Osteoporosis

Dr SAMEER

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 Osteoporosis is by far the most

common metabolic bone disease.
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 One out of two women and one in

eight men over age 50 will have an
osteoporosis-related fracture in their
lifetime
 Background
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 By the end of the first menopausal decade, 50% of

white females have osteopenia or osteoporosis

 Prevalence of osteoporosis increases from 15% in

50-59 yo to 70% in women aged 80 years

 Only 1/3 of all cases with osteoporosis have been

dx
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Impact on Quality of Life
 80% of women prefered death than a
serious hip fracture
(source: Salkeld G, et al. Quality of life related to fear of falling and hip
fracture in older women: a time trade off study. BMJ 2000; 320: 341-
6)

 The lifetime risk of death due to hip

fracture is now equal to that of breast
cancer in women, 2.8%
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Women’s problem?
 In wrist fractures the ratio of female to male
is 10:1
 But Hip Fractures the ratio is 2:1
 One year mortality following a hip fracture
in men is two times that of female
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Osteoporosis
Consensus Development Conference as
“progressive systemic skeleteal disease
characterized by low bone mass and
microarchitectural deterioration of bone
tissue, leading to enhanced bone fragility
and a consequent increase in fracture
risk."

*Consensus Development Conference Statement 1993

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BMD- Based Definition
 Normal: T-score + or -1 SD
 Osteopenia: T-score - 1 to -2.5 SD
 Osteoporosis: T-score -2.5 or less
 Severe Osteoporosis: T-score -2.5 or less
and fragility fracture
 Types of Osteoporosis
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Primary osteoporosis-progressive bone loss assoc

with aging (80%)

Type 1-due to estrogen deficiency-usually in

postmenopausal women
Type 2-senile involutional osteoporosis-after 35
yrs, affects both trabecular and cortical bone

Secondary osteoporosis-resulting from underlying

medical conditions (20%)
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Pathogenesis

End result of bone loss

Bone resorption > bone formation
 Menopause-related (Type I)
 Age-related (Type II)

Secondary osteoporosis
 High turnover osteoporosis
 Low turnover osteoporosis
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 The stages of bone remodeling are:

  Resting (or inactive): about 80% of the bone surface will
be in this stage at a given time
  Activation: cells on bone surface retract
  Resorption: osteoclasts remove bone, forming a
resorption pit
  Reversal: debris is removed from the pit
  Formation: osteoblasts fill the pit with new collagen
matrix
  Mineralization: the new matrix is mineralized, forming
new bone
 Osteoporosis occurs when bone resorption exceeds bone
formation, resulting in a net loss of bone tissue with
associated changes in bone architecture.
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Menopause-related Bone Loss-Type I
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 Rapid bone loss (esp in trabecular

bone)
 estradiol deficiency
 Peak Bone mass ~30 years
 Peak Bone Loss~1st decade of
postmenopause
1-2%/year
 Estrogen Deficiency
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Increased bone resorption

Estrogen promotes apoptosis of osteoclast

Estrogen deficiency causes local release of
prostaglandins, IL 6 and IL1 which stimulates bone
resorption.
Estrogen increases TGF-beta (Transforming growth
factor) from osteoblasts
Estrogen deficiency/ovariectomy increases TNF-alpha
(tumor necrosis factor) release from monocytes and
bone marrow which increases osteoclast recruitment
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THIRUVANANTHAPURAM Age-related Bone Loss-Type II

 Begins in 4th or 5th decade but continues

until 9th to 10th decade
 Slow loss of cortical and trabecular bone in
both men and women
 Partially due to decrease calcium absorption
or negative calcium balance
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Other Age-related Changes in Bone

