OSTEOPOROSIS AND ITS MANAGEMENT

Disusun Oleh:
Ahmad Marzuqi bin Abdullah
112015434

Pembimbing:
dr. Arsanto Triwidodo, SpOT(K) MHKes

KEPANITERAAN KLINIK ILMU KESEHATAN BEDAH

FAKULTAS KEDOKTERAN UNIVERSITAS KRISTEN KRIDA WACANA
RSUD KOJA
PERIODE 23 JANUARI 2017 1 APRIL 2017

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 CHAPTER I
INTRODUCTION
Osteoporosis is a systemic metabolic bone disease that is characterized by the
reduction in bone mass density. It is due to reduced bone mineral and matrix and
accompanied by the destruction of micro-architecture in the bone tissues. With consequent
decrease in bone strength, this will result in a higher tendency of becoming brittle bones.

Formation and bone resorption are mostly in balance in individuals aged around 30-40
years. The imbalance of bone resorption happened to start when women reach menopause
and men reach the age of 60 years.

Osteoporosis causes more than 8.9 million fractures each year in the world, with 4.5
million cases occur in the United States and Europe. Currently there are approximately 0.3
million hip fractures per year in the United States and 1.7 million in Europe. Almost all of
these events is associated with osteoporosis, whether primary or secondary. The ratio of
women and men in hip fracture is about 2 : 1. The incidence of wrist fractures in England and
America ranges from 400-800 per 100,000 women. Vertebral compression fracture is much
more difficult to predict because it is often asymptomatic. It is estimated that more than one
million American postmenopausal women will suffer a fracture of the spine in the course of
one year.

This literature was made to discuss about the pathogenesis, diagnosis and
management of osteoporosis which are often found in the advanced process. It is expected to
broaden our knowledge of us all in the early diagnosis and proper treatment of osteoporosis.

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 CHAPTER II

DISCUSSION

2.1 Definition

The word osteo literally means bone and the word porosis means cavities.
Osteoporosis is a systemic skeletal disease characterized by low bone mass and deterioration
of bone tissue microarchitecture resulting in bone fragility and an increased susceptibility to
fractures. National Institute of Health (NIH) proposed a new definition of osteoporosis as a
systemic skeletal disease characterized by compromised bone strength until the bones can
easily be broken. Operationally osteoporosis is defined based on the bone mineral density
(BMD) values. Based on WHO criteria, osteoporosis is when BMD values are at 2.5 standard
deviations (SD) or below the average value of healthy young adults (T score <-2.5 SD).1

Tabel 1: Osteoporosis definition based on WHO1

Definition Criteria
Normal BMD > -1 SD
Low bone mass
BMD is between -1SD and -2.5 SD
(osteopenia)
Osteoporosis BMD is below -2.5 SD
Severe osteoporosis BMD is below -2.5 SD and with bone fractures

2.2 Epidemiology

According to the National Osteoporosis Foundation (NOF), 9.9 million Americans

have osteoporosis and an additional 43.1 million have low bone density. In the United States,
two million fractures are attributed to osteoporosis annually, with 432,000 hospital
admissions, 2.5 million medical office visits and approximately 180,000 nursing home
admissions.2

Most studies assessing the prevalence and incidence of osteoporosis use the rate of
fracture as a marker for the presence of this disorder, although BMD also relates to risk of
disease and fracture. The risk of new vertebral fractures increases by a factor of 2-2.4 for
each standard deviation (SD) decrease of BMD measurement. Women and men with
metabolic disorders associated with secondary osteoporosis have a 2- to 3-fold higher risk of
hip and vertebral fractures.2

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 Risk for osteoporosis increases with age as BMD declines. Senile osteoporosis is most
common in persons aged 70 years or older. Secondary osteoporosis, however, can occur in
persons of any age. Although bone loss in women begins slowly, it speeds up around the time
of menopause, typically at about or after age 50 years. The frequency of postmenopausal
osteoporosis is highest in women aged 50-70 years.2,3

The number of osteoporotic fractures increases with age. Wrist fractures typically
occur first, when individuals are aged approximately 50-59 years. Vertebral fractures occur
more often in the seventh decade of life. Ninety percent of hip fractures occur in persons aged
50 years or older, occurring most often in the eighth decade of life.

Women are at a significantly higher risk for osteoporosis. Half of all postmenopausal
women will have an osteoporosis-related fracture during their lifetime; 25% of these women
will develop a vertebral deformity, and 15% will experience a hip fracture. Risk factors for
hip fracture are similar in different ethnic groups. Men have a higher prevalence of secondary
osteoporosis, with an estimated 45-60% of cases being a consequence of hypogonadism,
alcoholism, or glucocorticoid excess.3 Only 35-40% of osteoporosis diagnosed in men is
considered primary in nature. Overall, osteoporosis has a female-to-male ratio of 4:1.

2.3 Etiology

Osteoporosis has been divided into several classifications according to etiology and
localization in the skeleton. Osteoporosis is initially divided into localized and generalized
categories, and these two main categories are further classified further into primary and
secondary osteoporosis. Postmenopausal osteoporosis (PMO) is primarily due to estrogen
deficiency. Senile osteoporosis is primarily due to an aging skeleton and calcium deficiency.1

Primary osteoporosis

Patients are said to have primary osteoporosis when a secondary cause of osteoporosis
cannot be identified, including juvenile and idiopathic osteoporosis. Idiopathic osteoporosis
can be further subdivided into postmenopausal (type I) and age-associated or senile (type II)
osteoporosis, as described in Table 2, below.

Table 2: types of primary osteoporosis1,2

Type of Primary Osteoporosis Characteristics

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 Usually occurs in children or young
adults of both sexes

Normal gonadal function

Juvenile osteoporosis Age of onset: usually 8-14 years

Hallmark characteristic: abrupt bone

pain and/or a fracture following
trauma

Idiopathic osteoporosis

Occurs in women with estrogen

deficiency

Characterized by a phase of
Postmenopausal osteoporosis
accelerated bone loss, primarily from
(type I osteoporosis)
trabecular bone

Fractures of the distal forearm and

vertebral bodies common

Occurs in women and men as BMD

gradually declines with aging

Represents bone loss associated with

Age-associated or senile aging

osteoporosis (type II Fractures occur in cortical and

osteoporosis) trabecular bone

Wrist, vertebral, and hip fractures

often seen in patients with type II
osteoporosis

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Secondary osteoporosis

Secondary osteoporosis occurs when an underlying disease, deficiency, or drug causes

osteoporosis (see Table 3, below). Up to one third of postmenopausal women, as well as
many men and premenopausal women, have a coexisting cause of bone loss, of which renal
hypercalciuria is one of the most important secondary causes of osteoporosis and treatable
with thiazide diuretics.

