Osteoporosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Osteoporosis was first discovered by John Hunter, a British surgeon, in 1800’s. Osteoporosis may be classified as primary or secondary, based on etiology. Osteoporosis may also be divided into osteopenia, osteoporosis, and severe osteoporosis, based on disease severity. Osteoporosis occurs as a result of an imbalance between bone resorption and bone formation. Major contributing factors in the development of osteoporosis include estrogen deficiency and aging. These factors might lead to osteoporosis by reactive oxygen species (ROS) mediated damage to osteocytes. Decrease in the capability of autophagy in osteocytes is another important factor which makes them vulnerable to oxidative stress. Genes involved in the pathogenesis of osteoporosis can be categorized into four main groups which include the osteoblast regulatory genes, osteoclast regulatory genes, bone matrix elements genes, and hormone/receptor genes. Osteoporosis must be differentiated from other diseases associated with a decrease in bone mineral density (BMD) such as idiopathic transient osteoporosis of hip, osteomalacia, scurvy, osteogenesis imperfecta, multiple myeloma, homocystinuria, and hypermetabolic resorptive osteoporosis. Osteoporosis is a major health problem involving 43.9% (43.4 million) of male and female population in the United States. Risk of osteoporosis increases with age. Osteoporosis usually involves individuals of age 80 years and older. White females and African-American males have the highest incidence among other races. Risk factors for osteoporosis are of two types, non-modifiable and modifiable factors. Non-modifiable risk factors include age, sex, menopause, and family history. Modifiable risk factors include smoking, alcohol consumption, immobility, glucocorticoid abuse, and use of proton pump inhibitor (PPI). Risk of fracture due to osteoporosis threatens one out of two postmenopausal women and one out of four men older than 50 years. The 10-year risk for any osteoporosis-related fracture in 65-year-old white woman with no other risk factor is 9.3%. According to USPSTF guidelines, all women ≥ 65 years along with women < 65 years old with high risk of fracture must be screened for osteoporosis. There is no recommendation to screen men for osteoporosis. Screening for osteoporosis can be done by dual energy x-ray absorptiometry (DXA) of both hips and lumbar spine, and quantitative ultrasonography of the calcaneus. If left untreated, most of the patients with osteoporosis may develop fractures. With appropriate and timely usage of medications along with calcium and/or vitamin D supplementation, the outcome of osteoporosis is usually good. Apart from risk of death and other complications, osteoporotic fractures are associated with a decreased quality of life secondary to immobility and emotional disturbances. The impact of osteoporosis and osteoporotic fractures on human life becomes intense with aging. There are various lifestyle modifications that can prevent the development of osteoporosis, such as calcium and vitamin D supplementation, diet, exercise, smoking cessation, minimizing alcohol consumption, and fall prevention. The mainstay of treatment in primary osteoporosis is lifestyle modifications. High risk patients and patients with past history of osteoporotic fracture, require medical therapy. Bisphosphonates are the first line treatment for osteoporosis. Raloxifene is the second line treatment for osteoporosis in postmenopausal women and is also used for prevention. Denosumab is a human monoclonal antibody designed to inhibit RANKL (RANK ligand), a protein that acts as the primary signal for bone removal. Denosumab is used to treat osteoporosis in elder men and postmenopausal women. Teriparatide and abaloparatide are human recombinant parathyroid hormones used to treat postmenopausal women with osteoporosis at high risk of fracture or to increase bone mass in men with osteoporosis.

Osteoporosis was first discovered by John Hunter, a British surgeon, in 1800’s and he was also the first one to introduce the process of remodeling. Jean Lobstein, a French pathologist during 1830’s, found that there are normal holes in every bone but bones in people with specific age and diseases, have holes of larger than normal size. He named this kind of bones as porous, and the disease was named as osteoporosis.

Osteoporosis is classified into several subtypes based on disease etiology and disease severity. Osteoporosis may be classified as primary or secondary diseases, depending upon the disease etiology. It can also be classified based upon the disease severity into osteopenia, osteoporosis, and severe osteoporosis. Osteoporosis is rare in children and adolescents, classified as secondary osteoporosis (due to some comorbidities or medications) and idiopathic osteoporosis (without significant pathological causes).

The pathophysiology of osteoporosis basically is an imbalance between bone resorption and bone formation. Major contributing factors to the development of osteoporosis include estrogen deficiency and aging. The main pathway, through which these factors might lead to osteoporosis is reactive oxygen species (ROS) damage to osteocytes. Decreasing the capability of autophagy in osteocytes is another important issue; which make them vulnerable to oxidative stresses. Genes involved in the pathogenesis of osteoporosis can be broadly categorized into four main groups: osteoblast regulatory genes, osteoclast regulatory genes, bone matrix elements genes, and hormone/receptor genes.  

Osteoporosis is caused by conditions that can lead to the disturbed balance between bone formation and bone resorption. The most common conditions include aging, menopause, nutritional deficiency of calcium and/or vitamin D, chronic renal failure, immobility, hyperparathyroidism, and chronic glucocorticoid abuse.

Osteoporosis must be differentiated from other diseases that cause a decrease in the bone mineral density (BMD), such as idiopathic transient osteoporosis of hip, osteomalacia, scurvy, osteogenesis imperfecta, multiple myeloma, homocystinuria, and hypermetabolic resorptive osteoporosis.

Osteoporosis is a major health problem involving 43.9% (43.4 million) of the male and female population in the United States. The disease incidence is increased by age. The most common involved age group is 80 years and older. White females and African-American males have the highest incidence among the other races. The incidence of lifetime osteoporotic fracture, as the most important outcome of osteoporosis, is approximately one out of every two women and also one in four men over 50 worldwide. More than 1.5 million fractures occurred secondary to osteoporosis per year; among which are 300,000 hip fracture, 700,000 vertebral fracture, 250,000 wrist fracture, and more than 300,000 other bones fractures. Major epidemiological studies conducted in the US, estimated that 10.3% (10.2 million) of people older than 50 years are affected with osteoporosis. Osteoporosis affects about 75 million people in Europe, USA, and Japan.

Risk factors for osteoporosis are of two types, including non-modifiable and modifiable (potentially) factors. Non-modifiable risk factors are age, sex, menopause, and family history. Modifiable (potentially) factors are smoking, alcohol consumption, immobility, glucocorticoid abuse, and proton pump inhibitor (PPI).

The risk of fracture due to osteoporosis is threatening especially to one out of two postmenopausal women and also one out of five men older than 50. The 10-year risk for any osteoporosis-related fractures in a 65-year-old white woman with no other risk factor is 9.3%. According to the guidelines of USPSTF, all women ≥ 65 years old along with women < 65 years old with a high risk of fracture are the target of screening for osteoporosis, but there is not any recommendation to screen men for the disease. There are two major methods, suggested for screening osteoporosis, that include; dual energy x-ray absorptiometry (DXA) of both hip and lumbar spine bones, and quantitative ultrasonography of the calcaneus.

If left untreated, most of the patients with osteoporosis develop fractures. With the appropriate and timely usage of medications along with calcium and/or vitamin D supplementation, the outcome of osteoporosis is usually good. Apart from the risk of death and other complications, osteoporotic fractures are associated with deep venous thrombosis, kyphosis, and a reduced quality of life due to immobility.

Osteoporosis is usually asymptomatic, until the patient experiences an osteoporotic fracture. The hallmark symptom of osteoporotic fracture is bone pain. Following osteoporotic fractures, the major signs appear, gradually; which include immobility, bed sores, decrease in height, and stooped posture.

Osteoporosis is generally asymptomatic initially, until the bone mass loss leads to a fracture. Fractures can be divided into acute and chronic ones; involving the femoral neck and vertebral bones, respectively. The main feature of femoral fracture is immobilization and the main feature of vertebral fracture is Dowager’s hump appearance. Any other secondary causes of the disease (e.g., chronic corticosteroid use or hyperthyroidism) may have their own symptoms; signifying a risk factor for osteoporosis.

There is a limited role for laboratory tests in the diagnosis of osteoporosis, however, they may be used for differentiating primary versus secondary causes of the disease. Laboratory tests for the diagnosis of osteoporosis include some baseline tests like complete blood count (CBC), serum calcium, phosphate, alkaline phosphatase, and 25-(OH)-vitamin D. The tests for diagnosing secondary osteoporosis include 24 hr serum calcium, serum protein electrophoresis, and serum thyroid hormones.

There are no electrocardiogram (ECG) findings associated with osteoporosis.

An X-ray may be helpful in the diagnosis of osteoporosis. The main X-ray finding suggestive of osteoporosis is the bone mass loss. Primarily, the loss is mainly in bony trabecula, than the cortex. The most common bones monitored for osteoporosis are the femoral neck, lumbar vertebrae, and calcaneus. Plain radiography needs at least 30-50% of the bone loss to demonstrate decreased bone density; therefore, it is not a very sensitive modality.

Bone CT scan may be helpful in the diagnosis of osteoporosis. CT scan finding suggestive of osteoporosis includes decreased bone mineral density (BMD). In order to describe the bone strength more precisely, it seems necessary to do quantitative assays such as dual energy X-ray absorptiometry (DXA) and CT scan (especially volumetric quantitative CT (vQCT)). Modalities for assessing osteoporotic fracture risk, without any destruction or invasion, include high-resolution CT (hrCT) and micro CT (μCT). The only tests that are possible in vivo are hrCT and vQCT.