 Increase parathyroid hormone

 Decreased 25-OH-Vitamin D
 Decreased Insulin-like Growth Factor 1
concentration
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High turnover osteoporosis-increased bone resorption

greater than increased bone formation

 Estrogen deficiency-amenorrhea/Bilateral
oophorectomy
 Hyperparathyroidism
 Hyperthyroidism
 Hypogonadism in young men and women
 Steroids, unfractionated heparin, ?coumadin (low
gamma carboxylated osteocalcin), ?cyclosporine,
medroxyprogesterone acetate, vitamin A
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Low turnover osteoporosis-decreased bone

formation more pronounced than decreased bone
resorption

 Liverdisease-primary biliary cirrhosis

 Anorexia nervosa
 Age above 50 years
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Glucocorticoid Excess
 Reduces bone formation and accelerates bone resorption.
 Reduction in bone formation
Direct inhibitory effect and increase apoptosis in osteoblasts
Decreased production of IGF-I (insulin growth factor-I)
Decreased testosterone production
 Increased in bone resorption (non-mature osteoclasts)
Increased in osteocyte apoptosis
Inhibition of gonadotropin secretion thus causing a decrease in
estrogen and androgen secretion (In vitro studies on rat bone and
osteoclast)
Increased PTH secretion resulting in 2 hyperparathyroidism which
causes decreased intestinal calcium absorption and increases renal
calcium excretion
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Glucocorticoid Excess

Bone loss is related to dose. Doses as little as

10mg a day may have adverse effects on BMD
 In a prospective, randomized, controlled trial, RA pts receiving 10 mg prednisone qd for
20 wks vs placebo showed a 7% decrease in spine BMD cf placebo.

 RA pts treated with avg 5.6 mg of prednisone qd s calcium-vitamin D supplementation

showed BMD decline of 2% and 0.9% in the lumbar spine and greater trochanter,
respectively per year.

 In a prospective, longitudinal study, pts beginning with mean dose of prednisone

21mg/day lost a mean of 27% BMD in the lumbar spine during the first year of therapy.
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THIRUVANANTHAPURAM How About Inhaled Steroids?
High-dose inhaled steroids (800 ug qd)
have systemic effects and may
adversely affect BMD
A prospective trial with 109 premenopausal women on high dose inhaled
steroids demonstrated that there was slight accelerated boneloss in the hip

Cross-sectional studies have demonstrated an inverse correlation between the

daily dose and the cumulative dose of inhaled glucocorticoid and spine
density in asthmatic patients.

Cross-sectional studies in asthmatics have found that mean total body

calcium content in pts taking inhaled steroids was 8.8 % lower than
normal subjects.
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Determinants of Peak Bone Mass

Peak bone mass related to

Genetics
Physical activity
Diet
Concomitant diseases
Lifestyle-tobacco
Other drugs
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THIRUVANANTHAPURAM Determinants of Peak Bone Mass
Genetics
Family History
Maternal inheretnce-
genes for vitamin D receptor, Sp-1 cleavage site for collagen gene, LDL
receptor related protein 5 (LRP 5)
Race
White
Low BMD@ femoral neck (T<-2.5)
• 21% Caucasians
• 16% Mexicans
• 10% African Americans

Women
According to age-adjusted rate of hip fx in a large US population-based study of hip fx in older persons,
white women, white men, black women and black men(8.07/4.28/3.06,2.38/1000)
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THIRUVANANTHAPURAM Determinants of Peak Bone Mass

Physical Activity
Diet
-anorexia nervosa
Concomitant diseases
-Hyperparathyroidism
-Vitamin D deficiency
-Calcitonin deficiency
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THIRUVANANTHAPURAM Determinants of Peak Bone Mass

Lifestyle
Consumption of high dose
• Tobacco-increase estrogen metabolism
• Caffeine
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THIRUVANANTHAPURAM Determinants of Peak Bone Mass
Other drugs

Glucocorticoids
Heparin and ?coumadin
Anticonvulsants
Loop diuretics
High dose methotrexate
High dose Vitamin A (>5000 ug/d)-not topical isotretinoin
Methoxyprogesterone acetate (5-10 mg/day vs 150mg q 12
wks)
?Cyclosporine
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THIRUVANANTHAPURAM Who should be screened for Postmenopausal Osteoporosis?

 The WHO recommendations

 Radiographic evidence of osteopenia
and/or vertebral deformity
 Loss of height, thoracic kyphosis
 Previous low-trauma fracture (i.e., a fall
from standing height)
 Prolonged corticosteroid therapy
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THIRUVANANTHAPURAM Who should be screened for Postmenopausal Osteoporosis?

