Osteoporosis ("porous bones", from Greek: ὀστέον/osteon meaning "bone" and

πόρος/poros meaning "pore") is a disease of bones that leads to an increased risk of

fracture.[1] In osteoporosis the bone mineral density (BMD) is reduced, bone
microarchitecture is deteriorating, and the amount and variety of proteins in bone is
altered. Osteoporosis is defined by the World Health Organization (WHO) as a bone
mineral density that is 2.5 standard deviations or more below the mean peak bone mass
(average of young, healthy adults) as measured by DXA; the term "established
osteoporosis" includes the presence of a fragility fracture.[2] The disease may be classified
as primary type 1, primary type 2, or secondary.[1] The form of osteoporosis most
common in women after menopause is referred to as primary type 1 or postmenopausal
osteoporosis. Primary type 2 osteoporosis or senile osteoporosis occurs after age 75 and
is seen in both females and males at a ratio of 2:1. Finally, secondary osteoporosis may
arise at any age and affects men and women equally. This form of osteoporosis results
from chronic predisposing medical problems or disease, or prolonged use of medications
such as glucocorticoids, when the disease is called steroid- or glucocorticoid-induced
osteoporosis (SIOP or GIOP).

Osteoporosis risks can be reduced with lifestyle changes and sometimes medication; in
people with osteoporosis, treatment may involve both. Lifestyle change includes diet and
exercise, and preventing falls. Medication includes calcium, vitamin D, bisphosphonates
and several others. Fall-prevention advice includes exercise to tone deambulatory
muscles, proprioception-improvement exercises; equilibrium therapies may be included.
Exercise with its anabolic effect, may at the same time stop or reverse osteoporosis.
Osteoporosis is a component of the frailty syndrome.

Contents
[hide]

• 1 Signs and symptoms

o 1.1 Fractures
o 1.2 Falls risk
• 2 Risk factors
o 2.1 Nonmodifiable
o 2.2 Potentially modifiable
o 2.3 Diseases and disorders
o 2.4 Medication
• 3 Pathogenesis
• 4 Diagnosis
o 4.1 Conventional radiography
o 4.2 Clinical decision rule
o 4.3 Dual energy X-ray absorptiometry
o 4.4 Other measuring tools
o 4.5 Screening
• 5 Prevention
 o 5.1 Lifestyle
o 5.2 Medication
• 6 Treatment
o 6.1 Antiresorptive agents
o 6.2 Bone anabolic agents
o 6.3 Other agents
o 6.4 Nutrition
o 6.5 Exercise
• 7 Prognosis
• 8 Epidemiology
o 8.1 Hip fractures
o 8.2 Vertebral fractures
o 8.3 Wrist
o 8.4 Rib Fractures
• 9 History
• 10 Awareness
• 11 See also
• 12 References

• 13 External links

[edit] Signs and symptoms

Osteoporosis itself has no specific symptoms; its main consequence is the increased risk
of bone fractures. Osteoporotic fractures are those that occur in situations where healthy
people would not normally break a bone; they are therefore regarded as fragility
fractures. Typical fragility fractures occur in the vertebral column, rib, hip and wrist.

[edit] Fractures

Fractures are the most dangerous aspect of osteoporosis. Debilitating acute and chronic
pain in the elderly is often attributed to fractures from osteoporosis and can lead to
further disability and early mortality.[3] The fractures from osteoporosis may also be
asymptomatic. The symptoms of a vertebral collapse ("compression fracture") are sudden
back pain, often with radiculopathic pain (shooting pain due to nerve root compression)
and rarely with spinal cord compression or cauda equina syndrome. Multiple vertebral
fractures lead to a stooped posture, loss of height, and chronic pain with resultant
reduction in mobility.[4]

Fractures of the long bones acutely impair mobility and may require surgery. Hip
fracture, in particular, usually requires prompt surgery, as there are serious risks
associated with a hip fracture, such as deep vein thrombosis and a pulmonary embolism,
and increased mortality.
Fracture Risk Calculators assess the risk of fracture based upon several criteria, including
BMD, age, smoking, alcohol usage, weight, and gender. Recognised calculators include
FRAX[5] and Dubbo.

[edit] Falls risk

The increased risk of falling associated with aging leads to fractures of the wrist, spine
and hip. The risk of falling, in turn, is increased by impaired eyesight due to any cause
(e.g. glaucoma, macular degeneration), balance disorder, movement disorders (e.g.
Parkinson's disease), dementia, and sarcopenia (age-related loss of skeletal muscle).
Collapse (transient loss of postural tone with or without loss of consciousness) leads to a
significant risk of falls; causes of syncope are manifold but may include cardiac
arrhythmias (irregular heart beat), vasovagal syncope, orthostatic hypotension (abnormal
drop in blood pressure on standing up) and seizures. Removal of obstacles and loose
carpets in the living environment may substantially reduce falls. Those with previous
falls, as well as those with a gait or balance disorder, are most at risk.[6]

[edit] Risk factors

Risk factors for osteoporotic fracture can be split between non-modifiable and
(potentially) modifiable. In addition, there are specific diseases and disorders in which
osteoporosis is a recognized complication. Medication use is theoretically modifiable,
although in many cases the use of medication that increases osteoporosis risk is
unavoidable. Caffeine is not a risk factor osteoporosis.[7]

[edit] Nonmodifiable

The most important risk factors for osteoporosis are advanced age (in both men and
women) and female gender; estrogen deficiency following menopause or oophorectomy
is correlated with a rapid reduction in bone mineral density, while in men a decrease in
testosterone levels has a comparable (but less pronounced) effect. While osteoporosis
occurs in people from all ethnic groups, European or Asian ancestry predisposes for
osteoporosis.[8] Those with a family history of fracture or osteoporosis are at an increased
risk; the heritability of the fracture as well as low bone mineral density are relatively
high, ranging from 25 to 80 percent. There are at least 30 genes associated with the
development of osteoporosis.[9] Those who have already had a fracture are at least twice
as likely to have another fracture compared to someone of the same age and sex.[10] A
small stature is also a non-modifiable risk factor associated with the development of
osteoporosis.[1]

