Osteoporosis

is a bone disorder
characterized
1. by low bone density,
2. impaired bone
architecture,
3. and compromised bone
strength predisposing to
fracture.
 Pathophysiology
1-Bone loss occurs when resorption exceeds formation (when the bone resorption greatly exceeds the
ability of osteoblasts to form new bone).

2-Men and women begin to lose bone mass starting in the third or fourth decade because of reduced
bone formation. Estrogen deficiency during menopause increases osteoclast activity,
increasing bone resorption more than formation.

3-Men are at a lower risk for developing osteoporosis and osteoporotic fractures because of larger
bone size, greater peak bone mass, increase in bone width with aging, fewer falls, and shorter life
expectancy. Male osteoporosis results from aging or secondary causes.

4-Age-related osteoporosis results from hormone, calcium, and vitamin D deficiencies; less exercise;
and other factors.

5-Drug-induced osteoporosis may result from systemic corticosteroids, excessive thyroid hormone
replacement, antiepileptic drugs (eg, phenytoin,phenobarbital), depot medroxyprogesterone acetate,
and other agents.
 Clinical presentation

1-Many patients are unaware that they have osteoporosis

and only present after fracture. Fractures can occur after
bending, lifting, or falling or independent of any activity.

2-The most common fractures involve vertebrae, proximal

femur, and distal radius (wrist or Colles fracture).
3-Vertebral fractures may be
asymptomatic or present with
moderate to severe back pain that
radiates down a leg. Pain usually
subsides after 2–4 weeks, but
residual back pain may persist.

4-Multiple vertebral fractures decrease

height and sometimes curve the
spine (kyphosis or lordosis).

5-Patients with a non vertebral fracture

frequently present with severe
pain, swelling, and reduced function
and mobility at the fracture site.
Diagnosis
1-Physical examination
findings may include bone
pain, postural changes (ie,
kyphosis), and loss of
height (>1.5 in [3.8 cm]).
 
2-Bone mineral
density(BMD)is measured
by dual-energy x-ray
absorptiometry (DXA) scan.
 Treatment
Goals of Treatment:

