Novartis Osteoporosis Slide Kit

7/31/2019 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


7/42Poole, K. E S et al. BMJ 2006;333:1251-1256

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



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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



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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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Thank you!

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