Transcript Outline for FOSAMAX PLUS Slide Set

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 and
susceptibility to fracture”
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. 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.
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 1999;2(3):323–342; Boivin GY et al Bone
2000;27(5):687–694.
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 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.
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 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.
Slide 14
Prospective Cohort Study
Incidence of fractures
(fractures per 1000 patient-years)
Decreased BMD In Vivo Has Been
Associated with Fracture Incidence
60
Spine
Distal radius
Calcaneus
50
 In a meta-analysis, the link
between low BMD and
fracture risk was similar to
or stronger than
40
– Diastolic blood pressure
and stroke
– Serum cholesterol
and coronary disease
30
20
10
0
2 SD
1 SD
Mean
–1 SD
–2 SD
Bone mass
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
8000
6000
r2=0.92
p<0.0001
T11 failure load (N)
Femoral failure load (N)
Increases in BMD Lead to Greater
Bone Strength In Vitro
6000
4000
2000
0
r2=0.88
p<0.001
5000
4000
3000
2000
1000
0
0
0.2
0.4
0.6
0.8
Trochanteric BMD (g/cm2)
Test set-up
to determine
bone strength
1.0
0
0.25 0.50 0.75 1.00 1.25 1.50
Lumbar spine (lateral) BMD (g/cm2)
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 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.
Slide 20
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) microCT 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%
85.8%
71.1%
63.5%
20%
10%
0%
65-74
75-84
85+
Age
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
Annual Mortality Rate
Hip Fracture Mortality
50%
40%
30%
20%
10%
0%
50-64
All Hip Fx
65-74
Male Hip Fx
75-84
85+
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. 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.
Slide 31
Vitamin D Production
Sun
ProD3  PreD3  Vitamin D3
Skin
Diet
Vitamin D3
Vitamin D2
Liver
25(OH)D
Kidney
Increase
calcium and
phosphorus
absorption
Intestine
(+) Low PO42–
PTH (+)
1,25(OH)2D
Bone
Mobilize
calcium
stores
Maintain serum calcium and phosphorus
Metabolic functions
Bone health
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.
Neuromuscular functions
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
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 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
Appropriate
neuromuscular
function
Bone mineral
density
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. 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.
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 absorptiona
AUC (mghr/L)
5
+65%
4
3
2
1
0
Pretreated
with vitamin Db
(n=24)
Not pretreated
with vitamin Dc
(n=22)
aP<0.001
bSerum
vitamin D 32 ng/mL
vitamin D 20 ng/mL
Adapted from Heaney RP et al. J Am Coll Nutr. 2003;22:142–146.
cSerum
Slide 36
In a clinical study,
Vitamin D Supplementation Decreased
Fracture Risk
 5-year randomized, double N=2686
 Age 65 to 85 years
 Vitamin D = 100,000 IU
once every 4 months
(equivalent to 800 IU/day)
Fracture relative risk
(hip, wrist, forearm, spine)
blind, controlled trial
1.2
P=0.02
1.0
–33%
0.8
0.6
0.4
0.2
0.0
Untreated
(n=1341)
Adapted from Trivedi D et al. BMJ. 2003;326:469.
Treated
(n=1345)
Slide 37
Effect of Vitamin D and Calcium
Supplementation on Risk of Falling
 122 women
Reduction in falls
 Age: 63 to 99 years
1.2
 Randomized, double-blind,
1.0
P=0.01
controlled trial
 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.
Fall risk
– Calcium 1200 mg/day
– Calcium 1200 mg/day
+ vitamin D 800 IU/day
0.8
–49%
0.6
0.4
0.2
0.0
Calcium
only
(n=44)
Calcium +
vitamin D
(n=45)
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
81.8%
N=2589
Prevalence (%)
80
70
71.4%
63.9%
60
53.4%
57.7%
Latin
America
Europe
60.3%
50
40
30
20
10
0
All
Middle
East
Asia
Australia
Regions
*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 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
bIn
France, the United Kingdom, and Germany
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
1000mg
After menopause
Not on oestrogen
1500mg
On oestrogen
1500mg
>65 yrs old
1000mg
Slide 45
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
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