2-After low bone

1-The primary
mass or 3-Goals in patients with
goal of
osteoporosis osteoporotic fractures
osteoporosis care
develops, the include reducing pain
is prevention.
objective is to and deformity,
Optimizing peak
stabilize or improving function,
bone mass when
improve bone reducing falls and
young reduces the
mass and strength fractures, and
future incidence
and prevent improving quality of life
of osteoporosis.
fractures.
 Nonpharmacologic Therapy
1-All individuals should have a balanced diet with adequate
intake of calcium and vitamin D. Protein is required for bone
formation.
2-Alcohol consumption should not exceed 1–2 drinks per day for
women and 2–3 drinks per day for men. Ideally, caffeine intake
should be limited to 2 or fewer servings per day .Smoking
cessation helps optimize peak bone mass, minimize bone loss,
and ultimately reduce fracture risk.
3-Weight-bearing aerobic and strengthening exercises can
decrease risk of falls and fractures by improving muscle strength,
coordination, balance,and mobility.
4-Fall prevention programs can decrease falls,
fractures, other injuries, and nursing home and
hospital admissions.
5-Vertebroplasty and kyphoplasty involve
injection of cement into fractured vertebra for
patients with debilitating pain from
compression fractures. Recent research
demonstrated only short term benefit with no
major pain relief and the potential for post-
procedure complications.
 Pharmacologic Therapy
General Approach
1-Combined with adequate calcium and vitamin D intakes,
alendronate, risedronate, zoledronic acid, and denosumab
are the prescription medications of choice because they
reduce both hip and vertebral fracture risks.
2-Abaloparatide, bazedoxifene/conjugated equine estrogens,
ibandronate, raloxifene, romosozumab, and teriparatide are
second-line alternatives because they decrease vertebral but
not hip fracture risks.
3-Calcitonin is last-line therapy. Estrogen and testosterone
are not used for osteoporosis treatment but can have a
positive bone effect when prescribed for other conditions.
 Antiresorptive Therapy
Calcium Supplementation
1-Calcium generally maintains or increases BMD slightly, but its effects are
less than those of other therapies. There are insufficient data to support
using calcium and vitamin D supplementation to reduce fracture
incidence.
2-Because the fraction of calcium absorbed decreases with increasing
dose, maximum single doses of 600 mg or less of elemental calcium are
recommended.
3-Calcium carbonate is the salt of choice because it contains the highest
concentration of elemental calcium (40%) and is typically least expensive.
It should be ingested with meals to enhance absorption in an acidic
environment.
4-Calcium citrate (21% calcium) has acid-independent absorption and
need not be taken with meals. It may have fewer GI side effects than
calcium carbonate.
.
5-Tricalcium phosphate contains 38% calcium. It may be
useful in patients with hypophosphatemia that cannot
be resolved with increased dietary intake.
6-Constipation is the most common calcium-related
adverse reaction; treat with increased water intake,
dietary fiber , and exercise.
7-Calcium carbonate can sometimes cause flatulence or
upset stomach. Calcium causes kidney stones rarely.
8-Calcium can decrease the oral absorption of some
drugs including iron, tetracyclines, quinolones,
bisphosphonates, and thyroid supplements
 Vitamin D Supplementation
1-Vitamin D supplementation using 700–800 units per day has been
shown to significantly reduce the incidence of both hip and non
vertebral fractures with small increases in BMD.
2-Supplementation is usually provided with daily nonprescription
cholecalciferol (vitaminD3) products. Higher-dose prescription
ergocalciferol(vitaminD2) regimens given weekly, monthly, or quarterly
may be used for replacement and maintenance therapy.
3-Current guidelines recommend treating patients with osteoporosis to a
25-hydroxyvitamin D concentration of at least 30 ng/mL or 30–50 ng/mL.
4-Because the half-life of vitamin D is about 1 month, recheck the
vitamin D concentration after about 3 months of therapy.
5-Medications that can induce vitamin D
metabolism include rifampin, phenytoin,
barbiturates, valproic acid, and carbamazepine.
6-Vitamin D absorption can be decreased by
cholestyramine, colestipol, orlistat, and mineral
oil. Vitamin D can enhance the absorption of
aluminum ;therefore, aluminum-containing
products should be avoided to prevent aluminum
toxicity.
 Bisphosphonates
1-Bisphosphonates mimic pyrophosphate, an endogenous bone resorption
inhibitor. Therapy leads to decreased osteoclast maturation, number,
recruitment, and life span.
2-Incorporation into bone gives bisphosphonates long biologic half-lives of up
to10 years.
3-Ibandronate is not a first-line therapy because of the lack of hip fracture
reduction data.
4-BMD increases are dose dependent and greatest in the first 12 months of
therapy. After discontinuation, the increased BMD is sustained for a prolonged
period that varies per bisphosphonate.
5-Alendronate, risedronate, and IV zoledronic acid are FDA indicated for postmenopausal, male,
and glucocorticoid-induced osteoporosis. IV and oral ibandronate are indicated only for
postmenopausal osteoporosis.

6-Weekly alendronate,weekly and monthly risedronate, and monthly oral and quarterly IV
ibandronate therapy produce equivalent BMD changes to their respective daily regimens.
7-Oral bisphosphonates must be administered correctly to optimize clinical
benefit and minimize adverse GI effects.
A-Each oral tablet should be taken in the morning with at least 6 oz (180
mL) of plain water (not coffee, juice, mineral water, or milk) at least 30
minutes (60 minutes for oral ibandronate) before consuming any food,
supplements, or medications.
B-An exception is delayed-release risedronate, which is administered
immediately after breakfast with at least 4 oz (120 mL) of plain water.
C-The patient should remain upright (sitting or standing) for at least
30minutes after alendronate and risedronate and 1 hour after ibandronate
to prevent esophageal irritation and ulceration.
D-If a patient misses a weekly dose, it can be taken the next day. If more than
1 day has elapsed, that dose is skipped. If a patient misses a monthly dose, it
can be taken up to 7 days before the next scheduled dose.
8-The most common bisphosphonate adverse effects include nausea, abdominal
pain, and dyspepsia. Esophageal, gastric, or duodenal irritation, perforation,
ulceration, or bleeding may occur.
9-The most common adverse effects of IV bisphosphonates include fever, flu-
likesymptoms, and local injection-site reactions.
10-Rare adverse effects include osteonecrosis of the jaw (ONJ) and
subtrochanteric femoral (atypical) fractures. ONJ occurs more commonly inpatients
with cancer receiving higher-dose IV bisphosphonate therapy.
11-The optimal duration of bisphosphonate therapy is unknown. Some experts
recommend considering a bisphosphonate holiday in postmenopausal women after
5 years of oral bisphosphonates or 3 years of IV bisphosphonates if no significant
fracture history, hip BMD T-score is above –2.5, and fracture risk is no thigh.
12-In women with a high fracture risk or lower hip BMD T-scores, continuing oral
bisphosphonates for 10 years or IV bisphosphonates for 6years should be
considered.
13-A bisphosphonate holiday should last for ≤5 years with BMD and patient
assessment done every 2–4 years.
 Denosumab
1-Denosumab is a RANK ligand inhibitor that inhibits
osteoclast formation and increases osteoclast apoptosis.
It is indicated for treatment of osteoporosis in women and
men at high risk for fracture, for glucocorticoid-induced
osteoporosis, to increase bone mass in men receiving
androgen-deprivation therapy for non metastatic prostate
cancer, and in women receiving adjuvant aromatase
inhibitor therapy for breast cancer who are at high risk for
fracture.
 