Magnetic resonance imaging (MRI) technique is very precise in measuring trabecular bone structure, so, it could be a suitable surrogate for multiple sites bone biopsy. As DXA can measure both trabecular and cortical at the same time, thus MRI would be a better choice to assess the trabecular bone part only. The most impressing aspect of MRI in diagnosing osteoporosis is the ability to take in vivo images of trabecular bones. The plain resolution starts at about 150 μm and slice thickness starts at 300 μm; measuring trabecular bones precisely.

There are no echocardiography findings associated with osteoporosis. Quantitative ultrasound may be helpful in the diagnosis of osteoporosis.Ultrasound findings diagnostic of osteoporosis, include bone mass loss, mainly trabecular bone that is the major bone type affected in osteoporosis. Problems with DXA method have led physicians to choose some methods with fewer side-effects and limitations, such as ultrasound (especially quantitative), which could diagnose osteoporosis with lower radiation, lower price, and also higher availability. Most common site of ultrasound application is peripheral parts, such as calcaneus and phalanges.

The most important modality for measuring bone mineral density (BMD), on which every osteoporosis diagnostic and therapeutic decision is based on, is dual energy X-ray absorptiometry (DEXA). DEXA is a 2-dimensional image of a 3-dimensional subject, mainly depends on the size of the bone which is studied. DEXA is the gold standard for the diagnosis of osteoporosis and fracture risk assessment. Finite element modeling (FEM) is an engineering computer-based simulation software that typically simulates the physical loading effects on materials. The effects may be strain or compression, while the subject is determined as net-like elements connected to each other. BMD is focused on density and does not imply for microstructure or architecture of bones. One of the most powerful methods to determine the microstructure is trabecular bone score (TBS) as a complementary method for DEXA.

There are no additional diagnostic findings for osteoporosis.

There are various lifestyle modifications that can be implemented to prevent the development or progression and to treat osteoporosis. They include calcium and vitamin D supplementation, diet, exercise, smoking cessation, alcohol consumption, and also fall prevention. The patient should consume 1200 to 1500 mg of calcium daily, either via dietary means (e.g., 8 oz glass of milk contains approximately 300 mg of calcium) or via supplementation. New vitamin D intake recommendations are 400-800 IU daily in adults up to age 50, and 800 – 1,000 IU daily in those over 50. Multiple studies have shown that aerobics, weight lifting, and resistance exercises can all maintain or increase BMD in postmenopausal women. In addition to maintaining adequate vitamin D levels and physical activity, as described above, several strategies have been demonstrated to reduce falls.  

The mainstay of treatment in primary osteoporosis is based on life style modifications. Most of the time in high risk patients and people with past history of osteoporotic fracture, medical therapy is necessary. Bisphosphonates are the first line treatment for osteoporosis. Raloxifene is the second line treatment of osteoporosis in postmenopausal women, for both treatment and prevention. Denosumab is a human monoclonal antibody designed to inhibit RANKL (RANK ligand), a protein that acts as the primary signal for bone removal. It is used to treat osteoporosis in older men and postmenopausal women. Teriparatide and Abaloparatide are human recombinant parathyroid hormones used to treat postmenopausal osteoporosis in women with high risk of fracture or to increase bone mass in men with osteoporosis.

Surgery is not the first-line treatment option for patients with osteoporosis. Vertebroplasty, kyphoplasty, lordoplasty, and vesselplasty are procedures that usually reserved for patients with either pathological or osteoporotic vertebral fractures in patients, refractory to medical therapy. Surgery options for osteoporosis are very limited. In case of hip fracture, open reduction internal fixation or in rare cases total hip replacement surgery are the options.

In osteoporosis, some of the lifestyle modification strategies would be beneficial for both primary prevention and also initial treatment; because osteoporosis majorly depends on lifestyle, in every stage of the disease. Lifestyle modification, as well as calcium supplementation, are the best early and long-term measures for the prevention of osteoporosis. There are also medications available that can be used to prevent worsening of osteoporosis. The primary prevention of osteoporosis is particularly important because the micro-architectural changes that occur in osteoporosis are largely irreversible.

Effective measures for the secondary prevention of osteoporosis include pharmacological therapy and also lifestyle modification as soon as osteoporosis is diagnosed.

44 million people of more than 50 years old in the US are suffering from osteoporosis, more than half of over 50 years people. Remaining the current conditions and utilities, it is estimated that more than 61 million people in 2020 would be suffering from osteoporosis. Women constitute 80% of the osteoporotic population. Parathormone (PTH) analogues (teriparatide and abaloparatide) have more prices and quality-adjusted life years (QALYs) in contrast with zoledronate. Teriparatide and abaloparatide are $43,440 and $22,061 more costly than zoledronate. In Europe the whole cost of medical therapies for osteoporosis in 2010 was €37 billion, in which 66% was for acute fractures management, 29% was for long-term fracture outcome management, and 5% was for medical prevention. On the other hand, the holistic burden of osteoporosis in Europe assumed to be the loss of 1,180,000 life years (QALY), most of them because of prior osteoporotic fractures. Regarding that one QALY is equal value of 2xGDP, it is assumed that the total burden of osteoporosis become €60.4 billion, in 2010. Surprisingly, the QALY number will rise from 1.2 million in 2010 to about 1.4 million years in 2025, with 20% increase.  

Some future antiresorptive drugs that are not yet improved by US food and drug administration (FDA), include calcitriol, genistein, other bisphosphonates (etidronate, pamidronate, and tiludronate), PTH (1-84), sodium fluoride, strontium ranelate, and also tibolone.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Osteoporosis was first discovered by John Hunter, a British surgeon, in 1800’s and he was also the first to introduce the process of remodeling. Jean Lobstein, a French pathologist during 1830’s, found that there are normal holes in every bone but bones in people with specific age and diseases, have holes of larger than normal size. He named this kind of bone as porous, and the disease was named as osteoporosis.

The historical perspective of osteoporosis has been given below:

Initial identification of bone resorption Dowager’s hump seen in Egyptian mummies 4000 years ago                                                                                                                           Osteoporosis discovered by: John Hunter, a British surgeon in: 1800’s                                                                       Osteoporosis name coined by: Jean Lobstein, a French pathologist in: 1830’s       Age-related bone loss defined by: Astley Cooper, an English surgeon in: 1830’s                                                                     Postmenopausal bone loss defined & Postmenopausal osteoporosis treated with estrogen by: Fuller Albright, an American endocrinologist in: 1940’s                                   Bone densitometers developed by: Norman, an American researcher in: 1950                                   Bisphosphonates discovered by: Herbert Fleisch, a physiologist from Switzerland in: 1960’s                                   Osteoporosis publicized by: National Institute of Health (NIH) in: 1984                                   Specific cytokines that influence osteoclasts activity discovered in: 1990’s                                   T-score used to classify and define bone mineral density (BMD) by: world health organization (WHO) in: 1994                                   Selective estrogen receptor modulators (SERMs) introduced in market in: 1998                                   Expert panel for prevention, diagnosis, and treatment of osteoporosis assembled by: National Institute of Health (NIH) in: 2000

• 4000 years old Egyptian mummies showed the first sign of osteoporosis known as “Dowager’s hump”. Bones with holes, were seen for the first time during this period.
• John Hunter found that the bones in the human body turn over continuously. When some old or dysfunctioned bone tissue is eliminated, it is substituted by new tissue. This process later became to be known as remodeling.
• In 1830’s, Jean Lobstein, a French pathologist, found that there are holes in every bone; but bones of people of specific age and suffering from certain diseases may have bigger holes than normal. Jean Lobstein named this kind of bone as porous, and the disease was named as osteoporosis.^[1]
• In 1830’s, the association between age-related reductions in bone density and fracture risk was determined by Astley Cooper. The recognition of the pathological appearance of osteoporosis is attributed to the French pathologist, Lobstein.^[2]
• In 1940’s, an American endocrinologist, Fuller Albright from Massachusetts General Hospital, established an association between osteoporosis and postmenopausal state. Fuller Albright started the treatment of menopausal women with estrogen in order to prevent bone loss.^[3]
• In 1960’s, researchers developed more sensitive methods to detect early bone loss, such as bone densitometers.
• In 1960’s, bisphosphonates which inhibit bone resorption, revolutionized the treatment of osteoporosis after they were discovered by Herbert Fleisch.^[4]
• In 1984, the National Institute of Health (NIH) declared osteoporosis as a significant threat to health and the possibility that bone loss may be reduced by estrogen therapy, calcium supplementation, good nutrition, and exercise.^[5]
• In 1980’s and 1990’s researchers discovered the specific cytokines which influence the activity of osteoclasts, the components that lead to bone breakdown.^[6]
• In 1994, World Health Organization (WHO) first used T-score for classification of various amounts of bone mineral density (BMD). The sample population consisted of young, healthy individuals, matched for sex and race.^[7]
• In 1998, selective estrogen receptor modulators (SERMs), such as raloxifene, were introduced in the market. SERMs also help with the treatment of breast tumors and stimulate the growth of uterine cells.^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Osteoporosis is classified based on etiology and severity of the disease. Osteoporosis may be divided into primary and secondary types, based on disease etiology. On the basis of disease severity, it can be classified as osteopenia, osteoporosis, and severe osteoporosis. Osteoporosis is rare in children and adolescents. Secondary osteoporosis results from various comorbidities or the use of certain medications, whereas, idiopathic osteoporosis has no known cause.

