DXA t score z score vertebral fracture fragility fracture manangement bisphosphonate calcitonin

1. Osteoporosis
Guide Dr M D MOTLAG

2. Osteoporosis
• Osteoporosis is defined as a reduction in the strength of bone that
leads to an increased risk of fractures.

4. Osteoporosis related #

5. FACTORS LEADING TO FRACTURE
• more frequently with increasing age, as bone tissue is lost
progressively
• Postmenopausal women
• loss of ovarian function at menopause (typically around age 50)
Life-time osteoporotic fracture risk for a woman who reaches the age of 50 is about 50%
and corresponding risk for a 50-year old man is about 20%

6. Factors leading to fracture

7. OTHER FACTORS
• Prior fractures
• Fractures are themselves risk factors for future fractures
• a family history of osteoporosis-related fractures (particularly hip
fractures),
• low body weight,
• cigarette consumption,
• excessive alcohol consumption
• Chronic diseases with inflammatory components that increase
skeletal remodeling,
• such as rheumatoid arthritis

10. Pathophysiology

11. BONE REMODELLING

12. PATHOPHYSIOLOGY

13. In a process involving cell-cell
interactions, RANK ligandbinds to
the RANK receptor on osteoclast
progenitors, stimulating osteoclast
differentiation and activation.
Alternatively, a soluble decoy
receptor, referred to as
osteoprotegerin, can bind RANK
ligand and inhibit osteoclast
differentiation
RANK ligand, a member of the tumor necrosis factor (TNF) family, is expressed on the
surface of osteocytes, osteoblasts, and stromal fibroblasts.

15. Macrophage colony-
stimulating factor
(M-CSF)

16. • Osteoblasts (or stromal cell precursors), which have PTH/PTHrP
receptors, are crucial to this bone-forming effect of PTH;
• osteoclasts, which mediate bone breakdown, lack such receptors
• PTH-mediated stimulation of osteoclasts is indirect, acting in part, through
cytokines released from osteoblasts to activate osteoclasts

18. Carbonic anhydrase (type II
isoenzyme) within the
osteoclast generates the
needed protons specific αvβ3
integrin
The active osteoclast surface forms a ruffled
border that contains a specialized proton-
pump ATPase that secretes acid that solubilizes
the mineral phase
The bone matrix is
resorbed in the acid
environment adjacent
to the ruffled border by
proteases, such as
cathepsin K, that
act at low pH

19. • Bone remodeling has two primary functions:
• (1) to repair microdamage within the skeleton to maintain skeletal strength
and ensure the relative youth of the skeleton
• (2) to supply calcium when needed from the skeleton to maintain serum
calcium

21. N & C peptide of procollagen type 1

22. ALP is raised in conditions a/w increased
osteoblastic activity
Raised ALP (d/t osteoblastic activity) ALP is normal in
• Paget disease,
• Bone metastases,
• Rickets, osteomalacia*,
• osteoporosis and
• multiple myeloma

23. • Bone remodeling occurs through well coordinated activity of
osteocytes, osteoblasts, and osteoclasts

24. In young adults, resorbed bone is replaced by an
equal amount of new bone tissue. Thus, the mass
of the skeleton remains constant after peak bone
mass is achieved by the age of about 20.

25. increase in osteoclastic activity
decrease in osteoblastic activity
After age 30–45, however, the resorption and formation
processes become imbalanced, and resorption exceeds
formation
becomes exaggerated in women after menopause

26. cortical bone trabecular bone
• cortical bone increased porosity on
cortical bone strength
• decreased apposition of new bone on the
periosteal surface decreases the
biomechanical strength of long bones
• if the osteoclasts penetrate trabeculae, they leave
no template for new bone formation to occur, and,
consequently, rapid bone loss ensues and
cancellous connectivity becomes impaired
Increased recruitment of bone remodeling sites in permanent
loss of tissue and disrupted skeletal architecture.