Table 3: Causes of secondary osteoporosis4

Cause Examples

Genetic/congenital Renal hypercalciuria one of the most important

secondary causes of osteoporosis; can be treated with
thiazide diuretics

Cystic fibrosis

Ehlers-Danlos syndrome

Glycogen storage disease

Gaucher disease

Marfan syndrome

Menkes steely hair syndrome

Riley-Day syndrome

Osteogenesis imperfecta

Hemochromatosis

Homocystinuria

Hypophosphatasia

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 Idiopathic hypercalciuria

Porphyria

Hypogonadal states

Androgen insensitivity

Anorexia nervosa/bulimia nervosa

Female athlete triad

Hyperprolactinemia
Hypogonadal states
Panhypopituitarism

Premature menopause

Turner syndrome

Klinefelter syndrome

Endocrine disorders Cushing syndrome

Diabetes mellitus

Acromegaly

Adrenal insufficiency

Estrogen deficiency

Hyperparathyroidism

Hyperthyroidism

Hypogonadism

Pregnancy

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 Prolactinoma

Calcium deficiency

Magnesium deficiency

Protein deficiency

Vitamin D deficiency

Bariatric surgery

Deficiency states Celiac disease

Gastrectomy

Malabsorption

Malnutrition

Parenteral nutrition

Primary biliary cirrhosis

Inflammatory bowel disease

Inflammatory Ankylosing spondylitis

diseases Rheumatoid arthritis

Systemic lupus erythematosus

Hematologic and Hemochromatosis

neoplastic disorders
Hemophilia

Leukemia

Lymphoma

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 Multiple myeloma

Sickle cell anemia

Systemic mastocytosis

Thalassemia

Metastatic disease

Anticonvulsants

Antipsychotic drugs

Antiretroviral drugs

Aromatase inhibitors

Chemotherapeutic/transplant drugs: cyclosporine,

tacrolimus, platinum compounds, cyclophosphamide,
ifosfamide, high-dose methotrexate

Furosemide
Medications
Glucocorticoids and corticotropin: prednisone (5
mg/day for 3 mo)

Heparin (long term)

Hormonal/endocrine therapies: gonadotropin-releasing

hormone (GnRH) agonists, luteinizing hormone-
releasing hormone (LHRH) analogues,
depomedroxyprogesterone, excessive thyroxine

Lithium

Selective serotonin reuptake inhibitors (SSRIs)

Miscellaneous Alcoholism

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 Amyloidosis

Chronic metabolic acidosis

Congestive heart failure

Depression

Emphysema

Chronic or end-stage renal disease

Chronic liver disease

HIV/AIDS

Idiopathic scoliosis

Immobility

Multiple sclerosis

Ochronosis

Organ transplantation

Pregnancy/lactation

Sarcoidosis

Weightlessness

2.4 Pathogenesis bone formation

Bone is a specialized and mineralised connective tissue that acts as a support to the
body to stand stable. Together with cartilage, they formed the skeletal system, that has three
main functions, which are mechanical function as supportive and the place of insertion of the

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muscles to move, as a protection for the vital organs and bone marrow , and lastly as a
reserve metabolic functions of calcium and phosphate which are used for the maintenance of
homeostasis that is essential to life.

Human bones consist of 80% corticular bones and 20% trabecular bones. Cortical
bones and trabecular bones are made of the same cells and the same matrix elements, but
there are differences in their structure and functions. The main structural difference
quantitatively is 80% to 90% of bone volume 6 kortikular is calcification, while only 15% to
25% of the trabecular volume is calcified (the rest is bone marrow, blood vessels, and
connective tissue). The main function of cortical bone serves as a mechanical (locomotor)
and protector, while trabecular bone as a metabolic function and also plays a role in bone
biomechanics process, especially the spine.5

Remodeling is a process where there is a turn-over from the bones that may allow the
maintenance of the form, quality and quantity of the frameworks. This process is
characterized by the coordinated activation of osteoclasts and osteoblasts, which occurs in
bone multicellular unit (BMUs) in which the activation process of resorption and formation
occur sequentially and continuously.5

Osteoblasts are the cells that responsible for bone formation process, which serves in
the synthesis of bone matrix called osteoid, the protein component of bone tissue. Osteoclasts
are the bone cells responsible for the bone resorption process. Osteoclasts are multinucleated
giant cells and derived from the mononuclear hemopoetic.

In the process of bone formation, osteoblasts begin to work. For differentiation and
maturation, osteoblasts need local growth factors, such as fibroblast grow factor (FGF), bone
morphogenetic proteins (BMPs) and Wnt proteins. Besides that, transcription factors are also
necessary, named as core binding factor-1 or Runx2 or Osterix (Osx).5 These osteoblast
precursors will undergone proliferation and differentition to form preosteoblasts and then
advance into mature osteoblasts. Osteoblasts will be coating bone matrix (osteoid) which
were produced prior to calcification and this calcification process takes about 10 days.
Osteoblast membrane is rich in alkaline phosphatase and contain receptors for parathyroid
hormone and prostaglandin but do not have the receptors for calcitonin. Other than that,
osteoblasts also expressed estrogen receptors, vitamin D3 and a variety of cytokines, such as
colony stimulating factor 1 (CSF1), receptor activator of nuclear factor ligand (RANKL) and
osteoprotegerin (OPG). RANKL plays a role in the maturation of osteoclast precursors as the

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osteoclast precursors have the RANK receptor on their surface. Whereas the effects of
RANKL will be inhibited by OPG.5

Osteocytes are stelat shaped cells that have overhung the cytoplasm (processus) very
long to be related to processes of osteocytes other and also with linning bone cells. In the
matrix, osteocytes located in the cavity, called lacuna, while prosesusnya located in in a
tunnel which is called canaliculi.

