novartis osteoporosis slide kit
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Osteoporosis
and
Current trends in themanagement of osteoporosis
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OsteoporosisA definition
A systemic skeletal disease characterized by lowbone mass and micro-architectural deterioration of
bone tissue, with a consequent increase in bonefragility and susceptibility to fracture.
Source: Osteoporos Int (2008) 19:399428,Am J Med 94:646650
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Characteristics
Osteoporosis primarily affects trabecular bone.
Trabecular bone is much less dense than cortical bone
and has a higher remodeling rate, so osteoporosis
affects trabecular bone to a greater degree than
cortical bone.
Bones that break include:
Wrist Spine
Hip
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Normal & Osteoporotic Bone
David W. Dempster, PhD, 2000.
NormalBone
OsteoporoticBone
Men have about 30% more
bone mass than women
African Americans get 10%higher peak bone mass
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Bone Turnover
Bone turnover is rate of bone
formation and resorption.
Bone resorption is coupled to
bone formation.
During growth, turnover high,
formation> resorption. Net bonegain.
During adulthood, turnover
moderate, formation< resorption.
Net bone loss.
Women loose bone mass faster
after menopause, but it happens
to men too
2004 Surgeon Generals Report on Bone Health and Osteoporosis: What It Means To You.
Poole, K. E S et al. BMJ 2006;333:1251-1256
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Pathogenesis of Osteoporotic Fractures
Aging Menopause Other Risk Factors
Decreased
Bone Mass
Low Peak
Bone Mass
Low BoneDensity
Poor BoneQuality
Fractures
Propensity toFall
Figure reprinted from National Osteoporosis Foundation, Physicians Guide to Prevention and Treatment of Osteoporosis. Modified from RiggsBL, Melton LJ: Etiology, Diagnosis and Management. New York: Raven Press; 1988.
Genetics
Genetics
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Age affects fracture riskindependently of bone
mineral density
For any given bone density,
the fracture probability
increases with age.
e.g.At a T score of -2, the 10
year hip fracture probability
at the age of 50, is around5% but at the age of 80 it is
around 30%
Age and Fracture risk
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Epidemiology: India
An estimated 61 million people in
India are reported to be affected by
Osteoporosis and Indians have
lower bone density than their North
American and European
counterparts
Osteoporotic fractures occur 10-20
years earlier in Indians as
compared to Caucasians and 50%women have osteoporosis and in
actual numbers it accounts for 30
million women.
Ind. Soc.Bone & Min. Res: Mithal A, Rao DS, Zaidi M. 1998; 115-13, J Obstet Gynecol India 2005; 55(3):265-267, J Bone Miner Res, 14 1999 (suppl).Abstract., Indian J Med Res 127, March 2008, pp 263-268
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Osteoporosis: Loves Women
1 in 2 women and 1 in 4 Men over the age of 50
will have an osteoporosis-related fracture in their
lifetimes
Sources
1. National Osteoporosis Foundation. Americas Bone Health: The State of Osteoporosis and Low Bone Mass in Our Nation. Washington, DC: National Osteoporosis Foundation; 2002:5.2. National Osteoporosis Foundation. Fast facts. Available at: http://www.nof.org/osteoporosis/diseasefacts.htm. Accessed April 24, 2006.
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Increased Risk Based on Heredity and Body Frame
Caucasian/Asian Females (post
menopause)
Personal history of osteoporosis or
fracture as adult
History of low trauma fracture in firstdegree relative
Small thin frame
Heredity affects peak bone mass and
is a generic component forosteoporosis risk.
Current smoking
Advancing age
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Risk Factors for Osteoporotic Fractures
Impaired vision despite correction
Dementia
Poor health/family
Estrogen deficiency at an early age
(< 45 yrs)
Frequent falls
Life-long low calcium intake
Low physical activity Excessive alcohol consumption
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Osteoporosis Classification: Type 1
Postmenopausal osteoporosis Due to gonadal (ie, estrogen, testosterone)
deficiency resulting in accelerated bone loss
Post menopause, women experience an
accelerated bone loss of 1-5% per year forthe first 5-7 years causing increased
fractures
Brief science behind type 1: increased
recruitment and responsiveness of
osteoclast precursors leading to increased
bone resorption.
Bone loss begins to occur faster than bone
formation.