27. Regulation of bone remodelling
• Bone remodeling regulated by
• multiple hormones, including estrogens (in both genders), androgens, vitamin
D, and parathyroid hormone (PTH),
• locally produced growth factors, such as IGF-I, transforming growth factor β
(TGF-β), PTH–related peptide (PTHrP),
• interleukins (ILs), prostaglandins,
• members of the tumor necrosis factor (TNF) superfamily

28. • mechanical loading
• hormonal or cytokine factors
Wnt activation
• increasing formation and activity of
osteoblasts
• decreases RANKL secretion, which inhibits
production and activity of osteoclasts
Sclerostin (osteocyte protein)

31. INHIBITORS OF WNT SIGNALLING
• Sclerostin is the product of the SOST gene and a negative regulator of
Wnt signaling . It binds to both LRP5 and LRP6 and prevents activation
of the Wnt receptor complex . This results in inhibition of bone
formation .
• DKK family members, particularly DKK-1 (Dickkopf-1), inhibit the Wnt
pathway by binding to the LPR5/6 receptor .
• Wnt signaling can also be blocked by other proteins, such as soluble
frizzled-related protein, that bind to Wnt ligands .

35. Other factors

36. insufficient calcium intake
secondary
hyperparathyroidism
enhanced gastrointestinal
calcium absorption.
reduces renal calcium loss.
hydroxylation of vitamin D
in the kidney, leading to
increased levels of 1,25-
dihydroxyvitamin D
[1,25(OH)2D]
increased remodeling rates
accelerate loss of bone
tissue.
CALCIUM NUTRITION

37. Calcium intake
<400mg Detrimental to bone
600-800 Suboptimal
1000-1200 Recommended daily intake
> risk of renal stones, and perhaps
cardiovascular calcification

38. VITAMIN D
northern latitudes
especially winter
individuals with poor
nutrition, obesity
malabsorption,
chronic liver or renal
disease
Dark-skinned
individuals
use of potent
sunscreens
Secondary hyperparathyroidism Osteoporosis

39. Role of estrogen
cessation of ovarian
function at the time of
menopause
Breast cancer
treatment with
aromatase inhibitors
b/l ovary removal Estrogen deficiency
activation of new bone
remodeling sites
exaggeration of the
imbalance between
bone formation and
resorption

40. Lossofestrogen
increases production of RANKL
reduces production of osteoprotegerin,
increasing osteoclast formation and
recruitment.
life span of osteoblasts may be decreased,
the longevity and activity of osteoclasts
are increased

41. Estrogen receptor
• Marrow cells (macrophages, monocytes, osteoclast precursors,
mast cells) as well as bone cells (osteoblasts, osteocytes, osteoclasts)
express ERs α and β.

43. Effect of estradiol in bone remodelling
multiple cellular targets in bone, including
osteoclasts, immune cells, and osteoblasts
decrease osteoclast number and decreased
bone resorption

44. •
in situations of estrogen deprivation, the life span of osteoblasts may be decreased,
whereas the longevity and activity of osteoclasts are increased

45. Paracrine actions of estrogen
• increasing OPG production by osteoblasts
• Increasing IGF-I and TGF-β
• suppressing IL-1 (α and β), IL-6, TNF-α, and osteocalcin synthesis.

46. • vertebral fractures are the most common early skeletal consequence
of estrogen deficiency
• remodeling is initiated at the surface of bone, it follows that trabecular
bone—which has a considerably larger surface area (80% of the total) than
cortical bone—will be affected preferentially by estrogen deficiency
• Fractures occur earliest at sites where trabecular bone contributes most to
bone strength;

51. PHYSICAL ACTIVITY
• prolonged bed rest or paralysis  increased bone turn over
• Continuing physical activity into the later years appears to slow
cognitive decline, another major reason for including exercise
programs for the aging population.