[edit] Potentially modifiable

• Excess alcohol—small amounts of alcohol do not increase osteoporosis risk and

may even be beneficial, but chronic heavy drinking (alcohol intake greater than 3
units/day),[11] especially at a younger age, increases risk significantly.[12]
 • Vitamin D deficiency[13]—low circulating Vitamin D is common among the
elderly worldwide.[14] Mild vitamin D insufficiency is associated with increased
Parathyroid Hormone (PTH) production.[14] PTH increases bone resorption,
leading to bone loss. A positive association exists between serum 1,25-
dihydroxycholecalciferol levels and bone mineral density, while PTH is
negatively associated with bone mineral density.[14]
• Tobacco smoking—tobacco smoking inhibits the activity of osteoblasts, and is an
independent risk factor for osteoporosis.[11][15] Smoking also results in increased
breakdown of exogenous estrogen, lower body weight and earlier menopause, all
of which contribute to lower bone mineral density.[14]
• Malnutrition—nutrition has an important and complex role in maintenance of
good bone. Identified risk factors include low dietary calcium and/or phosphorus,
magnesium, zinc, boron, iron, fluoride, copper, vitamins A, K, E and C (and D
where skin exposure to sunlight provides an inadequate supply). Excess sodium is
a risk factor. High blood acidity may be diet-related, and is a known antagonist of
bone.[16] Some have identified low protein intake as associated with lower peak
bone mass during adolescence and lower bone mineral density in elderly
populations.[14] Conversely, some have identified low protein intake as a positive
factor, protein is among the causes of dietary acidity. Imbalance of omega 6 to
omega 3 polyunsaturated fats is yet another identified risk factor.[1]
• High protein diet—Research has found an association between diets high in
animal protein and increased urinary calcium loss from the bones.[17][18][19]
• Underweight/inactive—bone remodeling occurs in response to physical stress,
and weight bearing exercise can increase peak bone mass achieved in
adolescence.[14] In adults, physical activity helps maintain bone mass, and can
increase it by 1 or 2%.[citation needed] Conversely, physical inactivity can lead to
significant bone loss.[14] (Incidence of osteoporosis is lower in overweight people.)
[20]

• Excess physical activity—excessive exercise can lead to constant damage to the

bones which can cause exhaustion of the structures as described above. There are
numerous examples of marathon runners who developed severe osteoporosis later
in life.[who?] In women, heavy exercise can lead to decreased estrogen levels, which
predisposes to osteoporosis. In addition, intensive training without proper
compensatory increased nutrition increases the risk.[citation needed]
• Heavy metals—a strong association between cadmium, lead and bone disease has
been established. Low level exposure to cadmium is associated with an increased
loss of bone mineral density readily in both genders, leading to pain and increased
risk of fractures, especially in the elderly and in females. Higher cadmium
exposure results in osteomalacia (softening of the bone).[21]
• Soft drinks—some studies indicate that soft drinks (many of which contain
phosphoric acid) may increase risk of osteoporosis;[22] Others suggest soft drinks
may displace calcium-containing drinks from the diet rather than directly causing
osteoporosis.[23]

[edit] Diseases and disorders

Many diseases and disorders have been associated with osteoporosis.[24] For some, the
underlying mechanism influencing the bone metabolism is straight-forward, whereas for
others the causes are multiple or unknown.

• In general, immobilization causes bone loss (following the 'use it or lose it' rule).
For example, localized osteoporosis can occur after prolonged immobilization of
a fractured limb in a cast. This is also more common in active patients with a high
bone turn-over (for example, athletes). Other examples include bone loss during
space flight or in people who are bedridden or who use wheelchairs for various
reasons.
• Hypogonadal states can cause secondary osteoporosis. These include Turner
syndrome, Klinefelter syndrome, Kallmann syndrome, anorexia nervosa,
andropause,[25] hypothalamic amenorrhea or hyperprolactinemia.[25] In females, the
effect of hypogonadism is mediated by estrogen deficiency. It can appear as early
menopause (<45 years) or from prolonged premenopausal amenorrhea (>1 year).
A bilateral oophorectomy (surgical removal of the ovaries) or a premature ovarian
failure cause deficient estrogen production. In males, testosterone deficiency is
the cause (for example, andropause or after surgical removal of the testes).
• Endocrine disorders that can induce bone loss include Cushing's syndrome,[14]
hyperparathyroidism,[14] thyrotoxicosis,[14] hypothyroidism, diabetes mellitus type
1 and 2,[26] acromegaly and adrenal insufficiency. In pregnancy and lactation,
there can be a reversible bone loss.[24]
• Malnutrition, parenteral nutrition[14] and malabsorption can lead to osteoporosis.
Nutritional and gastrointestinal disorders that can predispose to osteoporosis
include coeliac disease,[14] Crohn's disease, lactose intolerance, surgery[25] (after
gastrectomy, intestinal bypass surgery or bowel resection) and severe liver disease
(especially primary biliary cirrhosis).[25] Patients with bulimia can also develop
osteoporosis. Those with an otherwise adequate calcium intake can develop
osteoporosis due to the inability to absorb calcium and/or vitamin D. Other micro-
nutrients such as vitamin K or vitamin B12 deficiency may also contribute.
• Patients with rheumatologic disorders like rheumatoid arthritis,[25] ankylosing
spondylitis,[25] systemic lupus erythematosus and polyarticular juvenile idiopathic
arthritis are at increased risk of osteoporosis, either as part of their disease or
because of other risk factors (notably corticosteroid therapy). Systemic diseases
such as amyloidosis and sarcoidosis can also lead to osteoporosis.
• Renal insufficiency can lead to osteodystrophy.
• Hematologic disorders linked to osteoporosis are multiple myeloma[25] and other
monoclonal gammopathies,[26] lymphoma and leukemia, mastocytosis,[25]
hemophilia, sickle-cell disease and thalassemia.
• Several inherited disorders have been linked to osteoporosis. These include
osteogenesis imperfecta,[25] Marfan syndrome,[25] hemochromatosis,[14]
hypophosphatasia, glycogen storage diseases, homocystinuria,[25] Ehlers-Danlos
syndrome,[25] porphyria, Menkes' syndrome, epidermolysis bullosa and Gaucher's
disease.
• People with scoliosis of unknown cause also have a higher risk of osteoporosis.
Bone loss can be a feature of complex regional pain syndrome. It is also more
 frequent in people with Parkinson's disease and chronic obstructive pulmonary
disease.