Osteoporosis may be classified based on etiology and severity of the disease.^[1][2][3]

Osteoporosis

Based on Severity

Based on Etiology

Children

Adults

Children, Adolescents, and Adults

Z-score measurement

T-score measurement

Bone loss due to other diseases?

Z-score > -2.0 without fracture history

Z-score < -2.0 and significant fracture history (2 or more long bone fractures before 10 years of age or 3 or more long bone fractures before 19 years of age) OR One or more vertebral fractures occurring in the absence of local disease or high-energy trauma

-1 > T-score > -2.5

T-score ≤ -2.5

T-score ≤ -2.5 plus history of fracture

No

Yes

Normal

Osteoporosis

Osteopenia

Osteoporosis

Severe osteoporosis

Primary osteoporosis

Secondary osteoporosis

On the basis of etiology, osteoporosis can be classified into:

Primary osteoporosis develops as a result of aging or menopause-related bone demineralization. In patients with primary osteoporosis, the bone density decreases as the age progresses.

Secondary osteoporosis results from more severe loss of bone mass due to pathologies associated with immobilization, medications (iatrogenic), endocrine dysfunction, cancer, and chronic kidney disease.^[1]

Osteoporosis may be classified based on the bone marrow density (BMD). The patients are classified according to the site and method of measurements. The used equipment and reference group of people may also be helpful in classification of osteoporosis. The major value used in the classification of osteoporosis is T-score. T-score may be defined as “patient measured BMD value minus the reference BMD value (sex-matched and with a preference for youth) divided by the reference standard deviation (SD) (sex-matched and with a preference for youth)”.^[2]

The classification of osteoporosis on the basis of BMD measured T-score is as follows:

• T-score less than -1 and more than -2.5: Osteopenia
• T-score equal to or less than -2.5: Osteoporosis
• T-score equal to or less than -2.5 with history of fracture: Severe osteoporosis

The exclusive utilization of T-score and comparing the reference normative data of people aged 20-29 years, as world health organization (WHO) criteria, is very inconsistent. Compared to other classification systems, it is better to standardize the normative data, by including older people and individuals with other findings including BMD measurement at multiple sites, in order to obtain a comprehensive classification system.^[2]

• Bone mass, as measured by DEXA, is reported as bone mineral content (BMC) (g) or areal BMD (g/cm2). These values are compared to reference values from individuals of similar age, sex, and ethnicity to calculate the Z-score, the number of SDs from the expected mean. Abundant pediatric reference data is now available for children and teenagers but not for infants.
• It is essential to select norms collected by using equipment from the same manufacturer as that used for the patient because of systematic differences in software. Peak bone mass is achieved in the second or third decade, depending on the skeletal site. Therefore, T-scores (which compare the patient’s BMD with that of a healthy young adult) should not be used before 20 years of age.
• The appropriate interpretation of DEXA results may require more than the calculation of Z-scores.
• Children with chronic illness often have delayed growth and pubertal development, factors that contribute to a low bone mass for age or sex. BMD, as measured by DEXA, corrects bone mineral for the area (height and width) but not for the volume (height, width, and thickness) of bone. For this reason, if 2 individuals with identical “true” volumetric bone density are compared, the shorter person will have a lower BMD than the taller one. Similarly, a child with delayed puberty will not have had the gains in bone size, geometry, and density that occur with sex steroid exposure.
• Controversy persists about the optimal method to adjust for variations in bone size, body composition, and maturity as well as the criteria by which the “best method” is defined; ideally, the adjustment method would prove to be a stronger predictor of fracture.
• The Pediatric Development Conference (PDC) guidelines recommend that BMD in children with delayed growth or puberty be adjusted for height or height age or compared with reference data with age, sex, and height-specific Z-scores.
• The terms “osteopenia” and “osteoporosis” are used in older adults to describe degree of deficits (lesser or greater) in bone mass. These terms should not be used to describe densitometry findings in pediatric patients. Instead, a BMC or BMD Z-score that is > 2 SDs below expected (< – 2.0) is referred to as “low for age”.
• The following criteria for osteoporosis in a pediatric patient were agreed on in the 2013 PDC guidelines:^[4]
  • One or more vertebral fractures occurring in the absence of local disease or high-energy trauma (measuring BMD can add to the assessment of these patients but is not required as a diagnostic criterion);
  • Low bone density (BMC or areal BMD Z-scores < – 2.0) and a significant fracture history (2 or more long bone fractures before 10 years of age or 3 or more long bone fractures before 19 years of age).
  • Lastly, it is important to recognize that there are certain diseases in pediatric population (e.g., end-stage renal disease and spinal vertebral fractures) in which DEXA does not accurately reflect fracture risk or bone health.

• Osteoporosis in children and adolescents is rare. Usually, it is due to some comorbidities or medications (secondary osteoporosis). Surprisingly, no significant causes have been found for rare cases (idiopathic osteoporosis).
• Irrespective of the cause, juvenile osteoporosis can be a significant problem because it occurs during the child’s prime bone-building years. From birth through young adulthood, children steadily accumulate bone mass, which peaks, sometimes, before age 30. The greater their peak bone mass, the lower their risk for osteoporosis later in life. After people reach their mid-thirties, bone mass typically begins to decline very slowly at first but the decline accelerates in their fifties and sixties. The lifestyle choices, especially the amount of calcium in the diet and the level of physical activity influence the development of peak bone mass and the rate at which bone is lost later in life.

• As the primary condition, juvenile idiopathic arthritis (also known as juvenile rheumatoid arthritis) provides a good illustration of the possible causes of secondary osteoporosis. In some cases, the disease process itself can cause osteoporosis.
• In other cases, the medication used to treat the primary disorder may reduce bone mass. For example, drugs such as prednisone used to treat severe cases of juvenile idiopathic arthritis, negatively affect bone mass.
• Finally, some behaviors associated with the primary disorder may lead to bone loss or reduction in bone formation. For example, a child with juvenile idiopathic arthritis may avoid physical activity, which is necessary for formation and maintainence bone mass, because it may aggravate his or her condition or cause pain.^[5]
• For children with secondary osteoporosis, the best course of action is to identify and treat the underlying disorder. In the case of medication-induced juvenile osteoporosis, it is best to treat the primary disorder with the lowest effective dose of the osteoporosis-inducing medication. Like all children, those with secondary osteoporosis also need a diet rich in calcium and vitamin D and as much physical activity as possible given the limitations of the primary disorder.^[5]

• Idiopathic juvenile osteoporosis (IJO) is a primary condition with no known cause. It is diagnosed after other causes of juvenile osteoporosis have been excluded. This rare form of osteoporosis typically occurs just before the onset of puberty in previously healthy children. The average age at onset is 7 years, with a range of 1 to 13 years. Most of the children experience complete recovery of bone.

• The first sign of IJO is usually pain in the lower back, hips, and feet, often accompanied by difficulty walking. Knee, ankle pain and fractures of the lower extremities may also occur. Physical malformations include kyphosis, loss of height, a sunken chest, or a limp. These physical malformations are sometimes reversible after IJO has run its course.

• X-rays of children with IJO often show low bone density, fractures of weight-bearing bones, and collapsed or deformed vertebrae. However, conventional X-rays may not be able to detect osteoporosis until significant bone mass has occurred. Newer methods such as dual energy x-ray absorptiometry (DXA), and quantitative computed tomography (QCT ) allow for earlier and more accurate diagnosis of low bone mass.

• There is no established medical or surgical therapy for juvenile osteoporosis. In some cases, no treatment may be needed because the condition usually goes away spontaneously. However, early diagnosis of juvenile osteoporosis is important so that steps can be taken to protect the child’s spine and other bones from fracture until remission occurs. These steps may include physical therapy, use of crutches, avoiding unsafe weight-bearing activities, and other supportive care. A well-balanced diet rich in calcium and vitamin D is also important. In severe, long-lasting cases of juvenile osteoporosis, bisphosphonates, approved by the Food and Drug Administration for the treatment of osteoporosis in adults, have been given to children experimentally.
• Most children with IJO experience complete recovery of bone tissue. Although growth may be somewhat impaired during the acute phase of the disorder, normal growth resumes and catch-up growth often occurs afterward. Unfortunately, in some cases, IJO can result in permanent disability such as kyphoscoliosis or collapse of the rib cage.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

The pathophysiology of osteoporosis consists of an imbalance between bone resorption and bone formation. Major factors contributing to the development of osteoporosis include estrogen deficit and aging. The main mechanism, by which these factors might lead to osteoporosis is reactive oxygen species (ROS) induced damage to osteocytes. Decreased capability of osteocyte autophagy is another important issue; which makes them vulnerable to oxidative stresses. Genes involved in the pathogenesis of osteoporosis can be categorized into four main groups namely, osteoblast regulatory genes, osteoclast regulatory genes, bone matrix elements genes, and hormone/receptor genes.   

Osteoporosis is mainly defined as bone mass loss and micro-architectural deterioration in bones. The final outcome of osteoporosis is fracture.

• In normal bone, there is constant remodeling of bone matrix. The process takes place in bone multicellular units (BMUs).^[1][2]

• The process through which loss of bone mass occurs is the activation of osteoclastogenic pathway.