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Osteoporosis Classification : Type 2 and Type 3
Senile osteoporosis Due to decreased formation of bone
and decreased renal production of
1,25(OH)2 D3 occurring late in life.
Results in loss of cortical and trabecularbone and increased risk for fractures of
the hip, long bones, and vertebrae.
Type 3 - secondary to medications (ieglucocorticoids) or other conditions
causing increased bone loss by various
mechanisms.
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Osteoporosis, the "silent
disease," has bone loss without
symptoms
Onset only occurs with suddenstrains, bumps, or fall causes a
fracture or a vertebra to collapse
Collapsed vertebrae may initially
be felt or seen in the form of
severe back pain, loss of height,
or spinal deformities such as
kyphosis or stooped posture.2
Symptoms
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What is BMD?
Bone Mineral Density is the term used to
express the amount of bone tissue either
within the entire skeleton or within a
portion of the skeleton
Accounts for about 70% of bone strength
It is the major, although not the only,determinant of resistance to fracture.
As a child grows, BMD increases until it
reaches a peak mass at around the age of
30 to 35 years.
Peak BMD tends to be greater in males
than females.
BMD stays at its peak value for a few
years until age-related bone loss begins.
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WHO T-score Definition for Bone Mineral Density
__|____|____|____|____|______^ -2 -1 0 +1 +2
| -- norm -- |(Normal Young Adult)
Category Definition by bone density
Normal T score between -1 and +1 SD
Low BMD
OsteopeniaT score between -1 and -2.5 SD
Osteoporosis A value of T score that is lower than - 2.5 SD
Severeosteoporosis
A value of T score that is lower than - 2.5 SD andfractures
Osteoporos Int (2008) 19:399428
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Osteoporosis Is Manageable & Fractures Are
Avoidable
Source: National Osteoporosis Foundation: Fast Facts. Available at: www.nof.org/osteoporosis/disease facts.htm.
http://www.nof.org/osteoporosis/disease%20facts.htmhttp://www.nof.org/osteoporosis/disease%20facts.htm -
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Osteoporosis Is Manageable & Fractures Are Avoidable
By age 20, 98% of a womans skeletal mass is established
Early
Proper nutrition: calcium and vitamin D
Weight-bearing exercise
Middle-age
Exercise
No smoking
Modest alcohol use
Older adult with risk factors
Bone density scan
With fracture, get osteoporosis evaluation
Source: National Osteoporosis Foundation: Fast Facts. Available at: www.nof.org/osteoporosis/disease facts.htm.
More research and education is essential
http://www.nof.org/osteoporosis/disease%20facts.htmhttp://www.nof.org/osteoporosis/disease%20facts.htm -
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When to Treat?
First lifestyle changes
Next follow guidelines as statedby National Osteoporosis
Foundation (NOF); recommendpharmacologic therapy topostmenopausal women with T-scores
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Non-Pharmacologic Measures
Falls have an important role in the
pathogenesis of fragility fractures,
particularly in frail and elderly people.
Multifaceted interventions have been
shown to reduce the frequency of falling.
Counsel all patients on risk reduction
Adequate daily intake of calcium and
Vitamin D
Weight bearing and muscle strengthening
exercises to reduce risk of falls and
fractures
smoking and alcohol abuse discouraged.
Physiotherapy and pain relief are important
in managing fractures.
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Calcium Requirements
Recommended elemental calciumneeds by age in mg/ca/day
Children ------------------- :800
Up to age 24 ------------- :1200-1500
Women 25 50 ---------- :1000
Pregnant and breast
feeding ------------------- :1200-1500
Women over 50
Taking ERT ---------- :1000
Not taking ERT ------ :1500
Women over 65 --------- :1500
Men 25 to 65 ------------ :1000
Men over 65 ------------ :1500
Meal 700 mg
CalciumSupplement
500 mg
Total 1200 mg
National Osteoporosis Foundation Report
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Sources of Calcium
Dietary:
8oz milk or yogurt = 300mg
2oz cheese = 400mg
Various salts of calcium, availablein the pharmaceutical products:
Calcium carbonate Ingest with meals
Calcium citrate Independentabsorption; use of pt. is taking H2blocker or proton pump inhibitor
Calcium gluconate
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Calcium Absorption
Factors affecting absorption: Vitamin D & Parathyroid hormone increase absorption
Absorption decreases with age and loss of estrogen at menopause
Dietary constituents e.g. phytate and oxalate decrease absorption
by formation of nonabsorbable complexes.