[edit] Medication

Certain medications have been associated with an increase in osteoporosis risk; only
steroids and anticonvulsants are classically associated, but evidence is emerging with
regard to other drugs.

• Steroid-induced osteoporosis (SIOP) arises due to use of glucocorticoids -

analogous to Cushing's syndrome and involving mainly the axial skeleton. The
synthetic glucocorticoid prescription drug prednisone is a main candidate after
prolonged intake. Some professional guidelines recommend prophylaxis in
patients who take the equivalent of more than 30 mg hydrocortisone (7.5 mg of
prednisolone), especially when this is in excess of three months.[27] Alternate day
use may not prevent this complication.[28]
• Barbiturates, phenytoin and some other enzyme-inducing antiepileptics - these
probably accelerate the metabolism of vitamin D.[29]
• L-Thyroxine over-replacement may contribute to osteoporosis, in a similar
fashion as thyrotoxicosis does.[24] This can be relevant in subclinical
hypothyroidism.
• Several drugs induce hypogonadism, for example aromatase inhibitors used in
breast cancer, methotrexate and other anti-metabolite drugs, depot progesterone
and gonadotropin-releasing hormone agonists.
• Anticoagulants - long-term use of heparin is associated with a decrease in bone
density,[30] and warfarin (and related coumarins) have been linked with an
increased risk in osteoporotic fracture in long-term use.[31]
• Proton pump inhibitors - these drugs inhibit the production of stomach acid; it is
thought that this interferes with calcium absorption.[32] Chronic phosphate binding
may also occur with aluminium-containing antacids.[24]
• Thiazolidinediones (used for diabetes) - rosiglitazone and possibly pioglitazone,
inhibitors of PPARγ, have been linked with an increased risk of osteoporosis and
fracture.[33]
• Chronic lithium therapy has been associated with osteoporosis.[24]

[edit] Pathogenesis

Osteoclast, with bone below it, showing typical distinguishing characteristics: a large cell
with multiple nuclei and a "foamy" cytosol.
The underlying mechanism in all cases of osteoporosis is an imbalance between bone
resorption and bone formation. In normal bone, there is constant matrix remodeling of
bone; up to 10% of all bone mass may be undergoing remodeling at any point in time.
The process takes place in bone multicellular units (BMUs) as first described by Frost in
1963.[34] Bone is resorbed by osteoclast cells (which derive from the bone marrow), after
which new bone is deposited by osteoblast cells.[9]

The three main mechanisms by which osteoporosis develops are an inadequate peak bone
mass (the skeleton develops insufficient mass and strength during growth), excessive
bone resorption and inadequate formation of new bone during remodeling. An interplay
of these three mechanisms underlies the development of fragile bone tissue.[9] Hormonal
factors strongly determine the rate of bone resorption; lack of estrogen (e.g. as a result of
menopause) increases bone resorption as well as decreasing the deposition of new bone
that normally takes place in weight-bearing bones. The amount of estrogen needed to
suppress this process is lower than that normally needed to stimulate the uterus and breast
gland. The α-form of the estrogen receptor appears to be the most important in regulating
bone turnover.[9] In addition to estrogen, calcium metabolism plays a significant role in
bone turnover, and deficiency of calcium and vitamin D leads to impaired bone
deposition; in addition, the parathyroid glands react to low calcium levels by secreting
parathyroid hormone (parathormone, PTH), which increases bone resorption to ensure
sufficient calcium in the blood. The role of calcitonin, a hormone generated by the
thyroid that increases bone deposition, is less clear and probably not as significant as that
of PTH.[9]

Osteoblasts, several displaying a prominent Golgi apparatus, actively synthesizing

osteoid containing two osteocytes.

The activation of osteoclasts is regulated by various molecular signals, of which RANKL

(receptor activator for nuclear factor κB ligand) is one of best studied. This molecule is
produced by osteoblasts and other cells (e.g. lymphocytes), and stimulates RANK
(receptor activator of nuclear factor κB). Osteoprotegerin (OPG) binds RANKL before it
has an opportunity to bind to RANK, and hence suppresses its ability to increase bone
resorption. RANKL, RANK and OPG are closely related to tumor necrosis factor and its
receptors. The role of the wnt signalling pathway is recognized but less well understood.
Local production of eicosanoids and interleukins is thought to participate in the
regulation of bone turnover, and excess or reduced production of these mediators may
underlie the development of osteoporosis.[9]
Trabecular bone (or cancellous bone) is the sponge-like bone in the ends of long bones
and vertebrae. Cortical bone is the hard outer shell of bones and the middle of long bones.
Because osteoblasts and osteoclasts inhabit the surface of bones, trabecular bone is more
active, more subject to bone turnover, to remodeling. Not only is bone density decreased,
but the microarchitecture of bone is disrupted. The weaker spicules of trabecular bone
break ("microcracks"), and are replaced by weaker bone. Common osteoporotic fracture
sites, the wrist, the hip and the spine, have a relatively high trabecular bone to cortical
bone ratio. These areas rely on trabecular bone for strength, and therefore the intense
remodeling causes these areas to degenerate most when the remodeling is imbalanced.
[citation needed]
Around the ages of 30-35, cancellous or trabecular bone loss begins. Women
may lose as much as 50%, while men lose about 30%.[1]

[edit] Diagnosis

Multiple osteoporotic wedge fractures demonstrated on a lateral thoraco-lumbar spine X-

ray
A scanner used to measure bone density with Dual energy X-ray absorptiometry.