• The two main cells involved in osteoclastogenic pathway are osteoblasts and osteoclasts.
• Bone resorption is caused by osteoclasts, after which new bone is deposited by osteoblasts.
• Osteoclasts determine the final outcome of bone resorption.^[2][3]
• Normal balance between osteoblast and osteoclast activities within a bone is influenced by macrophages and innate adaptive immunity. This leads to the formation of a normal bone.
• Whenever there is a disturbance of this balance leading to increased osteoclastic activity relative to osteoblastic activity, the result is resorption, and eventual bone mass loss.^[2]

• In addition to estrogen, calcium plays a significant role in bone turnover.
• Deficiency of calcium and vitamin D leads to impaired bone deposition.
• The parathyroid glands react to low calcium levels by secreting parathyroid hormone (parathormone, PTH) increasing bone resorption in a bid to ensure adequate calcium levels in the blood.^[4]
• The role of calcitonin, a hormone produced by the thyroid that increases bone deposition, is less clear and probably less significant.^[3]

• Manolagas in 2010, suggested that main pathogenesis of osteoporosis shifted from estrogen-based theory to age-related issue.
• The theory consists of reactive oxygen species (ROS) as the main factor involved in the osteoporosis.
• According to Manolagas theory, loss of estrogen and androgen in the body would make bone tissue more vulnerable to ROS, making the osteocytes prone to deterioration.^[5]
• When ROS become elevated in bone tissue, several factors would be increased include T and B lymphocytes, nuclear factor kappa-B (NF-kB), and also osteoclastogenic cytokines (e.g., IL-1, IL-6, IL-7, and receptor activator of NF-kB ligand (RANKL)). On the other hand, androgen may decrease all of them.^[6]
• RANKL is thought to be the most important factor needed for formation of osteoclasts.

• Xiong proposed that osteoblast and its progenitor cells are not the main sources of RANKL essential for osteoclast formation and remodeling in adult bones.
• Osteoprotegerin (OPG) binds RANKL before it has an opportunity to bind to RANK thereby suppressing its ability to increase bone resorption.
• RANKL, RANK, and OPG are closely related to tumor necrosis factor (TNF) and its receptors.
• The role of the wnt signaling pathway is recognized, but not clearly understood.

Genes involved in the pathogenesis of osteoporosis can be categorized into four main groups. Mutation in any of these genes can lead to the development of some rare diseases. These genes include:

• Osteoblast regulatory genes
• Osteoclast regulatory genes
• Bone matrix elements genes
• Hormone/receptor genes.

Group	Gene	Function	Related Disease
Osteoblast regulatory	Lipoprotein receptor-related protein 5 (LRP5)	Co-receptors for canonical Wnt signalling pathway	Osteoporosis-pseudoglioma syndrome (OPPG) High bone mass (HBM) disease
	Transforming growth factor (TGF)-β1	Effects on both osteoblast and osteoclast function, in vitro	Camurati-Engelmann (CED) disease
	Bone morphogenic proteins (BMPs)	Modulation of bone mineral density (BMD) along with limited roles in limb differentiation	Low bone mineral density (BMD) Osteoporosis
	Sclerostin	Inhibitory effects on Wnt signaling pathway	Van Buchem bone dysplasia Sclerosteosis bone dysplasia
	Core binding factor A1 (CBFA1)	Differentiate osteoblasts in order to bone formation	Cleidocranial dysplasia (CCD)
Osteoclast regulatory	Cathepsin K	Regulating bone mineral density (BMD) with influencing osteoblasts and osteoclasts	Pycnodysostosis syndrome
	Vacuolar proton pump a3 subunit (TCIRG1)	Osteoclast-specific proton pump generation	Osteopetrosis, recessive forms
	Chloride Channel 7 (CLCN7)	Coding chloride channels frequently expressed in osteoclasts	Osteopetrosis, severe forms
Bone matrix element	Collagen type Iα I	Major conforming element in the bones	Osteogenesis imperfecta
Hormone and receptor	Vitamin D receptor (VDR)	Modulating vitamin D effects on bone formation	Vitamin D-resistant rickets
	Estrogen receptor α	Influences fracture risk independent of an effect on bone mineral density (BMD)	Bone mass loss Osteoporosis

• Wnt pathway is a critical pathway in developing various organs, such as extremities, central nervous system (CNS), osteoblasts and chondrocytes.
• The downstream protein after Wnt/LPR5/LPR6 activation is β-cathenin.
• Some extracellular proteins like Dickkopf (Dkk) could bind to LPR5 and LPR6, decreasing and inhibiting the Wnt signaling pathway.
• OPPG is osteoporosis along with blindness due to vitreous opacity while HBM is an abnormal increase of bone mineral density (BMD).^[7][8][9]

• The major family of TGF-β plays an important role in cell differentiation before and after birth.
• The most important member of the family in bone and fibrous tissues is TGF-β1, encoded by TGF-β1 gene.
• TGF-β1 plays the main role in determining osteoporosis susceptibility.
• If TGF-β gene becomes inactivated, it may result in major inflammation and severe osteoporosis.
• Polymorphisms within the intron 4 of the TGF-β1 gene has been shown to be the main cause of severe osteoporosis.
• Mutations in TGF-β1 gene causes Camurati-Engelmann (CED) disease, which is a rare disease of hyperostosis and sclerosis of long bones metaphysis.^[10][11]

• BMPs are also members of the superfamily of TGF-β proteins.

• Various changes in different codon location among the gene sequence have been proved to cause low bone mineral density (BMD) and also osteoporosis in patients.^[12]

• Sclerostin is a protein with cysteine contained knots in its structure that share some homologous sequences with anti-BMP proteins.

• SOST gene has a major role in BMD regulations, while the patient with heterozygous mutation may be asymptomatic they usually have higher BMD.
• Decrease in BMD following SOST over expression may be due to inhibitory effects of sclerostin on Wnt signaling pathway, through binding and interacting LPR5 and LPR6 proteins.
• The mutations in the SOST gene may lead to van Buchem and Sclerosteosis bone dysplasias. These diseases are mainly severe osteosclerosis of skull, mandible, or any other trabecular bones.
• Sclerosteosis is more severe than van Buchem disease and mainly involves the upper extremity bones.^[13][14][15]

• CBFA1 is a major gene in bone formation. Laboratory animals with a mutated version or without the wild version of CBFA1 gene have failure of development of bone.

• The major role of the gene is to differentiate osteoblasts in order to construct the bones.
• Lack of the CBFA1 gene in the human body may lead to cleidocranial dysplasia (CCD), a disease in which patient has clavicular hypoplasia or complete aplasia, patent fontanels, short stature, teeth abnormalities, and other skeletal deformities.^[16]

• A mutation in cathepsin K gene may cause Pycnodysostosis syndrome that is a rare syndrome of bone dysplasia along with osteosclerosis and short stature.^[17]

• It seems that this gene has some role in the regulation of bone mineral density (BMD).
• The majority of recessive forms of osteopetrosis are caused by inactivation of TCIRG1 gene.^[18]

• It controls the acidification of the environment and facilitate the resorption of the bone.
• Inactivation mutations of the gene may lead to severe forms of osteopetrosis.^[15]

• Collagen type 1 gene is one of the most important genes in osteoporosis as collagen type 1 is the major conforming element in the bones.
• mutation in the collagen type 1 gene may cause osteogenesis imperfecta, in which the bone mineral density (BMD) is increased and the bones become fragile.^[19]

• Aging
• Anorexia nervosa
• Calcium abnormalities
• Chronic corticosteroid use
• Chronic renal failure
• Deep vein thrombosis (DVT)
• Fractures
• Gonadal dysgenesis
• Hyperparathyroidism
• Hypophosphatemic rickets
• Immobility
• Menopause
• Multiple myeloma
• Mixed connective tissue disease
• Paget’s disease of bone
• Primary hypoparathyroidism
• Short stature

On gross pathology, decreased bone density and small pores in diaphysis of bones are characteristic findings of osteoporosis. In advanced forms of the disease some pathological fractures may be seen.

• Bone with osteoporosis shows increased number of osteoclasts and decreased number of osteoblasts under the microscope.
• Autophagy is the mechanism through which osteocytes evade oxidative stress.
• The capability of autophagy in cells decreases as they age, a major factor of aging.
• As osteocytes grow, viability of cells decrease thereby decreasing the bone mass density.^[21]

​ ​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Raviteja Guddeti,M.B.B.S.[3], Eiman Ghaffarpasand, M.D. [4]

Osteoporosis may be caused by conditions that can lead to the disturbed balance between bone formation and bone resorption. Common causes of osteoporosis include aging, menopause, nutritional deficiency of calcium and/or vitamin D, chronic renal failure, immobility, hyperparathyroidism, and chronic glucocorticoid abuse.

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours, if left untreated. There are no life-threatening causes of osteoporosis. However, complications resulting from untreated osteoporosis are common.

