Osteoporosis

Dr Mampedi Bogoshi † Trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA Slide 1

Discussion Points

 Osteoporosis Burden of Disease  Risk Factors  Vitamin D and Calcium  Recommendations and management Slide 2

Bone development

 Peak bone mass between 25 and 35.

 Bones thicken  Bones are at their strongest  From 35 to menopause bone mass slowly declines.

 Gradually your body starts to lose more bone than it makes.

Slide 3

Osteoporosis Burden of Disease

Slide 4

What is Osteoporosis?

“….a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility susceptibility to fracture” and Slide 5

Risk factors for osteoporosis:

    

Age Low Oestrogen Women are at a greater risk than men, Thin or have a small frame White or Asian race

     

Women who are postmenopausal, including those who have had early or surgically induced menopause Cigarette smoking, Eating disorders such as anorexia nervosa or bulimia, low amounts of calcium in the diet, Heavy alcohol consumption, Inactive lifestyle, Certain medications, e.g. corticosteroids and anticonvulsants

 

Rheumatoid arthritis itself is a risk factor for osteoporosis.

Family History

Slide 6

Fracture Risk and Bone Quality

 Bone quality may be defined as the

ability of bone to resist fracture

 Changes in the rate of bone turnover can affect mineralization, microarchitecture, and bone mass – Changes in key properties of bone can lead to alterations in bone strength and the ability of bone to resist fractures  The primary goal in treating osteoporosis should be fracture prevention Adapted from

Osteoporosis Prevention, Diagnosis, and Therapy.

1992;2(3):323 –342; Boivin GY et al

Bone

2000;27(5):687 NIH Consensus Statement. 2000;17(1):1 –694; Dempster DW

Osteoporos Int

–45; Miller PD et al 2002;13(5):349 –352.

J Clin Densitom

Slide 7

Bone Quality

4 bone properties affect bone strength: 1) BMD 2) Bone Turnover 3) Bone Microarchitecture 4) Bone Mineralisation Slide 8

How Key Properties of Bone Affect Fracture Risk

BMD Bone Turnover Bone Strength Fracture Risk Alters microarchitecture and bone mineralization

Adapted from Garnero P et al

J Bone Miner Res

1996;11(3):337 –349; Miller PD et al

J Clin Densitom

2000;27(5):687 –694.

1999;2(3):323 –342; Boivin GY et al

Bone

Slide 9

1) Bone Quality

Slide 10

Bone Turnover

 Bone turnover (remodeling) is a continuous process of bone resorption followed by bone formation – Measured noninvasively by assessing biochemical markers of bone remodeling e.g. ALP  Higher bone turnover has been shown to be linked to increased rates of bone loss and increased risk of fracture – Patients with higher* bone turnover were 4.1 times more likely to suffer a fracture  Greater decreases risk of fracture** in bone turnover are associated with lower CTx=C-telopeptide of type I collagen; NTx=N-telopeptide of type I collagen *In a clinical study to evaluate markers of bone turnover as predictors of hip fracture in elderly women followed for 22 months **In a meta-analysis of 18 clinical trials of antiresorptive therapy to examine the association between BMD and risk of nonvertebral fractures Adapted from Kanis JA. Pathogenesis of osteoporosis and fracture. In:

Osteoporosis

. Malden: Blackwell Science, Inc., 1996:22 –55; Miller PD et al

J Clin Densitom

1999;2(3):323 –342; Garnero P et al

J Bone Miner Res

1996;11(10):1531 –1538; Hochberg MC et al

J Clin Endocrinol Metab

2002;87(4):1586 – 1592.

Slide 11

2) BMD

Slide 12

How Key Properties of Bone Affect Fracture Risk

BMD Bone Turnover Bone Strength Fracture Risk Alters microarchitecture and bone mineralization

Slide 13

Bone Mineral Density

 BMD measurement is a noninvasive technique used to establish or confirm a diagnosis of osteoporosis and provide an assessment of fracture risk – 1 SD decrease in BMD has been shown to correlate with 1.5- to 2-fold increases in fracture risk  >80% of bone strength in two separate

in vitro

was related to BMD studies* *Two separate cadaveric studies of correlation between BMD and strength of the proximal femur and BMD and thoracic vertebral strength in elderly patients Adapted from National Osteoporosis Foundation.