52. CHRONIC DISEASES
• including nutrition, reduced physical activity levels, and factors that
affect rates of bone remodeling
• Type I and Type II diabetes mellitus

54. MEDICATIONS
• Glucocorticoids  MC CAUSE
• thyroid hormone
• Anticonvulsants
• cyclosporine and tacrolimus
• proton pump inhibitors
• Aromatase inhibitors
• thiazoledinediones
• antidepressants, including the Selective Serotonin Reuptake
Inhibitor (SSRIs)

55. Glucocorticoids
induction of glucocorticoid myopathy
increase the risk of falls
reduction of adrenal
androgens and suppression of
ovarian and testicular
secretion of estrogens and
androgens
inhibition of
osteoblast
function and an
increase in
osteoblast
apoptosis
• impaired synthesis of new bone
• stimulation of bone resorption
• impairment of the
absorption of calcium
across the intestine
• increase of urinary
calcium loss
secondary
hyperparathyroidism
Mechanism

58. Effect of smoking

59. Smoking
directly by toxic
effects on
osteoblasts
modifying estrogen
metabolism
cigarette
smokers reach
menopause 1–2
years earlier
than the general
population
Respiratory and
other intercurrent
illness
• frailty,
• decreased exercise,
• poor nutrition,
• need for additional medications (e.g.,
glucocorticoids for lung disease)

61. DIAGNOSIS
• Osteoporosis is characterized by low bone mass, microarchitectural
disruption, and increased skeletal fragility.
• A clinical diagnosis of osteoporosis may be made in the presence of :
• Fragility fracture, particularly at the spine, hip, wrist, humerus, rib, and pelvis
• or
• T-score ≤-2.5 standard deviations (SDs) at any site based upon bone mineral
density (BMD) measurement by dual-energy x-ray absorptiometry (DXA)

62. MEASUREMENT OF BONE MASS
• DXA,
• single-energy x-ray absorptiometry (SXA),
• quantitative CT,
• ultrasound (US)

63. dual-energy x-ray absorptiometry (DXA)
• USED TO MEASURE BONE MINERAL DENSITY
• LESS RADIATION EXPOSURE

64. dual-energy x-ray absorptiometry (DXA)
padded table on which the patient lies
movable C-arm with a radiograph tube below the patient and a
detector above the patient

65. • The radiograph tube generates photon beams of two different energy
levels, thus the term "dual-energy."

66. two x-ray energies are used
Areal BMD(g/cm2) =
𝑏𝑜𝑛𝑒 𝑚𝑖𝑛𝑒𝑟𝑎𝑙 𝑐𝑜𝑛𝑡𝑒𝑛𝑡 (𝐵𝑀𝐶,𝑖𝑛 𝑔𝑟𝑎𝑚𝑠)
𝑏𝑜𝑛𝑒 𝑎𝑟𝑒𝑎 (𝐵𝐴,𝑖𝑛 𝑠𝑞𝑢𝑎𝑟𝑒 𝑐𝑒𝑛𝑡𝑖𝑚𝑒𝑡𝑒𝑟𝑠)

67. NEGATIVES OF DXA
• DXA is a two-dimensional scanning technique and cannot estimate
the depth or posteroanterior length of the bone
• Bone spurs, which are common in osteoarthritis, tend to falsely
increase bone density
• mostly of the spine and are a particular problem in measuring spine BMD in
older individuals

68. T-score Z-score
the value used for diagnosis of osteoporosis, is
calculated by subtracting the mean BMD of a young
adult reference population from the patient's BMD
and dividing by the standard deviation (SD) of young
adult population
used to compare the patient's BMD to a population of
peers, is calculated by subtracting the mean BMD of
an age, ethnicity, and sex-matched reference
population from the patient's BMD and dividing by the
SD of the reference population.

69. • T-score of 1 equals 1 SD
• average value given a score of zero and the range being +2.5 to –2.5

71. 60-year-old woman with a Z-score of –1 (1 SD below mean for age) has a T-
score of –2.5 (2.5 SD below mean for a young control group)

72. since >50% of fractures occur in individuals with low bone mass
(i.e., a T-score between –1.0 and –2.5), rather than
osteoporosis, attempts are ongoing to redefine the disease as a
fracture risk rather than a specific BMD