The diagnosis of osteoporosis can be made using conventional radiography and by

measuring the bone mineral density (BMD).[35] The most popular method of measuring
BMD is dual energy x-ray absorptiometry (DXA or DEXA). In addition to the detection
of abnormal BMD, the diagnosis of osteoporosis requires investigations into potentially
modifiable underlying causes; this may be done with blood tests. Depending on the
likelihood of an underlying problem, investigations for cancer with metastasis to the
bone, multiple myeloma, Cushing's disease and other above-mentioned causes may be
performed.

[edit] Conventional radiography

Conventional radiography is useful, both by itself and in conjunction with CT or MRI, for
detecting complications of osteopenia (reduced bone mass; pre-osteoporosis), such as
fractures; for differential diagnosis of osteopenia; or for follow-up examinations in
specific clinical settings, such as soft tissue calcifications, secondary
hyperparathyroidism, or osteomalacia in renal osteodystrophy. However, radiography is
relatively insensitive to detection of early disease and requires a substantial amount of
bone loss (about 30%) to be apparent on x-ray images.

The main radiographic features of generalized osteoporosis are cortical thinning and
increased radiolucency. Frequent complications of osteoporosis are vertebral fractures for
which spinal radiography can help considerably in diagnosis and follow-up. Vertebral
height measurements can objectively be made using plain-film x-rays by using several
methods such as height loss together with area reduction, particularly when looking at
vertical deformity in T4-L4, or by determining a spinal fracture index that takes into
account the number of vertebrae involved. Involvement of multiple vertebral bodies leads
to kyphosis of the thoracic spine, obvious to the clinician as "dowager's hump."
[edit] Clinical decision rule

A number of clinical decision rules have been created to predict the risk of osteoporotic
fractures. The QFracture score was developed in 2009 and is based on age, BMI,
smoking status, alcohol use, rheumatoid arthritis, cardiovascular disease, type 2 diabetes,
asthma, use of tricyclic antidepressants or corticosteroids, liver disease, and a history of
falls in men. In women hormone replacement therapy, parental history of osteoporosis,
gastrointestinal malabsorption, and menopausal symptoms are also taken into account.[36]
A website is available to help apply this score.[37]

[edit] Dual energy X-ray absorptiometry

Dual energy X-ray absorptiometry (DXA, formerly DEXA) is considered the gold
standard for the diagnosis of osteoporosis. Osteoporosis is diagnosed when the bone
mineral density is less than or equal to 2.5 standard deviations below that of a young
adult reference population. This is translated as a T-score. The World Health
Organization has established the following diagnostic guidelines:[2][14]

• T-score -1.0 or greater is "normal"

• T-score between -1.0 and -2.5 is "low bone mass" (or "osteopenia")
• T-score -2.5 or below is osteoporosis

When there has also been an osteoporotic fracture (also termed "low trauma-fracture" or
"fragility fracture"), defined as one that occurs as a result of a fall from a standing height,
the term "severe or established" osteoporosis is used.[2]

The International Society for Clinical Densitometry takes the position that a diagnosis of
osteoporosis in men under 50 years of age should not be made on the basis of
densitometric criteria alone. It also states that for pre-menopausal women, Z-scores
(comparison with age group rather than peak bone mass) rather than T-scores should be
used, and that the diagnosis of osteoporosis in such women also should not be made on
the basis of densitometric criteria alone.[38]

[edit] Other measuring tools

Quantitative CT differs from DXA in that it gives separate estimates of BMD for
trabecular and cortical bone and reports precise volumetric mineral density in mg/cm3
rather than BMD's relative Z score. Among QCT's advantages: it can be performed at
axial and peripheral sites, is sensitive to change over time, can analyze a region of any
size or shape, excludes irrelevant tissue such as fat, muscle, and air, and does not require
knowledge of the patient's subpopulation in order to create a clinical score (e.g. the Z-
score of all females of a certain age). Among QCT's disadvantages: it requires a high
radiation dose, CT scanners are large and expensive, and because its practice has been
less standardized than BMD, its results are more operator-dependent. Peripheral QCT has
been introduced to improve upon the limitations of DXA and QCT.[35]
Quantitative ultrasound has many advantages in assessing osteoporosis. The modality is
small, no ionizing radiation is involved, measurements can be made quickly and easily,
and the cost of the device is low compared with DXA and QCT devices. The calcaneus is
the most common skeletal site for quantitative ultrasound assessment because it has a
high percentage of trabecular bone that is replaced more often than cortical bone,
providing early evidence of metabolic change. Also, the calcaneus is fairly flat and
parallel, reducing repositioning errors. The method can be applied to children, neonates,
and preterm infants, just as well as to adults. Once microimaging tools to examine
specific aspects of bone quality are developed, it is expected that quantitative ultrasound
will be increasingly used in clinical practice.[35]

[edit] Screening

The U.S. Preventive Services Task Force (USPSTF) recommended in 2002 that all
women 65 years of age or older should be screened with bone densitometry.[39] The Task
Force recommends screening women of any age with increased risk factors that puts
them at risk equivalent to a 65 year old without additional risk factors.[40] The best risk
factor for indicating increased risk is lower body weight (weight < 70 kg), with less
evidence for smoking or family history. There was insufficient evidence to make
recommendations about the optimal intervals for repeated screening and the appropriate
age to stop screening. Clinical prediction rules are available to guide selection of women
ages 60–64 for screening. The Osteoporosis Risk Assessment Instrument (ORAI) may be
the most sensitive strategy[41]

Regarding the screening of men, a cost-analysis study suggests that screening may be
"cost-effective for men with a self-reported prior fracture beginning at age 65 years and
for men 80 years and older with no prior fracture".[42] Also cost-effective is the screening
of adult men from middle age on to detect any significant decrease in testosterone levels,
say, below 300.