• Aging
• Alcoholism
• Calcium deficiency
• Chronic renal failure
• Gonadal dysgenesis
• Hyperparathyroidism
• Hyperthyroidism
• Hypophosphatemic rickets
• Idiopathic
• Immobility
• Menopause
• Mixed connective tissue disease
• Paget’s disease of bone
• Prednisolone
• Primary hypoparathyroidism

Cardiovascular	Werner syndrome, Storm syndrome
Chemical / poisoning	Ethanol
Dermatologic	Dyskeratosis Congenita, Fanconi-ichthyosis-dysmorphism, Nodulosis-arthropathy-osteolysis syndrome, Osteoporosis — oculocutaneous — hypopigmentation syndrome, Xylosylprotein 4-beta-galactosyltransferase (XGPT) deficiency, Tuberous sclerosis, Winchester syndrome
Drug Side Effect	Cyproterone, Dexamethasone, Exemestane, Flunisolide, Goserelin, Heparin, Isotretinoin, Methylprednisolone,Oxcarbazepine, Pergolide, Pramipexole, Prednisolone, Prednisone, Triamcinolone
Ear Nose Throat	Eccentrochondrodysplasia, Otospondylomegaepiphyseal dysplasia, Osteochondrodysplatic dwarfism — deafness — retinitis pigmentosa, Rajab-Spranger syndrome
Endocrine	Adrenal adenoma, Adrenal incidentaloma, Adrenocortical carcinoma, Andropause, Acromegaly, Aromatase deficiency, Cushing’s disease, Cushing’s syndrome, Diabetes Mellitus, Functioning pancreatic endocrine tumor, Gonadal dysgenesis, Hashimoto’s Thyroiditis, Hyperadrenalism, Hyperparathyroidism, Hyperthyroidism, Hypogonadotropic hypogonadism — Syndactyly, Hypopituitaryism, Multiple endocrine neoplasia type 1, Oncogenic osteomalacia, Ovarian insufficiency due to FSH resistance, Primary hypoparathyroidism, Sub clinical hypothyroidism, Galactorrhoea–Hyperprolactinaemia, Prader-Willi syndrome, Ovarian insufficiency, Wolcott-Rallison syndrome
Environmental	No underlying causes
Gastroenterologic	Celiac Disease, Cholestasis, Chronic Hepatitis, Chronic Liver Disease, Crohn’s disease, Cystic Fibrosis, Fanconi-Albertini-Zellweger syndrome, Haemochromatosis, Maldigestion, Primary biliary cirrhosis, Tricho-hepato-enteric syndrome, Ulcerative colitis, Wilson’s Disease, Wolman syndrome, Wolcott-Rallison syndrome
Genetic	Abderhalden-Kaufmann-Lignac syndrome, Acroosteolysis neurogenic, Albright’s hereditary osteodystrophy, Chromosome 1, deletion q21 q25, Down Syndrome, Ehlers-Danlos syndrome – progeroid form, Geroderma osteodysplastica, Hajdu-Cheney syndrome, Hutchinson Gilford Syndrome, Hyper IgE syndrome/Job syndrome, Iridogoniodysgenesis and skeletal anomalies, Larsen syndrome- recessive type, Lobstein disease, Lockwood-Feingold syndrome, Lysinuric protein intolerance, Marfan syndrome, Metaphyseal chondrodysplasia Spahr type, Metaphyseal dysplasia Pyle type, Menkes Disease, Morquio syndrome, Osteogenesis imperfecta, Osteolysis hereditary multicentric, Osteoporosis-pseudoglioma syndrome, Otospondylomegaepiphyseal dysplasia, Pelizaeus-Merzbacher disease, recessive, acute infantile, Pena Shokeir syndrome, Prolidase deficiency, Sakati syndrome, Singleton-Merten syndrome, Sponastrime dysplasia, Spondyloepimetaphyseal dysplasia with multiple dislocations, Spondylometaphyseal dysplasia with dentinogenesis imperfecta, Spondylo-ocular syndrome, Snyder-Robinson syndrome, Storm syndrome, Thick skull syndrome, Urban rogers meyer syndrome, Spinocerebellar ataxia –dysmorphism, Wolcott-Rallison syndrome
Hematologic	Alpha thalassemia, Beta thalassemia, Diamond-Blackfan anemia, Generalized mastocytosis, Hemoglobin H disease, Leukemia, Lymphoma, Multiple Myeloma, Sickle cell anemia, Waldenstrom’s macroglobulinemia
Iatrogenic	Glucocorticoid-induced osteoporosis, Anticonvulsant-induced osteoporosis
Infectious Disease	No underlying causes
Musculoskeletal / Ortho	Albright’s hereditary osteodystrophy, Boyd-Stearns syndrome, Ehlers-Danlos syndrome- progeroid form, Female athlete triad, Fanconi-ichthyosis-dysmorphism, Fontaine-Farriaux-Lanckaert syndrome, Gnathodiaphyseal dysplasia, Geroderma osteodysplastica, Hyperostosis corticalis deformans juvenilis, Hajdu-Cheney syndrome, Hyper IgE syndrome/Job syndrome, Hypertrichotic osteochondrodysplasia, Kaler-Garrity-Stern syndrome, Lobstein disease, Lockwood-Feingold syndrome, Osteogenesis imperfecta, Pena Shokeir syndrome, Oncogenic osteomalacia, Osteoporosis — macrocephaly — mental retardation — blindness, Otospondylomegaepiphyseal dysplasia, Osteochondrodysplatic dwarfism — deafness — retinitis pigmentosa, Paget’s disease of bone, Pointer syndrome, Prader-Willi syndrome, Richieri-Costa Da Silva syndrome, Riley Shwachman syndrome, Schwartz-Jampel Syndrome, Singleton-Merten syndrome, Sponastrime dysplasia, Spondyloepimetaphyseal dysplasia with multiple dislocations, Spondylometaphyseal dysplasia with dentinogenesis imperfecta, Spondylo-ocular syndrome,Shprintzen-Golberg craniosynostosis, Systemic infantile hyalinosis, Torg osteolysis syndrome, Snyder-Robinson syndrome, Thick skull syndrome, Winchester syndrome, Xylosylprotein 4-beta-galactosyltransferase (XGPT) deficiency
Neurologic	Acroosteolysis neurogenic, Brown-Sequard Syndrome, Fanconi-Albertini-Zellweger syndrome, Lactotroph adenoma, Osteopaenia — myopia — hearing loss — intellectual deficit — facial dysmorphism, Pelizaeus-Merzbacher disease, recessive, acute infantile, Rajab-Spranger syndrome, Snyder-Robinson syndrome, Spinocerebellar ataxia — dysmorphism, Shprintzen-Golberg craniosynostosis , Tuberous sclerosis, Werner syndrome, Wilson’s Disease
Nutritional/Metabolic	Anorexia nervosa, Calcium deficiency, Copper deficiency, Cystathionine beta-synthase deficiency, Dibasic aminoaciduria 2, Excessive Dieting, Fabry’s disease, Glycerol kinase deficiency, Homocystinuria, Hyperglycerolemia – infantile form, Haemochromatosis, Hypophosphatemic rickets, Infantile sialic acid storage disorder, Lysinuric protein intolerance, Menkes Disease, Methylmalonic acidemia, Oxalosis, Peroxisomal bifunctional enzyme deficiency, Prolidase deficiency, Protein deficiency, Underweight, Vitamin C deficiency/Scurvy
Obstetric/Gynecologic	Female athlete triad, Menopause, Ovarian insufficiency, Pregnancy
Oncologic	Adrenal adenoma, Adrenal incidentaloma, Adrenocortical carcinoma, Functioning pancreatic endocrine tumor, Leukemia, Lactotroph adenoma, Lymphoma, Multiple Myeloma
Opthalmologic	Eccentrochondrodysplasia, Osteopaenia — myopia — hearing loss — intellectual deficit — facial dysmorphism, Osteoporosis — macrocephaly — mental retardation — blindness, Osteoporosis-pseudoglioma syndrome, Osteochondrodysplatic dwarfism — deafness — retinitis pigmentosa, Osteoporosis — oculocutaneous — hypopigmentation syndrome, Spondylo-ocular syndrome, Schwartz-Jampel Syndrome, Winchester syndrome, Werner syndrome
Overdose / Toxicity	No underlying causes
Psychiatric	Depression
Pulmonary	Chronic obstructive pulmonary disease, Cystic Fibrosis
Renal / Electrolyte	Abderhalden-Kaufmann-Lignac syndrome, Chronic acidosis, Chronic hypophosphatemia, Chronic renal failure, Fanconi-ichthyosis-dysmorphism, Fanconi-Albertini-Zellweger syndrome, Kidney disease, Renal osteodystrophy, Short stature — hyperkaliemia — acidosis
Rheum / Immune / Allergy	Ankylosing spondylitis, Dyskeratosis Congenita, Rheumatoid disease, Sarcoidosis
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Dental	No underlying causes
Miscellaneous	Aging, Alcoholism, Athletes, Bonnet-Dechaume-Blanc syndrome, Davis syndrome, Idiopathic, Immobility, Lack of exercise, Marie-Bamberg syndrome, Mixed connective tissue disease, Orchidectomy, Postgastrectomy, Premature aging, Pseudoprogeria syndrome, Reflex sympathetic dystrophy syndrome, Zero gravity

Abderhalden-Kaufmann-Lignac syndrome Acromegaly[1] Acroosteolysis neurogenic Adrenal adenoma Adrenal incidentaloma Adrenocortical carcinoma Aging Albright’s hereditary osteodystrophy[2] Alcoholism[34] Alpha thalassemia Andropause[3] Ankylosing spondylitis Anorexia nervosa Anticonvulsant Aromatase deficiency Athletes Beta thalassemia Boyd-Stearns syndrome Brown-Sequard Syndrome[4] Calcium deficiency Celiac Disease Cholestasis Chromosome 1, deletion q21 q25 Chronic acidosis Chronic Hepatitis Chronic hypophosphatemia Chronic Liver Disease Chronic obstructive pulmonary disease Chronic renal failure[35] Copper deficiency[5] Crohn’s disease Cushing’s disease Cushing’s syndrome[6] Cyproterone[7][8] Cystathionine beta-synthase deficiency Cystic Fibrosis Depression[9] Dexamethasone Diabetes Mellitus Diamond-Blackfan anemia Dibasic aminoaciduria 2 Down Syndrome Dyskeratosis Congenital[10] Eccentrochondrodysplasia Ehlers-Danlos syndrome– progeroid form Ethanol Excessive Dieting Exemestane Fabry’s disease Fanconi-Albertini-Zellweger syndrome Fanconi-ichthyosis-dysmorphism Female athlete triad Flunisolide Fluticasone (aerosol) Functioning pancreatic endocrine tumor Galactorrhoea–Hyperprolactinaemia Generalized mastocytosis[11] Geroderma osteodysplastica[12] Glycerol kinase deficiency Glucocorticoids Gnathodiaphyseal dysplasia[13] Gonadal dysgenesis