Fats form insoluble salts like Ca stearate
Drugs (corticosteroids, phenytoin, etc.) decrease absorption
Diseases associated with steatorrhea, diarrhoea or chronic intestinal
malabsorption promote fecal loss.
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Elemental Calcium
Some calcium salts and their calcium content
Elemental calcium is the amount of calcium in a salt. It is expressed as percentage or amount of calcium
per gm. of a calcium salt.
Calcium salt Elemental Calcium contentper gm of salt
Calcium carbonate 40%
Calcium acetate 25%
Calcium chloride 27%
Calcium citrate 21%
Calcium gluconate 9%
Calcium lactate 13%
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Need for Calcium supplementation
Low calcium intake during skeletal growth can decrease peak
BMD and increase fracture risk in future life.
Calcium absorption decreases with age.
In postmenopausal women to maintain bone health and suppressPTH.
Low Ca intake may be a risk factor for Colon cancer
Hypertension
Minerals. In: Krauses Food, Nutrition & Diet Therapy 10th edn. W.B.Saunders USA 2000:110-152
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Calcium citrate
Contains 21% of elemental calcium
Calcium citrate is readily soluble: Approx. solubility is 7.3 mM/litre
Calcium citrate is more readily absorbed.
Calcium citrate does not need acidic environment for absorption
Can be taken without meals, not affected by the fasting state
Maybe a better choice for patients of achlorhydria or patients on anti-
ulcer therapy
Rheum Dis Clin N Am 2001;27(1):101-130
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Calcium citrate
Calcium citrate is better tolerated and can be used if bloating, flatulence,
eructation, constipation occur with other calcium salts.
Citrate forms a soluble complex with calcium and prevents its
crystallisation with oxalate.
Calcium citrate does not increase the risk of stone formation in urine innormal subjects.
Rheum Dis Clin N Am 2001;27(1):101-130Clin Geriatr Med 2003;19(2):321-35.
Cli i l T i l C l i Cit t i P t l
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Clinical Trial - Calcium Citrate in Postmenopausal
women
Aim: To find the effect of calcium citrate on bone density in early
& mid-postmenopausal women
Subjects: 63 postmenopausal women (5-10 years after menopause)
Intervention: Ca citrate 800mg. Daily or placebo for 1-2 years.
Evaluation: Bone density at L2-L4 spine, femoral neck, radial shaft.
Results:
Ca citrate Placebo
L2-L4 BMD after 2
yrs.
+1.03% -2.38%
Radial shaft BMD
after 2 yrs.
-0.02% -3.03%
Conclusion: Ca citrate supplementation averted bone loss and stabilised bone
density in the spine, femoral neck and radial shaft in women
relatively soon after menopause.
Am J Ther. 1999;6(6):303-311
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Safety of Calcium citrate
Long-term calcium citrate supplementation does not increase the
propensity for crystallisation of calcium salts in urine.
This maybe due to:- Lesser increase in urinary calcium excretion
Decrease in urinary phosphate
Increase in urinary citrate.
J Urology 1994;152:324-327.
Calcium citrate supplementation does not increase the risk of stone
formation in healthy postmenopausal women.
Compared to placebo, calcium citrate increased urinary calcium and citrate but decreased urinary oxalate and phosphate.
J Urology 2004;172:958-961.
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Functions of Vitamin D
Maintenance of calcium and phosphorus homeostasis
Absorption of Calcium from intestine
Mobilization of calcium and phosphorus in bone
Helps restore plasma calcium levels in hypocalcemia
Suggested role in cell differentiation, immune system
Functional maintenance of cell membranes
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Vitamin D for Pharmacologic use
Cholecalciferol (Vitamin D3)
Calcitriol (1, 25-dihydroxycholecalciferol) - active Vitamin D
Alfacalcidol (1 a-hydroxycholecalciferol) - Vitamin D analog
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We Need More Vitamin D as Age Advances
Age
Daily
vitamin Dneeds inInternationalUnits (IU)
600 IU
200 IU
400 IU
0
100
200
300
400
500
600
up to 50 51-70 over 70
The National Osteoporosis Foundation recommends limiting Vitamin D to 800 IU/day unless unless prescribed
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Vitamin D Deficiency
Primary Vitamin D deficiency
Inadequate precursors (Vitamin D and/or 25(OH)D3) due to- Inadequate sunlight exposure
Inadequate nutritional vitamin D intake
Diagnosis: Low serum 25(OH)D3 level
Primary 1, 25(OH)2D3 deficiency
Defect in the synthesis of 1, 25(OH)2D3 due to impaired ability of
kidney.