 Hypogonadism in either sex (possibly to

include most postmenopausal women)
 Chronic disorders associated with
osteoporosis (e.g., hyperthyroidism and
hyperparathyroidism)
 A maternal history of hip fracture
 A low body mass index (less than 19
kg/m²)
 A low calcium intake
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THIRUVANANTHAPURAM Who should be screened for Postmenopausal Osteoporosis?

 Subjects with t score less than 2.5 should

be offered appropriate treatment,
 intervention can also be directed at
menopausal women with BMD values
between -1 and -2.5 SD
 The more general use of bone densitometry may be costly but it is
less costly than indiscriminate and frequently expensive treatment."
Genant (1999) et al.
 History and Physical
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Ask about risk factors

Tobacco hx, exercise hx
Calcium intake
Record height and weight
Pay attention to sign and sx of remediable secondary
causes or contributing factors to osteoporosis
Cushing’s syndrome, steroid tx, diabetes,
hyperparathyroidism, gastrointestinal or hepatic
diseases, immobilization.
Signs of cancer, especially multiple myeloma
Reproductive hx-time of menopause, sx of hypogonadism
(decreased libido, impotence, testicular atrophy)
 Laboratory studies
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 CBC, chem, mineral panel, TSH, LFT

Normal bicarbonate, calcium, creatinine, TSH excludes
metabolic acidosis, renal insufficiency,
hyperthyroidism, hyperparathyroidism
Normal calcium, phosphate, alkaline phosphatase and
albumin rules out osteomalacia
Normal cbc, total protein, calcium and creatinine makes
multiple myeloma unlikely
Serum testosterone should be checked in men with
osteoporosis, esp if they had diminished libido,
impotence or testicular atrophy
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Additional Laboratory Studies
 25-OH vitamin D and PTH should be obtained in elderly with
poor Vitamin D intake or has hx of GI diseases (malabsorption or gastrectomy), liver
disease, or anticonvulsant tx. Vitamin D deficiency is associated with low 25-OH
Vitamin D and high PTH (secondary hyperPTH)
 Urinary cortisol excretion or overnight
dexamethasone suppression test should be ordered if
Cushings syndrome is suspected
 PTH should be measured in pts with hypercalcemia, hypercalciuria, hx of
renal stones or osteopenia that his most prominent in cortical sites
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Laboratory studies
Markers for bone turnover are not recommended
routinely for the diagnosis of osteoporosis

 Useful for monitoring efficacy of antiresportive

therapy
1/3 of women with estrogen tx and 1/6 of women on
bisphosphonate tx continue to lose bone; therefore, some
feel that it should be ck’d at baseline and in 3 months to
ensure that proper effects are occurring as many will not
have repeat DEXA in 2 yrs.

 May indicate future risk of bone loss and

fractures
 Methods of Screening
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1. Dual x-ray absorptiometry

2. Single photon absorptiometry
3. Dual photon absorptiometry
4. Quantitative computed tomography
5. Ultrasonography
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Dual x-ray absorptiometry

 Gold standard
 1/10 the radiation of the CXR
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Terminology
 Bone Mass
 Bone Mineral Content
 Bone Mineral Density (BMD)
 T Score
 Z Score
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 Bone Mass Amount of bone tissue in the

whole skeleton or in a particular segment of
bone.

 Bone Mineral Content The amount of

mineral contained in a defined section of
bone.
 How BMC is measured?
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 Calcium absorbs much more radiation than protein or soft

tissue. The amount of x-ray energy that is absorbed by
calcium in a section reflects the bone mineral content
(BMC)
 BMD
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 Bone mineral density is defined as the

average concentration of mineral per
unit area of bone

 Gms/cm2
 Volumetric Bone Mineral Density
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 HOLOGIC DEXA Scanner
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Z score
 A Z-SCORE is the number of standard deviations
the measurement is above or below the AGE-
MATCHED MEAN bone mineral density.

 A Z score of 0 means that the patient has a value

that is exactly at the mean for her age.
 A Z score of -2.0 means that the patient has a
BMD, that is 2 SDs below the mean BMD value
of others of the same age.
 T Score
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 A T-SCORE is the number of standard deviations

the bone mineral density measurement is above or
below the YOUNG-NORMAL MEAN bone
mineral density.

