Osteoporosis Risk Factors
In 2010, the FDA approved denosumab (Prolia) for treatment of osteoporosis in postmenopausal women who are at high risk for fracture. It may also be considered for women who cannot tolerate or who have not been helped by other osteoporosis treatments. Denosumab is the first biologic drug approved for osteoporosis treatment and prevention of fractures. It is given in a doctor’s office as a twice-yearly injection.
In 2010, the FDA warned that long-term (more than 5 years) use of bisphosphonate drugs may increase the risk for thigh bone fracture.
Osteoporosis is a skeletal disease in which bones become brittle and prone to fracture. In other words, the bone loses density. Bone density is the amount of bone tissue (such as calcium and minerals) in a certain volume of bone. Osteoporosis is diagnosed when bone density has decreased to the point where the risk of fractures is high even without severe stress or injury to the bones.
The Function of Bones. The skeleton has a dual function:
The skeleton holds 99% of the body's calcium. The remaining 1% circulates in the blood and is essential for crucial bodily functions, ranging from muscle contraction to nerve function to blood clotting.
Bone Turnover: the Breakdown and Rebuilding of Bones. Bone tissue is constantly being broken down and reformed again. This turnover is necessary for growth, for repair of minor damage that occurs from everyday stress, and for the maintenance of a properly functioning body. Two essential cells are involved in this process:
Each year, about 10 - 30% of the adult skeleton is remodeled in this way. The balance of bone build-up (formation) and break down (resorption) is controlled by a complex mix of hormones and chemical factors. If bone resorption occurs at a greater rate than bone build up, your bone loses density and puts you at risk for osteoporosis.
Until a healthy adult is around age 40, the process of formation and resportion is a nearly perfectly coupled system, with one phase balancing the other. As a person ages, or in the presence of certain conditions, this system breaks down and the two processes become out of sync. Some individuals have a very high turnover rate of bone, some have a very gradual turnover, but the breakdown of bone eventually overtakes the build-up.
In women, estrogen loss after menopause is particularly associated with rapid resorption and loss of bone density. Postmenopausal women are therefore at highest risk for osteoporosis and subsequent fractures.
Primary osteoporosis is the most common type of osteoporosis. It can be age-related and associated with the postmenopausal decline in estrogen levels, or related to calcium and vitamin D insufficiency.
Secondary osteoporosis is osteoporosis caused by other conditions, such as hormonal imbalances, diseases, or medications (such as corticosteroids or anti-seizure drugs).
Because the patterns of reforming and resorbing bone often vary from patient to patient, doctors believe several different factors account for this problem. Important chemicals (estrogen, testosterone, parathyroid hormone, and vitamin D) and blood factors that affect cell growth are involved with this process. Changes in levels of any of these factors can play a role in the development of osteoporosis.
Although normally associated with women, sex hormones play a role in osteoporosis in both genders, most likely by controlling the development and activity of both osteoclasts (bone breakers) and osteoblasts (bone builders).
Women and Estrogen. A woman experiences a rapid decline in bone density after menopause, when her ovaries stop producing estrogen. Estrogen comes in several forms:
The ovaries produce most of the estrogen in the body, but it can also be formed in other tissues, such as the adrenal glands, body fat, skin, and muscle. After menopause, some amounts of estrogen continue to be manufactured in the adrenals and in peripheral body fat. Even though the adrenals and ovaries have stopped producing estrogens directly, they continue to be a source of the male hormone testosterone, which converts into estradiol.
Estrogen may have an impact on bone density in various ways, including slowing bone breakdown (resorption).
Men and Androgens and Estrogen. In men, the most important androgen (male hormone) is testosterone, which is produced in the testes. Other androgens are produced in the adrenal glands. Androgens are converted to estrogen in various parts of a man’s body, including bone.
Studies have suggested that the falling levels of estrogen as well as testosterone may contribute to bone loss in elderly men. Both hormones appeared to be integral to bone function in men.
Low levels of vitamin D and high levels of parathyroid hormone (PTH) are associated with bone density loss in women after menopause:
Genetic factors may play a role in determining bone density.
Corticosteroids. Oral corticosteroids (also called steroids or glucocorticoids) can reduce bone mass in both men and women. It is not clear whether inhaled steroids carry the same risks, but some studies indicate that they may cause bone loss when taken at higher doses for long periods of time. (Children on inhaled steroids may have temporary impaired growth, but they do not appear to be at risk for bone loss.)
