Osteoporosis and Current trends in the management of osteoporosis

Osteoporosis
A definition

A systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.

Source: Osteoporos Int (2008) 19:399428, Am J Med 94:646650

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

Normal & Osteoporotic Bone

Men have about 30% more bone mass than women

African Americans get 10% higher peak bone mass

Normal Bone

Osteoporotic Bone

David W. Dempster, PhD, 2000.

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 bone gain. 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

Pathogenesis of Osteoporotic Fractures

Aging Menopause Other Risk Factors Genetics Decreased Bone Mass Genetics Low Peak Bone Mass

Low Bone Density

Poor Bone Quality Fractures Propensity to Fall

Figure reprinted from National Osteoporosis Foundation, Physicians Guide to Prevention and Treatment of Osteoporosis. Modified from Riggs BL, Melton LJ: Etiology, Diagnosis and Management. New York: Raven Press; 1988.

Age and Fracture risk

Age affects fracture risk

independently 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 around 5% but at the age of 80 it is around 30%

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

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

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.

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 first degree relative Small thin frame Heredity affects peak bone mass and is a generic component for osteoporosis risk. Current smoking Advancing age

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

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 for the 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.

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 trabecular bone and increased risk for fractures of the hip, long bones, and vertebrae. Type 3 - secondary to medications (ie glucocorticoids) or other conditions causing increased bone loss by various mechanisms.

Symptoms

Osteoporosis, the "silent disease," has bone loss without symptoms Onset only occurs with sudden strains, 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

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.

WHO T-score Definition for Bone Mineral Density

__|____|____|____|____|______ ^ -2 -1 0 +1 +2
| -- norm -- | (Normal Young Adult)

Category Normal Low BMD Osteopenia Osteoporosis Severe osteoporosis

Definition by bone density T score between -1 and +1 SD

T score between -1 and -2.5 SD

A value of T score that is lower than - 2.5 SD A value of T score that is lower than - 2.5 SD and fractures

Osteoporos Int (2008) 19:399428

Osteoporosis Is Manageable & Fractures Are Avoidable

Source: National Osteoporosis Foundation: Fast Facts. Available at: www.nof.org/osteoporosis/disease facts.htm.

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 Exercise

Middle-age

No smoking
Modest alcohol use Bone density scan

Older adult with risk factors

With fracture, get osteoporosis evaluation

More research and education is essential

Source: National Osteoporosis Foundation: Fast Facts. Available at: www.nof.org/osteoporosis/disease facts.htm.

When to Treat?

First lifestyle changes Next follow guidelines as stated by National Osteoporosis Foundation (NOF); recommend pharmacologic therapy to postmenopausal women with Tscores <-2.0 as measured by central DEXA regardless of risk factors, and <-1.5 if risk factors present

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.

Calcium Requirements
Recommended elemental calcium needs by age in mg/ca/day Children ------------------Up to age 24 ------------Women 25 50 ---------Pregnant and breast feeding ------------------Women over 50 Taking ERT ---------Not taking ERT -----Women over 65 --------Men 25 to 65 -----------Men over 65 -----------Meal Calcium Supplement Total
National Osteoporosis Foundation Report

:800 :1200-1500 :1000 :1200-1500

:1000 :1500 :1500 :1000 :1500

700 mg 500 mg 1200 mg

Sources of Calcium

Dietary: 8oz milk or yogurt = 300mg 2oz cheese = 400mg Various salts of calcium, available in the pharmaceutical products:

Calcium carbonate Ingest with meals Calcium citrate Independent absorption; use of pt. is taking H2 blocker or proton pump inhibitor Calcium gluconate

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.

Elemental Calcium
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.