Physician’s Guide to Prevention and Treatment of Osteoporosis

. Washington, DC: National Osteoporosis Foundation, 2003; Cummings SR et al

Lancet

1993;341(8837):72 –75; Bouxsein ML et al

Bone

1999;25(1):49 –54; Moro M et al

Calcif Tissue Int

1995;56(3):206 –209.

Slide 14

Prospective Cohort Study

Decreased BMD In Vivo Has Been Associated with Fracture Incidence

60 50 40 30 20 10 Spine Distal radius Calcaneus  In a meta-analysis, the link between low BMD and fracture risk was similar to or stronger than – Diastolic blood pressure and stroke – Serum cholesterol and coronary disease 0 2 SD 1 SD Mean –1 SD

Bone mass

–2 SD Evaluation of relationship between bone mineral content of four skeletal sites to the incidence of vertebral fracture over six years in 699 postmenopausal women Meta-analysis of prospective cohort studies from 1985 to 1994 containing data on baseline BMD and fracture follow-up to determine whether BMD would predict fracture Adapted from Miller PD et al

Calcif Tissue Int

1996;58(4):207 –214; Wasnich RD et al

J Nucl Med

1989;30(7):1166 –1171; Marshall D et al

BMJ

1996;312(7041):1254 –1259.

Slide 15

Two Separate Laboratory Studies

Increases in BMD Lead to Greater Bone Strength In Vitro

8000 6000 r 2 =0.92

p<0.0001

r 2 =0.88

p<0.001

5000 6000 4000 4000 3000 2000 2000 0 0 0.2

0.4

0.6

0.8

Trochanteric BMD (g/cm 2 )

1.0

1000 0 0 0.25 0.50

0.75

1.00

1.25 1.50

Lumbar spine (lateral) BMD (g/cm 2 )

Test set-up to determine bone strength Schematic of material testing system to break vertebra Laboratory studies to determine correlation between BMD and bone strength in human cadaveric specimens Adapted from Bouxsein ML et al

Bone

1999;25(1):49 –54; Moro M et al

Calcif Tissue Int

1995;56(3):206 –209.

Slide 16

3) Microarchitecture

Slide 17

How Key Properties of Bone Affect Fracture Risk

BMD Bone Turnover Bone Strength Fracture Risk Alters microarchitecture and bone mineralization

Slide 18

Microarchitectural Changes in Osteoporosis Over Time

Trabecular Bone Bone volume Trabecular thickness Trabecular number Horizontal struts Connectivity Plate perforation Cortical Bone Cortical porosity Cortical thickness Slide 19

Trabecular Bone Microarchitecture

 Bone microarchitecture is assessed invasively determine the bone’s structural parameters to  Excessive bone resorption architecture and alters trabecular increases cortical porosity  By normalizing turnover , it may be possible to preserve bone microstructure and decrease cortical porosity Adapted from Thomsen JS et al

Bone

2002;30(1): 267 –274; Dempster DW

Osteoporos Int

2002;13(5):349 –352; Bell KL et al

Bone

2000;27(2):297 – 304; Riggs BL, Melton LJ III

J Bone Miner Res

2002;17(1):11 –14; Boivin GY et al

Bone

2000;27(5):687 –694; Masarachia P et al. Posters presented at the 2003 American Society for Bone and Mineral Research meeting, Minneapolis, Minnesota, September 19 –23, 2003; Roschger P et al

Bone

2001;29(2):185 –191.

Slide 20

Assessing Trabecular Bone Microarchitecture

 Iliac crest bone biopsy is an invasive to obtain bone samples from humans procedure used  Bone biopsy samples are used for evaluating trabecular microarchitecture by 2-D and (3D) micro CT imagery  Trabecular microarchitecture changes have not been established to be predictive of fracture risk Adapted from Thomsen JS et al

Bone

2002;30(1):267 –274. Slide 21

Overall Limitations of Iliac Crest Biopsy

 Iliac crest is not an osteoporotic fracture site  Histomorphometric parameters vary even at contiguous sites in the iliac crest – Intersample variation of bone volume from two contiguous sites was 15.7% in one study (n=55 patients)*  Histomorphometric parameters at the iliac crest correlate poorly with those at the spine and hip *Evaluation of intersample variation for an individual and for patient groups in two contiguous transiliac crest samples in 55 patients (mean age 55 years); Adapted from Chavassieux PM et al

Calcif Tissue Int

1985;37(4):345 –350; Thomsen JS et al

Bone

2002;30(1):267 –274.