After the growth has stalled and the peak bone mass is reached, the bone formation
process will continue on the endosteal surface. The continuous process of bone resorption and
bone formation is called bone remodeling. The bone remodelling is the process of replacing
old bone or damaged, beginning with bone resorption by osteoclasts, followed by bone
formation by osteoblasts. The remodeling process begins with the activation of osteoclasts by
certain cytokines. Osteoclasts will leave cavities called lacunae howship on trabecular bone
or conical cavity (cutting cone) in cortical bone. After resorption is completed, then the
osteoblasts will conduct bone formation in the cavity left by the osteoclasts to form bone
matrix called osteoid, followed by primer mineralization in a short time and then continued
with secondary mineralization in a longer and slower process until the bones become hard.5

In normal young adults, approximately 30% of the total mass of the framework is
updated annually (half life = 20 months). In each unit remodeling, bone resorption by
osteoclasts lasts about three days, with a recovery period of 14 days and 70 days of bone
formation (total = 87 days). Linear bone formation rate was 0.5 mm / day. During this
process, approximately 0:01 mm bone remodeling refurbished in a single unit. Theoretically,
the matrix deposition and calcification balanced, and the balance between the activity of
osteoclasts and osteoblasts, the amount of bone formed in each unit equals the amount of
bone remodeling previously resorbed.5 Thus, the total mass of skeletal remains constant.
Homeostasis of this framework relies on the normal remodeling activity. The level of
activation of new remodeling units, only determine the level of turnover.

2.5 Pathogenesis of osteoporosis

The hallmark of osteoporosis is a reduction in skeletal mass caused by an imbalance

between bone resorption and bone formation. Under physiologic conditions, bone formation
and resorption are in a fair balance. A change in eitherthat is, increased bone resorption or
decreased bone formationmay result in osteoporosis.

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 Osteoporosis can be caused both by a failure to build bone and reach peak bone mass
as a young adult and by bone loss later in life. Accelerated bone loss can be affected by
hormonal status, as occurs in perimenopausal women; can impact elderly men and women;
and can be secondary to various disease states and medications.

Aging and loss of gonadal function are the 2 most important factors contributing to
the development of osteoporosis. Studies have shown that bone loss in women accelerates
rapidly in the first years after menopause. The lack of gonadal hormones is thought to up-
regulate osteoclast progenitor cells. Estrogen deficiency leads to increased expression of
RANKL by osteoblasts and decreased release of OPG; increased RANKL results in
recruitment of higher numbers of preosteoclasts as well as increased activity, vigor, and
lifespan of mature osteoclasts.1,6

Estrogen deficiency

Estrogen deficiency not only accelerates bone loss in postmenopausal women but also
plays a role in bone loss in men. Estrogen deficiency can lead to excessive bone resorption
accompanied by inadequate bone formation. Osteoblasts, osteocytes, and osteoclasts all
express estrogen receptors. In addition, estrogen affects bones indirectly through cytokines
and local growth factors. The estrogen-replete state may enhance osteoclast apoptosis via
increased production of transforming growth factor (TGF)beta.

In the absence of estrogen, T cells promote osteoclast recruitment, differentiation, and

prolonged survival via IL-1, IL-6, and tumor necrosis factor (TNF)alpha. A murine study, in
which either the mice's ovaries were removed or sham operations were performed, found that
IL-6 and granulocyte-macrophage CFU levels were much higher in the ovariectomized
mice. This finding provided evidence that estrogen inhibits IL-6 secretion and that IL-6
contributes to the recruitment of osteoclasts from the monocyte cell line, thus contributing to
osteoporosis.1,6

IL-1 has also been shown to be involved in the production of osteoclasts. The
production of IL-1 is increased in bone marrow mononuclear cells from ovariectomized rats.
Administering IL-1 receptor antagonist to these animals prevents the late stages of bone loss
induced by the loss of ovarian function, but it does not prevent the early stages of bone loss.
The increase in the IL-1 in the bone marrow does not appear to be a triggered event but,
rather, a result of removal of the inhibitory effect of sex steroids on IL-6 and other genes
directly regulated by sex steroids.

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 T cells also inhibit osteoblast differentiation and activity and cause premature
apoptosis of osteoblasts through cytokines such as IL-7. Finally, estrogen deficiency
sensitizes bone to the effects of parathyroid hormone (PTH).

Aging

In contrast to postmenopausal bone loss, which is associated with excessive osteoclast

activity, the bone loss that accompanies aging is associated with a progressive decline in the
supply of osteoblasts in proportion to the demand. This demand is ultimately determined by
the frequency with which new multicellular units are created and new cycles of remodeling
are initiated.

After the third decade of life, bone resorption exceeds bone formation and leads to
osteopenia and, in severe situations, osteoporosis. Women lose 30-40% of their cortical bone
and 50% of their trabecular bone over their lifetime, as opposed to men, who lose 15-20% of
their cortical bone and 25-30% of trabecular bone.1

Calcium deficiency

Calcium, vitamin D, and PTH help maintain bone homeostasis. Insufficient dietary
calcium or impaired intestinal absorption of calcium due to aging or disease can lead to
secondary hyperparathyroidism. PTH is secreted in response to low serum calcium levels. It
increases calcium resorption from bone, decreases renal calcium excretion, and increases
renal production of 1,25-dihydroxyvitamin D (1,25[OH] 2 D)an active hormonal form of
vitamin D that optimizes calcium and phosphorus absorption, inhibits PTH synthesis, and
plays a minor role in bone resorption.

Vitamin D deficiency

Vitamin D deficiency can result in secondary hyperparathyroidism via decreased

intestinal calcium absorption.

Osteoporotic fractures

Osteoporotic fractures represent the clinical significance of these derangements in

bone. They can result both from low-energy trauma, such as falls from a sitting or standing
position, and from high-energy trauma, such as a pedestrian struck in a motor vehicle
accident. Fragility fractures, which occur secondary to low-energy trauma, are characteristic
of osteoporosis.

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 Fractures occur when bones fall under excess stress. Nearly all hip fractures are
related to falls. The frequency and direction of falls can influence the likelihood and severity
of fractures. The risk of falling may be amplified by neuromuscular impairment due to
vitamin D deficiency with secondary hyperparathyroidism or corticosteroids.