Some calcium salts and their calcium content

Calcium salt Calcium carbonate Calcium acetate Calcium chloride Elemental Calcium content per gm of salt 40% 25% 27%

Calcium citrate
Calcium gluconate Calcium lactate

21%
9% 13%

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 suppress PTH. Low Ca intake may be a risk factor for

Colon cancer Hypertension

Minerals. In:

Krauses Food, Nutrition & Diet Therapy 10 th edn. W.B.Saunders USA 2000:110-152

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 antiulcer therapy

Rheum

Dis Clin N Am 2001;27(1):101-130

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 in normal subjects.

Rheum Dis Clin N Am 2001;27(1):101-130 Clin Geriatr Med 2003;19(2):321-35.

Clinical Trial - Calcium Citrate in Postmenopausal women

Aim: Subjects: Intervention: Evaluation: Results: To find the effect of calcium citrate on bone density in early & mid-postmenopausal women 63 postmenopausal women (5-10 years after menopause) Ca citrate 800mg. Daily or placebo for 1-2 years. Bone density at L2-L4 spine, femoral neck, radial shaft. Ca citrate
L2-L4 BMD after 2 yrs. Radial shaft BMD after 2 yrs. +1.03% -0.02%

Placebo
-2.38% -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

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.

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

Vitamin D for Pharmacologic use

Cholecalciferol (Vitamin D3) Calcitriol (1, 25-dihydroxycholecalciferol) - active Vitamin D

Alfacalcidol (1 a-hydroxycholecalciferol) - Vitamin D analog

We Need More Vitamin D as Age Advances

600 IU
600 500

400 IU 200 IU

Daily vitamin D needs in International Units (IU)

400
300 200 100 0

up to 50

51-70
Age

over 70

The National Osteoporosis Foundation recommends limiting Vitamin D to 800 IU/day unless unless prescribed

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.

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.

Vitamin D Therapy
Type of Vitamin D deficiency Primary Vitamin D Primary 1, 25(OH)2D3 deficiency 1, 25(OH)2D3 Resistance Treatment Vitamin D or Alfacalcidol or Calcitriol Calcitriol or Alfacalcidol Calcitriol or Alfacalcidol

Calcif

Tissue Int 1999;65:295-306.

Calcitriol & Alfacalcidol

Calcitriol vs Alfacalcidol
Calcitriol

is biologically active

Alfacalcidol

is biologically inert Gets converted in liver to calcitriol (active form)

Alfacalcidol

Acts

immediately on target tissues (intestinal mucosal cells) to produce biological effect (calcium absorption)
Rapid

has very limited intestinal action therefore does not produce immediate action
Not

increase in calcium absorption

Peak

so rapid increase in calcium absorption

Peak

serum concentration of calcitriol is seen in 2 hours

serum concentration of calcitriol is seen in 8-18 hours

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. IU)twice daily] or Calcium (1g. Elemental Ca

Patients: 622 postmenopausal women with osteoporosis (50 to 79 yrs. old)

Intervention: Calcitriol [0.25g (200

daily) for 3 years.

Results:
New vertebral fractures per 100 patient-years

35 30 25 25 20 15 10 5 0 2 years Calcitriol Calcium 3 years 9 10

32

Conclusion:

Continuous treatment of postmenopausal osteoporosis with calcitriol for 3 years is safe and significantly reduces the rate of new vertebral fractures.

N Engl J Med 1992;326(6):357-362

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 <11.0mg/dl); Mean dose of calcitriol = 0.62g/day Results:
Calcitriol BMD spine Total body calcium +1.94% +0.21%
No

Placebo - 3.92% -1.85%

Significance P=0.001 P=0.004

difference in vertebral fracture rates No difference in renal function

Conclusion: Treatment with calcitriol for 2 years was associated with increases in spine density
&

total body calcium. No adverse effects on renal function were seen.

Ann

Int Med. 1990;113:649-655.

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 & 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)

Calcium citrate
more soluble more bioavailable better absorbed

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 calcium efficiently Also, estrogen deficiency at menopause decreases renal production of calcitriol failure to absorb calcium efficiently Low blood calcium levels Secondary increase in PTH Bone resorption

Calcitriol
Most potent form of vit D Quick onset of action

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