73. FRAX (Fracture Risk Assessment)
• calculates the estimated risk over a ten-year time frame for major
osteoporosis-related fractures (clinical spine, hip, wrist and proximal
humerus) as well as hip fracture.
• age,
• gender,
• height,
• weight,
• fracture history,
• hip fracture in a parent,
• steroid use
• rheumatoid arthritis,
• other secondary causes
• bone density of the femoral neck

75. • FRAX
• imperfect tool,
• does not include any assessment of fall risk, and secondary causes are excluded when
BMD is entered.
• no additional fracture probability estimated for patients who have had multiple
fractures.
• DOESNOT DISTINGUISH WHETHER FRACTURE WAS RECENT OR REMOTE
• from an acute recent fracture versus the much lesser importance of the more remote fracture

76. • T-score <–2.5 in the lumbar spine, femoral neck, or total hip has been
defined as osteoporosis

77. OTHER INVESTIGATIONS
• CT scan can also be used to measure the spine and the hip, but is rarely used
clinically, in part because the radiation exposure and cost are both much higher
than with DXA.
• High resolution peripheral quantitative computed tomography (QCT)
• measure bone in the forearm or tibia,
• research tool that provides information on skeletal architecture non-invasively.
• Magnetic resonance imaging
• architectural information on the forearm
• primarily a research tool at present.
• Ultrasound
• measure bone mass by calculating the attenuation of the signal as it passes through bone
or the speed with which it traverses the bone.
• assesses properties of bone mass
• Because of its relatively low cost and mobility

78. Sites for measurement of BMD
• hip is the preferred site of measurement
• predicts the risk of hip fracture, the most important consequence of osteoporosis,
better than any other bone density measurement site.
• When hip measurements are performed by DXA, the spine can be
measured at the same time.
• In younger individuals such as perimenopausal or early postmenopausal
women, spine measurements may be the most sensitive indicator of bone
loss.
• Wrist
• due to severe degenerative spine disease or scoliosis
• prior spine or hip surgery.

80. INDICATIONS FOR BONE MASS
MEASUREMENT
• Women aged ≥65 and men aged ≥70; regardless of clinical risk factors
• postmenopausal women younger than 65 years of age with clinical risk factors for fracture
• Advancing age
• Previous fracture
• Glucocorticoid therapy
• Parental history of hip fracture
• Low body weight
• Current cigarette smoking
• Excessive alcohol consumption
• Rheumatoid arthritis
• Secondary osteoporosis (eg, hypogonadism or premature menopause, malabsorption, chronic liver disease,
inflammatory bowel disease)
• Adults who have a fracture at or after age 50
• Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g.,
glucocorticoids at a daily dose >5 mg prednisone or equivalent for >3 months associated with low
bone mass or bone loss

81. VERTEBRAL IMAGING
• vertebral fractures are often
asymptomatic
• vertebral fracture
assessment (VFA)
• DXA equipment can also be
used to obtain lateral images
of the thoracic and lumbar
spine

82. Indications for Vertebral Testing
• All women aged ≥70 and all men aged ≥80 if BMD T-score at
the spine, total hip, or femoral neck is <1.0
• Women aged from 65 to 69 and men aged from 70 to 79 if
BMD T-score at the spine, total hip, or femoral neck is <1.5
• Postmenopausal women and men aged ≥50 with specific risk
factors:
• Low-trauma fracture during adulthood (aged ≥50)
• Historical height loss of ≥1.5 in. (4 cm)
• Prospective height loss of ≥0.8 in. (2 cm)
• Recent or ongoing long-term glucocorticoid treatment

83. APPROACH TO THE PATIENT

84. • history and physical examination
• BMD test

85. •Serum 25(OH)D level
ASSESS VITAMIN D
•TSH
HYPERTHYROIDISM
•urinary free cortisol levels or a fasting serum cortisol should be measured
after overnight dexamethasoneCUSHINGS
SYNDROME
•serum albumin, cholesterol, and a complete blood count
•URINARY CALCIUM
•macrocytic—vitamin B12 or folate deficiency; microcytic—iron deficiency)MALABSORPTION

86. • TRIAL OF GLUTEN FREE DIET
• Transglutaminase IgA antibodies
• confirmation by endoscopic biopsy.
CELIAC DS
• rash, multiple allergies, diarrhea, or flushing,
• using 24-h urine histamine collection or serum
tryptase
mastocytosis
• Serum and urine electrophoresis and/or evaluation
for serum free light chains light chains in urine
• “punched-out” lesions
MYELOMA

87. MASTOCYTOSIS

88. • A bone marrow biopsy
• myeloma (in patients with equivocal electrophoretic results)
• mastocytosis,
• leukemia,
• other marrow infiltrative disorders such as Gaucher’s disease.

