Osteoporosis is a disease of bone in which the amount of bone is decreased and the strength of trabecular bone is reduced, cortical bone becomes thin and bones are susceptible to fracture. It is defined according to the bone mineral density (BMD) as measured by Dual Energy X-ray Absorptiometry. A BMD of 2.5 standard deviations below the 20 year old person standard is considered osteoporosis.

Scope of problem
It is estimated that 10 million Americans have established osteoporosis and another 34 million have osteopenia, or low bone mass, which leads to osteoporosis. It is responsible for 1.5 millions fractures annually, mostly involving the lumbar vertebrae, hip, and wrist. About 50% of women and 25% of men are expected to have osteoporosis in their lifetime. The estimated national direct expenditures (hospitals and nursing homes) for osteoporotic and associated fractures was $17 billion in 2001.

Etiology
Estrogen deficiency following menopause causes a rapid reduction in BMD. This, plus the increased risk of falling associated with aging, leads to fractures of the wrist, spine and hip. Other hormone deficiency states can lead to osteoporosis, such as testosterone deficiency. Glucocorticoid or thyroxine excess states also lead to osteoporosis. Lastly, calcium and/or vitamin D deficiency from malnutrition increases the risk of osteoporosis.

List of disorders associated with osteoporosis:

Hypogonadal states - Turner syndrome, Klinefelter syndrome, anorexia nervosa, hypothalamic amenorrhea, hyperprolactinemia.
Endocrine disorders - Cushing's syndrome, hyperparathyroidism, thyreotoxicosis, insulin-dependent diabetes mellitus, acromegaly, adrenal insufficiency
Nutritional and gastrointestinal disorders - malnutrition, parenteral nutrition, malabsorption syndromes, gastrectomy, severe liver disease (especially biliary cirrhosis), pernicious anemia.
Rheumatologic disorders - rheumatoid arthritis, ankylosing spondylitis
Hematologic disorders/malignancy - multiple myeloma, lymphoma and leukemia, mastocytosis, hemophilia,thalassemia.
Inherited disorders - osteogenesis imperfecta, Marfan syndrome, hemochromatosis, hypophosphatasia, glycogen storage diseases, homocystinuria, Ehlers-Danlos syndrome, porphyria, Menkes' syndrome, epidermolysis bullosa.
Other disorders - immobilization, chronic obstructive pulmonary disease, pregnancy and lactation, scoliosis, multiple sclerosis, sarcoidosis, amyloidosis

Pathogenesis
The underlying mechanism in all cases of osteoporosis is an imbalance between bone resorption and bone formation. Either bone resorption is excessive, or bone formation is diminished. Bone matrix is manufactured by the osteoblast cells, whereas bone resorption is accomplished by osteoclast cells. Trabecular bone is the sponge-like bone in the center of long bones and vertabrae. Cortical bone is the hard outer shell of bones. Because osteoblasts and osteoclasts inhabit the surface of bones, trabecular bone is more active, more subject to bone turnover, to remodeling. Long before any overt fractures occur, the small spicules of trabecular bone break and are reformed in the process known as remodeling. Bone will grow and change shape in response to physical stress. The bony prominences and attachments in runners are different in shape and size than those in weightlifters. It is an accumulation of fractures in trabecular bone that are incompletely repaired that leads to the manifestation of osteoporosis. The common osteoporotic fracture sited, the wrist, the hip and the spine, have a relatively high trabecular bone to cortical bone ratio. These areas rely on trabecular bone for strength.

Low peak bone mass is important in the development of osteoporosis. Bone mass peaks in both men and women between the ages of 25 and 35, thereafter diminishing. Achieving a higher peak bone mass through exercise and proper nutrition during adolescence is important for the prevention of osteoporosis.

Bone remodeling is heavily influenced by nutritional and hormonal factors. Calcium and Vitamin D are nutrients required for normal bone growth. Parathyroid hormone regulates the mineral composition of bone, with higher levels causing resorption of calcium and bone. Glucocorticoid hormones cause osteoclast activity to increase, causing bone resorption. Calcitonin, estrogen and testosterone increase osteoblast activity, causing bone growth. The loss of estrogen following menopause causes a phase of rapid bone loss. Similarly, testosterone levels in men diminish with advancing age and are related to male osteoporosis.