 A T score of 0 means that the patient has a BMD

value that is exactly at the mean for young adults.
 A T score of -2.5 means that the patient has a
BMD value that is 2.5 SDs below the mean.
 Spine Dexa
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 Spine Dexa
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 Hip Dexa
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 Hip Dexa
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THIRUVANANTHAPURAM Hip vs Spine vs other Peripheral Sites

 BMD at one site usually correlates well with

BMD at other sites (only 15% discordance)
 Some studies suggest the risk for fx at a
particular site is best estimated by measuring
BMD at that site.
 Best if can measure BMD at 2+ sites esp if you
suspect pt has regional osteopenia—ie pt with
childhood poliomyelitis
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Hip vs Spine vs other Peripheral Sites

 Hip is usually preferred at any age but spine

BMD is more reliable in those <65 yo bc less
vascular calcification and osteophytes
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Nonpharmacologic Treatment

1. Diet
2. Exercise
3. Tobacco cessation
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Diet

Take 1500 mg/day of elemental calcium in

divided doses with meals
Take 800 IU/day of vitamin D
Take 20 mg protein intake

*American diet usually provides only <600 mg Ca/day

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THIRUVANANTHAPURAM Calcium and Vitamin D
Estimation of calcium intake
Each serving is contains 300 mg
240 cc milk or yogurt, 1 oz hard cheese, 2
servings of ice cream
Calcium carbonate and other forms
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THIRUVANANTHAPURAM Calcium Carbonate

• Cheapest
• Doses >500 mg/d should be given as divided dose
• Poorly absorbed in achlorhyric pts unless taken with meals
but note that this might decrease iron absorption by 50%
• Chewable preparations are preferred given it poor
solubility
• Remember:
Calcium carbonate is 40% elemental therefore a 500mg tablet is only
200mg of elemental
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THIRUVANANTHAPURAM Calcium Citrate
• Well-absorbed even in fasting state

Calcium carbonate from oyster shells and bone meal

theoretically have lead but levels are so low and
calcium blocks lead absorption that it is unlikely to be a
health risk
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Calcium and Vitamin D
Factors that affect calcium absorption:
• Prior GI surgery or short-gut syndrome

Side effects of high calcium intake:

• Dyspepsia and constipation

• Risk of nephrolithiasis in o/w healthy pts appear to be

unfounded.
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Nonpharmacologic Treatment
Exercise
Prudently exercise for 30 minutes three times a week.
Any weight-bearing exercise is acceptable and preferable.
Detrimental if excessive exercise occurred leading to
amenorrhea
 Exercise
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According to a meta-analysis, both impact and

nonimpact exercise had a positive effect on
lumbar spine bone density but only impact
exercise had a positive effect at the femoral
neck in postmenopausal women
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Nonpharmacologic Treatment
Tobacco cessation

Tobacco accelerates bone loss by accelerating estrogen

metabolism

Evidence-twin studies show that twin that smoked 1 ppd

throughout adult life was associated with a 5-10%
reduction in bone density
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Pharmacologic Treatment
 Estrogen with progesterone
 Bisphosphonates
 Calcitonin
 Selective estrogen receptor modulators
 PTH
 Fluoride*
 Calcitriol*
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THIRUVANANTHAPURAM Estrogen with Progesterone

 FDA approved for prevention and treatment of

osteoporosis
 Considered 1st line especially in early
menopause unless pt does not wish to deal with
vaginal bleeding or mastalgia
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Risk:
Increased risk of breast cancer

Increased risk of endometrial hyperplasia and ca

(prevented with progesterone)
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Estrogen with Progesterone

Benefit:
Prevention of osteoporosis
Prevention of postmenopausal vasomotor instability sx like
hot flashes, sweats, and nocturnal awakenings
Relief of urogenital atrophy, dypareunia, urinary frequency
? Reduction in cardiovascular risk factors
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Estrogen with Progesterone

