slide 1 dr mampedi bogoshi osteoporosis † trademark of merck & co., inc., whitehouse station,...

Dr Mampedi Bogoshi

Osteoporosis

†Trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA

Discussion Points

Osteoporosis Burden of Disease

Risk Factors

Vitamin D and Calcium

Recommendations and management

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.

Osteoporosis

Burden of Disease

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 and susceptibility to fracture”

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

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. NIH Consensus Statement. 2000;17(1):1–45; Miller PD et al J Clin Densitom 1992;2(3):323–342; Boivin GY et al Bone 2000;27(5):687–694; Dempster DW Osteoporos Int 2002;13(5):349–352.

Bone Quality

4 bone properties affect bone strength:

1) BMD

2) Bone Turnover

3) Bone Microarchitecture

4) Bone Mineralisation

How Key Properties of Bone Affect Fracture Risk

Altersmicroarchitecture 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 1999;2(3):323–342; Boivin GY et al Bone 2000;27(5):687–694.

BMD

BoneTurnover

BoneStrength

FractureRisk

1) Bone Quality

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 in bone turnover are associated with lower risk of fracture**

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.

2) BMD


BoneStrength

FractureRisk

BoneTurnover


bone mineralization

BMD

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 was related to BMD in two separate in vitro 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.

Decreased BMD In Vivo Has Been Associated with Fracture Incidence

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

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.

Prospective Cohort Study

0

10

30

60

Inci

den

ce o

f fr

actu

res

(fra

ctu

res

per

100

0 p

atie

nt-

year

s)

50

40

20

2 SD 1 SD Mean –2 SD–1 SD

Bone mass

SpineDistal radiusCalcaneus

Increases in BMD Lead to Greater Bone Strength In Vitro

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.

Test set-up to determine bone strength

Two Separate Laboratory Studies

0

0

6000

8000

Fem

ora

l fa

ilu

re l

oad

(N

)

Trochanteric BMD (g/cm2)

r2=0.92p<0.0001

2000

4000

0.2 0.4 0.6 0.8 1.0 0

0

5000

6000

T11

fai

lure

lo

ad (

N)

Lumbar spine (lateral) BMD (g/cm2)

r2=0.88p<0.001

2000

4000

0.25 0.50 1.00 1.25 1.50

3000

1000

0.75

Schematic ofmaterial testingsystem tobreak vertebra

3) Microarchitecture


BoneStrength

FractureRisk

BoneTurnover


bone mineralization

BMD

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

Trabecular Bone Microarchitecture

Bone microarchitecture is assessed invasively to determine the bone’s structural parameters

Excessive bone resorption alters trabecular architecture and 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.

Assessing Trabecular Bone Microarchitecture

Iliac crest bone biopsy is an invasive procedure used to obtain bone samples from humans

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.

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.

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.

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

Epidemiology of Osteoporosis

Osteoporosis is known to increase with age.

Osteoporosis is more prevalent in women than men.

63.5%71.1%

85.8%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

65-74 75-84 85+

Age

Prevalence of osteoporosis for white female nursing home residents:

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

Increasing Risk of Osteoporotic Fracture in Women, by Age

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

0%

10%

20%

30%

40%

50%

50-64 65-74 75-84 85+

All Hip Fx Male Hip Fx Female Hip Fx

An

nua

l Mor

talit

y R

ate

Hip Fracture Mortality

Vitamin D: Its Importance in the Treatment

of Osteoporosis

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. 2003;49:273–278; Lips P et al. J Clin Endocrinol Metab. 2001;86:1212–1221; LeBoff MS et al. JAMA. 1999;281:1505–1511; Bischoff HA et al. J Bone Miner Res. 2003;18:343–351; Gallacher et al. Curr Med Res Opin. 2005;21:1355–1361.

Vitamin D Production

25(OH)D=25-hydroxyvitamin D; PTH=parathyroid hormone; 1,25(OH)2D=1,25-dihydroxyvitamin D

Adapted from Holick MF. Osteoporos Int. 1998;8(suppl 2):S24–S29.