[edit] Prevention
Methods to prevent osteoporosis include changes of lifestyle. However, there are
medications that can be used for prevention as well. As a different concept there are
osteoporosis ortheses which help to prevent spine fractures and support the building up of
muscles. Fall prevention can help prevent osteoporosis complications.

[edit] Lifestyle

Lifestyle prevention of osteoporosis is in many aspects inversions from potentially

modifiable risk factors. As tobacco smoking and unsafe alcohol intake have been linked
with osteoporosis, smoking cessation and moderation of alcohol intake are commonly
recommended in the prevention of osteoporosis. Many other risk factors, some
modifiable and others non modifiable such as genetic may be involved in osteoporosis.[43]

Exercise
Achieving a higher peak bone mass through exercise and proper nutrition during
adolescence is important for the prevention of osteoporosis. Exercise and nutrition
throughout the rest of the life delays bone degeneration. Jogging, walking, or stair
climbing at 70-90% of maximum effort three times per week, along with 1,500 mg of
calcium per day, increased bone density of the lumbar (lower) spine by 5% over nine
months. Individuals already diagnosed with osteopenia or osteoporosis should discuss
their exercise program with their physician to avoid fractures.[44]

Nutrition

Proper nutrition includes a diet sufficient in calcium and vitamin D. Patients at risk for
osteoporosis (e.g. steroid use) are generally treated with vitamin D and calcium
supplements and often with bisphosphonates. Vitamin D supplementation alone does not
prevent fractures, and always needs to be combined with calcium.[45][46] Calcium
supplements come in two forms: calcium carbonate and calcium citrate. Due to its lower
cost, calcium carbonate is often the first choice, however it needs to be taken with food to
maximize absorption. Calcium citrate is more expensive, but it is better absorbed than
calcium carbonate and can be taken without food. In addition, patients who are taking
proton pump inhibitors or H2 blockers do not absorb calcium carbonate well; calcium
citrate is the supplement of choice in this population.[47] In renal disease, more active
forms of Vitamin D such as cholecalciferol or (1,25-dihydroxycholecalciferol or calcitriol
which is the main biologically active form of vitamin D) is used, as the kidney cannot
adequately generate calcitriol from calcidiol (25-hydroxycholecalciferol) which is the
storage form of vitamin D.In vitamin D assays, vitamin D2 (ergocalitrol) is not accurately
measured, therefore vitamin D3 (cholecalciferol) is recommended for supplementation.[47]

High dietary protein intake increases calcium excretion in urine and has been linked to
increased risk of fractures in research studies.[48] Other investigations have shown that
protein is required for calcium absorption, but that excessive protein consumption inhibits
this process. No interventional trials have been performed on dietary protein in the
prevention and treatment of osteoporosis.[49]

[edit] Medication

Just as for treatment, bisphosphonate can be used in cases of very high risk. Other
medicines prescribed for prevention of osteoporosis include raloxifene, a selective
estrogen receptor modulator (SERM).

Estrogen replacement therapy remains a good treatment for prevention of osteoporosis

but, at this time, is not recommended unless there are other indications for its use as well.
There is uncertainty and controversy about whether estrogen should be recommended in
women in the first decade after the menopause.

In hypogonadal men testosterone has been shown to give improvement in bone quantity
and quality, but, as of 2008, there are no studies of the effects on fractures or in men with
a normal testosterone level.[26]
[edit] Treatment
There are several medications used to treat osteoporosis, depending on gender.
Medications themselves can be classified as antiresorptive or bone anabolic agents.
Antiresorptive agents work primarily by reducing bone resorption, while bone anabolic
agents build bone rather than inhibit resorption. Lifestyle changes are an important aspect
of treatment. A major problem is gaining long-term adherence to therapy from patients
with osteoporosis. Fifty percent of patients do not take their medications and most
discontinue within 1 year.[50]

[edit] Antiresorptive agents

• Bisphosphonates

Bisphosphonates are the main pharmacological measures for treatment. However,

newer drugs have appeared in the 1990s, such as teriparatide and strontium
ranelate.
In confirmed osteoporosis, bisphosphonate drugs are the first-line treatment in
women. The most often prescribed bisphosphonates are presently sodium
alendronate (Fosamax) 10 mg a day or 70 mg once a week, risedronate (Actonel)
5 mg a day or 35 mg once a week and/or ibandronate (Boniva) once a month.
A 2007 manufacturer-supported study suggested that in patients who had suffered
a low-impact hip fracture, annual infusion of 5 mg zoledronic acid reduced risk of
any fracture by 35% (from 13.9 to 8.6%), vertebral fracture risk from 3.8% to
1.7% and non-vertebral fracture risk from 10.7% to 7.6%. This study also found a
mortality benefit: after 1.9 years, 9.6% of the study group (as opposed to 13.3% of
the control group) had died of any cause, indicating a mortality benefit of 28%.[51]
There are currently no studies which examine the efficacy or side-effects of
zoledronic acid past the three-year period.[52]
Oral bisphosphonates are relatively poorly absorbed, and must therefore be taken
on an empty stomach, with no food or drink to follow for the next 30 minutes.
They are associated with inflammation of the esophagus (esophagitis) and are
therefore sometimes poorly tolerated; weekly or monthly administration
(depending on the preparation) decreases likelihood of esophagitis, and is now
standard. Although intermittent dosing with the intravenous formulations such as
zolendronate (zoledronic acid) avoids oral tolerance problems, these agents are
implicated at higher rates in a rare but severe bone disease called osteonecrosis of
the jaw.[53] For this reason, oral bisphosphonate therapy is probably to be
preferred, and doctors now recommend that any needed remedial dental work be
done before treatment begins.[54]

