Introduction
Background
Osteoporosis is a systemic skeletal disorder characterized by decreased bone mass and deterioration of bony microarchitecture. The result is fragile bones and an increased risk of fractures, even after minimal trauma. Osteoporosis is a chronic condition of multifactorial etiology and is usually clinically silent until a fracture occurs. Osteoporosis is a significant health problem in the United States and around the world.
Pathophysiology
Osteoporosis results from hereditary and environmental factors that affect both bone mass and bone quality. Traditionally, osteoporosis was described as type I (postmenopausal) or type II (senile). Postmenopausal osteoporosis (PMO) is primarily due to estrogen deficiency; senile osteoporosis is primarily due to an aging skeleton and calcium deficiency. However, it is increasingly recognized that multiple pathogenetic mechanisms interact in the development of the osteoporotic state, regardless of age.
Cortical and trabecular (cancellous) bone differ in architecture but are similar in molecular composition. Bone consists of cells and an extracellular matrix with mineralized and nonmineralized components. The composition and architecture of the extracellular matrix is what imparts mechanical properties to bone. Bone strength is determined by collagenous proteins (tensile strength) and mineralized osteoid (compressive strength).1 The greater the concentration of calcium, the greater the compressive strength.
Adult bone undergoes constant remodeling to maintain bone strength. Osteocytes, which are terminally differentiated osteoblasts embedded in mineralized bone, direct the timing and location of remodeling. Osteoblasts not only secrete and mineralize osteoid but also appear to control the bone resorption carried out by osteoclasts; thus, bone formation and resorption are coupled. Osteoclasts require weeks to resorb bone, whereas osteoblasts need months to produce new bone. Therefore, any process that increases the rate of bone remodeling results in net bone loss over time.2 Furthermore, in periods of rapid remodeling (eg, after menopause), bone is at an increased risk for fracture because the newly produced bone is less densely mineralized, the resorption sites are temporarily unfilled, and the isomerization and maturation of collagen is impaired.3
Molecular biologists have begun to elucidate the mechanisms of bone remodeling. For example, it is now understood that the receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK)/osteoprotegerin (OPG) system is the final common pathway for bone resorption. Osteoblasts and activated T cells in the bone marrow produce the RANKL cytokine. RANKL binds to the RANK receptor expressed by osteoclasts and osteoclast precursors to promote osteoclast differentiation. Osteoprotegerin is a soluble decoy receptor that inhibits RANK-RANKL by binding and sequestering RANKL.
Bone mass peaks by the third decade of life and slowly decreases afterward. The failure to attain optimal bone strength by this point is one factor that contributes to osteoporosis. Therefore, nutrition and physical activity are important during growth and development. Nevertheless, hereditary factors play the principal role in determining an individual’s peak bone strength. In fact, genetics account for up to 80% of the variance in peak bone mass between individuals.4
Estrogen deficiency not only accelerates bone loss in postmenopausal women but also plays a role in bone loss in men. Estrogen deficiency can lead to excessive bone resorption accompanied by inadequate bone formation. Osteoblasts, osteocytes, and osteoclasts all express estrogen receptors. In addition, estrogen affects bones indirectly through cytokines and local growth factors. The estrogen-replete state may enhance osteoclast apoptosis via increased production of transforming growth factor (TGF)–beta. In the absence of estrogen, T cells promote osteoclast recruitment, differentiation, and prolonged survival via interleukin [IL]–1, IL-6, and tumor necrosis factor (TNF)–alpha. T cells also inhibit osteoblast differentiation and activity and cause premature apoptosis of osteoblasts through cytokines such as IL-7. Finally, estrogen deficiency sensitizes bone to the effects of parathyroid hormone (PTH).
Calcium, vitamin D, and parathyroid hormone help maintain bone homeostasis. Insufficient dietary calcium or impaired intestinal absorption of calcium due to aging or disease can lead to secondary hyperparathyroidism. Parathyroid hormone is secreted in response to low serum calcium levels. Parathyroid hormone increases calcium resorption from bone, decreases renal calcium excretion, and increases renal production of 1,25-dihydroxyvitamin D (1,25[OH]2 D). It is this active hormonal form of vitamin D that optimizes calcium and phosphorous absorption from the gut, inhibits parathyroid hormone synthesis, and plays a minor role in bone resorption.
Vitamin D deficiency can result in secondary hyperparathyroidism via decreased intestinal calcium absorption. Interestingly, the effects of parathyroid hormone and 1,25[OH]2 D on bone are mediated via binding to osteoblasts and stimulating the RANKL/RANK pathway. Osteoclasts do not have receptors for parathyroid hormone or 1,25[OH]2 D.1
Endocrinologic conditions or medications that lead to bone loss (eg, glucocorticoids) can cause osteoporosis. Corticosteroids inhibit osteoblast function and enhance osteoblast apoptosis.5 Polymorphisms of IL-1, IL-6 and TNF-alpha, as well as their receptors, have been found to influence bone mass. Other factors implicated in the pathogenesis of osteoporosis include polymorphisms in the vitamin D receptor; alterations in insulin-like growth factor-1, bone morphogenic protein, prostaglandin E2, nitrous oxide, and leukotrienes; collagen abnormalities; and leptin-related adrenergic signaling.2
Osteoporotic fractures represent the clinical significance of these derangements in bone. Fractures occur when bones fall under excess stress. Nearly all hip fractures are related to falls.6 The frequency and direction of falls can influence the likelihood and severity of fractures. The risk of falling may be amplified by neuromuscular impairment due to vitamin D deficiency with secondary hyperparathyroidism or corticosteroids. Vertebral bodies are composed primarily of cancellous bone with interconnected horizontal and vertical trabeculae. Osteoporosis not only reduces bone mass in vertebrae but also decreases interconnectivity in their internal scaffolding.1 Therefore, minor loads can lead to vertebral compression fractures.