Slide 22

Slide 23

Slide 24

Consequences of Osteoporosis



Clinically, osteoporosis manifests in occurrence of characteristic low-trauma fractures, the best documented of these being hip, vertebral, and distal forearm fractures.

Source: The burden of musculoskeletal conditions at the start of the new millennium: a report of a WHO scientific group. WHO Technical Report Series 919, World Health Organization, Geneva 2003.

Slide 25

Slide 26

Epidemiology of Osteoporosis

 Osteoporosis is known to increase with age.

 Osteoporosis is more prevalent in women than men.

Prevalence of osteoporosis for white female nursing home residents :

90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 63.5% 71.1% 85.8% 65-74 75-84

Age

85+

Source: Zimmerman SI et al. The prevalence of osteoporosis in nursing home residents. Osteoporosis Int 1999;9:151-77.

Slide 27

Increasing Risk of Osteoporotic Fracture in Women, by Age

Source: Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. World Health Organ Tech Rep Ser 2003;919:i-x, 1-218, back cover. Slide 28

Hip Fracture Mortality

50% 40% 30% 20% 10% 0% 50-64 65-74 75-84 85+ All Hip Fx Male Hip Fx Female Hip Fx

Source: US Congress of Health Technology Assessment 1994, OTA-BP-H-120. US Government Printing Office, Washington DC.

Slide 29

Vitamin D: Its Importance in the Treatment of Osteoporosis

Slide 30

The Importance of Vitamin D

 Vitamin D is essential for ensuring intestinal absorption of calcium  Lack of vitamin D leads to increased release of PTH and bone resorption  Evidence suggests that vitamin D inadequacy increases risk of fracture  Vitamin D inadequacy also increases the risk of falls PTH=parathyroid hormone Adapted from Parfitt AM et al.

Am J Clin Nutr

. 1982;36:1014 –1031; Allain TJ, Dhesi J.

Gerontology.

Endocrinol Metab.

2001;86:1212 –1221; LeBoff MS et al.

JAMA.

1999;281:1505 2003;49:273 –1511; Bischoff HA et al. –278; Lips P et al.

J Bone Miner Res. J Clin

2003;18:343 –351; Gallacher et al.

Curr Med Res Opin.

2005;21:1355 –1361.

Slide 31

Vitamin D Production

Increase calcium and phosphorus absorption Skin Sun ProD 3  PreD 3  Vitamin D 3 Liver 25(OH)D Diet Vitamin D 3 Vitamin D 2 Intestine Kidney

PTH (+)

1,25(OH) 2 D

(+) Low PO 2 – 4

Bone Maintain serum calcium and phosphorus Mobilize calcium stores Neuromuscular functions Metabolic functions Bone health 25(OH)D=25-hydroxyvitamin D; PTH=parathyroid hormone; 1,25(OH) 2 D=1,25-dihydroxyvitamin D Adapted from Holick MF.

Osteoporos Int.

1998;8(suppl 2):S24 –S29.

Slide 32

Sources of Vitamin D

   Sunlight exposure – Major source of vitamin D, providing the majority of the body’s daily – requirement Vitamin D production is affected by season, duration of exposure, sunscreen use, and skin pigmentation Endogenous production – Ability of skin, liver, and kidneys to form and process vitamin D Dietary intake – Minor source of vitamin D – Vitamin D is rare in foods other than fatty fish, eggs, and supplemented – – – – dairy products* Even vitamin D –fortified dairy products may not contain level indicated on label Vitamin D can be supplied by multivitamins and supplements Supplements containing vitamin D alone are not readily available Patient compliance with supplementation therapy is inconsistent *Sold in the United States, Canada, Argentina (optional), Brazil, Guatemala, Honduras, Mexico, Philippines (optional), and Venezuela Adapted from Holick MF; Allain TJ, Dhesi J; Webb AR et al; Parfitt et al; Matsuoka LY et al; Holick MF; Lips P; Macleod CC et al; Omdahl JL et al; Chen TC et al; Holick MF et al; Heaney RP; Segal E et al; Webb AR et al; Faulkner H et al; Roche Vitamins Europe Ltd.