89. BIOCHEMICAL MARKERS FOR OSTEOPOROSIS
Bone formation Bone resorption
• Serum bone-specific alkaline
phosphatase
• Serum osteocalcin
• Serum propeptide of type I
procollagen
• Urine and serum cross-linked N-
telopeptide
• Urine and serum cross-linked C-
telopeptide

90. USES OF BIOCHEMICAL MARKERS
• monitoring the response to treatment
• CTX is the preferred marker
• monitoring the effects of 1-34hPTH, or teriparatide, which rapidly
increases bone formation and later bone resorption.
• P1NP is the most sensitive but osteocalcin is also a very good formation
marker

91. MANAGEMENT OF PATIENTS
WITH FRACTURES

92. MANAGEMENT OF PATIENTS WITH
FRACTURES
• management of acute fractures
• treatment of the underlying disease

93. HIP  SURGICAL • open reduction and internal fixation with pins and
plates, hemiarthroplasties, and total arthroplasties
• intense rehabilitation
Long bone fractures either external or internal fixation
vertebral, rib, and pelvic fractures supportive care, requiring no specific orthopedic
treatment

94. VERTEBRAL #
• Asymptomatic
• height loss
• because of the loss of vertebral body height during compression of the vertebral body.
• sudden-onset back pain (~25–30% )
• analgesics
• nonsteroidal anti-inflammatory agents and/or acetaminophen
• addition of a narcotic agent (codeine or oxycodone)
• CALCITONIN
• vertebroplasty or kyphoplasty
• percutaneous injection of artificial cement (polymethyl-methacrylate) into the vertebral body
• Short periods of bed rest followed by early mobilization is recommended
• as it helps prevent further bone loss associated with immobilization
• MUSCLE RELAXANTS & HOT FOMENTATION TO RELIEVE MUSCLE SPASM
• elastic-style brace may facilitate earlier mobilization

95. C/C PAIN IN VERTEBRAL #
Causes Rx modalities
• related to abnormal strain on muscles, ligaments,
and tendons
• secondary facet-joint arthritis associated with
alterations in thoracic and/or abdominal shape.
• multiple vertebral compression fractures d/t
kyphosis ribs sitting right on top of the iliac
crest bones
• chronic strain associated with trying to elevate the
head in a person with a significant thoracic kyphosis
• narcotic analgesics.
• Frequent intermittent rest in a supine
• or semireclining position
• Back and core-strengthening
• exercises may be beneficial.
• Heat treatments
• ultrasound and transcutaneous nerve stimulation

96. Psychological symptoms a/w of vertebral #
• Multiple vertebral fractures kyphosis 
anterior movement of the body’s center of
gravity, fear of fallingtendency to remain
indoors onset of social isolation.
• family support and/or psychotherapy.
• Medication when depressive features +

97. MANAGEMENT OF THE
UNDERLYING DISEASE

98. MANAGEMENT OF THE UNDERLYING DISEASE
Risk Factor
Reduction
• reduce the impact of
modifiable risk factors
associated with bone
loss and falling
• Medications • Glucocorticoid medication
• TSH testing for those on thyroid
hormone replacement
• Smoking cessation
• alcohol abuse treatment and a review
• Avoid drugs causing orthostatic hypotension and/or sedation
• environmental safety • eliminating exposed wires,
curtain strings, slippery rugs,
and mobile tables
• Avoiding stocking feet on wood
floors, checking carpet condition
(particularly on stairs), and
providing good light in paths to
bathrooms and outside the
home
• Treatment for impaired vision

