OSTEOPOROSIS

Definition
 Osteoporosis is defined as a “skeletal disorder characterized by
compromised bone strength or low bone mass predisposing a
person to an increased risk of fracture.
 “Brittle bone” disease
 May be natural consequence of aging to some extent … but also
preventable
 Bone strength reflects the integration of bone mass and quality.

 Clinically, osteoporosis is categorized as postmenopausal, age-

related, or secondary.

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 Epidemiology
 In the United States, 8 million women and 2 million men are
estimated to have osteoporosis.

 Men experience fewer osteoporosis-related fractures

(only approximately 20%) than women.

 Men's bones also have a mechanical advantage because

the larger bone diameter makes them more fracture-
resistant.
 The etiology of male osteoporosis tends to be
multifactorial. But in female is due to estrogen defieicncy.

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Bone composition
 The skeleton is composed of mostly cortical
bone “compact” (80%) with some trabecular
bone (20%). Trabecular bone “spongy” type
is 10 times more metabolically active
compared with cortical bone.

Bone is made of collagen and mineral

components. The collagen component gives
bone its flexibility and energy-absorbing
capability. The mineral component gives
bone its stiffness and strength.

 The correct balance of these substances is

needed.

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 Bone cells
There is two types of bone cell.
 Osteoblasts – help create new bone formation tissue
 Osteoclasts – help resorption of old bone tissue.
 the receptor activator of nuclear factor kappa B ligand
(RANKL) stimulates mature osteoclast activation and
bone adherence to resorb bone
 imbalance between bone formation and bone resorption lead to
osteoporosis
Bone cells
Etiology of osteoporosis

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 Pathophysiology
1. Bone loss occurs when bone resorption > bone formation,
leading to high bone turnover and decrease bone mineral
density (BMD).
2. Failure to reach a normal peak bone mass

3. In addition, the increased quantity of immature bone that is

not adequately mineralized leading reduced bone quality and
structural integrity are impaired.

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 POSTMENOPAUSAL
 Postmenopausal osteoporosis affects primarily trabecular
bone (vertebral bone) with fractures occurring predominantly
at vertebral and distal forearm sites.

 The rate of bone loss commonly accelerates at menopause

due to a decline in estrogen hormone production.

Estrogen deficiency increases bone resorption more than

formation.

Estrogen deficiency during menopause increases proliferation,

differentiation, and activation of new osteoclasts and prolongs
survival of mature osteoclasts

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 Age-related osteoporosis
 that affects both cortical and trabecular bone and leads to
vertebral, hip, and wrist fractures.
 Age birth – 30 years
 osteoblasts > osteoclasts

 Age > 30 years

 osteoblasts = osteoclasts, then osteoblasts < osteoclasts after 50

years

 Bone resorption increases with age. Age-related osteoporosis occurs

mainly because of calcium, and vitamin D deficiencies due to change in
their absorption and metabolism leading to accelerated bone turnover and
reduced osteoblast formation.

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 DRUG-INDUCED
 Secondary osteoporosis is caused by either diseases or
medications on both bone types.
 Disease include hyperparathyroidism, rheumatoid arthritis,
hypogonadism
 Systemic glucocorticoids, thyroid hormone replacement, some
antiepileptic drugs, depot medroxyprogesterone acetate and heparin
use.
 Some anticonvulsants, like phenobarbital and phenytoin, hasten
vitamin D metabolism and the resultant effects can lead to
osteoprosis.
 Heparin stimulate osteoclast activity (exact mech not known) Low-
molecular-weight heparins such as enoxaparin may pose less risk of
bone loss.

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 Risk factors
 Current Smoker
 Heavy alcohol intake
 low body mass index (<19 kg/m2),
 Family history: history of osteoporotic fracture in a first-degree
relative
 personal history of low-trauma fracture as an adult
 Old age
 rheumatoid arthritis, hypogonadism, hypeparathyroidism

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Diagnosis
 Osteoporosis is diagnosed by BMD (bone mineral density)
measurement or presence of a fragility fracture.

General:
Many patients are unaware they have osteoporosis until testing for a
fracture.

Fractures occur after bending, lifting, or independent of any activity.

Signs &Symptoms :
 Vertebra: mainly asymptomatic or sever lower back pain, decrease

height and sometimes curve the spine (kyphosis).

 Non vertebra: Pain, Immobility, swelling at fracture site.

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 Laboratory Investigation
 For secondary causes: Thyroid-stimulating hormone,
parathyroid hormone, complete blood count, creatinine, liver
enzymes, calcium, phosphorus, alkaline phosphatase, 25-
hydroxyvitamin D.