Diuretics. Diuretics, which are used to treat high blood pressure, have different effects on osteoporosis, depending on the type. Loop diuretics, such as furosemide (Lasix), increase the kidneys’ excretion of calcium, which can lead to thinning bones. Thiazide diuretics, on the other hand, protect against bone loss, but this protective effect ends after use is discontinued.
Contraceptives. Hormonal contraceptives that use progestin without estrogen (such as Depo-Provera injection or other progestin-based contraceptives), can cause loss of bone density. For this reason, the Food and Drug Administration (FDA) recommends that Depo-Provera injections should not be used for longer than 2 years.
Other Medications. Anticonvulsant (anti-seizure) drugs increase the risk for bone loss (as does epilepsy itself). Other drugs that increase the risk for bone loss include the blood-thinning drug heparin, and hormonal drugs that suppress estrogen (such as gonadotropin-releasing hormone agonists and aromatase inhibitors). Proton pump inhibitors (PPIs), which are used to treat gastroesophageal reflux disease (heartburn), may also increase the risk for bone loss and fractures. These drugs include omeprazole (Prilosec), lansoprazole (Prevacid), and esomeprazole (Nexium).
Medical Conditions. Osteoporosis can be secondary to several other conditions, including alcoholism, diabetes, hyperthyroidism, chronic liver or kidney disease, Crohn's disease, celiac disease, scurvy, rheumatoid arthritis, leukemia, cirrhosis, gastrointestinal diseases, vitamin D deficiency, lymphoma, hyperparathyroidism, and rare genetic disorders such as Marfan and Ehlers-Danlos syndrome.
About 10 million adults in the United States have osteoporosis, and another 34 million have low bone mass that places them at risk for developing osteoporosis.
Seventy percent of people with osteoporosis are women. Men start with higher bone density and lose calcium at a slower rate than women, which is why their risk is lower. Nevertheless, older men are also at risk for osteoporosis.
As people age, their risks for osteoporosis increase. Aging causes bones to thin and weaken.
Although adults from all ethnic groups are susceptible to developing osteoporosis, Caucasian and Asian women and men face a comparatively greater risk.
Osteoporosis is more common in people who have a small, thin body frame and bone structure.
People whose parents had a history of fractures may be more likely to have fractures.
Women. Events associated with estrogen deficiencies are the primary risk factors for osteoporosis in women. These include:
Men. Low levels of testosterone increase osteoporosis risk. Certain types of medical conditions (hypogonadism) and treatments (prostate cancer androgen deprivation) can cause testosterone deficiency.
Dietary Factors. Diet plays an important role in preventing and speeding up bone loss in men and women. Calcium and vitamin D deficiencies are important factors in the risk for osteoporosis. Other dietary factors may also be harmful or protective for certain people.
Exercise. Lack of exercise and a sedentary lifestyle increases the risk for osteoporosis. Conversely, in competitive female athletes, excessive exercise may reduce estrogen levels, causing bone loss. (The eating disorder anorexia nervosa can have a similar effect.) People who are chairbound or bedbound due to medical infirmities and who do not bear weight on the bones are at risk for osteoporosis.
Lack of Sunlight. The photochemical effect of sunlight on the skin is a primary source for vitamin D. Bone formation peaks in the summer and bone breakdown increases in the winter. People who avoid sun exposure to prevent skin cancer may be at risk for vitamin D deficiency, particularly if they are elderly.
Smoking. Women who smoke, particularly after menopause, have a significantly greater chance of spine and hip fractures than those who don't smoke. Men who smoke also have lower bone density.
Alcohol. Excessive consumption of alcoholic beverages can increase the risk for bone loss.
The maximum density that bones achieve during the growing years is a major factor in whether a person goes on to develop osteoporosis. People, usually women, who never develop adequate peak bone mass in early life are at high risk for osteoporosis later on. Children at risk for low peak bone mass include those who are:
Although to a large extent genetics predict bone health, exercise and good nutrition during the first three decades of life (when peak bone mass is reached) are still excellent safeguards against osteoporosis (and countless other health problems).
Bone density loss from osteoporosis is a major cause of disability and death in the elderly, mostly due to subsequent fractures. The lifetime risk of spinal fracture in women is about one in three, and for hip fracture is one in six. Women at highest risk for fractures are those with low bone density plus a history of fractures, particularly low-trauma fractures.
