‫مكتبة الشروق‬
Osteoporosis  Metabolic bone disease ( severe reduction in bone mineral density and risk of fractures. )
4 major types of cells in bone  osteocyte (in bone matrix ) , osteoblast & osteoprogenitor cell (peri &endosteum ) , osteoclast (in endosteum only)
osteoprogenitor cell  osteoblast  osteoid (organic portion) mineralization mature osteocyte
osteocytes
Osteoclasts
Osteoblasts (immature bone cell )
osteoprogenitor cell
Derived from hematopoietic precursors.
Derived from mesenchymal cells.
Terminally
Stem cell whose
divisions produce
Multinucleate cell  secrete acids &
Responsible for bone formation, secrete and
differentiated
osteoblast
enzymes  dissolve bone matrix (bone
mineralize osteoid (organic portion of the bone ).
osteoblasts.
resorption )
Require weeks to resorb bone
Need months to produce new bone.
Direct the timing and
Control bone resorption carried out by osteoclasts location of bone remodeling
Bone resorption is always followed by bone formation, a phenomenon referred to as coupling .
Any process that ↑ the rate of bone resorption results in net bone loss over time
Contents of bone matrix (laid down by ostroblasts )  25% water & 25 % ptn or organic matrix ( 95% collagen fibers , 5% chondroitin sulfate )
& 50% crystalized mineral salts hydroxyapatite (Ca phosphate ) + other ( lead , gold , strontium , plutonium , etc . )  provide regidity
Molecular mechanism of bone resorption and formation
The receptor activator of nuclear factor-Kappa B ligand (RANKL)/RANK /osteoprotegerin (OPG) system is the final common pathway for bone
resorption.
Osteoblasts and activated T cells in the bone marrow produce the RANKL cytokine; RANKL binds to RANK expressed by osteoclasts and
osteoclast precursors to promote osteoclast differentiation; osteoblasts produce OPG which inhibits RANK-RANKL by binding and sequestering
RANKL.
Dr.Mahmoud Salah
Page1
‫مكتبة الشروق‬
 Aging and loss of gonadal function are the 2 most important factors contributing to osteoporosis.
 Estrogen deficiency:
↑ bone loss in postmenopausal women and also in men.
Osteoblasts, osteocytes and osteoclasts all express estrogen receptors.
After menopause, estrogen deficiency leads to ↑ RANKL expression by osteoblasts and ↓ release of OPG.
↑ RANKL results in recruitment of higher number of preosteoclasts, ↑ activity, vigor and lifespan of mature osteoclasts.
In estrogen deficiency, T cells promote osteoclast recruitment, differentiation and prolonged survival via IL-1, IL-6 and (TNF)-alpha.
T cells also inhibit osteoblast differentiation and activity and cause premature apoptosis of osteoblasts through IL-7.
Estrogen deficiency sensitizes bone to the effects of PTH.
 Aging:
a. Mainly associated with ↓ osteoblasts production in proportion to the demand.
b. After the third decade of life (35 years ) , bone resorption exceeds bone formation.
 There are 206 bones in body ( bones that carry body weight lower limbs , hip bone , vertebral column (more expsoed to fractures )


Vertebral fractures ssigns and Symptoms:
physical examination, patients with vertebral compression fractures show:
 Asymptomatic until fracture occurs.
1. Point tenderness over the involved vertebra.
 2/3 of vertebral fractures are painless.
2. Thoracic kyphosis with ↑ cervical lordosis (dowager hump).
 Acute pain may follow a fall or minor trauma.
3. Ssubsequent loss of lumbar lordosis.
 Pain is localized to a specific, identifiable, vertebral level.
 Pain may be sharp, nagging (persistent) or dull.
4. ↓ Height of 2-3 cm after each vertebral compression fracture and




progressive kyphosis.
Movement ↑ pain; pain may radiate to the abdomen.
Paravertebral muscle spasms ↑ by activity and ↓ by lying supine.
Patients remain motionless in bed to ↓ pain.
Acute pain usually resolves after 4-6 weeks.
 Multiple fractures with severe kyphosis → Chronic pain

Hip fractures signs and symptoms:
Dr.Mahmoud Salah
Page2
‫مكتبة الشروق‬
1. Pain in the hip region, anterior thigh, medial thigh and or medial knee during weight-bearing or attempted weight-bearing of the involved
extremity.
2. ↓ Hip range of motion (ROM) (internal rotation and flexion). & External rotation of the involved hip while in the resting position.