Vertebral bodies are composed primarily of cancellous bone with interconnected

horizontal and vertical trabeculae. Osteoporosis not only reduces bone mass in vertebrae but
also decreases interconnectivity in their internal scaffolding. Therefore, minor loads can lead
to vertebral compression fractures.

An understanding of the biomechanics of bone provides greater appreciation as to

why bone may be susceptible to an increased risk of fracture. When vertical loads are placed
on bone, such as tibial and femoral metaphyses and vertebral bodies, a substantial amount of
bony strength is derived from the horizontal trabecular cross-bracing system. This system of
horizontal cross-bracing trabeculae assists in supporting the vertical elements, thus limiting
lateral bowing and fractures that may occur with vertical loading.

Disruption of such trabecular connections is known to occur preferentially in patients

with osteoporosis, particularly in postmenopausal women, making females more at risk than
males for vertebral compression fractures.

Osteoporosis versus osteomalacia

Osteoporosis may be confused with osteomalacia. The normal human skeleton is

composed of a mineral component, calcium hydroxyapatite (60%), and organic material,
mainly collagen (40%). In osteoporosis, the bones are porous and brittle, whereas in
osteomalacia, the bones are soft. This difference in bone consistency is related to the mineral-
to-organic material ratio. In osteoporosis, the mineral-to-collagen ratio is within the reference
range, whereas in osteomalacia, the proportion of mineral composition is reduced relative to
organic material content.

The Wnt signaling pathway and bone

The Wnt family is a highly conserved group of proteins that were initially studied in
relationship with cancer initiation and progression due to their involvement in intercellular
communication. In the past decade, the Wnt signaling cascade has been recognized as a
critical regulator of bone metabolism.

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 Wnt signaling plays a key role in the fate of mesenchymal stem cells (MSCs), which
are the progenitor cells of mature bone-forming osteoblasts. MSCs have the capability to
differentiate into adipocytes, chondrocytes, neurons, and muscle cells, as well as into
osteoblasts. Certain Wnt signaling pathways promote the differentiation of MSCs along the
osteoblast lineage. The emerging details about the specific molecules involved in the Wnt
pathway have improved the understanding of bone metabolism and led to the development of
new therapeutic targets for metabolic bone diseases.

Wnt signal activation may progress along one of three pathways, with the canonical
pathway involving -catenin being most relevant to bone metabolism. The canonical Wnt
signaling pathway is initiated by the binding of a Wnt protein to an extracellular co-receptor
complex consisting of Frizzled (Fr) and low density lipoprotein receptorrelated protein5
or 6 (LRP5, LRP6). This activation recruits another protein, Disheveled (Dvl) to the
intracellular segment of the Fz/Dvl co-receptor. This is where -catenin comes into play.6

-Catenin is an important intracellular signaling molecule and normally exists in a

phosphorylated state targeted for ubiquination and subsequent degradation within
intracellular lysosomes. Activation of the Wnt pathway leads to dephosphorylation and
stabilization of intracellular -catenin and rising cytosolic concentrations of -catenin. As the
concentration of -catenin reaches a critical level, -catenin travels to the nucleus, where it
activates the transcription of Wnt target genes. Ultimately, canonical Wnt signaling inhibits
the expression of transcription factors important in the differentiation of MSCs such as
peroxisome proliferator-activated receptor gamma (PPAR-) and promotes survival of
osteoblast lineage cells.

Several human bone abnormalities have been linked to the Wnt pathway. For
example, a single amino acid substitution in the LRP5 receptor gene has been associated with
high bone mass phenotypes in humans; specifically, the mutant LRP5 receptor had an
impaired interaction with the Wnt signal inhibitor Dickkopf-1 (Dkk-1). Similarly, other
missense mutations of LRP5 have been implicated in other high bone mass diseases such as
Van Buchem disease and osteopetrosis. Conversely, loss-of-function mutations of LRP5 have
resulted in a rare but severe congenital osteoporosis in humans.6

There are also several antagonists to the Wnt pathway. Two of the most well-known
are Dkk-1 and sclerostin (SOST). Dkk-1 is secreted by MSCs and binds to LRP-5 and LRP-
6, thereby competitively inhibiting Wnt signaling. Interestingly, serum levels of Dkk-1

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positively correlate with the extent of lytic bone lesions in patients with multiple myeloma.
Clinical trials of a monoclonal antibody to Dkk-1 are ongoing. Similarly, SOST, a product of
osteocytes, has also been found to antagonize the Wnt signaling pathway by binding to LRP5
and LRP6. A SOST antibody is also undergoing clinical trials for treatment of metabolic bone
disease.

Additional factors and conditions

Endocrinologic conditions or medications that lead to bone loss (eg, glucocorticoids)

can cause osteoporosis. Corticosteroids inhibit osteoblast function and enhance osteoblast
apoptosis. Polymorphisms of IL-1, IL-6 and TNF-alpha, as well as their receptors, have been
found to influence bone mass.

Other factors implicated in the pathogenesis of osteoporosis include polymorphisms

in the vitamin D receptor; alterations in insulin-like growth factor-1, bone morphogenic
protein, prostaglandin E2, nitrous oxide, and leukotrienes; collagen abnormalities; and leptin-
related adrenergic signaling.

2.6 Risk factors

Risk factors for osteoporosis, such as advanced age and reduced bone mineral density
(BMD), have been established by virtue of their direct and strong relationship to the
incidence of fractures; however, many other factors have been considered risk factors based
on their relationship to BMD as a surrogate indicator of osteoporosis.

Risk factors for osteoporosis include the following:2,3

Advanced age (50 years)

Female sex

White or Asian ethnicity

Genetic factors, such as a family history of osteoporosis

Thin build or small stature (eg, body weight less than 127 lb)

Amenorrhea

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 Late menarche

Early menopause

Postmenopausal state

Physical inactivity or immobilization

Use of certain drugs (eg, anticonvulsants, systemic steroids, thyroid supplements,

heparin, chemotherapeutic agents, insulin)

Alcohol and tobacco use

Androgen or estrogen deficiency

Calcium deficiency

2.7 Diagnosis

Until now, the early detection of osteoporosis is a very difficult thing to do.
Osteoporosis is a silent disease (silent), sometimes it does not give any signs or symptoms
until fracture occurs. Diagnosis of osteoporosis are sometimes only known after the
occurrence of fractures of the spine, hip bones, wrist bones or other fractures in older people,
either men or women. Usually the bone mass is reduced 30-40% and can only be detected by
conventional X-ray examination.

