Osteoporosis

Osteoporosis is a disease of bone in which bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is changed. Osteoporotic bones are more susceptible to fracture. Osteoporosis is defined by the World Health Organization (WHO) as either a bone mineral density 2.5 standard deviations below peak bone mass (20-year-old person standard) as measured by DEXA or any fragility fracture. While treatment modalities are becoming available, prevention is still the most important way to reduce fracture. Due to its hormonal component, more women, particularly after menopause, suffer from osteoporosis than men.

Osteoporosis can be thought of as analogous to "sarcopenia", which is the age-related loss of skeletal muscle. The combination of sarcopenia and osteporosis results in the significant frailty often seen in the elderly population

Clinical picture
Osteoporotic fractures are those that occur under slight amount of stresses that would not normally lead to fractures in nonosteoporotic people. Typical fractures occur in the vertebral column, hip and wrist. Collapse of a vertebra ("compression fracture") can cause one or a combination of the following: acute onset of back pain; a hunched forward or bent stature; loss of height; limited mobility and possibly disability. Fractures of the long bones acutely impair mobility and may require surgery. Hip fracture, in particular, usually requires prompt surgery, as there are serious risks associated with a hip fracture, such as deep vein thrombosis and a pulmonary embolism.

While osteoporosis occurs in men and pre-menopausal women, the problem is overwhelmingly prevalent in postmenopausal women.

Risk factors
Risk factors for osteoporotic fracture can be split between modifiable and non-modifiable:
 * Nonmodifiable: history of fracture as an adult, family history of fracture, female sex, advanced age, European or Asian ancestry, and dementia
 * Potentially modifiable: prolonged intake of the prescription drug prednisone, tobacco smoking, intake of soft drinks (containing phosphoric acid), low body weight <58 kg (127 lb), estrogen deficiency, early menopause (<45 years) or bilateral oophorectomy, premature ovarian failure, prolonged premenstrual amenorrhea (>1 year), low calcium and vitamin D intake, alcoholism, impaired eyesight despite adequate correction, recurrent falls, inadequate physical activity (i.e. too little or also if done in excess), high risk of falls, poor health/frailty. Coeliac disease can lead those with an otherwise adequate calcium intake to develop osteoperosis due to the inability to absorb calcium.  Osteoporotic fracture may indeed be the event that leads to diagnosis that coeliac disease (which affects around one in a hundred people in the West ) has affected the patient for many years.

Diagnosis
Dual energy X-ray absorptiometry (DXA, formerly DEXA) is considered the gold standard for diagnosis of osteoporosis. Diagnosis is made when the bone mineral density is equal to or greater than 2.5 standard deviations below that of a young adult reference population. This is translated as a T-score. The World Health Organization has established diagnostic guidelines as T-score -1.0 or greater is "normal", T-score between -1.0 and -2.5 is "low bone mass" (or "osteopenia") and -2.5 or below as osteoporosis. A low trauma or osteoporotic fracture, defined as one that occurs as a result of a fall from a standing height, is also diagnostic of osteoporosis regardless of the T-score.

In order to differentiate between "primary" (post-menopausal, regardless of age, or senile - related to age) and "secondary" osteoporosis, blood tests and X-rays are usually done to rule out cancer with metastasis to the bone, multiple myeloma, Cushing's disease and other causes mentioned above.

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, Kallmann syndrome, anorexia nervosa, hypothalamic amenorrhea, hyperprolactinemia
 * Other endocrine disorders - Cushing's syndrome, hyperparathyroidism, thyrotoxicosis, insulin-dependent diabetes mellitus, acromegaly, adrenal insufficiency
 * Nutritional and gastrointestinal disorders - malnutrition, parenteral nutrition, malabsorption syndromes (e.g. coeliac disease), gastrectomy, severe liver disease (especially primary biliary cirrhosis)
 * 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.
 * Medication:
 * Steroid-induced osteoporosis (SIOP) due to use of glucocorticoids - analogous to Cushing's syndrome and involving mainly the axial skeleton
 * Barbiturates (due to accelerated metabolism of vitamin D) and some other antiepileptics
 * Thiazide (a class of diuretics)
 * Other disorders - immobilization, scoliosis

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 vertebrae. 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. Common osteoporotic fracture sites, the wrist, the hip and the spine, have a relatively high trabecular bone to cortical bone ratio. These areas rely on trabecular bone for strength.

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. In addition to estrogen, follicle-stimulating hormone (FSH) affects BMD. In mice, lower levels of FSH mean less resorption by osteoclasts.

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%. However, excessive exercise can lead to constant damages to the bones which can cause exhaustion of the structures as described above. There are numerous examples of marathon runners who developed severe osteoporosis later in life.