2-Adverse reactions not associated with the injection site
include back pain, arthralgia, and infection. ONJ and
atypical femoral shaft fracture occur rarely. Denosumab is
contraindicated in patients with hypocalcemia until the
condition is corrected .
 Mixed Estrogen Agonists/Antagonists
and Tissue-Selective Estrogen Complexes
1- Raloxifene is an estrogen agonist/antagonist that is an estrogen
agonist on bone receptors but an antagonist at breast receptors, with
minimal effects on the uterus.
2-It is approved for prevention and treatment of postmenopausal
osteoporosis and for reducing the risk of invasive breast cancer in
postmenopausal women with and without osteoporosis.
3- Bazedoxifene is an estrogen agonist/antagonist that is an agonist at
bone and antagonist at the uterus and breast; however, it has no breast
cancer prevention effects. The proprietary product Duavee is
combined with conjugated equine estrogens (CEE), making it a tissue-
selective estrogen complex. It is approved for prevention of
postmenopausal osteoporosis and vasomotor menstrual symptoms.
4-The benefit is lost after discontinuation, and bone loss returns to
age- or disease-related rates.
5-Hot flushes are common with raloxifene but decreased with
bazedoxifene/CEE. Raloxifene rarely causes endometrial thickening
and bleeding;bazedoxifene decreases these events.
6-Leg cramps and muscle spasms are common with these agents.
Thromboembolic events are uncommon (<1.5%) but can be fatal.
Bazedoxifene/CEE has all of the contraindications and precautions
for estrogens as a class.
 Calcitonin
1-Calcitonin is an endogenous hormone released from the thyroid
gland when serum calcium is elevated. Salmon calcitonin is used
clinically because it is more potent and longer lasting than the
mammalian form.
2-Calcitonin is indicated for osteoporosis treatment for women at least 5
years past menopause.
3-An FDA Advisory Committee Panel voted against continued use for
postmenopausal osteoporosis, but it can be used if alternative
therapies are not appropriate. Only vertebral fractures have been
documented to decrease with intranasal calcitonin therapy.
4-Intranasal calcitonin may provide some pain relief in patients with
acute vertebral fractures, but such use should be short-term (4 weeks)
and not in place of other more appropriate analgesic or osteoporosis
therapy
 Hormone Therapies
1-Hormone therapies (estrogen and testosterone) are not
recommended solely for osteoporosis but have positive bone
effects when used for other indications.
2-Estrogen therapy can be a good choice for women going through
early menopause when protection against bone loss is needed in
addition to reduction of vasomotor symptoms.
3-Estrogen with or without a progestogen significantly decreases
fracture risk and bone loss in women. When estrogen therapy is
discontinued, bone loss accelerates and fracture protection is lost.
4-Testosterone is used to treat hypogonadism in men, but an
osteoporosis medication should be added when risk for
osteoporotic fracture is high.
 Formation Medications
Parathyroid Hormone Analogs
1- Abaloparatide is an analog of parathyroid hormone-related
peptide (PTHrP), and teriparatide is an analogs of parathyroid
hormone (PTH); these agents are indicated for the treatment of
postmenopausal women with osteoporosis at high risk for fracture.
2-Teriparatide is also FDA approved for men with idiopathic or
hypogonadal osteoporosis who are at high risk for fracture, men
intolerant to other osteoporosis medications, and patients with
glucocorticoid-induced osteoporosis.
3-Discontinuation of PTH analog therapy results in decreased BMD,
which can be alleviated with subsequent antiresorptive therapy.
4-Transient hypercalcemia can occur and is less
common with abaloparatide than teriparatide. Because
of an increased incidence of osteosarcomain rats, both
medications contain a box warning against use in
patients at increased risk for osteosarcoma; this
adverse effect has not occurred in people.
5-PTH analogs should not be used in patients with
hypercalcemia, metabolic bone diseases other than
osteoporosis, metastatic or skeletal cancers, or
premenopausal women of childbearing potential.
 Formation and Antiresorptive
Medication
1-Romosozumab prevent inhibition of bone formation
Romosozumab
and decrease bone resorption, an activity that
differentiates this medication from other anabolic
therapies.
2-It indicated for postmenopausal women at high risk for
fracture.
3-The most common adverse effects are headache and