History taking

A thorough history should be obtained to screen for and identify the presence of known
risk factors for osteoporosis and osteoporotic fracture. Specifically, the history should focus
on the following:7

Age (>50 years), sex (female), and race (white or Asian) ; the US Preventive Services
Task Force (USPSTF) recommendations include screening for osteoporosis in women
aged 65 years or older and in younger women with a fracture risk that is the same or
greater than that of a 65-year-old white woman who has no additional risk factors

Family history of osteoporosis, particularly maternal history of fractures

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 Reproductive factors, especially regarding early menopause and estrogen replacement
therapy: postmenopausal women are at high risk, as are women who have undergone
hysterectomy and oophorectomy

Hypogonadal states: men with hypogonadism secondary to any genetic or other

conditions are at higher risk; the USPSTF notes that there is insufficient current
evidence to assess the risk versus benefit of screening for osteoporosis in men

Smoking: smokers are at higher risk

Alcohol consumption

Low levels of physical activity: immobility increases the risk; spinal cord injury and
stroke cause physical impairment and are common causes of immobility

Strenuous exercise that results in amenorrhea (such as that which occurs in marathon
runners)

Calcium and vitamin D intake

History of low-trauma "fragility" fracture in patients aged 40 years or older: a fragility

fracture is defined as a fracture due to trauma that would not normally cause fracture
(a force equal to or less than that resulting from a fall from standing height)

Signs of vertebral fracture

Coexisting medical conditions associated with bone loss

Medications associated with bone loss

Risk factors for falls in older patients: these include poor balance,orthostatic
hypotension, weakness of the lower extremity muscles and deconditioning, use of
medications with sedative effects, poor vision or hearing, and cognitive impairment

The Fracture Risk Assessment (FRAX) tool, accessible to healthcare providers and
patients, is a validated instrument used to estimate 10-year risks for fractures, including those
for black, Asian, and Hispanic women. A 65-year-old white woman with no other risk factors
has a 9.3% 10-year risk for any osteoporotic fracture. Generally, estimated fracture risks in
nonwhite women are lower than those for white women of the same age.7

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 White women between the ages of 50 and 64 years with 10-year fracture risks based on
specific risk factors include the following persons:

A 50-year-old current smoker with a body mass index (BMI) less than 21 kg/m 2,
daily alcohol use, and parental fracture history
A 55-year-old woman with a parental fracture history
A 60-year-old woman with a BMI less than 21 kg/m 2 and daily alcohol use
A 60-year-old current smoker with daily alcohol use

Physical Examination

Patients with suspected osteoporosis should undergo a comprehensive physical

examination. The physical examination should begin with an inspection of the patient. Height
measurement with a stadiometer at each visit may be useful. Examination of active and
passive range of motion (ROM) assists in determining whether spine, hip, wrist, or other
osseous pathology may be present. A thorough neurologic examination is essential to rule out
spinal cord and/or peripheral nerve compromise.

The examination may elicit pain, or the patient may be pain free. Thoracic kyphosis
may be present secondary to vertebral compression fractures, a dowager hump, and a history
of loss of height. Patients may have an associated scoliosis.2,7

Areas of concern include the following:2,6,7

A history of loss of height

Low body weight (body mass index < 19 kg/m 2)

Signs that might indicate existing osteoporosis (eg, kyphosis or dowager hump; point
tenderness over a vertebra or other suspected fracture site)

Signs suggestive of secondary osteoporosis

Signs in older patients that may indicate increased fall risk (eg, difficulty with balance
or gait, orthostatic hypotension, lower-extremity weakness, poor vision or hearing,
cognitive impairment)

Signs of fracture

Patients with vertebral compression fractures may demonstrate a thoracic kyphosis

with an exaggerated cervical lordosis (dowager hump). This is followed by a loss of lumbar

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lordosis. After each episode of vertebral compression fracture and progressive kyphosis, the
patient's height may decrease by 2-3 cm. Patients with acute vertebral fractures may have
point tenderness over the involved vertebrae. Palpation of the spinous processes often does
not aid the examiner in localizing point tenderness, but percussion may be helpful in acute or
subacute vertebral compression fractures.

Patients with hip fractures may have severe pain with ambulation. A FABER (ie,
flexion in abduction and external rotation) hip joint test may reveal limited ROM with end-
range pain. Patients with hip fractures may show decreased weight-bearing on the fractured
side or an antalgic gait pattern. Patients with pubic and sacral fractures may report marked
pain with ambulation and tenderness to palpation, percussion, or both. Furthermore, patients
with sacral fractures may have pain with physical examination techniques used to assess the
sacroiliac joint, such as the FABER, Gaenslen, or squish test. Fractures in other parts of the
body, including the distal radius and humerus, are typically painful and result in limited range
of motion of the involved joint.1

Balance difficulties

Patients with osteoporosis are known to have decreased balance, possibly secondary
to differences in balance control strategies and sway amplitude. Patients may have difficulty
performing tandem gait and performing single limb stance. Poor balance may be noted
particularly in patients with severe kyphosis resulting from vertebral compression fractures
because their altered center of gravity makes ambulation with a stable base of support
difficult for them. Fractures are the most common and serious complication of osteoporosis.
Patients with osteoporosis are at high risk for recurrent fractures of the hips, vertebrae, ribs,
and wrists.

Radiology examination

Radiological examination to assess bone density is very insensitive. The diagnostic

value for typical plain radiology examination to assess early osteoporosis is less satisfying,
because this type of examination can only detect osteoporosis after a decline in bone mass
density of more than 30%. Typical radiology imaging of osteoporosis is the thinning of bone
cortex and trabecular area which looks more lucen.1,7 On the vertebrae, lateral and
anteroposterior radiographs can be used to detect compression fracture, wedge fracture or
biconcave fracture.