• Estrogen analogs

Estrogen replacement therapy remains a good treatment for prevention of

osteoporosis but, at this time, is not recommended unless there are other
indications for its use as well. There is uncertainty and controversy about whether
 estrogen should be recommended in women in the first decade after the
menopause.
In hypogonadal men testosterone has been shown to give improvement in bone
quantity and quality, but, as of 2008, there are no studies of the effects on
fractures or in men with a normal testosterone level.[26]

• Raloxifene

Selective Estrogen Receptor Modulators (SERMs) are a class of medications that

act on the estrogen receptors throughout the body in a selective manner.
Normally, bone mineral density (BMD) is tightly regulated by a balance between
osteoblast and osteoclast activity in the trabecular bone. Estrogen has a major role
in regulation of the bone formation-resorption equilibrium, as it stimulates
osteoblast activity. Some SERMs such as raloxifene, act on the bone by slowing
bone resorption by the osteoclasts.[55] Raloxifene has the added advantage of
reducing the risk of invasive breast cancer.[50] SERMs have been proven effective
in clinical trials.[56]

• Calcitonin

Calcitonin works by directly inhibiting osteoclast activity via the calcitonin

receptor. Calcitonin receptors have been identified on the surface of osteoclasts.[57]
Calcitonin directly induces inhibition of osteoclastic bone resorption by affecting
actin cytoskeleton which is needed for the osteoclastic activity.[58]

[edit] Bone anabolic agents

• Teriparatide

Recently, teriparatide (Forteo, recombinant parathyroid hormone residues 1–34)

has been shown to be effective in osteoporosis. It acts like parathyroid hormone
and stimulates osteoblasts, thus increasing their activity. It is used mostly for
patients with established osteoporosis (who have already fractured), have
particularly low BMD or several risk factors for fracture or cannot tolerate the
oral bisphosphonates. It is given as a daily injection with the use of a pen-type
injection device. In some countries, Teriparatide is licensed to be used for
treatment only if bisphosphonates have failed or are contraindicated. (In the US,
this restriction has not been imposed by the FDA.) Patients with previous
radiation therapy, or Paget's disease, or young patients, should avoid this
medication.

• Calcium salts

Calcium salts come as water insoluble and soluble formulations. Calcium

carbonate is the primary water insoluble drug, while calcium citrate, lactate, and
gluconate are water soluble. Calcium carbonate's absorption is improved in acidic
 conditions, while the water soluble salts are relatively unaffected by acidic
conditions.

• Sodium fluoride

Sodium fluoride treatment in patients with osteoporosis has been shown to cause
skeletal changes such as pronounced bone density with increased number and
thickness of trabeculae, cortical thickening, and partial obliteration of the
medullary space.[59]

[edit] Other agents

• RANKL inhibitors

Denosumab is a fully human monoclonal antibody that mimics the activity of

osteoprotegerin. It binds to RANKL, thereby preventing RANKL from interacting
with RANK and reducing its bone resorption. It was approved for use in the
treatment of osteoporosis by the European Commission on May 28, 2010 and by
the United States Food and Drug Administration on June 2, 2010.

• Strontium ranelate

Oral strontium ranelate is an alternative oral treatment, belonging to a class of

drugs called "dual action bone agents" (DABAs) by its manufacturer. It has
proven efficacy, especially in the prevention of vertebral fracture.[60] In laboratory
experiments, strontium ranelate was noted to stimulate the proliferation of
osteoblasts, as well as inhibiting the proliferation of osteoclasts.
Strontium ranelate is taken as a 2 g oral suspension daily, and is licenced for the
treatment of osteoporosis to prevent vertebral and hip fracture. Strontium ranelate
has side effect benefits over the bisphosphonates, as it does not cause any form of
upper GI side effect, which is the most common cause for medication withdrawal
in osteoporosis.[citation needed] In studies a small increase in the risk of venous
thromboembolism was noted,[61] the cause for which has not been determined.
This suggests it may be less suitable in patients at risk for thrombosis for different
reasons. The uptake of (heavier) strontium in place of calcium into bone matrix
results in a substantial and disproportionate increase in bone mineral density as
measured on DXA scanning,[62] making further followup of bone density by this
method harder to interpret for strontium treated patients. A correction algorithm
has been devised.[63]
Although strontium ranelate is effective, it is not approved for use in the United
States yet. However, strontium citrate is available in the US from several well-
known vitamin manufacturers. Most researchers believe that strontium is safe and
effective no matter what form it is used. The ranelate form is simply a device
invented by the Servier company of France so that they could patent their version
of strontium.[citation needed]
 Strontium, no matter what the form, must be water-soluble and ionized in the
stomach acid. Strontium is then protein-bound for transport from the intestinal
tract into the blood stream. Unlike drugs like sodium alendronate (Fosamax),
strontium doesn't inhibit bone recycling and, in fact, may produce stronger bones.
Studies have shown that after five years alendronate may even cause bone loss,
while strontium continues to build bone during lifetime use.[citation needed]
Strontium must not be taken with food or calcium-containing preparations as
calcium competes with strontium during uptake. However, it is essential that
calcium, magnesium, and vitamin D in therapeutic amounts must be taken daily,
but not at the same time as strontium. Strontium should be taken on an empty
stomach at night.[citation needed]