Haemochromatosis Hajdu-Cheney syndrome[14] Hashimoto’s Thyroiditis Hemoglobin H disease Heparin Homocystinuria Hutchinson Gilford Syndrome[15] Hyper IgE syndrome / Job syndrome Hyperadrenalism Hyperglycerolemia – infantile form Hyperostosis corticalis deformans juvenilis Hyperparathyroidism Hyperthyroidism Hypertrichotic osteochondrodysplasia Hypogonadotropic hypogonadism — Syndactyly Hypophosphatemic rickets Hypothalamic amenorrhea[36] Hyperprolactinemia Hypopituitaryism Idiopathic Immobility Infantile sialic acid storage disorder Iridogoniodysgenesis and skeletal anomalies Isotretinoin Kaler-Garrity-Stern syndrome[16] Kallmann syndrome Klinefelter syndrome[17] Kidney disease Lack of exercise Lactotroph adenoma Larsen syndrome, recessive type[18] Leukemia Lobstein disease Lymphoma Lysinuric protein intolerance Maldigestion Marfan syndrome Marie-Bamberg syndrome Menkes Disease[19] Menopause Metaphyseal chondrodysplasia Spahr type Metaphyseal dysplasia Pyle type Methylmalonic acidemia Mixed connective tissue disease Morquio syndrome Multiple endocrine neoplasia type 1 Multiple Myeloma Nodulosis-arthropathy-osteolysis syndrome[20] Oncogenic osteomalacia Oophorectomy – bilateral Orchidectomy Osteochondrodysplatic dwarfism — deafness — retinitis pigmentosa[21] Osteogenesis imperfecta Osteoporosis — macrocephaly — mental retardation — blindness[22] Osteoporosis — oculocutaneous — hypopigmentation syndrome[23] Osteoporosis-pseudoglioma syndrome[24]

Otospondylomegaepiphyseal dysplasia Ovarian insufficiency due to FSH resistance Ovarian insufficiency, familial Paget’s disease of bone Pelizaeus-Merzbacher disease, recessive, acute infantile Pergolide Pena Shokeir syndrome Peroxisomal bifunctional enzyme deficiency Pointer syndrome[25] Postgastrectomy Prader-Willi syndrome Prednisolone[37] Prednisone Premature ovarian failure Pregnancy[26] Premature aging Primary biliary cirrhosis Primary hypoparathyroidism Prolidase deficiency Protein deficiency Pseudoprogeria syndrome Reflex sympathetic dystrophy syndrome Renal osteodystrophy Rheumatoid disease Sakati syndrome Sarcoidosis Schwartz-Jampel Syndrome Sickle cell anemia[27] Shprintzen-Golberg craniosynostosis Singleton-Merten syndrome[28] Snyder-Robinson syndrome[29] Spinocerebellar ataxia-dysmorphism Sponastrime dysplasia[30] Spondyloepimetaphyseal dysplasia with multiple dislocations Spondylometaphyseal dysplasia with dentinogenesis imperfecta Spondylo-ocular syndrome[31] Storm syndrome Sub clinical hypothyroidism Systemic infantile hyalinosis Thick skull syndrome Torg osteolysis syndrome[32] Tricho-hepato-enteric syndrome Tuberous sclerosis Turner’s syndrome Ulcerative colitis Underweight Urban rogers meyer syndrome Vitamin C deficiency / Scurvy Waldenstrom’s macroglobulinemia Werner syndrome White Phosphorus poisoning Wilson’s Disease Winchester syndrome Wolcott-Rallison syndrome[33] Wolman syndrome Xylosylprotein 4-beta-galactosyltransferase (XGPT) deficiency Zero gravity

​ ​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2], Cafer Zorkun, M.D., Ph.D. [3], Raviteja Guddeti, M.B.B.S.[4]

Osteoporosis must be differentiated from other diseases that cause a decrease in the bone mineral density (BMD), such as idiopathic transient osteoporosis of hip, osteomalacia, scurvy, osteogenesis imperfecta, multiple myeloma, homocystinuria, and hypermetabolic resorptive osteoporosis.

Osteoporosis must be differentiated from other diseases that cause a decrease in the bone mineral density (BMD), such as idiopathic transient osteoporosis of hip, osteomalacia, scurvy, osteogenesis imperfecta, multiple myeloma, homocystinuria, and hypermetabolic resorptive osteoporosis. The major similarities and differences among the diseases are discussed in the following table:

Diseases	History and Physical Examination					Imaging findings			Laboratory Findings				Other Findings
	Bone pain	Fatigue	Short stature	Scoliosis	Bone tenderness	BMD	Sub-chondral cortical loss	Bone fracture	Vitamin C	Ca	Vitamin D	ALKph
Osteoporosis	+	–	+	–	+	↓↓↓	–	+	↓	–	–	–
Idiopathic transient osteoporosis of hip	+	–	–	–	–	↓↓	+	–	–	–	–	↑	Mostly pregnant women Self-limiting
Osteomalacia	–	–	–	–	–	↓	–	+	–	↓	↓	–
Scurvy	+	+	–	–	–	–	–	+	–	–	–	–	Mucosal bleeding Bleeding gums
Osteogenesis imperfecta	–	–	+	+	–	↓	–	+	–	–	–	–	Tooth defect Hearing problems Blue sclera
Multiple myeloma	+	+	–	–	+	↓	–	+	–	–	–	↑	Bone lytic lesions
Homocystinuria	+	–	–	–	–	↓	–	+	–	–	–	–	Visual impairment Homocysteine in urine

• It was initially thought to be seen in women during the third trimester of pregnancy but it is seen also in middle-aged men.
• Acute hip pain is the main feature of the disease, usually self-limited and resolves after 6-8 months.
• Sometimes it may be explained as early or benign avascular necrosis (AVN).
• Subchondral cortical loss and diffuse osteopenia of the femoral head and neck are the pathognomonic features.
• Treatment includes joint protection, limited weight bearing, and NSAIDs.^[1]

• Osteomalacia is the inability to mineralize the newly formed bone matrix, caused by the deficiency of vitamin D in adults.

• It is due to low turn-over of bone in which osteoblasts are deficient.
• Diffuse bone pain, fatigue, and fractures are the most common symptoms.
• It can also progress to osteoporosis.^[2]

• Vitamin C deficiency causes defective collagen synthesis, leading to dysfunction of every collagen containing organ such as bones.
• New bone formation is disturbed and the old bone becomes brittle due to lack and poor quality of collagen.
• Treatment is vitamin C replacement.^[3]

• Osteogenesis imperfecta is mainly induced by defect in the synthesis of collagen type I along with improper osteoblasts functioning.
• Short stature, scoliosis, tooth defects, hearing defects, blue sclera, and propensity for fractures are the main clinical features of the disease.^[4]

• Multiple myeloma is a malignant proliferation of the plasma cells, mostly in bone marrow.
• It accounts for 40% of all bone tumors.
• Diffuse bone pain and tenderness are common.
• Radiologically, osteolytic lesions could be found in the bones.
• The prognosis is poor.
• Chemotherapy is the mainstay of treatment.^[5]

• Homocystinuria is an autosomal recessive disorder that affects the metabolism of the amino acid methionine.
• Clinical features include failure to thrive, visual and musculoskeletal problems.^[6]

​ ​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Osteoporosis is a major health problem involving 43.9% (43.4 million) of the male and female population in the United States. The disease incidence is increased by age. The most common involved age group is 80 years and older. White females and African-American males have the highest incidence among the other races. The incidence of lifetime osteoporotic fracture, as the most important outcome of osteoporosis, is approximately one out of every two women and also one in four men over the age of 50 worldwide. More than 1.5 million fractures occurred secondary to osteoporosis per year; among which are 300,000 hip fracture, 700,000 vertebral fracture, 250,000 wrist fracture, and more than 300,000 other bones fractures. Major epidemiological studies conducted in the US, estimated that 10.3% (10.2 million) of people older than 50 years are affected with osteoporosis. Osteoporosis affects about 75 million people in Europe, USA, and Japan.

