Osteoporosis overview

# Overview
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.

# Historical Perspective
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.

# Classification
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).

# Pathophysiology
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.

# Causes
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.

# Differentiating Osteoporosis from other Diseases
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.

# Epidemiology and Demographics
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
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).

# Screening
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.

# Natural History, Complications and Prognosis
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.

# Diagnosis

## History and symptoms
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.

## Physical examination
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.

## Laboratory findings
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.

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

## X-ray
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.

## CT scan
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 (CT). The only tests that are possible in vivo are hrCT and vQCT.

## MRI
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 m and slice thickness starts at 300 m; measuring trabecular bones precisely.

## Echocardiography/Ultrasound
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.

## Other imaging findings
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.

## Other diagnostic studies
There are no additional diagnostic findings for osteoporosis.

# Treatment

## Medical therapy

### Life style modification
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.

### Pharmacotherapy
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
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.

## Primary Prevention
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.

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

## Cost-Effectiveness of Therapy
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.

## Future or Investigational Therapies
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.