Frequency
United States
Approximately 10 million people in the United States have osteoporosis. An additional 33.6 million people have low bone density of the hip and are at risk for osteoporosis.7
International
Osteoporosis is estimated to affect over 200 million people worldwide.8 An estimated 75 million people in Europe, the United States, and Japan have osteoporosis.9
One in 3 women older than 50 years will eventually experience osteoporotic fractures, as will 1 in 5 men.10 By 2050, the worldwide incidence of hip fracture is projected to increase by 240% in women and 310% in men.11
Mortality/Morbidity
Osteoporosis is the most common human bone disease. In 2005, over 2 million osteoporosis-related fractures occurred in the United States.12 Hip and vertebral fractures, in particular, are associated with increased morbidity and mortality.
Hip fractures
* Hip fractures increase the one-year risk of death by 10-20%.13,14
* Patients with hip fractures incur decreased independence and a diminished quality of life. Only one third of patients return to their prefracture level of function.15
* Among women who sustain a hip fracture, 50% spend time in a nursing home while recovering. In addition, 1 in 5 patients with hip fractures requires long-term nursing home care.7
* Persons with a hip fracture are twice as likely to experience another fracture as persons without fractures.16
Vertebral fractures
* Vertebral fractures increase the 5-year risk of mortality by 15%.17
* Only one third of people with radiographic vertebral fractures are diagnosed clinically.18
* Symptoms of vertebral fracture may include back pain, height loss, and disabling kyphosis.
* Compression deformities can lead to restrictive lung disease, abdominal pain, and early satiety.
* One in 5 postmenopausal women with a new vertebral fracture incurs another vertebral fracture within one year.19
Race
Whites (especially of northern European descent) and Asians are at an increased risk; however, osteoporosis can occur in persons of all races and ethnicities.
Sex
* Overall, osteoporosis has a female-to-male ratio of 4:1.7
* Eighty percent of hip fractures occur in women.20
Age
* The frequency of postmenopausal osteoporosis is highest in women aged 50-70 years.
* Senile osteoporosis is most common in persons aged 70 years or older.
* Secondary osteoporosis can occur in persons of any age.
* Ninety percent of hip fractures occur in persons aged 50 years or older.20
Clinical
History
Osteoporosis is typically asymptomatic until a fracture occurs. The history should focus on a thorough review of risk factors, which include the following:
* Age, sex, and race
* Family history of osteoporosis, particularly maternal history of fractures
* Reproductive factors, especially regarding early menopause and estrogen replacement therapy
* Lifestyle factors associated with decreased bone density
o Smoking
o Alcohol consumption
o Low levels of physical activity
o Strenuous exercise (such as occurs in marathon runners) that results in amenorrhea
* Calcium and vitamin D intake
* History of low-trauma "fragility" fracture in patients aged 40 years or older (A fragility fracture is defined as a fracture due to trauma that would not normally cause fracture [a force equal to or less than that resulting from a fall from standing height].)
* Signs of vertebral fracture: Vertebral fracture may be asymptomatic. Patients with vertebral fractures may note progressive kyphosis with loss of height. Some may report acute back pain after bending, lifting, or coughing.
o The pain is located in the midthoracic to lower thoracic or upper lumbar spine, where most vertebral fractures occur.
o The pain is described variably as sharp, nagging, or dull; movement may exacerbate pain. In some cases, pain radiates to the abdomen.
o Acute pain usually resolves after 4-6 weeks. In the setting of multiple fractures with severe kyphosis, the pain may become chronic.