[edit] Nutrition

• Calcium

Calcium is required to support bone growth, bone healing and maintain bone
strength and is one aspect of treatment for osteoporosis. Recommendations for
calcium intake vary depending country and age; for individuals at higher risk of
osteoporosis (after fifty years of age) the amount recommended by US health
agencies is 1,200 mg per day. Calcium supplements can be used to increase
dietary intake, and absorption is optimized through taking in several small
(500 mg or less) doses throughout the day.[64] The role of calcium in preventing
and treating osteoporosis is unclear — some populations with extremely low
calcium intake also have extremely low rates of bone fracture, and others with
high rates of calcium intake through milk and milk products have higher rates of
bone fracture. Other factors, such as protein, salt and vitamin D intake, exercise
and exposure to sunlight, can all influence bone mineralization, making calcium
intake one factor among many in the development of osteoporosis.[65] In the report
of WHO (World Health Organization) in 2007, because calcium is consumed by
an acid load with food, it influences osteoporosis.[66][67]
A meta-analysis of randomized controlled trials involving calcium and calcium
plus vitamin D supported the use of high levels of calcium (1,200 mg or more)
and vitamin D (800 IU or more), though outcomes varied depending on which
measure was used to assess bone health (rates of fracture versus rates of bone
loss).[68] The meta-analysis, along with another study, also supported much better
outcomes for patients with high compliance to the treatment protocol.[69] In
contrast, despite earlier reports in improved high density lipoprotein (HDL, "good
cholesterol") in calcium supplementation, a possible increase in the rate of
myocardial infarction (heart attack) was found in a study in New Zealand in
which 1471 women participated. If confirmed, this would indicate that calcium
supplementation in women otherwise at low risk of fracture may cause more harm
than good.[70]

• Vitamin D
 Several studies have shown that a high intake of vitamin D reduces fractures in
the elderly,[68][71] The Women's Health Initiative found that though calcium plus
vitamin D did increase bone density by 1% but it did not affect hip fracture. It did
increase formation of kidney stones by 17%.[72] This study has been criticised for
using an inadequate dose of vitamin D (400 U) and for allowing the control arm
to take supplemental vitamin D.
Calcium and vitamin D are currently recommended for the primary prevention of
osteoporosis and the primary and secondary prevention of osteoporotic fractures.
However, calcium and vitamin D may reduce fracture risk by only 16%.[73] This
study followed 2532 community-dwelling residents (median age, 73 years; 59.8%
female) over 3 years who supplemented with 400 IU vitamin D3 and 1000 mg
calcium as calcium carbonate daily.

• Vitamin K

In osteoporosis research, vitamin K has been extensively studied for its ability to
stimulate collagen production, promote bone health and decrease fracture risk.
Vitamin K is a category that includes vitamin K1 and vitamin K2. Vitamin K1
(phylloquinone) is found in green leafy vegetables. Vitamin K2 itself is a category
that contains various forms of vitamin K2, including menaquinone-4
(menatetrenone, MK4) and menaquinone-7 (MK7). Among the vitamin K
analogues, the form most researched for osteoporosis treatment and fracture
reduction is MK4. MK4 is produced via conversion of K1 in the body, in the
testes, pancreas and arterial walls.[74] MK7 is instead not produced in humans, but
converted from vitamin K1 in the intestines by bacteria.[75]
MK4 and MK7 are both found in the United States in dietary supplements for
bone health. The US FDA has not approved any form of vitamin K for the
prevention or treatment of osteoporosis. With respect to osteoporosis, MK7 has
never been shown to reduce fractures. However, MK4 has been shown to reduce
fractures in clinical trials and has been approved for the prevention and treatment
of osteoporosis by the Ministry of Health in Japan since 1995.[76] In Japan MK4 is
used in the amount of 45 mg daily for the prevention and treatment of
osteoporosis. As an approved medication in Japan it has been extensively studied
and shown to decrease fractures in clinical trials up to 87% independent of the
number of falls sustained.[77] In clinical trials MK4 (45 mg daily) prevented bone
loss and/or fractures caused by corticosteroids (e.g., prednisone, dexamethasone,
prednisolone),[78][79][80][81] anorexia nervosa,[82] cirrhosis of the liver,[83]
postmenopausal osteoporosis,[84][85][86][87][88][89] disuse from stroke,[90] Alzheimer’s
disease,[91] Parkinson disease,[92] primary biliary cirrhosis[93] and leuprolide
treatment (for prostate cancer).[94]
Pathological fractures is a serious problem resulting from skeletal unloading in
handicapped children. Sugiyama et al.[95] published a case report of an
institutionalized, bedridden 8-year-old girl with Arnold-Chiari malformation with
low BMD whose BMD increased with MK4 treatment. MK4 also inhibited
phenytoin-induced bone loss in rats;[96] prevented and increased bone formation in
neurectomized rats,[97][98] an animal model for immobilization osteoporosis;
 prevented and increased bone formation in orchidectomized (castrated) rats,[99] an
animal model for secondary osteoporosis caused by testosterone deficiency; and
improved healing time and bone quality in experimentally induced osteotomy in
rats alone and in the presence of glucocorticoids.[100] And MK4 therapy has been
cited as a potential strategy for drug-induced bone loss.[101]
The safety of MK4 in the doses used to treat and prevent osteoporosis (45 mg
daily) and in even higher amounts have been shown in multiple studies. In two
human studies, people using 45 mg per day of vitamin K2 (as MK4)[102] and even
up to 135 mg/day (45 mg three times daily) of MK4,[103] showed no increase blood
clot risk. Even doses in rats as high as 250 mg/kg body weight did not alter the
tendency for blood-clot formation to occur.[104] MK4 appears safe except in people
taking the blood clotting medication Coumadin (warfarin). Since warfarin, which
was originally used as a rat poison, decreases blood clot risk by interrupting the
vitamin K-dependent clotting factors, taking vitamin K in any amount interferes
with the actions of warfarin and can increase blood clot risk.