Skin

Liver

Kidney

DietVitamin D3

Vitamin D2

Intestine

Bone

ProD3 PreD3 Vitamin D3

25(OH)D

1,25(OH)2D

PTH (+)

UVBSun

(+) Low PO2–

4

Increase calcium and phosphorus absorption

Mobilize calcium stores

Maintain serum calcium and phosphorus

Metabolic functions Bone health Neuromuscular functions

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.

Recommendations for Vitamin D Intake

Europe

The Scientific Committee for Food of the Commission of the EuropeanCommunities 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 Daccording to age Adults up to age 50 200 IU Adults 51–70 400 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 assessthe 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.

Appropriateneuromuscular

function

Appropriateneuromuscular

function

Vitamin D Inadequacy* Has Important Consequences

*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. 2003;49:273–278; Holick MF. Osteoporos Int. 1998;8(suppl 2):S24–S29; DeLuca HF. Metabolism. 1990;39(suppl 1):3–9; Lips P. In: Advances in Nutritional Research. New York, Plenum Press, 1994:151–165; Pfeifer M et al. Trends Endocrinol Metab. 1999;10:417–420; Heaney RP. Osteoporos Int. 2000;11:553–555.

Bone mineraldensity

Bone mineraldensity

Parathyroidhormone

Parathyroidhormone

Calcium absorptionCalcium

absorption

Risk of fractureRisk of fracture

Artist rendition

Vitamin D Is Essential for Calcium Absorption

Calcium absorptiona

Pretreated with vitamin Db

(n=24)

Not pretreated with vitamin Dc

(n=22)aP<0.001bSerum vitamin D 32 ng/mLcSerum vitamin D 20 ng/mL

Adapted from Heaney RP et al. J Am Coll Nutr. 2003;22:142–146.

0

1

2

3

4

5+65%

AU

C (

mgh

r/L

)

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

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)

Adapted from Trivedi D et al. BMJ. 2003;326:469.

Fra

ctu

re r

elat

ive

risk

(hip

, wri

st, f

ore

arm

, sp

ine)

–33%

Untreated(n=1341)

Treated(n=1345)

P=0.02

0.0

0.2

0.4

0.6

0.8

1.0

1.2

In a clinical study,

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

Adapted from Bischoff HA et al. J Bone Miner Res. 2003;18:343–351.

Calcium only

(n=44)

Calcium + vitamin D

(n=45)

Fal

l ris

k

0.0

0.2

0.4

0.6

0.8

1.0

1.2

–49%

Reduction in falls

P=0.01

*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.

Pre

vale

nce

(%

)

0

10

30

40

60

80

90

Regions

N=2589

50

70

20

81.8%

MiddleEast

53.4%

71.4%

AsiaAll LatinAmerica

63.9%

Australia

60.3%

Europe

57.7%

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

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

According to a recent study,

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.

Low Patient Compliance With Vitamin D Supplements

Fewer than 1 in 5 women with osteoporosis take vitamin D supplementationa

33% of patients are taking supplements containing vitamin D onlyb

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

aIn France, the United Kingdom, and GermanybIn 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.

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.

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.

Daily Calcium Needs

11-24 years old 1200-1500mg

25 years-menopause 1000mg

After menopause

Not on oestrogen 1500mg

On oestrogen 1500mg

>65 yrs old 1000mg

Dairy

Source Calcium per serving

Non fat milk 302 mg per cup

Low fat yoghurt 300 mg/cup

Low fat milk 297 mg/cup

Ice Cream 176 mg/cup

Cottage cheese 155 mg/cup

Fish and Beans

Sardines (canned with bones) 371 mg/3 oz

Salmon (canned with bones) 167 mg/3 oz

Nutrition facts

Packaged foods have a labels

Calcium supplements

Vitamin D = 400IU of vitamin D daily

(milk, multivitamins and sunshine)

Keeping your bones strong

Protein rich or salty foods

medications

inactivity

smoking

Stay active

Resistance exercises

Weight bearing

Vary activities

slide 1 dr mampedi bogoshi osteoporosis † trademark of merck & co., inc., whitehouse station,...

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