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.

Epidemiology
It is estimated that 1 in 3 women and 1 in 5 men over the age of 50 worldwide have osteoporosis. It is responsible for millions of fractures annually, mostly involving the lumbar vertebrae, hip, and wrist.

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. However, because symptoms are often overlooked or thought to be a normal part of getting older, it is believed that only about one-third of vertebral compression fractures are actually diagnosed.

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.

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 (1,25-dihydroxycholecalciferol or calcitriol which is the main biologically active form of vitamin D) is used, as the kidney cannot adequately generate calcitriol from calcidiol (25-hydroxycholecalciferol) which is the storage form of vitamin D.

In osteoporosis (or a very high risk), bisphosphonate drugs are prescribed. The most often prescribed bisphosphonates are presently sodium alendronate (Fosamax®) 10 mg a day or 70 mg once a week, risedronate (Actonel®) 5mg a day or 35mg once a week or and ibandronate (Boniva® once a month).

Other medicines prescribed for prevention of osteoporosis include raloxifene (Evista®), a selective estrogen receptor modulator (SERM). Estrogen replacement remains a good treatment for prevention of osteoporosis but, at this time, is not recommended unless there are other indications for its use as well.

Recently, teriparatide (Forteo®, recombinant parathyroid hormone 1-34) has been shown to be effective in osteoporosis. It is used mostly for patients who have already fractured, have particularly low BMD or several risk factors for fracture or cannot tolerate the oral bisphosphonates. It is given as a daily injection with the use of a pen-type injection device. Teriparatide is only licensed for treatment if bisphosphonates have failed or are contraindicated (however, this differs by country).

Oral Strontium ranelate (Protelos® - Servier) is the first in a new class of drugs called a Dual Action Bone Agents (DABA's), and has proven efficacy in the prevention of vertebral and non-vertebral fractures (including hip fracture). Strontium Ranelate works by stimulating the proliferation of osteoblast (bone building) cells, and inhibiting the proliferation of osteoclast (bone absorbing) cells. This means that strontium Ranelate increases BMD by forming new bone, rather than just preserving existing bone. In comparison to bisphosphonates which only act on one aspect of bone remodeling, strontium ranelate also preserves bone turnover, allowing the microarchitecture of the bone to be continuously repaired as it would in healthy bone. Strontium ranelate is taken as a 2g oral suspension daily, and is licenced for the treatment of osteoporosis to prevent vertebral and hip fracture (this may differ by country). Strontium ranelate has show significant efficacy at reducing both vertebral, and non-vertebral fractures in patients over the age of 80, who are the most at risk where osteoporosis is concerned. This is unique to strontium ranelate as bisphosphonates can only show efficacy in vertebral fracture reduction, not non-vertabral. Strontium ranelate has side effect benefits over the bisphosphonates, as it does not cause any form of upper GI side effect, which is the most common cause for medication withdrawal in osteoporosis.

Changes to lifestyle factors and diet are also recommended; the "at-risk" patient should include 1500mg of calcium daily either via dietary means (for instance, an 8 oz glass of milk contains approximately 300 mg of calcium) or via supplementation. The body will absorb only about 500 mg of calcium at one time and so intake should be spread throughout the day. However, the benefit of supplementation of calcium alone remains, to a degree, controversial since several nations with high calcium intakes through milk-products (e.g. the USA, Sweden) have some of the highest rates of osteoporosis worldwide. A few studies even suggested an adverse effect of calcium excess on bone density and blamed the milk industry for misleading customers. Some nutrionists assert that excess consumption of dairy products causes acification, which leeches calcium from the system, and argue that vegetables and nuts are a better source of calcium and that in fact milk products should be avoided. In any case, thirty minutes of weight-bearing exercise such as walking or jogging, three times a week, has been shown to increase bone mineral density, and reduce the risk of falls by strengthening the major muscle groups in the legs and back.

In a recent study that examined the relationship between calcium supplementation and clinical fracture risk in an elderly population, there was a significant decrease in fracture risk in patients that received calcium supplements versus those that received placebo. However, this benefit only applied to patients who were compliant to their treatment regimen.

Increasing vitamin D intake has been shown to reduce fractures up to twenty-five percent in older people, according to recent studies.

There is some evidence to suggest bone density benefits from taking the following supplements (in addition to calcium and vitamin D): boron, magnesium, zinc, copper, manganese, silicon, strontium, folic acid, and vitamins B6, C, and K.

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

Hip 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, as well as deformity. Though rare, multiple vertebral fractures can lead to such severe hunch back that the resulting pressure on internal organs can impair one's ability to breathe.

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