1. CBC → Anemia
Lab Diagnosis ( for high risk osteoporosis ) :
2) TSH level → hyperthyroidism (  low TSH level ) : associated with osteoporosis.
3) Vit. D : insufficiency  osteoporosis.
4) Serum protein electrophoresis → Multiple myeloma may lead to osteoporosis.
5) 24 hour urine calcium/creatinine:
a. Hypercalciuria may be associated with osteoporosis; further investigation  measure intact PTH hormone and urine pH may be indicated.
b. Hypocalciuria may indicate malabsorption; further evaluated (measure serum Vit.D and testing for malabsorption syndromes e.g. Celiac sprue.)
6. Testosterone and LH/FSH: male hypogonadism is associated with osteoporosis.

T-score: is the bone mineral density (BMD) compared with what is normally expected in a healthy young adult of the same sex, or is the
number of units — called standard deviations — that the BMD is above or below the average.
 According to T-score bone condition is classified into:
1. Normal bone density: T-score is -1 or above.
2. Osteopenia: T-score is -1 to -2.5, may lead to osteoporosis.
3. Osteoporosis: T-score is -2.5 and below.

Z-score: is the BMD compared with that of persons matched for age and sex.
Z-score ≤ -2 → below the expected range for age.
Z-score > -2 → within the expected range for age.
Dr.Mahmoud Salah
Page3
‫مكتبة الشروق‬
a) Female sex and white race.
B) Delayed puberty and hypogonadism.
d) COPD disease and RA inflammatory cytokines →bone resorption).
C) Hyperparathyroidism, hyperthyroidism.
e) Poor nutrition, long-term low-calorie intake.
F) Early menopause (before age 45) or prolonged premenopausal amenorrhea.
g) Estrogen deficiency.
i) Drugs: glucocorticoids, heparin, anticonvulsants, excessive levothyroxine, (GnRH) agonists, lithium, cancer drugs.
j) Body mass index (BMI) < 21 kg/m2 or weight < 58 kg.
L) ↓ Calcium and vitamin D intake.
k) Family history of osteoporosis, spine or hip fractures.
M ) Sedentary lifestyle, ↓ mobility.
O) Dementia → Poor nutrition and poor health condition.
Q) Previous fractures and history of falls.
N) Cigarette smoking and alcoholism.
P) Impaired eyesight despite adequate correction ( ↑ Risk of falls).
R) Previous fracture not caused by severe trauma after age 40–45 in women.
 Recommendations to reduce risk of osteoporosis
 Avoid smoking and falls & Encourage regular weight-bearing and muscle-strengthening exercise. & adequate intake of calcium and vitamin D.
Assessment. : I ) Dual-energy x-ray absorptiometry (DXA): Gold standard.
II ) Quantitative computed tomography (QCT).
QCT
DXA
Dr.Mahmoud Salah
Page4
‫مكتبة الشروق‬
Radiography vs CT  both based differential attenuation of X-rays passing through body
 Radiography  shadowgraph (using X-ray light source )
 CT  cross-sectional image &image computed from pencil beam intensity measurements through only slice of interest
Routine exaimnation for vertebral volumn  imaging
Vertebral imaging: To identify vertebral fractures as they are often asymptomatic:for
(a) T-score: ≤ - 1.0 in women ≥ 70 y old, men ≥ 80 y old.
(b) T-score: ≤ -1.5 in women 65–69 y old, men 70–79 y old.
(c) Postmenopausal women or men ≥ 50 y old with the following risk factors.
(1) Low-trauma fracture: a fracture resulting from a fall from a standing position or lower
(2) Historical height loss ≥ 4 cm (since peak in adulthood).
(3) Prospective height loss ≥ 2 cm (measured at medical assessments).
(4) Recent or ongoing long-term glucocorticoid treatment.
d) Follow-up needed only if new back pain or further height loss is documented
IV. Fracture Risk Assessment Tool (FRAX) score: ( 10 years expectation )
(a) for patients with low BMD of hip.
(b) For women 40–90 y old and men ≥ 50 y old.
 Recommended BMD testing by DXA :
Initiation of drug therapy:
I.
Hip or spine fracture.
II. BMD T-score: ≤ −2.5.
III. BMD T-score: −1.0 to −2.5 at the femoral neck or spine and the 10-year
a) Women ≥ 65, men ≥ 70.
b) Men 50–69y of age with previous fractures or risk factors of
probability of hip fracture is ≥ 3% or the 10-year probability of major
osteoporosis-related fracture is ≥ 20% based on the FRAX system.