* Coexisting medical conditions associated with bone loss (see Causes)
* Medications associated with bone loss (see Causes)
* Risk factors for falls in older patients
o Poor balance
o Orthostatic hypotension
o Weakness of the lower extremity muscles, deconditioning
o Use of medications with sedative effects
o Poor vision or hearing
o Cognitive impairment
Physical
Patients with suspected osteoporosis should undergo a comprehensive medical examination. Areas of concern include the following:
* Low body weight (body mass index <19 kg/m2)
* Signs that might indicate existing osteoporosis
o Kyphosis or dowager hump
o Point tenderness over a vertebrae or other suspected fracture site
* Signs that might indicate a secondary cause of osteoporosis (see Causes)
* Signs in older patients that may indicate increased fall risk
o Difficulty with balance or gait
o Orthostatic hypotension
o Lower-extremity weakness
o Poor vision or hearing
o Cognitive impairment
Causes
Primary causes
* Estrogen deficiency
* Changes associated with aging
Secondary causes - Up to one third of postmenopausal women, as well as many men and premenopausal women, have a coexisting cause of bone loss.21,22
Risk factors for secondary osteoporosis
* Endocrine disorders -Hyperparathyroidism, hypogonadism, hyperthyroidism, diabetes mellitus, Cushing disease, prolactinoma, acromegaly, adrenal insufficiency
* Gastrointestinal/nutritional conditions -Inflammatory bowel disease, celiac disease, malnutrition, history of gastric bypass surgery, chronic liver disease, anorexia nervosa, vitamin D or calcium deficiency
* Renal disease - Chronic kidney disease, idiopathic hypercalciuria
* Rheumatologic diseases -Rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus
* Hematologic disease -Multiple myeloma, thalassemia, leukemia, lymphoma, hemophilia, sickle cell disease, systemic mastocytosis
* Genetic disorders -Cystic fibrosis, osteogenesis imperfecta, homocystinuria, Ehlers-Danlos syndrome, Marfan syndrome, hemochromatosis, hypophosphatasia
* Other - Porphyria, sarcoid, immobilization, pregnancy/lactation, chronic obstructive pulmonary disease (COPD), parenteral nutrition, HIV/AIDS
Medications known to cause or accelerate bone loss
* Corticosteroids - Prednisone (≥ 5 mg/d for ≥ 3 mo)23
* Anticonvulsants - Phenytoin, barbiturates, carbamazepine (These agents are associated with treatment-induced vitamin D deficiency.)
* Heparin (long-term)
* Chemotherapeutic/transplant drugs - Cyclosporine, tacrolimus, platinum compounds, cyclophosphamide, ifosfamide, methotrexate
* Hormonal/endocrine therapies - Gonadotropin-releasing hormone (GnRH) agonists, luteinizing hormone-releasing hormone (LHRH) analogs, depomedroxyprogesterone, excessive thyroid supplementation
* Lithium
* Aromatase inhibitors - Exemestane, anastrozoleDifferential Diagnoses
Hyperparathyroidism
Multiple Myeloma
Osteomalacia and Renal Osteodystrophy
Paget Disease
Other Problems to Be Considered
Metastases
Leukemia
Lymphoma
Mastocytosis
Pediatric osteogenesis imperfecta
Scurvy
Sickle cell anemia
Homocystinuria
Workup
Laboratory Studies
Laboratory studies are used to establish baseline conditions or to exclude secondary causes of osteoporosis.
* CBC count
* Serum chemistries including calcium, phosphate, creatinine, liver function tests, electrolytes: levels of serum calcium, phosphate, and alkaline phosphatase are usually normal in persons with primary osteoporosis, although alkaline phosphatase levels may be elevated for several months after a fracture.
* Thyroid-stimulating hormone
* 25-hydroxyvitamin D [25(OH)D]
Other laboratory studies used to evaluate for secondary causes include the following:
* Twenty-four-hour urine calcium to assess for hypercalciuria
* Intact parathyroid hormone
* Testosterone level (in males)
* Sedimentation rate
* Urinary free cortisol and tests for adrenal hypersecretion
* Serum and urine protein electrophoresis
* Antigliadin and antiendomysial antibodies for celiac disease
* Serum tryptase, urine N-methylhistamine for mastocytosis
* Bone marrow biopsy if a hematologic disorder is suspected
Markers of bone turnover (both formation and resorption) may be elevated in high–bone-turnover states (eg, early postmenopausal osteoporosis) and may be useful in some patients for monitoring early response to therapy. However, further study is needed to determine their clinical utility in osteoporosis management. Some of these biochemical measures include the following:
* Bone formation markers - Bone-specific alkaline phosphatase, osteocalcin, type I procollagen peptides
* Bone resorption markers - Urinary deoxypyridinoline and cross-linked N- and C-telopeptide of type I collagen
Imaging Studies
Dual-energy x-ray absorptiometry
Dual-energy x-ray absorptiometry (DXA) is the standard study used to establish or confirm a diagnosis of osteoporosis, to predict future fracture risk, and to assess changes in bone mass over time. DXA is used to calculate bone mineral density (BMD) at the hip and spine. Although measurement at any site can be used to assess overall fracture risk, measurement at a particular site is the best predictor of fracture risk at that site. Whenever possible, the same technologist should perform subsequent measurements on the same patient using the same machine. This method can be used in both adults and children. Factors that may result in a falsely high bone density determination include spinal fractures, osteophytosis, and extraspinal (eg, aortic) calcification.
The National Osteoporosis Foundation and the International Society for Clinical Densitometry (ISCD) recommend that BMD be measured in the following patients:
* Women aged 65 years and older and men aged 70 years or older, regardless of clinical risk factors
* Younger postmenopausal women and men aged 50-70 years with clinical risk factors for fracture
* Women in menopausal transition with a specific risk factor associated with increased risk for fracture (ie, low body weight, prior low-trauma fracture, use of a high-risk medication)
* Adults with fragility fractures
* Adults who have a condition (eg, rheumatoid arthritis) or who take a medication (eg, glucocorticoids, ≥5 mg of prednisone daily for ≥3 mo) associated with low bone mass or bone loss
* Anyone being considered for pharmacologic therapy for osteoporosis
* Anyone being treated for osteoporosis (to monitor treatment effect)
* Anyone not receiving therapy in whom evidence of bone loss would lead to treatment
Bone density data from a DXA are reported as T-scores and Z-scores. T-scores represent the number of standard deviations (SD) from the mean bone density values in healthy young adults, whereas Z-scores represent the number of SD from the normal mean value for age- and sex-matched controls.