Osteoporosis causes more than 1.5 million fractures annually. About 50% of women and 25% of men over age 50 will suffer an osteoporosis-related fracture during their lifetime. Spinal vertebreal fractures are the most common type of osteoporosis-related fracture, followed by hip fractures, wrist fractures, and other types of broken bones. About 80% of these fractures occur after relatively minor falls or accidents.
Risk Factors for Fracture and Falling. In addition to low bone density, falling is the primary risk factor for fractures. Additional risk factors for fracture are those that increase the risk for falling. They include:
Hip fractures can increase the risk of death in both men and women. Complications of hip fractures include hospital-acquired infections and blood clots in the lungs.
Many people confuse osteoporosis with arthritis and mistakenly believe it is safe to wait for symptoms such as swelling and joint pain to occur before seeing a doctor. However, arthritis is entirely different from osteoporosis. Osteoporosis is quite advanced before symptoms appear.
All too often, osteoporosis becomes apparent in dramatic fashion: A fracture of a vertebra (backbone), hip, forearm, or any bony site if sufficient bone mass is lost. These fractures frequently occur after apparently minor trauma, such as bending over, lifting, jumping, or falling from the standing position.
Pain, disfigurement, and debilitation are common in the latter stages of the disease. Early spinal compression fractures may go undetected for a long time, but after a large percentage of calcium has been lost, the vertebrae in the spine start to collapse, gradually causing a stooped posture called kyphosis, or a "dowager’s hump." Although this is usually painless, patients may lose as much as 6 inches in height.
Because osteoporosis can occur with few symptoms, testing is important. Bone density testing is recommended for:
Risk factors that may indicate a need for bone mineral density testing include:
Central DXA. The standard technique for determining bone density is a form of bone densitometry called dual-energy x-ray absorptiometry (DXA). DXA is simple and painless and takes 2 - 4 minutes. The machine measures bone density by detecting the extent to which bones absorb photons that are generated by very low-level x-rays. (Photons are atomic particles with no charge.) Measurements of bone mineral density are generally given as the average concentrations of calcium in areas that are scanned.
Central DXA measures the bone mineral density at the hip, upper thigh bone (femoral neck), and spine.
Other Tests. Other tests may be used, but they are not usually as accurate as DXA. They include ultrasound techniques, DXA of the wrist, heels, fingers, or leg (peripheral DXA) and quantitative computed tomography (QCT) scan.
Screening tests using these technologies are sometimes given at health fairs or other non-medical settings. These screening tests typically measure peripheral bone density in the heels, fingers, or leg bones. The results of these tests may vary from DXA measurements of spine and hip. While these peripheral tests may help indicate who requires further BMD testing, a central DXA test is required to diagnose osteoporosis and to monitor treatment response.
Osteoporosis is diagnosed when bone density has decreased to the point where fractures will happen with mild stress, the so-called fracture threshold. This is determined by measuring bone density and comparing the results with the norm, which is defined as the average bone mineral density in the hipbones of a healthy 30-year-old adult.
The doctor then uses this comparison to determine the standard deviation (SD) from this norm. Standard deviation results are given as Z and T scores:
Results of T-scores indicate:
The lower the T-score, the lower the bone density, and the greater the risk for fracture. In general, doctors recommend beginning medication when T-scores are -2.5 or below. Patients who have other risk factors may need to begin medication when they have osteopenia (scores between -1 and -2.5). Osteopenia is considered a precursor to osteoporosis.
In certain cases, your doctor may recommend that you have a blood test to measure your vitamin D levels. A standard test measures 25-hydroxyvitamin D, also called 25(OH)D. Depending on the results, your doctor may recommend you take vitamin D supplements.
Healthy lifestyle habits, including adequate intake of calcium and vitamin D, are important for preventing osteoporosis and are also a useful accompaniment to medical treatment.
A combination of calcium and vitamin D can reduce the risk of osteoporosis. (For strong bones, people need enough of both calcium and vitamin D.) The National Osteoporosis Foundation (NOF) recommends:
Dietary Sources. Good dietary sources of calcium include:
Certain types of foods can interfere with calcium absorption. These include foods high in oxalate (such as spinach and beet greens) or phytate (peas, pinto beans, navy beans, wheat bran). Diets high in animal protein, sodium, or caffeine may also interfere with calcium absorption.