99. Nutritional Recommendations Calcium • calcium supplementation to
bring intake to about 1200 mg/d
• Diet & calcium suppiliments
Vitamin D • Diet
Other nutrients • Vitamin k
Exercise

100. Calcium intake

101. • Best sources of calcium include
• dairy products (milk, yogurt, and cheese),
• nondaily milks (almond, rice, soy), and
• fortified foods such as certain cereals, waffles, snacks, juices, and crackers

103. Calcium suppliments
• Doses of supplements should be ≤600 mg per single
dose, as the calcium absorption fraction decreases at
higher doses
• Calcium carbonate are best taken with food since they
require acid for solubility.
• eructation and constipation
• Calcium citrate supplements can be taken at any
time.
• To confirm bioavailability, calcium supplements can
be placed in distilled vinegar. They should dissolve
within 30 min.
• Before starting calcium suppliments
• Check urine 24 hr calcium to avoid exacerbating
hypercalciuria
• S/E
• Renal stone
• Coronary artery d/s

104. Vitamin D
• higher doses (≥1000 IU) may be
required in the elderly and
chronically ill.
• For those with osteoporosis or
those at risk of osteoporosis
1000–2000IU/day can usually
maintain serum 25(OH)D above
30 ng/mL

105. Research concerning
cola intake is controversial but suggests a possible link to
reduced
bone mass through factors that are independent of caffeine

106. • Magnesium is abundant in foods, and magnesium deficiency is quite
rare in the absence of a serious chronic disease. Magnesium
supplementation may be warranted in patients with inflammatory
bowel disease, celiac disease, chemotherapy, severe diarrhea, mal-
nutrition, or alcoholism.
• Dietary phytoestrogens, which are derived primarily from soy
products and legumes (e.g., garbanzo beans [chickpeas] and
lentils), exert some estrogenic activity but are insufficiently potent to
justify their use in place of a pharmacologic agent in the treatment of
osteoporosis.

107. Other Nutrients
Vitamin K required for optimal carboxylation
of osteocalcin
long-term warfarin therapy,
have been associated with reduced
bone mass

108. Exercise
• attain the maximal genetically determined peak bone mass
• improves coordination, balance, and strength, thereby reducing the
risk of falling.
• Exercise habits should be consistent, optimally at least three times a
week.
• walking program is a practical way to start.
• Other activities such as dancing, racquet sports, cross-country skiing, and
use of gym equipment, are also recommended, depending on the patient’s
personal preference and general condition.
• beneficial effect wanes if exercise is discontinued

109. PHARMACOLOGIC TREATMENT
OF OSTEOPOROSIS

110. Indication for Rx
• Patients presenting with typical osteoporosis related fractures
(certainly hip and spine)in the setting of a BMD T-Score is ≤–2.5
• in postmenopausal women with fracture or multiple risk factors
even if BMD is not in the osteoporosis range

111. Drugs used
antiresorptive agents anabolic agent
• hormone/estrogen therapy
• selective estrogen receptor
modulators (SERMS)
• bisphosphonates,
denosumab, and calcitonin
• Teriparatide
• abaloparatide
• romosozumab Under FDA review

112. Estrogens
• esterified estrogens 0.3 mg/d,
• conjugated equine estrogens 0.625 mg/d,
• 5 μg/d for ethinyl estradiol.
• For transdermal estrogen,
• the commonly used dose supplies 50 μg estradiol per day

113. Progestins
• In women with a uterus, daily progestin or cyclical progestins at
least 12 days per month are prescribed in combination with
estrogens to reduce the risk of uterine cancer.
• May increase risk of breast cancer
• Medroxyprogesterone acetate
• norethindrone acetate

114. SERMs
raloxifene prevention and treatment of osteoporosis
as well as the prevention of breast cancer
(not associated with
an increase in the risk of uterine cancer or
benign uterine disease)
• increases the risk of deep vein
thrombosis
• increase the risk of death from stroke
among older women. it is not usually
recommended for women aged >70 years.
tamoxifen the prevention and treatment of breast
cancer.
Increases risk of uterine cancer
bazodoxiphene in combination with conjugated
estrogen for treatment of menopausal
symptoms and prevention of bone loss.
Bazedoxifene protects the uterus and
breast from effects of estrogen and
makes the use of progestin unnecessary