* Criteria by the World Health Organization (WHO) define a normal T-score value as within 1 SD of the mean bone density value in a healthy young adult.
o T-score of -1 to -2.5 SD indicates osteopenia.
o T-score of less than -2.5 SD indicates osteoporosis.
o T-score of less than -2.5 SD with fragility fracture(s) indicates severe osteoporosis.
* For each SD reduction in BMD, the relative fracture risk is increased 1.5-3 times.
* The WHO BMD diagnostic classification should not be applied to premenopausal women, men younger than 50 years, or children. Z-scores adjusted for ethnicity or race should be used, with Z-scores of -2.0 or lower defined as "below the expected range for age" and those above -2.0 being "within the expected range for age." The diagnosis of osteoporosis in these groups should not be based on densitometric criteria alone.
WHO fracture risk algorithm
This algorithm (www.shef.ac.uk/FRAX/) was developed to calculate the 10-year probability of a hip fracture and the 10-year probability of any major osteoporotic fracture (defined as clinical spine, hip, forearm, or humerus fracture) in a given patient. These calculations account for femoral neck BMD and other clinical risk factors, as follows:24
* Age
* Sex
* Personal history of fracture
* Low body mass index
* Use of oral glucocorticoid therapy
* Secondary osteoporosis (ie, coexistence of rheumatoid arthritis)
* Parental history of hip fracture
* Current smoking status
* Alcohol intake (3 or more drinks per day)
This algorithm is useful in identifying patients with low bone mass (having T-scores in the osteopenic range) who are most likely to benefit from treatment. The National Osteoporosis Foundation recommends osteoporosis treatment in patients with low bone mass in whom a US-adapted WHO 10-year probability of a hip fracture is 3% or more or in whom the risk for a major osteoporosis-related fracture is 20% or more.7
Vertebral fracture assessment
Densitometric spine imaging can be performed at the time of DXA scanning to detect vertebral fractures. Vertebral fracture assessment (VFA) is not available with all DXA machines. When available, VFA should be considered when the results may influence clinical management of the patient.25
Radiography
Obtain radiographs of the affected area in symptomatic patients. Lateral spine radiography can be performed in asymptomatic patients in whom a vertebral fracture is suspected, in those with height loss in the absence of other symptoms, or in those with pain in the thoracic or upper lumbar spine.
* Radiographs may show fractures or other conditions such as osteoarthritis, disc disease, or spondylolisthesis.
* Plain radiography is not as accurate as BMD testing. Approximately 30-80% of bone mineral must be lost before radiographic lucency becomes apparent on radiographs.26
Additional imaging modalities
* Quantitative CT scanning: This is used to measure BMD as a true volume density in g/cm3, which is not influenced by bone size. This technique can be used in both adults and children but assesses BMD only at the spine. Other limitations include significant radiation exposure, high cost, and possible interference by osteophytes.
* Peripheral DXA: This is used to measure BMD at the wrist. Peripheral DXA may be most useful in identifying patients at very low fracture risk who require no further workup.
* Quantitative ultrasonography of the calcaneus: This is a low-cost portable screening tool. This method does not involve radiation but is not as accurate as other methods and cannot be used to monitor the response to treatment because of its lack of precision.
Procedures
Undecalcified iliac bone biopsy with double tetracycline labeling is rarely necessary but may be considered when no cause for osteoporosis is apparent, therapy is not eliciting a response, or osteomalacia is suspected. Tetracycline double labeling is a process used to calculate data on bone turnover. In this procedure, patients are given tetracycline, which binds to newly formed bone. This appears on biopsy samples as linear fluorescence. A second dose of tetracycline is given 11-14 days after the first dose; this appears on a biopsy sample as a second line of fluorescence. The distance between the two fluorescent labels can be measured to calculate the amount of bone formed during that interval.
Histologic Findings
Histologic examination of osteoporotic bone may reveal generalized thinning of trabeculae and irregular perforation of trabeculae, reflecting unbalanced osteoclast-mediated bone resorptionTreatment
Medical Care
Osteoporosis is typically asymptomatic until a fracture occurs. Patients identified as at risk for osteoporosis (including children and adolescents) should undergo preventive measures, including adequate calcium intake, vitamin D intake, and exercise. Counsel patients to avoid tobacco use. Identify and treat alcoholism.
Protective measures should be taken in patients who must take glucocorticoids for other medical conditions. These include using the minimum effective dose, discontinuing the drug as soon as possible, and supplementing with calcium and vitamin D.
The National Osteoporosis Foundation recommends that pharmacologic therapy should be reserved for postmenopausal women and men aged 50 years or older who present with the following:
* A hip or vertebral fracture (Vertebral fracture may clinical or morphometric [ie, identified on a radiograph alone].)