Dietary sources of vitamin D include:
However, many Americans do not get enough vitamin D solely from diet or exposure to sunlight.
Supplements. Adults who consume adequate amounts of calcium in their diets may not need to take a calcium supplement. But they may require vitamin D supplements, particularly if they do not get enough exposure to sunlight. Vitamin D is made in the skin using energy from the ultraviolet rays in sunlight. Because sun exposure increases the risk for skin cancer and premature skin aging, many Americans restrict their sunlight exposure. People's vitamin D levels decline as they age.
Calcium and vitamin D supplements can be taken as separate supplements or as a combination supplement. If separate preparations are used, they do not need to be taken at the same time.
Both calcium and vitamin D supplements may increase the risks for kidney stones. If you have a history of kidney stones, discuss with your doctor whether these supplements are appropriate for you.
Calcium supplements can also have other side effects and drug interactions:
Exercise is very important for slowing the progression of osteoporosis. Although mild exercise does not protect bones, moderate exercise (more than 3 days a week for more than a total of 90 minutes a week) reduces the risk for osteoporosis and fracture in both older men and women. Exercise should be regular and life-long. Before beginning any strenuous exercise program, older patients or those who have serious medical conditions should talk to their doctors.
Specific exercises may be better than others:
Other lifestyle changes that can help prevent osteoporosis include:
An important component in reducing the risk for fractures is preventing falls. Risk factors for falling include:
Recommendations for preventing falls or fractures from falls in elderly people include:
Two types of drugs are used to prevent and treat osteoporosis:
Both types of drugs are effective in preventing bone loss and fractures, although they may cause different types of side effects.
Bisphosphonates are the primary drugs for preventing and treating osteoporosis. They can help reduce the risk of both spinal and hip fractures, including among patients with prior bone breaks.
Studies indicate that these drugs are effective and safe for up to 5 years. Eventually, however, bone loss continues with bisphosphonates. This may be due to the fact that bone breakdown is one of two phases in a continuous process of rebuilding bone. Over time, blocking resorption interrupts this process and impairs the second half of the process -- bone formation.
Candidates. Clinical guidelines recommend that the following people should take or consider taking bisphosphonates:
Brands. Bisphosphonates for osteoporosis prevention and treatment are available in different forms:
Side Effects. The most distressing side effects of bisphosphonates are gastrointestinal problems, particularly stomach cramps and heartburn. These symptoms are very common and occur in nearly half of all patients. Other side effects may include irritation of the esophagus (the tube that connects the mouth to the stomach) and ulcers in the esophagus or stomach. Some patients may have muscle and joint pain. To avoid stomach problems, doctors recommend:
Other Concerns. In 2010, the FDA warned that bisphosphonates may increase the risk for atypical thigh bone (femoral) fractures if used long term (more than five years). The FDA recommends that doctors consider periodically reevaluating patients who have been on bisphosphanates for longer than five years. Patients should inform their doctors if they experience any new thigh or groin pain. (A femoral fracture is usually preceded by several months of dull, aching pain in the thigh or groin area.) Do not stop taking your medication unless your doctor tells you to do so.
Osteonecrosis (bone death) of the jaw is a rare side effect that has occurred mainly in patients who received intravenous bisphosphonates for cancer treatment (not osteoporosis). Many of these patients had major dental procedures before developing osteonecrosis. However, this bone decay condition has also been reported in some patients who have taken bisphosphonates by mouth (mainly alendronate). Symptoms may include jaw pain or swelling, gum infections, and poor healing of the gums. Talk to your doctor or dentist if you experience any jaw or gum discomfort while taking a bisphosphonate drug.
There have also been concerns raised that bisphosphonates may increase the risk for atrial fibrillation, a heart rhythm disorder common in elderly patients. The FDA is monitoring reports of atrial fibrillation among patients who use bisphosphonates but at this time does not recommend any changes to prescribing practices. To date, the FDA has not identified a link between these drugs and increased risk of atrial fibrillation.
Denosumab (Prolia) is a new drug approved for treatment of osteoporosis in postmenopausal women who are at high risk for fracture. Denosumab is the first “biological therapy” drug approved for osteoporosis. It is considered an antiresorptive drug, but it works in a different way than bisphosphonates. It is a monoclonal antibody that works by targeting RANKL, a chemical factor involved with bone resorption.