Progressive decline in renal function with age leading to reduction in
renal 25(OH)D-1--hydroxylase activity
Diagnosis:Low serum 1, 25(OH)2D3 level
Normal serum 25(OH)D3 level
Calcif Tissue Int 1999;65:295-306.
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Features of Vitamin D Deficiency/Resistance
Reduced intestinal Calcium absorption
Secondary hyperparathyroidism
Increased bone turnover
Bone loss
Increased risk of fractures
Calcif Tissue Int 1999;65:295-306.
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Vitamin D Therapy
Type of Vitamin D deficiency Treatment
Primary Vitamin D Vitamin D or Alfacalcidol or
Calcitriol
Primary 1, 25(OH)2D3deficiency
Calcitriol or Alfacalcidol
1, 25(OH)2D3 Resistance Calcitriol or Alfacalcidol
Calcif Tissue Int 1999;65:295-306.
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Calcitriol & Alfacalcidol
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Calcitriol vs Alfacalcidol
Calcitriol is biologically active
Acts immediately on targettissues (intestinal mucosal cells) to
produce biological effect (calciumabsorption)
Rapid increase in calciumabsorption
Peak serum concentration ofcalcitriol is seen in 2 hours
Alfacalcidol is biologically inertGets converted in liver to calcitriol
(active form)
Alfacalcidol has very limited
intestinal action therefore does not
produce immediate action
Not so rapid increase in calcium
absorption
Peak serum concentration of
calcitriol is seen in 8-18 hours
Treatment of Postmenopausal Osteoporosis with
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Treatment of Postmenopausal Osteoporosis with
Calcitriol or Calcium
Aim: To determine the effect of calcitriol on the rate of new vertebral fractures
& its safety in women with postmenopausal osteoporosis.
Patients: 622 postmenopausal women with osteoporosis (50 to 79 yrs. old)
Intervention: Calcitriol [0.25g (200 IU)twice daily] or Calcium (1g. Elemental Ca
daily) for 3 years.
Results:
9 10
25
32
0
5
10
15
20
25
30
35
2 years 3 yearsNewv
ertebralfractu
resper100patient-years
Calcitriol Calcium
Conclusion:Continuous treatment
of postmenopausal osteoporosis with
calcitriol for 3 years is safe andsignificantly reduces the rate of new
vertebral fractures.
N Engl J Med 1992;326(6):357-362
C l it i l i P t l O t i
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Calcitriol in Postmenopausal Osteoporosis
Aim: To study the efficacy of calcitriol in treatment of postmenopausal osteoporosis.
Design: 2-year, double-blind, randomised, parallel trial
Patients: 50 postmenopausal women with vertebral fractures
Intervention: Calcium intake=1000mg. in all patients at baseline
Calcium intake reduced to 600mg. and calcitriol dose adjusted
to maintain serum Ca
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Contains: Calcium citrate: 1200 mg (equivalent to 252 mg elemental Calcium)
Calcitriol: 0.25g
Indications:
Calcium and Vitamin D supplementation in
Prevention and treatment of vitamin D and calcium deficiency.
Vitamin D and calcium supplement as an adjunct to specific osteoporosis
treatment of patients who are at risk of vitamin D and calcium deficiency.
Rationale for combination of calcitriol &
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Rationale for combination of calcitriol &
calcium citrate
As age increases, HCl production decreases (10% of elderly women are achlorhydric)
As age increases, renal production of calcitriol decreases (age related decline in renal function occurs between age of 20 to 90 years)
As age increases, intestinal vit D receptors (VDR) decrease (VDR decrease from age 20 to 90 years)
As age increases, thus, there is failure to absorb calciumefficiently
Also, estrogen deficiency at menopause decreases renalproduction of calcitriol failure to absorb calcium efficiently
Low blood calcium levels
Secondary increase in PTH
Bone resorption
Calcium citrate more soluble
more bioavailable
better absorbed
Calcitriol
Most potent form of vit D Quick onset of action
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