* Other prior fractures and low bone mass (T-score between -1.0 and -2.5 at the femoral neck, total hip, or spine)
* T-score less than -2.5 at the femoral neck, total hip, or spine after appropriate evaluation to exclude secondary causes
* Low bone mass (T-score between -1.0 and -2.5 at the femoral neck, total hip, or spine) and secondary causes associated with high risk of fracture (eg, glucocorticoid use or total immobilization)
* Low bone mass (T-score between -1.0 and -2.5 at the femoral neck, total hip, or spine) and (1) 10-year probability of hip fracture of 3% or more or (2) a 10-year probability of any major osteoporosis-related fracture of 20% or more based on the US-adapted WHO algorithm24
Surgical Care
The goals of surgical treatment of osteoporotic fractures include rapid mobilization and return to normal function and activities.
* Fixation and stabilization of hip or wrist fracture
* Vertebroplasty to reduce vertebral fracture–associated pain
* Kyphoplasty to restore height or to treat the deformity associated with osteoporotic vertebral fractures
*
Osteoporosis. Lateral radiograph demonstrates mul...
Osteoporosis. Lateral radiograph demonstrates multiple osteoporotic vertebral compression fractures. Kyphoplasty has been performed at one level.
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Osteoporosis. Lateral radiograph demonstrates mul...
Osteoporosis. Lateral radiograph demonstrates multiple osteoporotic vertebral compression fractures. Kyphoplasty has been performed at one level.
*
Osteoporosis. Lateral radiograph of the patient s...
Osteoporosis. Lateral radiograph of the patient seen in previous image following kyphoplasty performed at 3 additional levels.
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Osteoporosis. Lateral radiograph of the patient s...
Osteoporosis. Lateral radiograph of the patient seen in previous image following kyphoplasty performed at 3 additional levels.
Consultations
* Rheumatologist or endocrinologist to assist with management and determination of underlying etiologies in complex cases
* Orthopedist to assist with fracture management
Diet
Adequate calcium and vitamin D intake are important in persons of any age, particularly in childhood as the bones are maturing. If dietary intake is inadequate, add supplements.
Calcium
* Premenopausal women and men younger than 50 years without risk factors for osteoporosis should receive a total of 1000 mg of calcium daily.
* Postmenopausal women, men older than 50 years, and other persons at risk for osteoporosis should receive a total of 1200-1500 mg of calcium daily.
* See the National Osteoporosis Foundation Web site for further calcium recommendations.
Vitamin D
* Adults younger than 50 years should receive 400-800 IU of vitamin D 3 daily.
* All adults older than 50 years should receive 800-1000 IU of vitamin D 3 daily.
* See the National Osteoporosis Foundation Web site for further vitamin D recommendations.
Activity
* Weight-bearing exercise has been shown to positively affect BMD. Regular exercise should be encouraged in all patients, including children and adolescents (in order to strengthen the skeleton during the maturation process). Exercise also improves agility and balance, thereby reducing the risk of falls.
* Physical therapists can assist in developing exercise regimens and instructing patients in proper techniques.
Medication
Antiresorptive agents, including bisphosphonates, the selective estrogen-receptor modulator (SERM) raloxifene, calcitonin, denosumab, and one anabolic agent, teriparatide, are currently available for osteoporosis treatment. All therapies should be given with calcium and vitamin D supplementation. The American College of Physicians reviewed the evidence and proposed guidelines for pharmacologic treatments of osteoporosis.27
A combination of calcium and vitamin D supplementation can reduce fracture risk.28 A meta-analysis was performed to evaluate the efficacy of oral supplemental vitamin D in preventing nonvertebral and hip fractures among individuals older than 65 years. The meta-analysis included 12 double-blind, randomized, controlled trials of nonvertebral fractures (n=42,279) and 8 randomized controlled trials of hip fractures (n=40,886) and compared oral vitamin D (with or without calcium) with either calcium alone or placebo. The results showed that nonvertebral fracture prevention with vitamin D is dose-dependent, and a higher dose reduced fractures by at least 20% in individuals aged 65 years or older.29
An additional meta-analysis (n=68,517) concluded that vitamin D alone is not effective in preventing fractures, although, when administered with calcium, hip fractures and total fractures (and possibly vertebral fractures) were reduced. The conclusions were based on 7 large studies that were randomized with at least one intervention arm in which vitamin D was given and included analysis of fractures as an outcome and at least 1000 participants.30
More information is needed regarding risks associated with long-term calcium supplementation. Bolland et al conducted a meta-analysis of patients taking calcium supplements (without coadministered vitamin D) and association with cardiovascular risks. An increased risk for myocardial infarction was associated with patients taking calcium supplements.31
Bisphosphonates are the most commonly used agents for osteoporosis. Oral and intravenous options are available. Trials have provided limited data about long-term treatment with bisphosphonates, and, recently, the optimal length of treatment with these medications has come into question. A patient's risk of fracture can be used to help guide length of treatment. Patients at high risk may be continued on bisphosphonates after 5 years; however, in some patients, especially those with a lower risk of fracture, bisphosphonate treatment may be stopped.32
Raloxifene, a SERM first studied for breast cancer prevention, decreases bone resorption through actions on estrogen receptors. Raloxifene may be most useful in younger postmenopausal women without severe osteoporosis.
