent) T score: -2.5 (age-independent)
T

0.72

+ 1SD
A

- 1SD

59

Age (yr)

Dual-Energy X-Ray Absorptiometry of the Spine and Hip of a 66-Year-Old Postmenopausal Woman

Raisz L. N Engl J Med 2005;353:164-171

DXA

Vertebral body
normal osteoporotic

DXA Sources of Error

Osteoarthritis Laminectomy Previous Fracture Osteomalacia Overlying Metal Hardware Soft Tissue Calcifications Severe Scoliosis Extreme obesity or ascites Vertebral deformities Inadequate reference population ranges Poor operating procedures
Adapted from Kanis, Lancet:359:1929, 2002 and Becker, The Endocrine Society, 2005

Diagnosis in Postmenopausal Women

WHO criteria should be used Normal = T-score -1 or greater Osteopenia = T-score between -1 and - 2.5 Osteoporosis = T-score -2.5 or less

Diagnosis in Premenopausal Women

WHO criteria should not apply to healthy pre-menopausal women. Z-scores should be used. Osteoporosis may be diagnosed if there is low BMD with risk factors. The diagnosis of osteoporosis should not be made on densitometric criteria alone.

10-Year Fracture Risk: age and BMD

Hip fracture risk (% per 10 Years) 20 80

15 70 10 60 5 50 0 -3

Fo ra ris k in given cre BM as D, e ag s w e ith

-2.5 -2 -1.5 -1 -0.5 BMD T-score

0.5

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

Incidence of osteoporotic fractures in women

40

Annual incidence per 1000 women

Vertebrae
30

20

Hip Wrist

10 50 60 70 Age (Years) 80

Wasnich RD, Osteoporos Int 1997;7 Suppl 3:68-72

Rationale for Diagnosis Position in Premenopausal Woman

Premenopausal women do not have same relationship between BMD and fracture risk as postmenopausal women, therefore WHO classification does not apply Major risk factors in premenopausal women elevate fracture risk sufficiently so that osteoporosis may be diagnosed if low BMD is also present

Bone Remodeling
Mesenchymal cells Hematopoietic cells

Osteoblast

Osteoclast Lining cells

Pathogenesis of osteoporosis
Resorbed cavity too large Newly formed packet of bone too small

Formation does not match resorption

Increased numbers of remodeling units

INCREASED BONE LOSS

Low BMD in Premenopausal Women

Low peak bone mass Accelerated bone loss

Determinants of Peak Bone Mass

Genetics

Nutrition

PEAK BONE MASS 20-22 years of age

Hormones

Lifestyle

Candidates genes involved in the genetics of peak bone mass and/or osteoporosis
Receptors
Vitamine D Receptor (VDR) Estrogen receptors Calcitonin receptor Calcium sensing receptor PTH Androgen Osteoprotegerin Glucocorticoids Tumor necrosis factor

Growth factor and cytokines

Interleukin 6 TGF- Beta IGF-I Bone morphogenetic protein 2 Interleukin-1 receptor antagonist Tumor necrosis factor alpha

Enzymes
Aromatase Methylenetetrahydrofolate reductase

Bone-associated proteins
Collagen type 1 Osteocalcin

Miscellaneous
Apolipoprotein E Heparin sulfate glycoprotein

Changes in BMD in response to calcium fortified foods in prepubertal girls distributed according their spontaneous calcium intake
Yearly BMD increase
30
P0.01

mg/cm2 x yr

20 Placebo 10 Calcium supplemented

low

Calcium intake

high

Bonjour JP et al, J Clin Invest 1997;99:1287-1294

Effect of physical exercise on PBM

500 400 300 200 100 0 Girls Boys
** **

16 14 12 10 8 6 4 2 0

**

**

Girls

Boys

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

* *

Girls

Boys

Peak total body BMC (g/year)

Peak lumbar spine BMC (g/year)

Peak femoral neck BMC (g/year)