Denosumab slows down the bone-breakdown process. However, because it also slows down the bone build-up and remodeling process, it is unclear what its longterm effects may be. Possible concerns are that denosumab may slow the healing time for broken bones or cause unusual fractures. For now, denosumab is recommended for women who cannot tolerate or who have not been helped by other osteoporosis treatments.
Denosumab is given as an injection in a doctor’s office twice a year (once every six months). Common side effects include back pain, pain in the arms and legs, high cholesterol levels, muscle pain, and bladder infection. Denosumab can lower calcium levels and should not be taken by women who have low blood calcium levels (hypocalcemia) until this condition is corrected.
Because denosumab is a biologic drug, it can affect or weaken the immune system and may increase the risk for serious infections. Other potential adverse effects include inflammation of the skin (dermatitis, rash, eczema) and inflammation of the inner lining of the heart (endocarditis). Denosumab may increase the risk of jaw bone problems such as osteonecrosis.
Raloxifene (Evista) belongs to a class of drugs called selective estrogen-receptor modulators (SERMs). These drugs are similar, but not identical, to estrogen. Raloxifene provides the bone benefits of estrogen without increasing the risks for estrogen-related breast and uterine cancers.
While there are many SERM drugs, raloxifene is the only one approved for both treatment and prevention of osteoporosis in postmenopausal women. Studies indicate that raloxifene can stop the thinning of bone and help build better quality and stronger bone. Raloxifene is recommended for postmenopausal women with low bone mass or younger postmenopausal women with osteoporosis. It can help prevent bone loss and reduce the risk of vertebral (spine) fractures. It is less clear how effective it is for preventing other types of fractures.
Side Effects. Raloxifene increases the risk for blood clots in the veins. Because of this side effect, raloxifene also increases the risk for stroke (but not other types of heart disease). These side effects, though rare, are very serious. Women should not take this drug if they have a history of blood clots, or if they have certain risk factors for stroke and heart disease. More common mild side effects include hot flashes and leg cramps.
Teriparatide (Forteo), an injectable drug made from selected amino acids found in parathyroid hormone, may help reduce the risks for spinal and non-spinal fractures. Although high persistent levels of parathyroid hormone (PTH) can cause osteoporosis, daily injections of low doses of this hormone actually stimulate bone production and increase bone mineral density. Teriparatide is usually recommended for patients with osteoporosis who are at high risk of fracture.
Side effects of PTH are generally mild and include nausea, dizziness, and leg cramps. No significant complications have been reported to date.
Early animal studies reported bone tumors in mice that were given parathyroid long-term. Such effects have not been observed in humans to date. However, people with Paget disease, (a disorder in which bone thickens but also weakens), should not take parathyroid hormone, because they are at higher than normal risk for bone tumors.
Produced by the thyroid gland, natural calcitonin regulates calcium levels by inhibiting the osteoclastic activity, the breakdown of bone. The drug version is derived from salmon and is available as a nasal spray (Miacalcin) and an injected form (Calcimar). Calcitonin is not used to prevent osteoporosis. It treats osteoporosis. It may be effective for spinal protection (but not hip) in both men and women. Calcitonin may be an alternative for patients who cannot take a bisphosphonate or SERM. It also appears to help relieve bone pain associated with established osteoporosis and fracture.
Side Effects. Side effects include headache, dizziness, anorexia, diarrhea, skin rashes, and edema (swelling). The most common adverse effect experienced with the injection is nausea, with or without vomiting. This occurs less often with the nasal spray. The nasal spray may cause nosebleeds, sinusitis, and inflammation of the membranes in the nose. Also, many people who take calcitonin develop resistance or allergic reactions after long-term use.
Hormone replacement therapy (HRT) was formerly used to prevent osteoporosis, but is rarely used for this purpose today. Studies have shown that estrogen increases the risk for breast cancer, blood clots, strokes, and heart attacks. For this reason, women need to balance the benefits that HRT has on bone-loss protection, with the risks it carries for other serious health conditions. The FDA recommends that women first try other medications for prevention of osteoporosis.
[For more information on HRT, see In-Depth Report #40: Menopause.]
New SERMs. Bazedoxifene (Viviant) and lasofoxifene (Fablyn) are two new selective estrogen receptor modulators (SERMs) that are currently being considered for approval by the FDA. The FDA is weighing the potential benefits of these drugs against their risks, which include stroke. If approved, the FDA may limit these drugs to certain groups of women, such as those at significantly high risk for fractures.
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Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.