Physical activity causes bone remodeling. People who remain physically active throughout life have a lower risk of osteoporosis. Conversely, people who are bedridden are at a significantly increased risk. Physical activity has its greatest impact during adolescence, affecting peak bone mass most. In adults, physical activity helps maintain bone mass, and can increase it by 1 or 2%.

Lastly, osteoporosis on its own would not be a significant disease, were it not for the falls which precipitate fractures. Age-related sarcopenia, or loss of muscle mass, loss of balance and dementia contribute greatly to the increased fracture risk in patients with osteoporosis. Physical fitness in later life is associated more with a decreased risk of falling than with an increased bone mineral density.

Risk Factors
Risk Factors for Osteoporosis Fracture

Nonmodifiable
Personal history of fracture as an adult
History of fracture in first-degree relative
Female sex
Advanced age
Caucasian race
Dementia
Potentially modifiable
Current cigarette smoking
Low body weight <58 kg (127 lb)
Estrogen deficiency
Early menopause (<45 years) or bilateral oophorectomy
Prolonged premenstrual amenorrhea (>1 year)
Low calcium intake
Alcoholism
Impaired eyesight despite adequate correction
Recurrent falls
Inadequate physical activity
Poor health/frailty

Natural History
Today, most cases of osteoporosis are diagnosed before symptoms develop. This is due to widespread screening for osteoporosis using the DEXA scan. With treatment, bone mineral density increases, and fracture risk decreases.

In the absence of treatment, overt osteoporosis is heralded by a fracture. Some fractures, like vertebral compression fractures or sacral insufficiency fractures, may not be apparent at first, appearing to patient and physician as a very bad back ache or completely without symptoms. Hip fractures and wrist fractures are more obvious.

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

An estimated 700,000 women have a first vertebral fracture each year. The lifetime risk of a clinically detected symptomatic vertebral fracture is about 15% in a 50-year-old white woman.

Distal radius fractures, usually of the Colles' type, are the third most common type of osteoporotic fractures. In the United States, the total annual number of Colles' fractures is about 250,000. The lifetime risk of sustaining a Colles' fracture is about 16% for white women. By the time women reach age 70, about 20% have had at least one wrist fracture.

Diagnosis
Dual Energy X-ray Absorptiometry is considered diagnostic for osteoporosis when bone mineral density (BMD) is under 2.5.

In order to differentiate between the possible causes of osteoporosis, blood tests and X-rays are usually done to rule out cancer with metastasis to the bone, multiple myeloma, Cushing's disease and the other causes mentioned above.

Treatment
Patients at risk for osteoporosis (e.g. steroid use) are generally treated with Vitamin D and calcium supplements. In renal disease, a different form of Vitamin D (D3) is used, as the kidney cannot adequately synthesise D3 from precursors.

In osteoporosis (or a very high risk), bisphosphonate drugs are prescribed. The most often prescribed bisphosphonate is alendronate (Fosamax®) 10 mg a day or 70 mg once a week.

Recently, teriparatide (Forsteo®, recombinant parathyroid hormone) has been shown to be effective in osteoporosis, either alone or together with alendronate.

Prognosis
Patients with osteoporosis are at a high risk for additional fractures (the best predictor of fracture is a previous fracture). Treatment can improve fracture risk considerably.

Fractures can lead to decreased mobility and an additional risk of deep venous thrombosis and/or pulmonary embolism. Vertebral fractures can lead to severe chronic pain of neurogenic origin, which can be hard to control.

Although osteoporosis patients have an increased mortality rate due to the complications of fracture, most patients die with the disease rather than of it.

Future directions
As more research takes place in the biological mechanisms of accellerated bone loss, new therapeutic agents are identified and introduced. Recent research seems to indicate that pharmacological inhibition of lipooxygenase 15 type 2 (see eicosanoid for some background) may produce new drugs to prevent and treat osteoporosis.