Inactive
Significantly greater than inactive, *P0.005, **P0.001

Average

Active

Bailey DA et al, J Bone Miner Res, 1999;14:1672-1679

Disorders Causing Bone Loss

Anorexia nervosa Malabsorption syndromes Primary
Hyperparathyroidism Hyperthyroidism Corticosteroid therapy Cushings syndrome Post-transplantation Chronic renal failure Drugs

Estrogen deficiency Premature menopause <45 y. Long-term secondary

amenorrhea >1y. Primary hypogonadism Other disorder associated with Osteoporosis

Maternal/ family history of hip fracture Prolonged immobilization

Kanis JA, Lancet, 2002;359:1929-1936

Secondary osteoporosis

Endocrine Nutritional Drug-induced Immobilization Others

Hyperthyroidism Glucocorticoids Hypogonadism Immunosuppressly Cushing Syndrome Anticonvulsants

Rheumatoid A. Diabetes Tumors

(Myeloma, etc.)

BMD and risk of fracture

For the same change in BMD, glucocorticoid-treated patients may be at higher risk of fracture

Estimated BMD Decreases1

Relative Risk of Fracture GIOP2 Postmen. OP3

Spine Hip
1 2

- 0.5 SD - 0.4 SD

3.0 2.2

1.5 1.4

For a cumulative dose of 13.9 g of prednisone (Van Staa et al, 2002) General Practice Research Database 3 From Marshall D et al, BMJ, 1996;312:1254-1259 Van Staa TP et al, Osteoporos Int, 2002;13:777-787

Management of glucocorticoid-induced osteoporosis

Guidelines a. Patients about to start a long term (>3 months) GC treatment General measures (smoking cessation-alcohol reduction) (exercise) Initiate calcium plus vitamin D DXA evaluation to consider BP T-score Cut-off to start BP GC dose b. Patients already taking GC treatment General measures (smoking cessation-alcohol reduction) (exercise) Initiate calcium plus vitamin D DXA evaluation to consider BP T-score Cut-off to start BP GC dose ACR, 2001 UK, 1998

Yes

Yes

Yes Yes Yes Yes -1.5 5 mg /d Not specified Yes Yes Yes -1 5mg/d Yes Yes Yes -1.5 Not specified

ACR: American College of Rheumatology, UK: National Osteoporosis Society

What Further Studies Should be Done?

Further Studies
PTH, Calcium, phosphate, 25-hydroxyvitamin D CBC Serum creatinine Alkaline phosphatase, aminotransferases TSH

Does she have osteoporosis? What should be done?

Non Pharmacological Approaches to the Prevention of Postmenopausal Osteoporosis

Adequate intake of dietary calcium & protein Regular physical activity Avoid tobacco Minimize risk of falls Recommend hip protectors in those prone to falls

Surgeon General Report 2004

Calcium has been singled out as a major public health concern today not only because it is a critical nutrient for bone but also because of national surveys that suggest that the average calcium intake of individuals is far below the levels recommended for optimal bone health

U.S. Department of Health and Human Services. Bone Health and Osteoporosis: A report of the Surgeon General. 2004;115

The Majority of Americans Are Not Receiving Adequate Levels of Vitamin D

According to an NHANES III
Percent Not Consuming Adequate Intake (AI) Vitamin D

survey of 3,444 women 51 years and older, over 70% of women 51 to 70 years of age were estimated not to meet adequate intake guidelines for vitamin D based on daily intake from diet and supplements (400 IU).

Vitamin D Intake (Diet + Supplement) NHANES III 100 90 80 70 60 50 40 30 20 10 0

* *

Nearly 90% of women older

than 70 years were estimated not to meet guidelines (600 IU).
NHANES = National Health and Nutrition Examination Survey.

Females 5170 y

Females >70 y

Moore C et al. J Am Diet Assoc. 2004;104:980983.

*Percent consuming adequate intake or above from diet + supplements significantly different from diet alone; P<0.05.

Consequences of Vitamin D Insufficiency

Calcium absorption1
When vitamin D status is sufficient, absorption of dietary calcium is approximately 30% to 40%. As vitamin D status declines, absorption of dietary calcium declines to about 10% to 15%.