arthralgia; hypercalcemia occurs in <1% of patients. Mild
injection site irritation occurs in6%–8% of patients.
4-Romosozumab antibodies may occur in 10%–20% of
patients but are generally not neutralizing and do not
reduce efficacy.
5-Serious cardiovascular events have been reported, and the
labeling contains a boxed warning of an increased risk of
myocardial infarction (MI),stroke, and cardiovascular death.
6-Romosozumab should not be used within 1 year of an MI or
stroke, and benefit–risk evaluation should be conducted in patients
with or at risk for these conditions.
7-Rare cases of ONJ and atypical femoral fractures have been
reported.
8-Therapy should be limited to 12 monthly doses. If osteoporosis
therapy remains warranted, continued therapy with an
antiresorptive agent should be considered.
 Sequential and Combination
1-In sequential therapy, an anabolic agent is given first to
Therapy
increase bone mass, followed by an antiresorptive agent. This
regimen is generally reserved for patients with severe
osteoporosis because of the cost of anabolic agents.
2-Starting with an antiresorptive first and then switching to
teriparatide results in lower BMD increases but may be especially
useful for patients who have fractured or continue to lose bone
mass while on antiresorptive therapy.
3-Combination therapy is rarely used because of no documented
fracture benefit, increased cost, and potential for more adverse
effects.
4-When raloxifene is used for breast cancer prevention,
another antiresorptive agent is sometimes prescribed,
especially if hip fracture risk is high
 Glucocorticoid-induced
1-Glucocorticoids decrease bone formation through
decreased proliferation and differentiation as well as enhanced apoptosis of
osteoblasts. osteoporosis
They also increase the number of osteoclasts,
increase bone resorption,
decrease calcium absorption,
and increase renal calcium excretion.
2-All glucocorticoid doses and formulations have been associated with
increased bone loss and fractures; however, risk is much greater with oral
prednisone doses ≥5 mg daily (or equivalent) and oral therapy vs inhaler or
intranasal therapy.
3-Bone losses are rapid, with up to 12%–15% loss over the first year; the
greatest decrease occurs in the first 6 months of therapy. Bone loss is
about2%–3% per year after the first year.
4-Perform an initial BMD assessment prior to or within 6 months of
glucocorticoid initiation for adults ≥40 years of age and for adults <40 years of
age with a history of fragility fracture or other risk factors.
.
5-Repeat BMD testing is recommended every 2–3 years during
osteoporosis therapy for those taking very high glucocorticoid doses
(≥30 mg prednisone per day or a cumulative dose >5 g in the past
year), or other risk factors for osteoporosis.
6-All patients starting or receiving systemic glucocorticoid
therapy (any dose or duration) should practice a bone-healthy
lifestyle and ingest 1000–1200 mg elemental calcium and 600–800
units of vitamin D daily to achieve therapeutic 25-hydroxyvitamin D
concentrations.
7-Use the lowest possible corticosteroid dose and duration.
8-Treatment guidelines divide recommendations for prescription
medication use by fracture risk and age. Alendronate, risedronate,
zoledronicacid, denosumab, and teriparatide are FDA approved for
glucocorticoid-induced osteoporosis.
9-Standard osteoporosis therapy doses are used. Oral bisphosphonates
are recommended first-line, although IV bisphosphonates can be used
in nonadherent patients or those unable to take the oral preparations.
10-Teriparatideis recommended for patients who cannot use
abisphosphonate, and denosumab is recommended if neither a
bisphosphonate nor teriparatide can be used.
11-Denosumab is not recommended as first-line therapy due to limited
safety data in this population.
12-Raloxifene does not have an FDA indication for this use, but there are
clinical data documenting improved BMD at the lumbar spine in patients
taking glucocorticoids.
.

Evaluation of therapeutic outcomes

1 2 Ask patients about possible
Assess medication fracture symptoms (eg,
adherence and bone pain, disability) at
tolerability at each visit. each visit. Assessment of
fracture, back pain, and
height loss can help identify
worsening osteoporosis.
Repeat a central DXA every 2 Obtain a central DXA BMD
years until BMD is stable, at measurement after 1–2 years
which time the reassessment or 3–5 years after initiating a
4 3
interval can be lengthened. medication therapy to
monitor response