115. MOA
• All SERMs bind to the ER, but each agent produces a unique
receptor-drug conformation. As a result, specific coactivator or co-
repressor proteins are bound to the receptor resulting in differential
effects on gene transcription that vary depending on other
transcription factors present in the cell.
• affinity of each SERM for the different ERα and ERβ subtypes, which
are expressed differentially in various tissues. These tissue-selective
effects of SERMs offer the possibility of tailoring estrogen therapy to
best meet the needs and risk factor profile of an individual patient.

117. Bisphosphonates

118. Alendronate, risedronate, ibandronate,
and zoledronic acid
• prevention and treatment of post-
menopausal osteoporosis
Alendronate, risedronate, and
zoledronic acid
• treatment of steroid-induced
osteoporosis
• treatment of osteoporosis in men
risedronate and zoledronic acid • prevention of steroid-induced
osteoporosis

119. Mode of Action
• Bisphosphonates are structurally related to pyrophosphates,
compounds that are incorporated into bone matrix.
• Bisphosphonates specifically impair osteoclast function and reduce
osteoclast number, in part by inducing apoptosis.

121. nitrogen-containing bisphosphonates also inhibit protein
prenylation, one of the end products in the mevalonic
acid pathway, by inhibiting the enzyme farnesyl
pyrophosphate synthase. This effect disrupts intracellular
protein trafficking and ultimately may lead to apoptosis

123. How to take bisphonate
• taken with a full glass of water
• before breakfast after an over-night fast
• as bisphosphonates are poorly absorbed.
• remain upright (standing or sitting)t for at least 30 min after taking
the medication to avoid esophageal irritation, and that food and
fluids (other than water) be avoided for the same duration

124. • S/E
• esophageal irritation
• contraindicated in stricture or inadequate emptying of the esophagus.
• osteonecrosis of the jaw (ONJ)
• atypical femoral fracture

125. osteonecrosis of the jaw (ONJ)
• Increased incidence
• follows a dental procedure in which bone is exposed (dental
extractions and implants).
• more common among cancer victims receiving high doses of
bisphosphonates for skeletal metastases
• It is presumed that the exposed bone becomes infected and
dies.
• Prevention
• Oral antibiotic rinses and oral systemic antibiotics

126. ONJ

127. Atypical femoral #
• The fractures occur on trivial trauma, are horizontal with a medial
beak and are non-comminuted
• occur in the subtrochanteric femoral region or across the femoral
shaft distal to the lesser trochanter
• preceded by pain in the lateral thigh or groin, that can be present for
weeks, months or even years before the fracture

129. Prophylactic Detection
• Usually bilateral (about 50% of the time) and when an abnormality is
found the other femur should be checked
• Routine x-rays
• cortical thickening or even a stress fracture
• but more commonly MRI
• Technetium bone scan is required
• Prophylactic rx
• minimum a period of modified weight bearing
• prophylactic rodding of the femur.

130. Alendronate
• 5 mg/d for prevention
• 10 mg/d for 9 months
• 5 mg/d for 2 years
• 70mg weekly
• low incidence of gastrointestinal side effects and ease of administration

131. Risedronate
• 35 mg once weekly
• 5 mg/d.

132. Ibandronate
• 2.5 mg/d
• 150 mg/month PO
• 3 mg every 3 months IV

133. Zolendronate
• potent bisphosphonate with a unique administration regimen
• 5 mg by 15 min IV infusion annually

134. • Calcitonin
• suppresses osteoclast activity by direct action on the osteoclast calcitonin
receptor.
• Osteoclasts exposed to calcitonin cannot maintain their active ruffled
border, which normally maintains close contact with underlying bone