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 Figure 1: comparison between normal x-ray photo of left foot with x-ray of
osteoporotic left foot

X-Ray Absorptiometry

Several large prospective studies have shown that BMD measurements of the distal
and proximal femur and the vertebral bodies can predict the development of the major types
of osteoporotic fractures. BMD has been shown to be the best indicator of fracture risk.
According to the National Osteoporosis Foundation (NOF), evaluating BMD on a periodic
basis is the best way to monitor bone mass and future fracture risk, although there is
controversy about how frequently to measure this.2

DXA is currently the criterion standard for the evaluation of BMD. Compared with
other screening tools (eg, calcaneal quantitative ultrasonography, the Simple Calculated
Osteoporosis Risk Estimation [SCORE]), DXA has been found to be efficacious and cost-
effective. DXA is not as sensitive as quantitative computed tomography (QCT) scanning for
detecting early trabecular bone loss, but it provides comparable costs, it is done on an

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outpatient basis, and there are no special requirements for performing it. Also, radiation
exposure is kept to a minimum.

DXA is used to calculate BMD at the lumbar spine, hip, and proximal femur (see the
images below). Densitometric spine imaging can be performed at the time of DXA scanning
to detect vertebral fractures. Vertebral fracture assessment (VFA) is not available with all
DXA machines. When available, VFA should be considered when the results may influence
clinical management of the patient. Peripheral DXA is used to measure BMD at the wrist; it
may be most useful in identifying patients at very low fracture risk who require no further
workup.8

Figure 2: Bone mass density at femoral site

Although measurement of BMD at any site can be used to assess overall fracture risk,
measurement at a particular site is the best predictor of fracture risk at that site. Whenever
possible, the same technologist should perform subsequent measurements on the same patient
using the same machine. This method can be used in both adults and children. Factors that
may result in a falsely high BMD determination include spinal fractures, osteophytosis,
scoliosis, and extraspinal (eg, aortic) calcification.

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 Bone density data from a DXA are reported as T-scores and Z-scores. The T-score is
the value compared to that of control subjects who are at their peak BMD, whereas the Z-
score reflects a value compared to that of patients matched for age and sex.8

The 2014 NOF guidelines recommend BMD measurement in the following patients:

Women age 65 years and older and men age 70 years and older, regardless of clinical
risk factors

Younger postmenopausal women and women in menopausal transition with clinical

risk factors for fracture

Men age 50-69 years with clinical risk factors for fracture

Adults who have a condition associated with low bone mass or bone loss (eg,
rheumatoid arthritis)

Adults who take a medication associated with low bone mass or bone loss (eg,
glucocorticoids, 5 mg of prednisone daily for 3 mo)

Differential diagnosis

Some diseases can cause a decrease in bone mass density and fractures. Therefore, if
there is a patient with a decrease in bone mass density or fractures, the underlying disease
need to be found first. Some diseases that may cause a decrease in bone mass density can be
made as a differential diagnosis. History and physical examination based on the clinical
symptoms is still needed to be done to make the diagnosis of osteoporosis, including the
underlying disease of osteoporosis (secondary osteoporosis). Investigations, such as
laboratories are very helpful in getting rid of the differential diagnosis of disease. As for some
illness or chronic condition that often leads to osteoporosis are as follows:

1. Multiple myeloma

Multiple myeloma (MM) is characterized by lytic bone lesions, accumulation of

plasma cells in the bone marrow, and the presence of monoclonal protein in the serum and
urine. MM should be contemplated in patients over 40 years with an unexplained anemia,
kidney dysfunction or the presence of bone lesions (only <2% of patients aged <40 years).
MM patients usually present with the symptoms like anemia, bone pain, pathologic fractures,
bleeding tendencies, and peripheral neuropathy. Multiple myeloma can be diagnosed from its

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classic triad (plasma cells, typically> 10% + M protein + lytic bone lesions). 1,2 Laboratory
tests for the diagnosis of MM is albumin-globulin, serum protein electrophoresis, Bence-
Jones protein urine, hypercalcemia, increased in ureum-creatinine and abnormal plasma cells
seen in blood films in 15% of patients.

2. Hyperparathyroidism

The main effects of parathyroid hormone are to increase the concentration of plasma
calcium by increasing the release of calcium and phosphate from bone matrix, increasing
calcium reabsorption by the kidney, and increasing renal production of 1,25-
dihydroxyvitamin D-3 (calcitriol), which increases intestinal absorption of calcium. 5,7
Hyperparathyroidism come in two forms which are primary and secondary. Primary
hyperparathyroidism is due to excessive functions of the parathyroid glands, usually the
adenoma. Primary hyperparathyroidism will result in high concentration of parathyroid
hormone serum, and high calcium serum. Secondary hyperparathyroidism is the excessive
production of parathyroid hormone due to stimulation by abnormal production. Secondary
hyperparathyroidism is a compensatory hyperplasia of all four glands which aims to correct a
decrease in serum calcium levels. Most patients with hyperparathyroidism are asymptomatic.
Its manifestations are especially on the kidneys and bones. Abnormalities in the kidneys that
can be found are recurrent nephrolithiasis, urinary tract obstruction, infection, and renal
function failure. Laboratory tests may show increased serum levels of parathyroid hormone,
high calcium serum, low phosphate, high alkali phosphatase, high urinary calcium and
phosphate, 25 hydroxyvitamin D is low, kidney function tests. On X-rays, the bones become
thin, decalcification occurs, and bone cystic may present.

2.8 Therapy

Pharmacological

Theoretically osteoporosis can be treated by inhibiting the work of osteoclasts or

increase the work of osteoblasts. However, the current distributed drugs are generally anti-
resorption drugs which includes estrogen, calcitonin, and bisphosphonates. Calcium and
Vitamin D does not have the effect of anti-bone resorption and bone stimulating, but they are
necessary to optimize the mineralization of osteoid after the bone formation process by
osteoblast cells.

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Bisphosphonates

Bisphosphonates are drugs used for the treatment of osteoporosis. Bisphosphonates

are pyrophosphate analog made up from two phosphonic acids tied to one another by a
carbon atom. Bisphosphonates can reduce bone resorption by the osteoclasts by binding to
the surface of the bone and inhibiting work of the osteoclasts thus reducing the production of
protons and lysosomal enzymes.