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 Bone density measurement
 . Measurement of central (hip and spine) BMD with dual-energy
x-ray absorptiometry (DXA) is the gold standard for osteoporosis
diagnosis predict fracture risk, and influence treatment decisions.
 Portable equipment can be used for osteoporosis screening in
the community. Bone pain, postural changes (i.e., kyphosis), and
loss of height are simple useful physical examination findings
warrants further investigation
 A T-score is a comparison of the patient’s BMD to BMD of a
healthy population. The T-score is the number of standard
deviations from the mean of the reference population.
Osteoporosis is a T-score at or below –2.5.

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 Treatment Desired Outcome
 reducing pain and deformity, and improving quality of life
 Optimize and stabilize bone mass
 reduce the future incidence of osteoporosis
 improving functional capacity and mobility
 identify risk factors for developing osteoporosis and resolve
reversible risks.

 This require both pharmacologic and non-pharmacologic

treatment

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 NON PHARMACOLOGIC TREATMENT
 Because excessive caffeine consumption increases calcium
excretion, caffeine intake should ideally be limited.
 Smoking cessation: Cigarette smoking is associated with up to an
80% increased relative risk for hip fracture.

 Alcohol increased risk for osteoporosis. Alcohol increases bone

resorption by increasing RANKL and decreases bone formation
by increasing oxidative stress
 Physical activity or exercise prevents osteoporotic fractures. It
decrease the risk of falls and fractures by improving muscle strength,
coordination, balance, and mobility.

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 Diet
 A well-balanced diet with adequate calcium and vitamin D is
essential for healthy bones mainly Dairy products (milk and
cheese).
 Vitamin K is a cofactor for carboxylation (activation)
of proteins, such as osteocalcin, involved in bone formation.
Vitamin K deficiency can contribute to bone loss and
increase fracture risk.(vit K supply is questionable)
 Isoflavones: phytoestrogens are plant-derived compounds
that possess weak estrogenic agonist and antagonist effects
throughout the body EX: Genistein is isoflavone in
soybeans available as a supplement or part of a calcium
combination product.

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PHARMACOLOGIC THERAPY
1-Antiresoptive therapy:
A-natural supplement:
(calcium, vitamin D)
B-prescription medication:
1.Biphosphonate,

2.RANK ligand inhibitor: Denosumab

3.Raloxifene,

4.Calcitonin,

5.Estrogen

2-Formation Medication: Teriparatide

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Guidelines of ACR

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 Calcium
 taken in adequate amounts to prevent bone destruction. Usually combined
with vitamin D and osteoporosis medications
 Calcium carbonate (Calcimate®) is the salt of choice because it
contains the highest concentration of elemental calcium (40%) and is the
least expensive. It should be ingested with meals to enhance absorption
from increased acid secretion.
 Calcium citrate or acetate: absorption is acid independent and need not
be taken with meals.
 maximum single doses of 600 mg or less of elemental calcium are
recommended
 SE: Constipation
treated with increased water intake, and
dietary fiber
 Vitamin D3
Vitamin D deficiency results from insufficient intake, decreased
sun exposure, decreased skin production, decreased liver and
renal metabolism
 Vitamin D and PTH work together to maintain calcium
homeostasis. Supplemental vitamin D maximizes intestinal
calcium absorption and has been shown to increase BMD
 Dose: 200–1000 units/day.
 Usually found as alone or combination with calcium or as
alfacalcidol “Bone one®”(vitamin D precursor)

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 Bisphosphonates
(eg. Alendronate (Fosamax), risedronate (Actonel), ibandronate
(bonaprove), zoledronic acid)
-Binds to bone, inhibits osteoclast activity
bisphosphonates provide the greatest BMD increases and fracture risk
reductions. Fracture reductions are demonstrated as early as 6 months.

BMD increases are dose dependent.

After discontinuation, the increased BMD is sustained for a prolonged

period for years
Taken once daily, once weekly, once monthly. Most patients prefer
once-weekly or once-monthly bisphosphonate administration over daily
therapy
 Bisphosphonates
-Available in tablet mainly or may injectable forms (IV)

-Tablets are poorly absorbed (bioavailability 1% to 5%) but work

well if taken correctly.

Take on empty stomach in the morning with at least 200 ml of plain

tap water (not coffee, juice, mineral water, or milk)
Remain upright and do not eat for ½-1 hour after taking

Duration of bisphosphonate therapy has not been defined, but safety

data exist for periods of 10 to 13 years
adverse effects are Esophageal, gastric, or duodenal irritation,
perforation, ulceration, or bleeding. Also, nausea, abdominal pain,
and dyspepsia.
Bisphosphonates
 Denosumab (Prolia)
 Denosumab is FDA approved for treatment of osteoporosis in
women and men at high risk for fracture. Also, to prevent
osteoprosis for men receiving androgen-deprivation therapy for
nonmetastatic prostate cancer and in women receiving adjuvant
aromatase inhibitor therapy for breast cancer.