135. Calcitonin
• Injectable calcitonin produces small increments in bone mass of the
lumbar spine
• an analgesic effect on bone pain, both in the subcutaneous and possibly in
the nasal form
• no proven effectiveness against nonvertebral fractures
• No role in prophylaxis
• No role in prevention of osteoporosis
• Uses
• Paget’s disease,
• hypercalcemia,
• osteoporosis in women >5 years past menopause (not sufficiently
potent to prevent bone loss in early post-menopausal women)
• nasal spray containing calcitonin (200 IU/d)
• S/E
• nausea and facial flushing with injectable
• Increased risk of malignancy

136. Denosumab
• twice yearly by subcutaneous administration
• Uses
• to increase bone mass in postmenopausal women with low bone mass
(above osteoporosis range)
• men with prostate cancer on androgen deprivation treatment
• in postmenopausal women with breast cancer treated with aromatase
inhibitor therapies
• reduces the risk of fractures in women on aromatase inhibitors
• also reduces the risk of breast cancer recurrence

137. MOA
• human monoclonal anti-body to RANKL, the final common effector
of osteoclast formation, activity, and survival.
• Denosumab binds to RANKL, inhibiting its ability to initiate
formation of mature osteoclasts from osteoclast precursors and to
bring mature osteoclasts to the bone surface and initiate bone
resorption.
• reducing the survival of the osteoclast.

139. S/E
• ONJ
• atypical femur fractures
• hypersensitivity reactions,
• hypocalcemia
• skin reactions including dermatitis, rash, and eczema
• DISCONTINUATION OF DENOSUMAB  REBOUND PHENOMENON
• the maturation of osteoclast precursors that have accumulated in marrow when
the drug was administered and can become mature bone resorbing cells once the
drug is withdrawnrebound increase in bone turnover and an apparent
acceleration of bone loss.
• temporary use of bisphosphonate treatment can prevent the rebound increase in
remodeling and rapid bone loss.

140. Anabolic Agents

141. PTH
• activates bone remodeling but still appears to favour bone
formation over bone resorption.
• PTH given by daily injection stimulates osteoblast recruitment and
activity through activation of Wnt signaling.
• increase in bone tissue and an apparent restoration of bone
microarchitecture

142. (1–34)PTH (teriparatide)
• produced substantial increments in bone mass and reduced the risk
of vertebral compression deformity.
• produces rapid and robust increases in bone formation and then
bone remodeling overall, resulting in substantial increases in bone
mass and improvements in microarchitecture, including cancellous
connectivity and cortical width
• In previously untreated women,
• teriparatide is best administered as monotherapy and followed by a potent
antiresorptive agent such as denosumab or a bisphosphonate.

143. S/E
• muscle pain, weakness, dizziness, headache, and nausea
• INCREASED RISK OF OSTEOSARCOMA

144. Abaloparatide
• synthetic analogue of human PTH-related peptide (PTHrP), which
has significant homology to PTH and also binds the PTH Type 1
Receptor

145. Romosozumab
• humanized antibody that
blocks the osteocyte
production of sclerostin
• INHIBITOR OF WNT
PATHWAY FOR ACTIVATING
OSTEOBLAST
• resulting in an increase in
bone formation and decline
in bone resorption.

146. Odanacatib, a cathepsin K inhibitor, inhibits the osteoclast collagenase enzyme, preventing
bone resorption but not affecting osteoclast viability

147. NONPHARMACOLOGIC APPROACHES
• Protective pads worn around
the outer thigh, which cover
the trochanteric region of the
hip

148. • Kyphoplasty
• vertebroplasty

149. TREATMENT MONITORING
• BMD as a monitoring tool
• Changes must exceed ~4% in the spine and 6% in the hip to be considered
significant in any individual
• should be repeated at intervals >2 years.
• Biochemical markers of bone turnover
• collagen C-telopeptide measured on a fasting serum sample in the morning
is the preferred marker of bone resorption,
• osteocalcin or the propeptide of type 1 collagen (P1NP) for formation.
• repeated ≥4 months after therapy is initiated.
• change in bone turnover markers must be 30–40% lower than the baseline to be
significant because of the biologic and technical variability in these tests