• The incidence of osteoporosis is approximately 7,000 per 100,000 individuals worldwide.^[1]
• The incidence of lifetime osteoporotic fracture, as the most important outcome of osteoporosis, is approximately 50,000 per 100,000 for female and 25,000 per 100,000 over 50 male individuals worldwide. More than 1.5 million fractures occur secondary to osteoporosis per year, among which are 300,000 hip fracture, 700,000 vertebral fracture, 250,000 wrist fracture, and more than 300,000 other bones fractures.^[1]
• Osteoporosis is the main cause of 8.9 million fractures in a year, worldwide. Hence, it can be assumed that osteoporosis leads to one fracture in every 3 seconds.^[2]
• The estimated women population under the burden of osteoporosis influence is about 200 million, worldwide; two third of them are of age 90, two fifth of them with age 80, one fifth of them 70, and one tenth of them 60 years old.
• In women, the rates of fracture in forearm, humerus, hip, and spine are 80%, 75%, 70%, and 58%, respectively. However, women encounter the fractures 1.6 times more commonly than men, constituting a total of 61% of osteoporotic fractures.^[2]
• It is estimated that in 2050, the rate of hip fracture will increase by 310% and 240% in male and females, respectively, in contrast with 1990.^[3]
• When the lifetime risks of fractures in hip, forearm, and vertebrae is clinically interpreted, it comes out to be 40%, that is the same as cardiovascular events.^[4]
• It is assumed that large percentage (almost 80%) of individuals with high risk of fracture and already history of at least one osteoporotic fracture, are neither identified nor treated.^[5]
• International Osteoporosis Foundation (IOF) study, done in 11 countries, showed that the following factors lead to lack of osteoporosis diagnosis and management:
  • Denial of personal risk by postmenopausal women
  • Lack of dialogue about osteoporosis with their doctor
  • Restricted access to diagnosis and treatment before the first fracture.^[6]

• The prevalence of osteoporosis is 3,871 per 100,000 patients.

• osteoporosis affects about 75 million people in Europe, USA, and Japan.^[7]

• The prevalence of osteoporosis increase with age in both genders. The highest diagnosis of osteoporosis is found among people 80 years and older.
• 35% of women and 11% of men older than 80years are affected with osteoporosis. .^[8][9]

• Osteoporosis usually affects individuals of all races.
• 20% of white postmenopausal women, 10% of Hispanic women, and just 5% of African-American women are affected by osteoporosis (defined as T-score of less than -2.5).

• Females are more prone to develop osteoporosis than men.
• The lifetime risk of fractures is three times more in women than in men, but men are associated with higher mortality rates than that of women.

• WHO estimation of the osteoporosis population in Europe is 22 million females and 5.5 million males in 2010 (total of 27.5 million) which is going to rise about 23% until 2025 (total of 33.9 million).
• New fractures in the EU during 2010 was estimated at 3.5 million, including approximately 620,000 hip fractures, 520,000 vertebral fractures, 560,000 forearm fractures and 1,800,000 other fractures.
• The number of fractures in a year assumed to grow from 3.5 million in 2010 to 4.5 million in 2025, suggesting a 28% increase.
• 43,000 people have died in 2010 because of osteoporosis complications. It is assumed that osteoporotic fractures are the main reason of 26,300 life-year lost in Europe, in 2010.^[10]

• From 1987-1997, in a 10-year period, the rate of osteoporosis increased by 56%, among which 41% were women and 10.4% were men older than 50 years old.^[11]

• In Finland, hip fracture rate was found to be increased by 70% from 1992 to 2002, in a 10-year period.^[12]

• In Georgia, it is assumed that only one patient with hip fracture out of four seeks medical care.^[13]

• In Germany, a study of fracture rate showed that 45% of men and 31% of women between 25 to 74 years old experience fracture, while 42% of men and 40% of women between 65 to 74 years old had fractures due to osteoporosis.^[14]

• Hip fracture rate was increased by 7.6% from 1977 until 1992, in a five year period.^[15]

• More than half of the people with hip fracture are not hospitalized whereas more than 70% are not admitted for hip surgery.^[16]

• The prevalence of postmenopausal osteoporosis is 11.5%. It is assumed that among Romanian women older than 55 years old, one out of three is affected with osteoporosis or osteopenia.^[16]

• In Russia, 14 million people (about 10%) are affected with osteoporosis, while 20 million suffer from osteopenia.
• About 34 million people are at high risk for osteoporotic fracture.

• Generally, hip fracture rate increased by 40% from 1998 to 2005 during a seven year period.^[16]

• The incidence of hip fracture cases increased to 54% from 1998 to 2002 during a 14-year period.
• This increase was observed more in women (64%) than men (19%).^[17]

• Lifetime osteoporotic fractures are 46% in women and 22% in men.^[18]

• About 23% of women and 11% of men over 50 years of age are expected to have an osteoporotic fracture.
• Also, 15% of women and 8% of men have the risk of vertebral fractures.
• The total death rate resulting from hip fractures is the same as breast cancer deaths.^[19]

• About 7 million women (28% of all women) have bone mass loss and are at risk of osteoporosis.
• Most Ukrainians experience vitamin D insufficiency or deficiency.^[16]

• Half of women and one-fifth of men older than 50 years are predicted to have osteoporotic fracture.^[20]

• About one and a half million Canadians, mostly postmenopausal and elderly are suffering from osteoporosis.
• About 25% of women and 12.5% of men older than 50 years experience vertebral fractures.
• It is assumed that total amount of hip fractures are 30,000 annually which may quadruple by 2030. ^[21]

• About 44 million people older than 50 years old in the US are suffering from osteoporosis.
• More than half of them are over 50 years old. Remaining the current conditions and utilities, it is estimated that more than 61 million people in 2020 will be involved in osteoporosis. Women constitute 80% of the osteoporotic population.^[22]

• PTH analogs (teriparatide and abaloparatide) have more QALYs and are costly in contrast with zoledronate. Teriparatide and abaloparatide are $43,440 and $22,061 more costly than zoledronate.

• It is estimated that in a period of 60 years, from 1990 to 2050, Latin America is experiencing a 5 times increase in hip fracture, in men and women between 50 to 64 years of age. Surprisingly, it will be 8 times for age of more than 65 years.^[23]
• Regarding 655,648 hip fractures in 2050, it will directly cost about $13 billion.^[24]
• 23% to 30% of the patients with hip fracture will die in the first year after fracture, more in men compared to women.^[25]
• Vertebral fractures prevalence is 15% in women more than 50 years of age, in which 7% is among 50-60 years and 28% is among more than 80 years women.^[26]

• Half of the women, >65 year old, suffer from osteopenia and one fourth of them with osteoporosis. It is estimated to be 5.24 million osteopenic and 2.62 million osteoporotic women in 2050. The population of above 50 years old are encountering 90 hip fractures a day (34,000 per year). It will be more than 63,000 one in women and more than 13,000 in men, by 2050. Vertebral fracture rate in postmenopausal women is 16.2%. The total burden of both hip and vertebral osteoporotic fractures, including hospitalization costs, is more than $190 million per each year.^[27]

• One person in every 17 people, totally about 10 million people are suffering from osteoporosis. 37.5% of men and 21% of women would have osteoporotic fracture during life.^[28] One person in every 3 patients encountering hip fracture would have osteoporosis, however, one out of five will receive treatment.^[29] The total economic burden of osteoporotic fracture is assumed to be $6 million.^[30]

• In Chile, 46% of women of more than 50 years of age were osteopenic and 22% were osteoporotic, in 1985.

• In Mexico, 25% of people have a low bone mineral density (BMD), making them prone to hip fracture (8.5% males and 4% females). The whole economic burden of hip fracture in 2006 was $97 million.^[31]

• In Venezuela, 5.5% of women and 1.5% men of 50 years of age would have the hip fracture. For other sites of fractures, the percentages are 13.6% and 3.5% for women and men, respectively. It is assumed that 9.6 hip fracture a day in 1995, will grow to 67 fractures a day in 2030. After 70 years of age, only one out of ten people may have normal bone mineral density.^[32]

• Vitamin D deficiency is really prevalent in this region, despite the abundance of day hours sun there. The rate of death after osteoporotic fracture in the area is 2-3 times of Western societies. The major reason for the issue is lack of utilities, less than one DXA scan for 1 million people in Morocco.^[33]

• Among postmenopausal women 53.9% have osteopenia and 28.4 have osteoporosis.^[34]

• In 2010, the hip fracture rate was 50,000 and will become 62,000 in 2020. The hip fracture rate of Iran is 0.85% of worldwide and 12.4% of the Middle-East whole burden.^[35]

• Hip fractures are growing from 1008 per year in 2008 to four times of the original size in 2050.^[16]

• Surprisingly, the age and BMD measures in patients with hip fractures are different from other countries, they are younger and have osteopenia instead of being old and osteoporotic.^[36]

• The total cost of managing femoral fracture is $ 1.14 billion.^[37]

• From approximately 15,000 vertebral osteoporotic fractures per year, only one-fifth seeking medical services.^[16]

• It is assumed that 24,000 hip fracture in male and female above 50 years of age will become 36,000 in 2020.^[38]

• In 2050, more than half of the whole hip fractures of the world would be from Asia. The main reason will be improving the utilities and increasing the medical services availability. Currently, more than half of the population of China are living in rural area, managing fractures conservatively at home and not seeking any medical services. On the other hand, major facilities, like densitometers, will become more accessible for everyone.^[39]

• In China, 70 million cases of osteoporosis are leading to 678,000 hip fractures, annually.
• Men are more suffering from hip fracture than women.
• The holistic prevalence of osteoporosis in women is about two folds of men.
• The total economic burden of one hip fracture is about $3,603, which may be measured as $1.5 billion per year. It is assumed to grow to $12.5 billion in 2020 and more than $ 264.7 billion in 2050. Facility limitation is the major problem of China in managing osteoporosis; in 2008 the whole DXA scanners number for the whole 1.3 billion Chinese was 450. ^[40][41]

• In a 6 million population, hip fracture management is of 1% of whole hospital economic burden that is $17 million.^[42]

• From 2003 to 2013, the prevalence of osteoporosis increased from 26 million to 36 million. 52% of osteopenia and 29% of osteoporosis was recorded.^[43]

• In Japan, the postmenopausal women are suffering with vertebral osteoporosis (35%) more than hip osteoporosis (9.5%). Hip fractures are growing from 153,000 in 2010 to 238,000 in 2030.^{[44] [45]}

• During a 10-year period, the number of hip fractures raised to 300%. In the population above 75 years of age, hip fracture occurs in 4.3 per 1000 women and 2.97 per 1000 men.