 Denosumab is a fully human monoclonal antibody that binds to

RANKL, blocking its activity on receptor

 No dosage adjustment is necessary in renal impairment

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Denosumab
 The BMD effects are similar to weekly alendronate.
 Activity appears to dissipate upon medication discontinuation
 The product is available as a refrigerated prefilled pen or
single-use vial administered subcutaneously

 Denosumab was generally well tolerated. Dermatologic

reactions not specific to the injection site such as dermatitis,
eczema, and rash. Serious infections including skin infections. If
any signs of skin infection such as cellulitis.

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 Parathyroid Hormone (eg. teriparatide)
 The first 34 amino acids in human parathyroid hormone, Stimulates
more bone formation than resorption
 (second line): Used for those who cannot tolerate bisphosphonates
or who continue to have fractures on bisphosphonates
 Discontinuation of therapy results in a decrease in BMD, but some
antifracture efficacy appears to be maintained.
 Provided as a daily SC injection or as pen. The initial dose
should be given lying or sitting to avoid orthostatic hypotension
 Transient hypercalcemia may occur (calcium monitoring)
 Estrogen Agonist/Antagonist (eg. Raloxifene)
 estrogen agonists antagonists (known previously as selective
estrogen receptor modulators or SERMs).

Raloxifene (Evista®) is an estrogen agonist on bone but an

antagonist on the breast and uterus.

is approved for prevention and treatment of postmenopausal

osteoporosis.

Less effective than bisphosphonates, After discontinuation, the

beneficial effect is lost and bone loss returns

SE: DVT and stroke risk. Endometrial bleeding.

 Estrogen therapy (ET)
 Protective anti-resorptive effect for post menopausal osteoprosis

 For short term treatment to avoid SE: Increases the incidence

of breast cancer, coronary heart disease, stroke, and venous
thromboembolism.
 less than those from bisphosphonates or teriparatide but greater
than those from raloxifene or calcitonin.
 Effect on BMD is dose dependent When ET is discontinued,
fracture protection is lost.
 Available as oral and transdermal preparation
 Calcitonin
Hormone released from the thyroid gland Binds to osteoclasts, inhibits
resorption

Salmon-derived because more potent and longer lasting

Less effective than other treatments (third line)

Helpful in reducing pain from fractures of spine mainly. it should be

prescribed for short-term treatment (4 weeks)

Nasal spray is most popular preparation > SC route. The intranasal dose is
200 units daily, alternating nares every other day. Subcutaneous
administration of 100 units daily is available but rarely used because of
adverse effects (allergic reaction, rhinitis and epistaxis) and high cost
 Testosterone
 Although it is not FDA indicated for osteoporosis, the male
osteoporosis guideline recommends testosterone alone for men
with testosterone concentrations <200 ng/dL if low fracture
risk and in combination with an osteoporosis medication if
fracture risk is High
 Testosterone is converted to estradiol, which decreases bone
resorption in men and women.
 Testosterone has increased BMD in men with low testosterone
concentrations, but has no effect if testosterone concentrations
are normal

 Preparation: capsule or injection, gels

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 EVALUATION OF THERAPEUTIC OUTCOM
 BMD measurements can be obtained every 1 to 2 years for
monitoring bone loss and treatment response.

 Patients should be asked about possible fracture symptoms (e.g.,

bone pain, disability) at each visit.

 Medication adherence and tolerance and side effects should be

evaluated at each visit.
 GLUCOCORTICOID-INDUCED OSTEOPOROSIS
 The most commonly drug-induced osteoporosis. It Decrease
osteoblast activity, increase resorption, decrease calcium
absorption, increase renal calcium excretion
 Oral daily doses greater than 7.5 mg of prednisone or
equivalent show significant risk.
 Bone losses are rapid, with the greatest decrease occurring during
the first 6 to 12 months of therapy.
 inhaled glucocorticoids have no effect on BMD or fracture risk
unless high doses is used (greater than 800 to 1200 mcg for
beclomethasone (clenil) 800 to 1000 mcg for
budesonide(miflonide), 750 mcg for fluticasone (flixotide)

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 TREATMENT
 According to the American College of Rheumatology (ACR) guidelines.
All patients starting or receiving long-term systemic glucocorticoid
therapy should:

 1-receive at least 1,500 mg elemental calcium and 800 to 1,200 units of

vitamin D daily and practice a bone-healthy lifestyle.

 2- measuring BMD at the beginning of chronic therapy and follow up

monitoring with DXA in 6 to 12 months.

 3-receive preventive bisphosphonate therapy if GC will be used for

more than 3 months.
 4-Bisphosphonates are the best therapeutic choice for patients with
teriparatide is the second choice.

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