Teriparatide is currently the only anabolic agent in use for osteoporosis treatment. Bouxsein et al retrospectively analyzed data from the Fracture Prevention Trial and the Multiple Outcomes of Raloxifene Evaluation trial for the risk of new vertebral fractures adjacent to existing vertebral fractures in postmenopausal osteoporotic women in patients on teriparatide or raloxifene. At baseline, 1226 untreated postmenopausal women had 1 or more vertebral fractures. During the 2-year follow-up, 196 (16%) had a total of 292 new vertebral fractures; 47% of fractures were adjacent to a previously existing fracture. Teriparatide reduced the risk of any new, new adjacent, and new nonadjacent vertebral fractures by 72%, 75%, and 70%, respectively, compared with placebo, whereas raloxifene reduced the risk by 54%, 54%, and 53%, respectively, compared with placebo.33 Teriparatide should be considered in younger and older postmenopausal women with severe osteoporosis.
Pooled mortality data from large clinical trials of raloxifene (60 mg/d) were analyzed by Grady et al (2010). When compared with placebo, all-cause mortality was 10% lower among older postmenopausal women receiving raloxifene. The primary reduction was in noncardiovascular, noncancer deaths.34
Calcitonin is an option for patients who are not candidates for other available osteoporosis treatments.
Denosumab, a humanized monoclonal antibody directed against receptor activator of nuclear factor-kappa B ligand (RANKL), was approved by the US Food and Drug Administration (FDA) in June 2010. Denosumab decreases bone resorption by inhibiting osteoclast activity. In a randomized placebo-controlled trial, Cummings et al studied 7868 women aged 60-90 years with osteoporosis who received either denosumab 60 mg SC or placebo every 6 months for 36 months. Compared with placebo, denosumab decreased the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis.35 Smith et al reported a reduction in incident vertebral fractures when denosumab was used in 734 men receiving androgen-deprivation therapy for prostate cancer compared with placebo. In the Smith study, denosumab significantly increased lumbar spine, hip, femoral neck, and radial BMD.36
Hormone replacement therapy (HRT) was once considered a first-line therapy for the prevention and treatment of osteoporosis in women. Data from the Women's Health Initiative confirmed that HRT can reduce fractures. However, HRT was associated with an increased risk of breast cancer, myocardial infarction, stroke, and venous thromboembolic events.37 HRT is approved for management of menopausal symptoms and prevention of osteoporosis. It is no longer recommended as a treatment of osteoporosis in postmenopausal women.
Evidence indicates that strontium ranelate (available in Europe) reduces the risk of fracture. Strontium is not approved for the treatment of osteoporosis in the United States.
Bisphosphonate Derivative
Bisphosphonates are stable analogues of inorganic pyrophosphate. Bisphosphonates have a high affinity for hydroxyapatite crystals, and by binding at sites of active bone resorption, these agents can inhibit osteoclastic resorption. All oral bisphosphonates have a poor absorption and a bioavailability of less than 5%. Bone uptake is 20-80%, with the remainder being rapidly excreted through the kidney.38 Bisphosphonates are approved in the United States for the prevention and treatment of postmenopausal osteoporosis, osteoporosis in males, and steroid-induced osteoporosis.
Alendronate sodium (Fosamax); alendronate sodium/cholecalciferol (Fosamax Plus D)
Increases BMD at spine by 8% and hip by 3.5%. Reduces the incidence of vertebral fractures by 47% and nonvertebral fractures by 50% over 3 y. Approved for treatment and prevention of postmenopausal osteoporosis, male osteoporosis, and steroid-induced osteoporosis. Tab is available with 2800 or 5600 IU of vitamin D 3 . Also available in PO solution taken weekly.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Treatment: 70 mg PO qwk or 10 mg PO qd
Prevention: 35 mg PO qwk or 5 mg PO qd
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
Coadministration with calcium-containing products and other multivalent cations decreases absorption (separate dosing by 30 minutes); increased GI distress with aspirin, NSAIDs, or other GI irritants
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; inability to stand or sit upright for at least 30 min; hypocalcemia; esophageal abnormalities (eg, stricture, achalasia) that might delay esophageal emptying
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Upper GI disease; renal insufficiency (CrCl <35 mL/min); treat disturbances of mineral metabolism; ensure adequate vitamin D and calcium intake; discontinue if esophageal reaction (eg, dysphagia, odynophagia, retrosternal pain, worsening heartburn) occurs; not for use in breastfeeding women
Risedronate sodium (Actonel); risedronate sodium with calcium carbonate (Actonel with calcium)
Increases BMD at spine by 5.4% and hip by 1.6%. Reduces vertebral fractures by 41% and nonvertebral fractures by 39% over 3 y. Approved for treatment and prevention of postmenopausal osteoporosis, male osteoporosis, and steroid-induced osteoporosis.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Treatment or prevention in women:
5 mg PO qd OR
35 mg PO qwk OR
75-mg tab PO on 2 consecutive days monthly OR
150-mg tab PO qmo
Treatment in men:
35 mg PO qwk
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
Coadministration with calcium-containing products and other multivalent cations decreases absorption (separate dosing by 30 min); caution with aspirin, NSAIDs, or other GI irritants
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; hypocalcemia; inability to stand or sit upright for at least 30 min