 Dose of conjugated estrogen (Premarin) 0.625

mg/day
 Other oral estrogens are effective—ethinyl estradiol 35 ug, estrone SO4 0.625
to 1.25 mg, and esterified estrogen (estratab) 0.3, 0.625, 1.25 mg and
micronized estradiol 0.5 mg
 Transdermal estrogens have similar effects but does not have the favorable
lipid effects as the orals.
 Bone loss begins once taken off tx
 Treatment
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Generally believed that women who start estrogens

earlier and indefinitely experience greater
increases in BMD
Based on meta-analysis of trials of estrogen therapy
suggested that the reduction in fracture risk was mainly
in women who started estrogen soon after the
menopause
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THIRUVANANTHAPURAM Estrogen with Progesterone

 Concomitant administration of a progestin to

prevent endometrial hyperplasia does not interfere
with the beneficial effect of estrogen on bone
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THIRUVANANTHAPURAM Bisphosphonates

 Considered 1st line, especially those >60 years

 Contraindicated in pts with esophageal stricture or

motility dysfnc. Numerous endoscopic studies
have compared alendronate and risedronate for
adverse effects on the esophagus, stomach and
duodenum with conflicting results. Note these
studies often were 2 wks and it is unknown
whether these endoscopic lesions will result in
clinically significant outcomes.
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 High affinity for bone leads to rapid clearing of bisphosphonates (BPs)

from the circulation and localization to hydroxyapatite in bone mineral
surfaces, in particular, localization to sites of osteoclast activity.
 The bone surface under the osteoclast is acidified during resorption.
 The ability of BPs to bind to calcium is reduced in an acid
environment. Therefore, the BPs are freed from the bone surface and
are then more readily taken up by the neighboring osteoclast, which is
highly endocytic during bone resorption. The exact mechanism of
internalization has not been determined.
 Once internalized, BPs act as analogs to pyrophosphate and interfere
with intracellular metabolic pathways required for normal cell
function. This includes:
 Disruption of the ruffled border
 Inhibition of lysosomal enzymes
 This may ultimately lead to apoptosis, or cell death.
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Alendronate

 FDA approved in 1995 for tx of osteoporosis-

10/70 mg

 Almost 1000 postmenopausal women (mean age 64) were randomized to alendronate vs
placebo for 3 years resulted in an increase in BMD of 8.8% in lumbar spine and 5.9% in
hip cf placebo

 Fracture Intervention Trial I (FIT)-in postmenopausal women with low hip BMD
with known vertebral fx at baseline were randomized to alendronate vs placebo. It found
that new radiographic vertebral fxs were decreased by 47% and that hip fx and wrist fx
were reduced by 51% and 48%, respectively in the alendronate group
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Combination Therapies

Since estrogen and bisphosphonates use

different mechanism to inhibit bone
resorption, combination therapy has an
additive effect.
 Treatment
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Calcitonin
 FDA approved in 1994 for treatment only

 Endogenous hormone secreted by parafollicular C

cell of the thyroid. It acts directly on osteoclasts to

inhibit bone resorption.
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THIRUVANANTHAPURAM Calcitonin

 Nasal 200 IU/day

 Watch for tachyphylaxis
 Generally considered 3rd line therapy except in pts with
substantial pain from an acute osteoporotic fractures.
Once acute pain has subsided or if it does not subside in 4
weeks, then would switch to another tx
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Selective estrogen receptor modulators
Selective estrogen receptor modulators SERMs
Raloxifene and tamoxifen
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THIRUVANANTHAPURAM Raloxifene (Evista)

 Approved by the FDA for the prevention and

treatment of osteoporosis.
 Increase BMD of spine and femoral neck by 2% and
decreases vertebral fx
 It has estrogen activity in bone and CV tissue but
not in reproductive tissue
 It increases bone mineral density and reduces total
and LDL cholesterol s causing endometrial
hyperplasia
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Raloxifene (Evista)-60 mg

 Less potent antiresportive agent than

conjugated estrogen (0.625mg) or low dose
alendronate in postmenopausal women
with normal or low bone density

 Based on the MORE study—

– NNT 42 with previous vertebral fx
– NNT 113 without previous vertebral fx
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THIRUVANANTHAPURAM What about anabolic agents—PTH?

