Published: August 2010
Primary osteoporosis is a metabolic bone disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and increased fracture risk.1 It also has normal mineral-to-collagen ratio. Primary osteoporosis represents bone mass loss that is unassociated with any other illness and is related to aging and loss of the gonadal function in women and the aging process in men.
Secondary osteoporosis can result from a variety of the chronic conditions that significantly contribute to bone mineral loss, or it can result from the effects of medications and nutritional deficiencies (Box 1).
|Box 1: Causes of Secondary Osteoporosis
|Conditions Causing Nutritional Deficencies|
The World Health Organization (WHO) defines osteoporosis as bone density that is 2.5 standard deviations (SDs) or more below the young adult mean value (T-score <−2.5). Patients with bone density between 1 and 2.5 SDs below average (T-score −1 to −2.5) are said to have osteopenia.2 Decreased bone density imparts increased risk for bone fracture. Every 1 SD decrease in bone density of the spine increases risk for new vertebral fracture by factor of 2.0 to 2.4.3
Osteoporosis is the most common metabolic bone disease. About 54% of postmenopausal white women in the United States have osteopenia and 30% have osteoporosis. Men and nonwhite women at risk add 30 million to 54 million affected persons in the United States.
About 2.0 million osteoporotic fractures occur each year in the United States. Approximately one half are vertebral fractures, one quarter are hip fractures, and one quarter are Colles’ fractures.1
Significant ethnic and geographic differences exist in the prevalence of osteoporosis and osteoporotic fractures. The risk of hip fracture is considerably higher in whites than in blacks. Two factors contribute to this difference: higher peak bone mass (highest bone mass achieved by a person in his or her lifetime) and slower postmenopausal bone loss in African American women.4 Bone mineral density (BMD) is lower in Asians than in whites. However, when adjusted for body size, most of the difference disappears, suggesting that the lower BMD in Asians is due to their smaller body size.
Decreased BMD and osteoporotic fracture rate increases with age. Wrist fracture incidence starts increasing at about 50 years of age, vertebral fractures in the 60s, and hip fractures in the 70s.
Increased mortality rate associated with hip and vertebral fractures may be the worst consequence, but the loss of independence and lowered quality of life of patients might be the greatest burden of the osteoporosis.5
Osteoporosis in men has been recognized as an important health problem. Incidence of hip fracture increases exponentially with age in men as well as in women, although the incidence in men occurs about 5 to 10 years later than in women.6
Basic mechanisms responsible for development of osteoporosis are poor bone mass acquisition during growth and development and accelerated bone loss in the period after peak bone mass is achieved. Both processes are modulated by environmental and genetic factors.
About two thirds of the risk for fracture in postmenopausal women is determined by premenopausal peak bone mass.5 Peak bone mass is higher in blacks than in whites and Asians, and it is higher in men than women.
Approximately half of the bone mass is accumulated during pubertal development.7 This is associated with the increase in sex hormone levels and is almost completed with closure of the end plates. There is only minimal additional accumulation of the bone minerals during the next 5 to 15 years (skeletal consolidation). Peak bone mass is achieved during the third decade of life.
Studies in twins and mother-daughter pairs suggest that 40% to 80% of the variability in the bone mass is determined by genetic factors. The genes implicated in osteoporosis include those for the estrogen receptor, transforming growth factor-β, and apolipoprotein E and collagen.
Bone loss, in contrast, appears to be mostly determined by environmental factors (nutritional, behavioral, and medications). However, genetic factors also play a role, mostly acting on a person's estrogen status.
Important nutritional factors include dietary calcium intake, Vitamin D status, protein intake, and caloric intake. Phosphorus, vitamins C and K, copper, zinc, and manganese also play a role.
Low calcium intake during childhood increases risk of fracture later in the life8 and is positively correlated with bone mineral mass at all ages. Supplementation is shown to reduce rate of bone loss and decreases incidence of fractures in calcium deficient elderly persons.
Optimal calcium intake varies among different age groups and is population specific. The typical U.S. diet is rich in sodium and protein, both of which increase urinary calcium excretion, thus increasing dietary requirements.
Vitamin D is essential for bone mineral metabolism through its role in calcium absorption and osteoclast activity. Vitamin D nutritional status is best assessed by measurement of serum 25(OH)-vitamin D levels. Vitamin D levels decrease with increasing age. Supplementation reduces the rate of all fractures in the elderly population.
Protein or caloric malnutrition predisposes to falls and decreases soft tissue cover over bony prominences. Protein intake is the major determinant of outcome after hip fracture, and serum albumin level is the single best predictor of survival in these patients. The body weight history of girls and women with anorexia nervosa is the most important predictor for the development of osteoporosis.
Behavioral factors important in pathogenesis of osteoporosis include physical activity, smoking, and alcohol consumption.