Slide 33

Recommendations for Vitamin D Intake

Europe

The Scientific Committee for Food of the Commission of the European Communities recommends  400 IU of vitamin D daily for the elderly (age  65)

United States

The Institute of Medicine has defined adequate daily intake of vitamin D according to age   Adults up to age 50 Adults 51 –70 200 IU 400 IU  Adults >70 600 IU No toxic effects were reported in 48 of 50 adults with vitamin D deficiency given a single intramuscular dose of 600,000 IU annually in a clinical study to assess the efficacy and tolerability profile of high vitamin D intake.

Adapted from European Commission.

Report on Osteoporosis in the European Community: Action on Prevention

. Luxembourg: Office for Official Publications of the European Communities, 1998;

Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride

. Washington, DC: Institute of Medicine, National Academy Press, 1997; Diamond TH et al.

Med J Aust.

2005;183:10 –12.

Slide 34

Vitamin D Inadequacy* Has Important Consequences

Calcium absorption Parathyroid hormone Bone mineral density Appropriate neuromuscular function Risk of fracture

Artist rendition *Vitamin D inadequacy is defined as serum 25(OH)D <30 ng/mL.

Adapted from Parfitt AM et al.

Am J Clin Nutr.

1982;36:1014 –1031; Allain TJ, Dhesi J.

Gerontology.

Osteoporos Int.

1998;8(suppl 2):S24 –S29; DeLuca HF.

Metabolism.

1990;39(suppl 1):3 2003;49:273 –9; Lips P. In: –278; Holick MF.

Advances in Nutritional Research

. New York, Plenum Press, 1994:151 2000;11:553 –555.

–165; Pfeifer M et al.

Trends Endocrinol Metab.

1999;10:417 –420; Heaney RP.

Osteoporos Int

. Slide 35

Vitamin D Is Essential for Calcium Absorption

Results of 2 randomized, crossover studies conducted approximately 1 year apart in 34 postmenopausal women

Calcium absorption a

5

+65%

4 3 2 1 0

Pretreated with vitamin D b (n=24)

a

P

<0.001

b Serum vitamin D 32 ng/mL c Serum vitamin D 20 ng/mL Adapted from Heaney RP et al.

J Am Coll Nutr.

2003;22:142 –146.

Not pretreated with vitamin D c (n=22)

Slide 36

In a clinical study,

Vitamin D Supplementation Decreased Fracture Risk

 5-year randomized, double blind, controlled trial  N=2686  Age 65 to 85 years  Vitamin D = 100,000 IU once every 4 months (equivalent to 800 IU/day) 1.2

1.0

0.8

0.6

0.4

0.2

0.0

P

=0.02

–33% Untreated (n=1341) Treated (n=1345)

Adapted from Trivedi D et al.

BMJ.

2003;326:469.

Slide 37

Effect of Vitamin D and Calcium Supplementation on Risk of Falling

 122 women  Age: 63 to 99 years  Randomized, double-blind, controlled trial – – Calcium 1200 mg/day Calcium 1200 mg/day + vitamin D 800 IU/day  12-week duration  Mean serum 25(OH)D 12 ng/mL at baseline 1.2

1.0

0.8

0.6

0.4

0.2

0.0

Reduction in falls Calcium only (n=44)

P

=0.01

–49% Calcium + vitamin D (n=45)

Adapted from Bischoff HA et al.

J Bone Miner Res.

2003;18:343 –351.

Slide 38

According to a recent study,

A High Prevalence of Vitamin D Inadequacy* Was Seen Across All Geographic Regions

In a cross-sectional, international study in postmenopausal women with osteoporosis

90 80 70 60 50 40 30 20 10 0

N=2589 63.9% 53.4% 57.7% 81.8% 71.4% 60.3%

All Latin America Europe Middle East

Regions

Asia Australia *Vitamin D inadequacy was defined as serum 25(OH)D <30 ng/mL.

Study Design: Cross-sectional, international study of 2589 community-dwelling women with osteoporosis from 18 countries to evaluate serum 25(OH)D distribution Adapted from Lips P et al.

J Intern Med

. In press.