[edit] Exercise

Multiple studies have shown that aerobics, weight bearing, and resistance
exercises can all maintain or increase BMD in postmenopausal women.[105] Many
researchers have attempted to pinpoint which types of exercise are most effective
at improving BMD and other metrics of bone quality, however results have
varied. The BEST (Bone-Estrogen Strength Training) Project at the University of
Arizona identified six specific weight training exercises that yielded the largest
improvements in BMD; this project suggests squat, military press, lat pulldown,
leg press, back extension, and seated row, with three weight training sessions a
week of two sets of each exercise, alternating between moderate (6-8 reps at 70%
of 1-rep max) and heavy (4-6 reps at 80% of 1-rep max).[106] One year of regular
jumping exercises appears to increase the BMD and moment of inertia of the
proximal tibia[107] in normal postmenopausal women. Treadmill walking,
gymnastic training, stepping, jumping, endurance, and strength exercises all
resulted in significant increases of L2-L4 BMD in osteopenic postmenopausal
women.[108][109][110] Strength training elicited improvements specifically in distal
radius and hip BMD.[111] Exercise combined with other pharmacological
treatments such as hormone replacement therapy (HRT) has been shown to
increases BMD more than HRT alone.[112]
Additional benefits for osteoporotic patients other than BMD increase include
improvements in balance, gait, and a reduction in risk of falls.[113]

[edit] Prognosis Hip fractures per 1000 patient-years[114]

WHO category Age 50-64 Age > 64 Overall
Although osteoporosis patients have an
Normal 5.3 9.4 6.6
increased mortality rate due to the
complications of fracture, it is rarely Osteopenia 11.4 19.6 15.7
lethal. Osteoporosis 22.4 46.6 40.6
Hip fractures can lead to decreased mobility and an additional risk of numerous
complications (such as deep venous thrombosis and/or pulmonary embolism,
pneumonia). The 6-month mortality rate following hip fracture is approximately 13.5%,
and a substantial proportion (almost 13%) of people who have suffered a hip fracture
need total assistance to mobilize after a hip fracture.[115]

Vertebral fractures, while having a smaller impact on mortality, can lead to severe
chronic pain of neurogenic origin, which can be hard to control, as well as deformity.
Though rare, multiple vertebral fractures can lead to such severe hunch back (kyphosis)
that the resulting pressure on internal organs can impair one's ability to breathe.

Apart from risk of death and other complications, osteoporotic fractures are associated
with a reduced health-related quality of life.[116]

[edit] Epidemiology
Osteoporosis is a major public health threat which afflicts 55% of Americans aged 50 and
above. Of these, approximately 80% are women.[117] It is estimated[citation needed] that 1 in 3
women and 1 in 12 men over the age of 50 worldwide have osteoporosis. It is responsible
for millions of fractures annually, mostly involving the lumbar vertebrae, hip, and wrist.
Fragility fractures of ribs are also common in men.

[edit] Hip fractures

Main article: hip fractures

Hip fractures are responsible for the most serious consequences of osteoporosis. In the
United States, more than 250,000 hip fractures annually are attributable to osteoporosis.
[118]
It is estimated that a 50-year-old white woman has a 17.5% lifetime risk of fracture of
the proximal femur. The incidence of hip fractures increases each decade from the sixth
through the ninth for both women and men for all populations. The highest incidence is
found among men and women ages 80 or older.[119]

[edit] Vertebral fractures

Between 35-50% of all women over 50 had at least one vertebral fracture. In the United
States, 700,000 vertebral fractures occur annually, but only about a third are recognized.
In a series of 9704 of women aged 68.8 on average studied for 15 years, 324 had already
suffered a vertebral fracture at entry into the study; 18.2% developed a vertebral fracture,
but that risk rose to 41.4% in women who had a previous vertebral fracture.[120]

[edit] Wrist

In the United States, 250,000 wrist fractures annually are attributable to osteoporosis.[118]
Wrist fractures are the third most common type of osteoporotic fractures. The lifetime
risk of sustaining a Colles' fracture is about 16% for white women. By the time women
reach age 70, about 20% have had at least one wrist fracture.[119]

[edit] Rib Fractures

Fragility fractures of the ribs are common in men as young as age thirty-five on. These
are often overlooked as signs of osteoporosis as these men are often physically active and
suffer the fracture in the course of physical activity. An example would be as a result of
falling while water skiing or jet skiing. However, a quick test of the individual's
testosterone level following the diagnosis of the fracture will readily reveal whether that
individual might be at risk.

[edit] History
The link between age-related reductions in bone density and fracture risk goes back at
least to Astley Cooper, and the term "osteoporosis" and recognition of its pathological
appearance is generally attributed to the French pathologist Jean Lobstein.[121] The
American endocrinologist Fuller Albright linked osteoporosis with the postmenopausal
state.[122] Bisphosponates, which revolutionized the treatment of osteoporosis, were
discovered in the 1960s.[123]

[edit] Awareness
Various organizations have been established to raise awareness on osteoporosis.

The National Osteoporosis Society, established in 1986, is a United Kingdom charity

dedicated to improving the diagnosis, prevention and treatment of osteoporosis.[124]

The National Osteoporosis Foundation (headquartered in Washington, D.C., US) seeks

to prevent osteoporosis and related fractures, to promote lifelong bone health, to help
improve the lives of those affected by osteoporosis and to find a cure through programs
of awareness, advocacy, public and health professional education and research.[2]

The International Osteoporosis Foundation (IOF) (headquartered in Nyon,

Switzerland) functions as a global alliance of patient, medical and research societies,
scientists, health care professionals, and international companies concerned about bone
health.[3]

The Orthopaedic Research Society (headquartered in Rosemont, IL, US) is a research

and professional development society that has emphasized osteoporosis research,
treatment and prevention for many years.[4]