Bone mass is higher in top-level athletes than in nonathletes. This is particularly pronounced in athletes engaging in strength training. The data are hard to interpret because top athletes might have different skeletal and muscular characteristics than the average population even before beginning training. However, mechanical loading is shown to increases bone mass, and with decreasing mechanical load, bone mass is lost. The relationship between load and BMD is curvilinear and much more pronounced at low levels of loads. In completely immobilized patients, bone mass loss may be up to 40% in 1 year. On the other hand, active people who further increase their levels of physical activity may expect only modest gains in BMD.9
Optimal bone metabolism is the result of hormonal, nutritional, and mechanical harmony, and a deficit in one area is usually impossible to overcome by improvements in others.
Chronic alcohol use has been associated with decreased BMD in the femoral neck and lumbar spine and is commonly listed as a risk factor for osteoporosis. Prevalence of osteoporosis in alcoholics is 28% to 52%.10 Other nutritional deficiencies associated with chronic alcohol abuse play an important role in development of osteoporosis in alcoholics. Smoking is often associated with alcoholism and is an independent risk factor for low bone mass.11 Smoking affects peak bone mass development and accelerates bone loss.
Among several medications (see Box 1), glucocorticoids are the most important cause of bone loss (mostly trabecular). Fractures occur most commonly in vertebrae, ribs, and the ends of the long bones. Bone loss occurs very rapidly and may be as high as 20% during the first year of steroid use. The incidence of osteoporotic fractures in patients taking corticosteroids for more than 6 months is 30% to 50%. The dose of steroid that is detrimental to BMD in most people appears to be more than 7.5 mg of prednisone daily.12
Female sex hormones (estrogens) are mandatory for acquisition of the peak bone mass and for maintenance of bone in women and men. Estrogen deficiency is considered a principal cause of postmenopausal osteoporosis.13 It might play important role in male osteoporosis as well. Risk factors for low BMD are summarized in Box 2.
|Box 2: Risk Factors Associated with Development of Osteoporosis
The clinical expression of osteoporosis is a skeletal fracture. Vertebral fracture is the most common. Many patients (up to two thirds) remain asymptomatic after compressive vertebral fracture, and osteoporosis is diagnosed accidentally on the x-rays taken for other reasons. Incidence of new fracture has been estimated to be 19% in the year after the initial fracture.14
Fracture usually occurs during routine daily activities such as bending of the body, coughing, or lifting and is most common in the lumbar spine and the lower thoracic vertebrae. Occurrence of the fracture may be accompanied by acute onset of pain, which might disappear or turn into chronic dull back pain. Multiple fractures can lead to significant height loss and development of thoracic kyphosis (Dowager's hump). Patients notice protuberance of the abdomen, a change in the way clothes fit, and loss of the waist. Restrictive respiratory problems are seen because of diminished volume of the thoracic cage and poor expansion with breathing.
Hip fractures are another common fracture seen in osteoporotic persons and affect about 15% of women and 5% of men older than 80 years. They usually occur after falls or other trauma, but subchondral-insufficiency fractures of the femoral head have been described.
Fractures of the distal radius (Colles’ fractures) occur more often in patients with osteoporosis and may be caused by falls on an outstretched hand or after minor trauma.
History and physical examination are important for identifying secondary causes of osteoporosis and to record behavioral risk factors, use of medications, and presence of signs and symptoms of osteoporotic complications. Use of risk factors as a prescreening device to select patients for further diagnostic procedures is inefficient and fails to identify a substantial portion of patients who have osteoporosis.
Laboratory evaluation should be aimed toward diagnosis of secondary osteoporosis. The specific test used depends on the specific clinical situation (Table 1).
T4 and FTI
|Hypogonadism||Testosterone in men
Estradiol in females
LH and FSH
|Cushing's syndrome||24-hour free urinary cortisol
Dexamethasone suppression test
|Addison's disease||ACTH stimulation test|
|Renal disease||Serum creatinine
|Liver disease||Liver function tests|
|Malabsorption||24-hour urinary calcium excretion
Serum albumin level
|Multiple myeloma||Serum protein electrophoresis
Urine for Bence Jones proteinuria
Erythrocyte sedimentation rate
|Hemochromatosis||Serum iron panel|
|Renal tubulopathy||Urinalysis including pH
Urine calcium, phosphorus, amino acid, and glucose
Iliac bone biopsy with double
|Inflammatory and rheumatic diseases||Erythrocyte sedimentation rate
Anti DNA antibodies
ACTH, adrenocorticotropic hormone; ANA, antinuclear antibody; FSH, follicle-stimulating hormone; FTI, free thyroxine index; IGF, insulin-like growth factor; LH, luteinizng hormone; PTH, parathyroid hormone; RF, rheumatoid factor; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone.