• In Singapore, hip fracture in men and women has increased to 1.5 times and 5 times, respectively, in 1998 compared to 1960’s.^[46]

• The total economic burden of the osteoporosis is $7.4 billion, annually.
• There are 2.2 million cases of osteoporosis, while 42% of men and 51% of women are encountering bone density loss.
• The lifetime risk of women for fragility fractures is about twice the risk of men.^[47]

• The total economic burden of osteoporosis is more than $1.15 billion, annually.
• It is assumed to be increased by more than 30%, in 2020.
• Women encounter osteoporotic fractures more than men.
• 5% of all fractures occurred in hip^[48]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Risk factors for osteoporosis disease are of two types, including non-modifiable and modifiable (potentially) factors. Non-modifiable risk factors include age, sex, menopause, and family history. Modifiable (potentially) risk factors include smoking, alcohol consumption, immobility, glucocorticoid abuse, and use of proton pump inhibitor (PPI).

• Age > 50
• Menopause (lack of estrogen)
• Family history of fracture or osteoporosis
• History of at least two fractures^[1]
• Alcohol consumption
• Smoking (inhibits activity of osteoblasts)^[2]
• Insufficient physical activity (lack of bone remodeling)
• Glucocorticoids (steroid-induced osteoporosis)^[3]
• Proton pump inhibitors^[4]

• Low body mass index (BMI): being overweight protects against osteoporosis, either by increasing load or through the leptin hormone^[5]
• Low calcium and vitamin D intake: calcium and/or vitamin D deficiency from malnutrition
• Excess physical activity: constant damage to bone and amenorrhea in females
• Heavy metals: higher cadmium exposure results in osteomalacia (softening of the bone).^[6] Lead exposure also causes osteoporosis.
• Soft drinks: phosphoric acid may increase chances of osteoporosis^[7][8]
• Female athlete triad syndrome
• Barbiturates^[9]

Primary Disorders

• Juvenile rheumatoid arthritis
• Diabetes
• Osteogenesis imperfecta
• Hyperthyroidism
• Hyperparathyroidism
• Cushing’s syndrome
• Malabsorption syndromes
• Anorexia nervosa
• Kidney disease

Medications

• Anticonvulsants
• Corticosteroids
• Immunosuppressive agents

Behaviors

• Prolonged inactivity or immobility
• Inadequate nutrition (especially lack of calcium and vitamin D)
• Excessive exercise leading to amenorrhea
• Smoking
• Alcohol abuse

• Low body mass index (BMI)
• Aging
• Smoking
• Alcoholism
• Chronic corticosteroid use
• Rheumatoid arthritis
• Osteoporosis because of other diseases
• Family history of osteoporotic fracture (especially hip)
• Falling

• Environmental risk factors
  • Lack of assistive devices in bathrooms
  • Obstacles in the walking path
  • Loose throw rugs
  • Slippery conditions
  • Low level lighting
• Medical risk factors
  • Age
  • Medications causing sedation (narcotic analgesics, anticonvulsants, and psychotropics)
  • Anxiety and agitation
  • Orthostatic hypotension
  • Arrhythmias
  • Poor vision
  • Dehydration
  • Previous falls or fear of falling
  • Depression
  • Reduced problem solving or mental acuity and diminished cognitive skills
  • Vitamin D insufficiency [serum 25-hydroxyvitamin D (25(OH)D)<30 ng/ml (75 nmol/L)]
  • Urgent urinary incontinence
  • Malnutrition
• Neurological and musculoskeletal risk factors
  • Kyphosis
  • Reduced proprioception
  • Poor balance
  • Weak muscles/sarcopenia
  • Impaired transfer and mobility
  • Deconditioning

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

The risk of fracture due to osteoporosis is threatening, affecting one out of two postmenopausal women and one out of five men older than 50 years. The 10-year risk for any osteoporosis-related fractures in a 65-year-old white woman with no other risk factor is 9.3%. According to the guidelines of USPSTF, all women ≥ 65 years old along with women < 65 years old with a high risk of fracture are the target of screening for osteoporosis, but there is not any recommendation to screen men for the disease. Dual energy x-ray absorptiometry (DXA) of both hip and lumbar spine bones and quantitative ultrasonography of the calcaneus are two major methods suggested for screening osteoporosis.

The risk of fracture due to osteoporosis is threatening, affecting one out of two postmenopausal women and one out of five men older than 50 years. Osteoporosis usually affects the Caucasian population. The rate of osteoporosis is higher in the elderly. The 10-year risk for any osteoporosis-related fractures in a 65-year-old white woman with no other risk factor is 9.3%. The 10-year probability of hip fracture can be estimated by the FRAX tool based on the presence or absence of clinical risk factors in addition to the bone mineral density (BMD) at the femoral neck.

The US Preventive Services Task Force (USPSTF) divides the population into three groups, categorizing them on the basis of their need to be screened for osteoporosis. They include:

• Women of age ≥ 65 year, without any fracture history or pathological reason for osteoporosis
• Women of age <65 years, with 10-year fracture risk of not less than a 65-year-old white woman (who has not any other risk factor)
• Men with no history of osteoporosis

According to the guidelines of USPSTF, the first two groups (women) are the target of screening for osteoporosis. There is no recommendation to screen the third group (men) for the disease.^[1][2]

The USPSTF recommendations from 2018 included:

• “The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in women 65 years and older. (B recommendation)”
• “The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in postmenopausal women younger than 65 years at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool. (B recommendation) “”
• “The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis to prevent osteoporotic fractures in men. (I statement).”

Clinical prediction rules are available to guide the selection of women for screening.

• [ORAI https://www.physio-pedia.com/The_Osteoporosis_Risk_Assessment_Instrument_(ORAI)]
• FRAX has the best area under the ROC curve according the
• A previous study found that the Osteoporosis Risk Assessment Instrument (ORAI) is the most sensitive strategy.^[3]

Regarding the screening process for 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“.^[4]

The American College of Physicians recommended^[5]:

• “clinicians obtain dual-energy x-ray absorptiometry for men who are at increased risk for osteoporosis and are candidates for drug therapy”
  • “High-quality evidence shows that age, low body weight, physical inactivity, and weight loss are strong predictors of an increased risk for osteoporosis in men.”
  • “There is also moderate-quality evidence that previous fragility fracture, systemic corticosteroid therapy, androgen deprivation therapy, and spinal cord injury are predictors of an increased risk for osteoporosis in men. Cigarette smoking and low dietary intake of calcium predict low bone mass.”

UpToDate recommends^[6] recommends treatment if “prednisone >30 mg/day for >1 month”.

There are two major methods, that are suggested to be used for screening for osteoporosis:

• Dual energy x-ray absorptiometry (DXA) of both hip and lumbar spine bones
• Quantitative ultrasonography of the calcaneus

Advantages of ultrasonography over DXA scan:

Although quantitative ultrasonography has numerous advantages when compared to DXA but still current diagnostic and treatment criteria rely on DXA of the hip and lumbar spine. The advantages include:

• Lower cost
• More portable
• Lower ionizing radiation exposure

After an initial screening is done for bone mineral density (BMD), optimal intervals to repeat the tests include:

• 15 years for women with normal bone density or mild osteopenia: T-score of greater than −1.50
• 5 years for women with moderate osteopenia: T-score of −1.50 to −1.99
• 1 year for women with advanced osteopenia: T-score of −2.00 to −2.49 ^[7]

Organizations	Women	Men
National Osteoporosis Foundation (NOF) [8]	BMD testing for: All ≥ 65 years old Postmenopausal <65 years old, based on risk factor profile	BMD testing for: All men ≥70 years old Men aged 50-69 years old, based on fracture risk profile*
World Health Organization (WHO) [9]	Indirect records suggest screening women ≥65 years old, while no direct record suggests using BMD testing for holistic screening programs	–
American College of Physicians [5]	–	Clinicians should investigate older men for osteoporosis risk factors DXA is used to screen men with increased risk Men with increased risk may be the candidates for drug therapy for osteoporosis
American Congress of Obstetricians and Gynecologists (ACOG) [10]	BMD testing for: Age ≥65 years Postmenopausal <65 years old, with 1 or more risk factors	–

§ Fracture risk profiles are mentioned in the table below.^[11]

	Adults ≥ 40 years of age	Adults <40 years of age
High fracture risk	Prior osteoporotic fracture(s) Hip or spine bone mineral density T score ≤ -2.5, in men age ≥50 years and postmenopausal women FRAX 10-year risk of major osteoporotic fracture ≥ 20% FRAX 10-year risk of hip fracture ≥ 3%	Prior osteoporotic fracture(s)
Moderate fracture risk	FRAX 10-year risk of major osteoporotic fracture 10–19% FRAX 10-year risk of hip fracture >1% and <3%	Hip or spine bone mineral density Z score <-3 or Rapid bone loss (≥10% at the hip or spine over 1 year) and Continuing glucocorticoid treatment at ≥7.5 mg/day for ≥6 months
Low fracture risk	FRAX 10-year risk of major osteoporotic fracture <10% FRAX 10-year risk of hip fracture ≤1%	None of above risk factors other than glucocorticoid treatment

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