PTH
Low levels of vitamin D lead to increased release of PTH,2 which increases bone resorption and decreases bone mass.

1. Holick MF. Curr Opin Endocrinol Diabetes. 2002;9:8798. 2. Lips P. Endocr Rev. 2001;22:477501.

Sources of Vitamin D
Sunlight exposure
Major source of vitamin D.1,2 Vitamin D production is affected by season, duration of exposure, sunscreen use, and skin pigmentation.2

Endogenous production
Skin and kidneys form and process vitamin D4; this may decrease with age.2

Dietary intake
Minor source of vitamin D.2 Vitamin D is rare in foods other than fatty fish and fortified food products, such as milk and breakfast cereals.3,4
1. Holick MF. J Cell Biochem. 2003;88:296303. 2. Holick MF. Osteoporos Int. 1998;8(suppl 2):S24S29. 3. Lips P. Adv in Nutr Res. 1994:151165.
.

What is the Optimal Intake of Vitamin D?

Defining the Upper Limit of Vitamin D Intake: There is limited information regarding doses of vitamin D associated with acute toxicity, although intermittent (yearly or twice yearly) single doses of vitamin D as high as 600,000 IU have been given without reports of toxicity.

Important contribution of Calcium (Osteoporosis Studies)

All studies that formed the basis of osteoporosis indications for risedronate, alendronate, ibandronate, teriparatide, raloxifene and calcitonin required calcium supplementation in the study design

Sunyecz JA et al. Journal of Womens Health 2005;14(2):180-192

Future Monitoring

DXA for Monitoring Therapy

Slow response time. Increased signal to noise ratio.

Garnero P & Delmas PD, Curr Opin Rheumatol, 2004;16:428-434

DXA for Monitoring Therapy

Decreases in BMD while on therapy do not always indicate treatment failure. Some who lose BMD the first year, gain during the second year regression to the mean. Even when BMD declines during therapy, fracture risk may decrease.

Biochemical markers of bone turnover

Formation markers
Osteocalcin Bone specific alkaline phosphatase Procollagen type-1 N-propeptide Procollagen type-1 C-propeptide

Resorption markers
Hydroxyproline Hydroxylysine Pyridinoline Deoxypyridinoline Bone sialoprotein Acid phosphatase Tartrate-resistant acid phosphatase Type-1 collagen telopeptides (CTX, NTX)

Association between BMD, resorption markers and fracture risk

5
4.8

Risk of hip fracture

4 3 2 1 0
low hip BMD high CTX low hip BMD + high CTX

(odds ratio)

2.7 2.2

Garnero P et al, J Bone Miner Res, 1996;11:1531-1538

2 Years later
Her T-score is -2.9. She is oligomenorrheic and having hot flashes. Her FSH on day 3 of the menstrual cycle is 42.

Does she have osteoporosis?

Does she need drug therapy?

Osteoporosis Therapy

Drugs used in osteoporosis treatment

HRT SERM/Raloxifene Calcitonin Bisphosphonates - Alendronate - Risedronate - Ibandronate
- Zoledronic Acid

Parathyroid hormone (PTH)

Anti-fracture Efficacy of Therapeutic Agents

Drug
Alendronate, Risedronate Ibandronate Zoledronic Acid HRT PTH Raloxifene Calcitonin

Vertebral fractures +++ +++ +++ ++ +++ +++ +

Non-vertebral fractures (hip) ++ + ++ 0

Adapted from Delmas PD, Lancet, 2002;359:2018-2026

Conclusions
In premenopausal women, low bone mass alone is not adequate to establish a diagnosis of osteoporosis. Low BMD in premenopausal women may result from low peak bone mass or accelerated bone loss. Premenopausal women with low BMD deserve careful follow up.

Conclusions
Bone density testing is appropriate in premenopausal women with history of a fragility fracture or known secondary cause of osteoporosis Adequate calcium and vitamin D intake are fundamental components of osteoporosis therapy.

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