Slide 39

Reasons for High Prevalence of Vitamin D Inadequacy in Postmenopausal Women

 Lack of sunlight exposure, including women who use sunscreen  Vitamin D is not common in the diet  Ability to synthesize vitamin D in the skin decreases with age  Lack of compliance taking daily supplements Adapted from Marcus R. In:

Goodman & Gilman’s The Pharmacological Basis of Therapeutics.

10th ed. New York: McGraw-Hill Medical Publishing Division, 2001:1715 –1743; Bringhurst FR. In:

Harrison’s Principles of Internal Medicine.

16th ed. New York: McGraw-Hill Medical Publishing, 2005:2238 –2249; Matsuoka LY.

J Clin Endocrinol Metab.

1987;64:1165 –1168; Parfitt AM.

Am J Clin Nutr.

1982;36:1014 –1031; Allain TJ, Dhesi J.

Gerontology.

2003;49:273 –278; Holick MF et al.

Lancet.

1989;2:1104 –1105; MacLaughlin J, Holick MF.

J Clin Invest.

1985;76:1536 –1538; Resch H et al. Poster presented at: ECCEO; March 15–18, 2006; Vienna, Austria; Gaugris S et al. Poster presented at: ECTS and IBMS; June 25 –29, 2005; Geneva, Switzerland; Hanley DA et al. Poster presented at: ECCEO; March 15–18, 2006; Vienna, Austria.

Slide 40

Low Patient Compliance With Vitamin D Supplements

 Fewer than 1 in 5 women with osteoporosis take vitamin D supplementation a  33% of patients are taking supplements containing vitamin D only b  In Austria, where calcium and vitamin D supplementation are free to patients – 73% of patients take calcium and vitamin D combination supplements – 20% of patients take supplementation regularly a In France, the United Kingdom, and Germany b In the United Kingdom and Mexico Adapted from Gaugris S et al. Poster presented at: ECTS and IBMS; June 25 –29, 2005; Geneva, Switzerland; Resch H et al. Poster presented at: ECCEO; March 15 –18, 2006; Vienna, Austria.

Slide 41

Summary of the Importance of Vitamin D in the Treatment of Osteoporosis

 Vitamin D is essential for calcium absorption  Postmenopausal women have difficulty getting enough Vitamin D  Vitamin D inadequacy is widespread in postmenopausal women  Vitamin D supplementation has been shown to reduce the risk of fracture and falls Adapted from Parfitt AM et al.

Am J Clin Nutr.

1982;36:1014 –1031; Gaugris S et al.

QJM

. 2005;98:667 –676; Bettica P et al.

Osteoporos Int.

1999;9:226 –229; Lips P et al.

J Clin Endocrinol Metab.

2001;86:1212 –1221; Lips P et al.

J Intern Med

. In press; Trivedi DP et al.

BMJ.

2003; 326:469; Bischoff HA et al.

J Bone Miner Res.

2003;18:343 –351. Slide 42

Bone turnover

 The properties of bone quality are unfavorably altered by increased bone turnover. The consequences of increased bone turnover associated with osteoporosis can include: – – – – Decreased bone mass Decreased mineralization Increased porosity Disrupted architecture/trabecular connectivity  Biochemical markers are valuable tools in research investigations because they measure bone turnover. They are not commonly used in clinical practice for the treatment and management of osteoporosis. Slide 43

Slide 44

Daily Calcium Needs 11-24 years old 1200-1500mg 25 years-menopause After menopause Not on oestrogen On oestrogen >65 yrs old 1000mg 1500mg 1500mg 1000mg

Slide 45

Dairy Source Non fat milk Low fat yoghurt Low fat milk Ice Cream Cottage cheese Fish and Beans Sardines (canned with bones) Salmon (canned with bones) Calcium per serving 302 mg per cup 300 mg/cup 297 mg/cup 176 mg/cup 155 mg/cup 371 mg/3 oz 167 mg/3 oz Slide 46

Nutrition facts

 Packaged foods have a labels  Calcium supplements  Vitamin D = 400IU of vitamin D daily (milk, multivitamins and sunshine) Slide 47

Keeping your bones strong

 Protein rich or salty foods  medications  inactivity  smoking Slide 48

Stay active

 Resistance exercises  Weight bearing  Vary activities Slide 49