Bisphosphonates taken orally are absorbed in the small intestine and its absorption is
very poor. The absorption of this drug can also be hampered if taken together with calcium,
other divalent cations, and various other drinks except water. Ideally taken in the morning on
an empty stomach. After that the patient is not allowed to eat anything and lying down for at
least 30 minutes. Approximately 20-50% of the bisphosphonate absorbed, will be attached to
the bone surface after 12-24 hours.1 After binding to the bone and act on the osteoclasts,
bisphosphonate will remain in the bone for months or even years, but no longer active.
Bisphosphonates that are not attached to the bone, will not undergone metabolism in the body
and will be excreted in the intact form through the kidneys, so be careful of administration of
this drug to the patients with renal failure. The side effects of bisphosphonate is reflux
esophagitis, osteonecrosis of the jaw, hypocalcemia and atrial fibrillation. Therefore, patients
who obtained bisphosphonates, their calcium intake should be watched too.

Type of bisphosphonates used for the treatment of osteoporosis:

1. Risedronate, a third generation aminobisfosfonate is extremely potent. To cope with Paget's

disease required a dose of 30 mg / day for 2 months, while for osteoporosis needed a dose of
35 mg / week or 5 mg / day continuously or 75 mg two consecutive days once a month or 150
mg once a month. Contra indications for risedronate administration is hypocalcemia,
pregnant women, breastfeeding women and renal impairment (creatinine clearance <30 ml /
min).

2. Alendronate, a potent aminobisfosfonates. For the treatment of osteoporosis, alendronate

can be administered with a dose of 10 mg / day every day continuously, because it does not
interfere with bone mineralization. Currently, a dose of 70 mg once a week is practiced. For
the prevention of osteoporosis in postmenopausal women and glucocorticoid-induced
osteoporosis a dose of 5 mg / dl is administered. Patient with a Paget's disease is given a dose

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of 40 mg / day for 6 months. Alendronate is not recommended in patients with renal
impairment (creatinine clearance <35 ml / min).

3. Ibandronate, is also a third generation bisphosphonate. It can be taken orally with a dose of
2.5 mg / day or 150 mg once a month. Ibandronate can also be administered intravenously at
a dose of 3 mg, once in 3 months. Contra indications for ibandronate administration is
hypocalcemia.3

4. Zoledronate, currently the strongest bisfosfonate. It can be administered by intravenous

drip for 15 minutes at a dose of 5 mg. For osteoporosis treatment a dose of 5 mg once a year
is enough, while for the treatment of hypercalcemia due to malignancy can be given 4 mg per
drip every 3-4 weeks depending on the patients response. Contra indications for zoledronate
administration is hypocalcemia, pregnant and lactating mothers.

Selective estrogen receptor modulators

Selective estrogen receptor modulators (SERMs) are considered to provide the

beneficial effects of estrogen without the potentially adverse outcomes. Raloxifene (Evista) is
a SERM indicated for the treatment and prevention of osteoporosis in postmenopausal
women. The usual dose is 60 mg given orally daily. It can also be given in combination with
calcium and vitamin D. It is the first SERM studied for breast cancer prevention, and it
decreases bone resorption through actions on estrogen receptors.

Raloxifene has been shown to prevent bone loss, and data in females with
osteoporosis have demonstrated that this agent causes a 35% reduction in the risk of vertebral
fractures. It has also been shown to reduce the prevalence of invasive breast cancer.
Raloxifene may be most useful in younger postmenopausal women without severe
osteoporosis. It has been shown to increase the incidence of deep vein thrombosis, stroke, and
hot flashes. In 601 postmenopausal women who had daily therapy with raloxifene, BMD was
increased, serum concentrations of total low-density lipoprotein cholesterol were lowered,
and the endometrium was not stimulated.

Parathyroid hormones

Teriparatide (Forteo) is a recombinant human parathyroid hormone (1-34) (PTH [1-

34]) and is the only available anabolic agent for the treatment of osteoporosis. It is indicated
for the treatment of women with postmenopausal osteoporosis who are at high risk of
fracture, who have been intolerant of previous osteoporosis therapy, or in whom osteoporosis

27 | P a g e
treatment has failed to increase bone mass. It is indicated in men with idiopathic or
hypogonadal osteoporosis who are at high risk of fracture, who have been intolerant of
previous osteoporosis therapy, or in whom osteoporosis therapy has failed. Teriparatide is
also approved for the treatment of patients with glucocorticoid-induced osteoporosis. Before
treatment with teriparatide, levels of serum calcium, PTH, and 25(OH)D need to be
monitored.1,7

Teriparatide cannot be given for more than 2 years. It is contraindicated in patients

with pre-existing hypercalcemia, severe renal impairment, pregnancy, breast-feeding mothers,
history of bone metastases or skeletal malignancies, and patients who are at an increased
baseline risk for osteosarcoma including those with Paget disease, unexplained elevated
alkaline phosphatase, children and young adults with open epiphyses or prior radiotherapy of
the skeleton.

Indications for PTH in men and women are a bone density decline while on
bisphosphonate therapy, bone density stabilization while on extremely low-level
bisphosphonate therapy, a fracture occurring while on bisphosphonate therapy, or a very low
initial bone turnover rate for which an anabolic effect is clearly warranted. Teriparatide
should be considered in younger and older postmenopausal women with severe osteoporosis.

Calcitonin

Calcitonin-salmon (Fortical, Miacalcin) is a hormone that decreases osteoclast

activity, thereby impeding postmenopausal bone loss. It is indicated for the treatment of
women who are more than 5 years post menopause and have low bone mass relative to
healthy premenopausal women. Calcitonin-salmon should be reserved for patients who refuse
or cannot tolerate estrogens or in whom estrogens are contraindicated. It is recommended in
conjunction with adequate calcium and vitamin D intake to prevent the progressive loss of
bone mass. It is available as an injection and as an intranasal spray. The intranasal spray is
delivered as a single daily spray that provides 200 IU of the drug. The drug can be delivered
subcutaneously, but this route is rarely used.2,3,7

Results from a single controlled clinical trial indicate that calcitonin may decrease
osteoporotic vertebral fractures by approximately 30%. In the first 2 years, calcitonin has
been found to increase spinal bone mineral density (BMD) by approximately 2%. Calcitonin
also has an analgesic property that makes it ideally suited for the treatment of acute vertebral
fractures.