(c) Assess need for pharmacological treatment in osteopenia
Follow up on BMD-DXA every 2 years.
osteoporosis.
c) All postmenopausal women with medical causes of bone loss.
 Major risk factors: < 2 years.
& Normal T-score: > 2 years
Bisphosphonates & Calcium & Vit. D & Selective estrogen receptor modulators & Calcitonin-salmon & Teriparatide & Denosumab & hormones
Dr.Mahmoud Salah
Page5
‫مكتبة الشروق‬
1. Bisphosphonates (Alendronate, risedronate, ibandronate, zoledronic acid).
2. Calcium
a. Inhibits normal and abnormal bone resorption.
a. Maintain normal Ca conc. and prevent hypocalcemia associated
b. 1st -line therapy; exception: ibandronate 2nd -line therapy.
c. Reduces vertebral and nonvertebral fractures (except: ibandronate
with other drug treatments for osteoporosis.
b. Elemental Ca intake: Avoid doses higher than 2500 mg/day.
Higher doses may  risk of constipation, contribute to kidney
reduces only vertebral fractures).
d. Contraindications:
stones, and inhibit absorption of zinc or iron.
1. Hypocalcemia: correct before therapy; ensure adequate Ca&vit. D intake.
2. Abnormalities of esophagus (oral bisphosphonates ↑ esophagitis,  risk is
higher in patients non-adherent to use instructions)
c. Most common forms: Ca carbonate (take with food), Ca citrate.
3. Vitamin D:  calcium reabsorption. & Goal: 30 ng/mL in adults.
4) Calcitonin-salmon:
3. Inability to stand or sit upright for 30 min (sit or stand upright for at least
30 min after administration to esophageal side effects).
4. Oral bisphosphonates should be taken with plain water only, not coffee,
a. Inhibition of bone resorption.
b. For tt of osteoporosis in women > 5 years post-menopause
c. Not a 1st -line drug; useful for bone pain caused by vertebral
juice, or mineral water (polyvalent cations → ↓ absorption).
5. Wait at least 30mins after taking bisphosphonate before taking any drugs,
compression fractures.
d. Efficacy: Nasal calcitonin ↓ risk of vertebral fractures, rapid
food, or drinks except for water. Except : With ibandronate, must wait 60
onset (emergency use).
mins. (risedronate Na, delayed release must be taken with food )
5) Teriparatide (the only anabolic drug):
a. Recombinant human PTH  regulates bone metabolism, intestinal Ca absorption, and renal tubular Ca and phosphate reabsorption.
b. Efficacy: Reserved for treating women at risk of fracture, ( with very low BMD (T-score lower than –3.0) & a previous vertebral fracture.
↓ Vertebral fractures and nonvertebral fractures; not ↓ hip fractures.
CI: ↑ risk of osteosarcoma (those with paget disease, open epiphysis or previous external beam or implant radiation therapy involving skeleton).
6) Denosumab: for postmenopausal women with osteoporosis and for men and women with bone loss associated with prostate or breast cancer.
a. Inhibits osteoclast-mediated bone resorption, Mab against (RANKL)
Dr.Mahmoud Salah
B) Considered alternative first-line therapy.
Page6
‫مكتبة الشروق‬
d. Efficacy: ↓ risk of spinal and hip fractures.
e. Safety issues:
I.
Possible opportunistic infections, skin infections such as cellulitis.
II.
Hypocalcemia: Patients should take Ca and vit, D together with denosumab; those with impaired renal function are
more likely to have hypocalcemia.
III.
Contraindicated in pregnancy.
Selective estrogen receptor modulators  Raloxifene & Conjugated estrogens and bazedoxifene
Raloxifene
Conjugated estrogens and bazedoxifene
For : Prevention & TT of osteoporosis in postmenopausal women.
I.
Mechanism: Selective estrogen receptor modulator.
(a) ↓ Bone resorption.
II.
B) ↓ Overall bone turnover.
Efficacy: A) ↓ The risk of vertebral fractures.
IV. Contraindications:
Contraindications:
(a) Similar to those of raloxifene.
(b) Avoid additional estrogens (black box warnings).
(a) ↑ Risk of DVT and PE (black box warning, discontinue 72 hrs
prior to and during prolonged immobilization).
(c) ↑ Risk of dementia in women > 65 y old (black box warnings).
(d) Estrogens should be prescribed at the lowest effective doses and for the
(b) ↑ Risk of death due to stroke in postmenopausal women with CHD
(black box warning).
II. Mechanism: Selective estrogen receptor modulator plus estrogen.
III. Efficacy: ↓ risk of vertebral and non-vertebral fractures.
B) ↓ Total cholesterol and LDL-C; does not reduce risk of CHD.
III.
I. Indication: Prevention of osteoporosis in postmenopausal women.
shortest duration consistent with treatment goals and risks for the
individual woman
(c) Pregnancy and lactation.
(e) Breast cancer and estrogen dependent neoplasia.
(d) Ospemifene (pharmacodynamic synergism).
(f) Hepatic impairment.
V. Drug interactions: Metabolized by cytochrome P450 (CYP) 3A4;
inducers or inhibitors of CYP3A4 may affect estrogen levels.
8. Hormone therapy (estrogen and progestogens).
Dr.Mahmoud Salah
Page7