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Upper GI disease; renal insufficiency (CrCl <30 mL/min); correct any preexisting hypocalcemia or other mineral or bone disturbances prior to starting therapy; ensure adequate vitamin D and calcium intake; discontinue if esophageal reaction (eg, dysphagia, odynophagia, retrosternal pain, worsening heartburn) occurs; not for use in breastfeeding women
Ibandronate sodium (Boniva)
Increases BMD at spine by 5.7-6.5% and hip by 2.4-2.8%. Reduces vertebral fractures by 50% with intermittent (non-daily) dosing over 3 y. No effects on reduction of nonvertebral fractures. Approved for postmenopausal osteoporosis.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Treatment or prevention in postmenopausal osteoporosis:
Oral: 150 mg PO qmo or 2.5 mg PO qd
Intravenous: 3 mg IV q3mo
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
Multivalent cations (eg, calcium, aluminum, magnesium, iron) decrease absorption, administer at least 1 h prior to vitamin and mineral supplements; NSAIDs may aggravate GI irritation
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; uncorrected hypocalcemia; inability to stand or sit upright for at least 60 min following drug administration
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Upper GI disease; renal insufficiency (CrCl <30 mL/min); correct any preexisting hypocalcemia or other mineral or bone disturbances prior to starting therapy; ensure adequate vitamin D and calcium intake; discontinue if esophageal reaction (eg, dysphagia, odynophagia, retrosternal pain, worsening heartburn) or severe musculoskeletal pain occurs; renal toxicity rarely reported with IV dose; not for use in breastfeeding women
Zoledronic acid (Reclast)
Most potent bisphosphonate available. Increases BMD at spine by 4.3-5.1% and hip by 3.1-3.5% compared with placebo. Reduces the incidence of spine fractures by 70%, hip fractures by 41%, and non-vertebral fractures by 25% over 3 y. Approved for the treatment of postmenopausal osteoporosis.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
5 mg IV over 15 min once yearly
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
Aminoglycosides may enhance hypocalcemic effect of zoledronic acid; NSAIDs may enhance GI adverse events; thalidomide may enhance adverse effects
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; hypocalcemia
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Aspirin-sensitive asthma; concomitant cancer/chemotherapy/steroids or dental procedure in patients with cancer may increase risk of osteonecrosis of the jaw; caution in renal insufficiency (CrCl <30 mL/min); correct preexisting hypocalcemia or other mineral or bone disturbances prior to starting therapy; ensure adequate vitamin D and calcium intake; not for use in breastfeeding women
Hormone, Parathyroid
Teriparatide is a biological product that contains a portion of human parathyroid hormone. When given intermittently, it increases bone remodeling with the net effect of increased bone mass and improved skeletal microarchitecture. (This is in contrast to continuous exposure to parathyroid hormone, which increases bone resorption with a net effect of decreased trabecular bone volume). Teriparatide is approved in the United States for postmenopausal osteoporosis and primary or hypogonadal osteoporosis in men.
Teriparatide (Forteo)
Anabolic agent increases BMD at lumbar spine by 9-13% and hip by 3-6% compared with placebo. Reduced the risk of spine fractures by 65% and nonspinal fractures by 54% in patients after an average of 18 mo of therapy. Approved for postmenopausal osteoporosis and male osteoporosis.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
20 mcg SC qd
Pediatric
Not recommended
* Dosing
* Interactions
* Contraindications
* Precautions
None reported
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; increased risk for osteosarcoma (including those with Paget disease of bone or unexplained elevations of alkaline phosphatase, open epiphyses, or prior radiation therapy involving skeleton); children or growing adults; patients with bone metastases or history of skeletal malignancies and those with metabolic bone diseases other than osteoporosis
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Monitor for hypercalcemia; may cause orthostatic hypotension (particularly following first several doses), dizziness, or leg cramps; therapy limited to 2 y owing to osteogenic sarcomas in rat studies
Selective Estrogen Receptor Modulator
Selective estrogen receptor modulators (SERMs) act as weak estrogens in some organ systems, while acting as estrogen antagonists in others. Raloxifene is approved for the prevention and treatment of postmenopausal osteoporosis.
Raloxifene (Evista)
Increases BMD at spine and hip. Reduces the incidence of spine fractures by 30-55% over 3 y.
Most suitable in women <70 y at moderate risk for osteoporosis who have infrequent vasomotor symptoms of menopause (eg, hot flashes) and who are at moderate-to-high risk for breast cancer.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
60 mg PO qd
Pediatric
Not recommended
* Dosing
* Interactions
* Contraindications
* Precautions
May antagonize warfarin; avoid with anion exchange resins (eg, cholestyramine); caution with other drugs that are highly protein bound (eg, diazepam, diazoxide, lidocaine)
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; thrombophlebitis; pregnancy
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Not for use in premenopausal women; not recommended for use with concomitant estrogen replacement therapy; discontinue 72 h before prolonged immobilization or surgery associated with thromboembolism and resume once fully ambulatory; hepatic dysfunction; not recommended for use in breastfeeding women
Calcitonin
This agent is a peptide hormone used to treat and prevent osteoporosis in patients in whom bisphosphonates and estrogen are contraindicated or not tolerated. It also has some analgesic effects in patients with fractures.