• PTH preferentially stimulates bone formation vs

resorption.
 Treatment
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Fluoride
Not recommended
Stimulates bone formation (trebecular >>cortical)
especially in the spine.
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Fluoride

More recent studies have used lower doses of a slow

released preparation (50 mg/day) or MFP (sodium
monofluorophosphate at 20mg/day—a highly soluble
fluoride salt that has less GI side effects )

Currently not FDA approved or available in the US

Fluoride has a narrow therapeutic window

 Treatment
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Calcitriol-1,25 hydroxy Vitamin D

FDA approved for secondary causes of osteoporosis such

as hypoparathyroidism, hypocalcemia, metabolic bone
dz in renal pts.
Action-promotes calcium absorption
0.25ug bid
Must be on a low calcium diet
Monitor for hypercalcemia, hypercalciuria and renal
insufficiency
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THIRUVANANTHAPURAM What about Statins?

Data from observational studies are conflicting.

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Glucocorticoid-related Osteoporosis

Treatment:
• Bone density usually increases after discontinuation of the
exogenous steroids.
• Note that little bone loss occurs in pts tx with steroids >7.5
mg/d, median 10mg/day if supplemented with 1500 mg/d
calcium and Vit D 800 IU/d
• Supplement with calcium (1000 mg elemental) and Vit D
(500 IU)
RA pts on avg of 5.6 mg/d prednisone and on chronic calcium
(1000mg elemental) and Vit D (500 IU) gained 0.7 and 0.8% bone
per year at the lumbar spine and trochanter, respectively (cf 2 and
0.9% loss on placebo)
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Glucocorticoid-related Osteoporosis

Bisphosphonates:
Calcium
Vit D
 Inhaled steroids
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How about inhaled steroids?

Recommendations:

Keep dose of inhaled glucocorticoids below 400 ug/d or

at least <800 ug/d
Use spacers to reduce the amount of glucocorticoid
swallowed
Using fluticasone or budesonide instead of
beclomethasone at equivalent doses may have fewer
systemic effects
 Osteoporosis in Men
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 Less common than in women

1.5 million men >65yo have osteoporosis
3.5 million >65 yo have osteopenia
 Hip fractures begin 5-10 yrs later than in women
 Prevalence of hip/vertebral fx is approx 1/3 that in women
 Osteoporosis in Men
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Pathogenesis:
BMD related to:
peak bone mass (in 20yrs)
rate of bone loss (1%/year)
*over a lifetime
20% cortical bone loss
30% trebecular bone loss
 Bone Loss in Men:
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Related to :
Genetics
Tobacco and Etoh
Calcium supplementation
Physical activity and muscle strength
Low testosterone
Low estradiol levels
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Etiology of osteoporosis in men

Can be identified in 40-60% with osteoporotic fx

Hypogonadism
Glucocorticoid therapy
Gastrointestinal diseases
Vitamin D deficiency
Anticonvulsant tx
Alcohol abuse
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Which Men Should We Screen?

 The World Health Organization does recommend

screening hypogonadal men, since results may
influence treatment :
 Low-impact fractures (fragility fractures)
 Hypogonadism
 Radiographic osteopenia or compression fracture
 Long-term treatment with glucocorticoids
 Primary hyperparathyroidism
 .
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1. Treatment of the cause-ie tob, steroids
2. Weight bearing exercises
3. Bisphosphonates-alendronate 70mg/day, iv
pamidronate (60 mg iv over 2 hrs q 12 wks for
48 wks).
4. Testosterone replacement-controversial

*All should be on Calcium 1000mg/d and Vit D 800

IU/day
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 BMD is it worth?
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 Bone mineral density predicts fracture better than

blood pressure predicts stroke and cholesterol
level predicts MI.
 Bone density by any method at any site predicts
the risk of osteoporotic fracture.
 Each standard deviation decrease in bone mineral
density (BMD) doubles the risk of fracture
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After Fracture?
 After the first hip fracture, 30% of patients will
fracture the second hip
 nearly 20% of the women who develop a new
vertebral fracture will fracture again within a
year.
 And the five year survival rate following a
vertebral fracture is equally worse as a hip fracture
 It is clear that bone loss cannot be completely
reversed but fracture risk can be decreased by
intervention
 Awareness
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 Almost two thirds of hip fracture cases are not

prescribed treatment within the year after a
fracture

 Source: IOF 2000 International Survey: www.osteofound.org

 Torgerson DJ, Dolan P. Ann Rheum Dis 1998; 57: 378-9
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