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 Calcitonin is an option for patients who are not candidates for other available
osteoporosis treatments. Common side effects of nasally administered calcitonin include
nasal discomfort, rhinitis, irritation of nasal mucosa, and occasional epistaxis. Nausea, local
inflammatory reactions at the injection site, sweating, and flushing are side effects noted with
parenteral use.

Denosumab

Denosumab (brand name: Prolia) is an antibody directed against a factor (RANKL)

involved in the formation of cells that break down bone. 1 Denosumab improves bone mineral
density and reduces fracture in postmenopausal women with osteoporosis. It is administered
as an injection under the skin once every six months. Although denosumab is generally well
tolerated, side effects can include skin infections (cellulitis) and eczema. A mild transient
lowering of blood calcium levels has also been reported, but this is not usually a problem in
patients with good kidney function, who are taking enough calcium and vitamin D.

Because it is a newer drug and there are no long-term safety data, denosumab is
usually reserved for patients who are intolerant of or unresponsive to oral and/or intravenous
bisphosphonates. Denosumab should not be given to patients with low blood calcium until it
is corrected.

Calcium and vitamin D

Commonly used calcium supplements include calcium carbonate and calcium citrate.
Calcium carbonate is generally less expensive and is recommended as a first choice option.
Calcium carbonate has better absorption with food, as opposed to calcium citrate, which is
better absorbed in the fasting state. Also, fewer tablets are needed with calcium carbonate
than with calcium citrate.

Vitamin D is available as ergocalciferol (vitamin D2) and cholecalciferol (vitamin

D3). Vitamin D is metabolized to active metabolites. These metabolites promote the active
absorption of calcium and phosphorus by the small intestine, elevating serum calcium and
phosphate levels sufficiently to permit bone mineralization. Ergocalciferol, the form mostly
used in supplements and fortified foods, is absorbed with similar efficiency to cholecalciferol,
the main dietary form, with similar effects on suppression of PTH.3,7

Non-pharmacological

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 Physical therapy focuses on improving a patient's strength, flexibility, posture, and
balance to prevent falls and maximize physical function. Postural retraining is key in this
population. Spinal bone mineral density (BMD) is directly correlated with the strength of the
back extensors; therefore, maintaining and strengthening the back extensors should be
emphasized. In studies by Sinaki and colleagues, strengthening the back extensor muscles
reduced kyphosis and decreased the risk of sustaining vertebral compression fractures.7

As soon as the course of therapy allows, weight-bearing exercises should be initiated.

Regular weight-bearing exercises are essential for the maintenance of bone mass and should
be encouraged in all patients, including children and adolescents (to strengthen the skeleton
during the maturation process). Exercise also improves agility and balance, thereby reducing
the risk of falls.

Surgery

Surgeries in patients with osteoporosis were done in case it involved fractures,

especially hip fractures. Some of the principles that must be considered in the surgical
treatment of patients with osteoporosis are:2,7

1. Advanced age patients with osteoporosis related fracture, if required surgery, should be
done immediately. This is to avoid prolonged immobilization and further complications of
fracture.

2. The purpose of surgical treatment is to obtain a stable fixation until the patients
mobilisation can be achieved as early as possible.

3. Calcium intake should still be considered for patients who had undergone surgery, until the
callus mineralization turned perfect.

4. Although the required surgery had been done, medical management of osteoporosis with
bisphosphonates or raloxifene or hormone replacement therapy, or calcitonin should still be
given.

In fractures of the vertebral body, do vertebroplasty or kyphoplasty. Verteboplasty is a

procedure of injecting bone cement into the fractured vertebral body, while kyphoplasty is a
procedure of injecting bone cement into a balloon that had previously been developed in the
collapsed vertebral body that was fractured.

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 CHAPTER III

CONCLUSION

Osteoporosis is a systemic metabolic bone disease that is characterized by reduced

bone mass density, due to reduction in bone matrix and minerals which is accompanied by
damage to the microarchitecture of the bone tissue, resulting in a tendency to form brittle
bones. Based on WHO criteria, osteoporosis is when the BMD values are at 2.5 standard
deviation (SD) or below the average value of healthy young adults (T score <-2.5 SD).

Osteoporosis is divided into two groups, namely primary osteoporosis (involutional)

and secondary osteoporosis. Primary osteoporosis is divided by 2, namely Type I
osteoporosis (postmenopausal osteoporosis) and type II osteoporosis (senile osteoporosis).

The cells that responsible for bone formation called osteoblasts, while osteoclasts are
responsible for bone resorption. In osteoporosis bone turnover abnormalities will occur in
which the process of bone resorption are more than the process of bone formation. This
situation resulted in a decrease in bone mass leading to osteoporosis. Densitometry
examination by using Dual Energy X-ray Absorptiometry is the gold standard for diagnosis
of osteoporosis.

Management of osteoporosis includes prevention and treatment efforts in the form of

non-pharmacological approaches (education and training / rehabilitation), pharmacology
(bisphosphonate, estrogen and others) and surgery when a fracture occurs. The goal of
treatment for osteoporosis to improve the quality of life, prevent complications and reduce
morbidity and mortality.

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 REFERENCES

1. Howard M. Brocklehursts textbook of geriatric medicine and gerontology

seventh edition. 2010. Philadelphia. Page 553-62
2. National Osteoporosis Foundation. Clinicians guide to prevention and
treatment of osteoporosis. 2014 issue. Accessed : 4 March 2017
3. Yeap SS. An update of the Malaysian clinical guidance on the management of
glucocorticoid-induced osteoporosis. January 2017. Malaysia. Accessed : 4
March 2017
4. Vivien L. A practical approach to secondary osteoporosis. Osteopororsis and
Sarcopenia, volume 2, issue 3, September 2016. Pages 134-9
5. John E. Guyton and hall textbook of medical physiology. 2016. New York.
Page 951-4
6. Kenneth E.S. Focal osteoporosis defects play a key role in hip fracture. Bone.
Volume 94, January 2017. Pages 124-34
7. Elaine Y. Osteoporosis in East Asia: Current issues in assessment and
management. Osteoporosis and Sarcopenia 2. 2016. Page 118-33
8. John D. Radiation exposure in X-ray based imaging techniques used in
osteoporosis. Musculoskeletal. 2010. Page 131-5

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