Calcitonin (Miacalcin, Calcimar, Cibacalcin)
Increases BMD at lumbar spine by 1-1.5%. Reduced incidence of spine fracture by 33% in group receiving 200 IU/d. Available in parenteral and intranasal forms; however, intranasal form is more convenient and better tolerated. Diminution of benefit may occur after 20 mo with parenteral form.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
200 IU (1 puff) qd in alternating nostrils
100 IU IM/SC qod
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
May potentiate oral anticoagulants and oxyphenbutazone; may alter insulin effects
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Perform periodic nasal examinations and discontinue if severe ulceration occurs with nasal spray use; monitor for hypocalcemic tetany initially and urine sediments over long term with injectable use; hypocalcemia may occur (supplement with calcium and vitamin D); examine urine sediment during prolonged therapy; caution in breastfeeding women
Estrogen Derivative
Estrogen is approved for the prevention of osteoporosis and relief of menopause-associated vasomotor symptoms and vulvovaginal atrophy. The lowest effective dose at the shortest duration necessary should be used. The FDA recommends that other approved nonestrogen treatments should be considered first for osteoporosis prevention.
Estrogens (conjugated)
Contains a mixture of estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. Mixture of sodium estrone sulfate and sodium equilin sulfate. Contains, as concomitant components, sodium sulfate conjugates, 17-alpha-dihydroequilenin, 17-alpha-estradiol, and 17-beta-dihydroequilenin.
Restores estrogen levels to concentrations that induce negative feedback at gonadotrophic regulatory centers, which in turn reduces release of gonadotropins from pituitary. Increases synthesis of DNA, RNA, and many proteins in target tissues.
Multiple aspects of menopause respond to estrogen replacement therapy, including vasomotor symptoms and atrophic vaginitis. Also reduces bone resorption and may increase osteoblast activity.
Routinely prescribing conjugated estrogens to premenopausal women is not recommended. Use this medication in postmenopausal women who are incontinent and who have had a hysterectomy. For postmenopausal women with an intact uterus, cautiously recommend a short-term low-dose of Premarin, with frequent monitoring.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Prophylaxis: Initial, 0.3 mg PO qd given continuously or in cyclical regimens (25 d on, 5 d off); adjust to lowest level that will provide effective control
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
May reduce hypoprothrombinemic effect of anticoagulants; coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes may reduce estrogen levels; pharmacologic and toxicologic effects of corticosteroids may occur as a result of estrogen-induced inactivation of hepatic P450 enzyme; loss of seizure control has been noted when administered concurrently with hydantoins
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; known or suspected pregnancy; breast cancer; undiagnosed abnormal genital bleeding; active thrombophlebitis or thromboembolic disorders; history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast or prostatic malignancy)
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as abnormal or excessive uterine bleeding or mastodynia; estrogens may cause some degree of fluid retention (exercise caution); prolonged unopposed estrogen therapy may increase risk of endometrial hyperplasia
Monoclonal Antibody
Binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption.
Denosumab (Prolia)
Monoclonal antibody that specifically targets RANK ligand, an essential regulator of osteoclasts. Indicated for prevention of fracture in postmenopausal women with osteoporosis and high fracture risk (ie, history of osteoporotic fracture, failed other treatments).
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
60 mg SC q6mo
Pediatric
Safety and efficacy not establishedFollow-up
Further Outpatient Care
DXA should be repeated every 2-3 years if the baseline test results are normal. DXA should be performed every 1-2 years in patients who are undergoing osteoporosis treatment.
Deterrence/Prevention
Primary prevention of osteoporosis starts in childhood. Patients require adequate calcium intake, vitamin D intake, and weight-bearing exercise. Patients should be counseled on smoking cessation and moderated alcohol intake. Patients who have disorders or who take medications that can cause or accelerate bone loss should receive calcium and vitamin D supplementation (see Causes).
Complications
The most serious consequences of osteoporosis include fractures and, in some patients, death due to postfracture complications.
Respiratory compromise can occur in patients with multiple vertebral fractures that result in severe kyphosis.
Prognosis
If full recovery is not achieved, osteoporotic fractures may lead to chronic pain, disability, and, in some cases, death.
Patient Education
* Educate patients about osteoporosis and encourage them to follow preventive measures, including adequate calcium and vitamin D intake, exercise, cessation of smoking, and moderation of alcohol consumption.
* For excellent patient education resources, visit eMedicine's Bone Health Center; Eating Disorders Center; Esophagus, Stomach, and Intestine Center; and Women's Health Center.
* Also, see eMedicine's patient education articles Understanding Osteoporosis Medications, Anorexia Nervosa, Inflammatory Bowel Disease, Menopause, and Hormone Replacement and Osteoporosis.
Miscellaneous
Medicolegal Pitfalls
Osteoporosis is a preventable disease with potentially devastating consequences. Failure to identify at-risk patients, to educate them, and to implement preventive measures may lead to tragic consequences.
Special Concerns
* Recognize the increased mortality and morbidity associated with osteoporotic fractures.
* Many patients have a coexisting cause of bone loss. This should be investigated and treated.
* WHO criteria for T-scores should not be applied to premenopausal women, men younger than 50 years old, and children. Z-scores should be used for these individuals, and, in these cases, a diagnosis of osteoporosis should not be based on densitometric criteria alone.