Assessment of bone metabolism using markers of bone turnover can yield useful information and guide management decisions in some cases. These tests are noninvasive and can indicate changes in the bone metabolism much faster than measurements of BMD. However, their role in patient management is still being defined. Box 3 lists the tests.
|Box 3: Biochemical Markers of Bone Metabolism
|Serum Markers of Bone Formation|
|Amino-terminal propeptide of type I collagen
Bone-specific alkaline phosphatase
Carboxy-terminal propeptide of type I collagen
Osteocalcin (bone Gla protein)
|Urine Markers of Bone Resorption|
C-telopeptide of collagen cross-links
N-telopeptide of collagen cross-links
Total and free deoxypyridinoline
Total and free pyridinoline
|Serum Markers of Bone Resorption|
C-telopeptide of collagen cross-links
N-telopeptide of collagen cross-links
Tartarate resistant acid phosphatase
During bone resorption, type I collagen is degraded, and the degradation products are released into circulation and excreted from the body via the kidneys. These degradation products are the most useful bone mineral metabolism markers. Clinical use of the bone metabolism markers determined in the urine has been limited by the need to collect 24-hour urine or to correct results for creatinine levels. Serum markers are free of these problems, but there are marked circadian variations in serum levels, and timing of blood sample collection may be important.
With successful antiresorptive therapy there is a decrease in levels of bone mineral resorption markers within 4 to 6 weeks a decrease in and bone mineral formation markers in 2 to 3 months.15 These levels remain reduced for the duration of therapy.
Although diagnosis of osteoporosis is clinical, BMD must be measured to establish the diagnosis. The American Association of Clinical Endocrinologists lists indications for BMD determination:
Techniques of measurement include quantitative ultrasound, measuring the speed of sound and attenuation of the ultrasonic beam in the bone. Measurements are limited to peripheral bone (usually the calcaneus) and are very precise (coefficient of variation <1%). Currently, ultrasound results suggesting osteoporosis should be followed by BMD measurement using dual x-ray absorptiometry (DEXA).
DEXA is widely accepted as a standard technique for BMD measurements. Standard measurement consists of imaging the spine in the anteroposterior (AP) projection and imaging the hip area. Spinal measurements in the lateral projection are also possible and may be better for predicting spinal fracture than the AP projection. Approximately 15% of patients have high bone density at one site and low bone density at another, and measurements at multiple sites is desirable. DEXA measures area (apparent) bone density rather than true, volumetric bone density. Density is expressed as bone mineral content per unit of projected bone area (g/cm2).
Quantitative computed tomography (QCT) is only method able to measure true (volumetric) bone density, expressed as g/cm3. However, QCT is seldom used due to expense, higher radiation dose, and lower reproducibility than DEXA.
General preventive measures against osteoporosis should be emphasized whenever possible. Adequate dietary calcium intake is one of the mainstays (Table 2). The needs may be met through a diet rich in calcium (e.g., milk, dairy products, calcium-fortified fruit juices) or by use of calcium supplements. Patients with untreated hypercalciuria should not take calcium supplements because of the risk of renal calculi. Vitamin D should be prescribed whenever there is suspicion of inadequate intake and particularly in elderly patients. About 800 IU/day is considered sufficient. Good nutrition with adequate caloric and protein intake should be promoted.
|US RDA Ca||800 mg/d||1200 mg/d||800 mg/d||800 mg/d|
|Consensus development conference Ca||None provided||1200 mg/d||1000 mg/d||1500 mg/d|
|NIH Consensus Development Conference||800-1200 mg/d||1200-1500 mg/d||1000 mg/d||<65 yr on HRT: 1000 mg
All others: 1500 mg/d.
HRT, hormone replacement therapy; NIH, U.S. National Institutes of Health; RDA, U.S. recommended daily allowance.
Use of tobacco and excessive alcohol use should be strongly discouraged. Regular exercise is integral for development of the skeleton during growth and development and might slow bone loss in the elderly. In addition, it promotes agility, flexibility, and strength, possibly preventing falls.
Selective estrogen-receptor modulators (SERMs) are a group of medications that are useful in treating osteoporosis and that may be free of undesirable estrogen effects on reproductive tissues.16 They consist of tissue-selective receptor agonists raloxifene and tamoxifen, which have both estrogen agonist and antagonist properties. Raloxifene has estrogen-like activity on estrogen receptors in bone and cardiovascular tissue but not in endometrium and breast. Raloxifene preserves bone density, decreases serum total cholesterol level, and inhibits aortic accumulation of cholesterol. It does not cause endometrial or breast tissue hyperplasia.
In clinical trials, raloxifene caused a modest increase in BMD in all tested skeletal sites (2.4% in lumbar spine and 2.0% for whole body) over 2 years. These changes persisted during the third year, and markers of bone turnover were suppressed to the normal premenopausal range in raloxifene-treated women. It appears that the antagonistic effect on breast has a protective effect on the incidence of breast cancer in women treated with raloxifene. There was no increase in endometrial cancer, but an increased incidence of thromboembolic disease is observed. Raloxifene is approved for osteoporosis prevention by the U.S. Food and Drug Administration (FDA).
Bisphosphonates are medications that inhibit bone resorption and have minimal side effects. After administration they attach to bone surfaces. During osteoclast resorption of the bone, bisphosphonates are released and prevent osteoclast activity.17 Bisphosphonates are widely used for prevention and treatment of osteoporosis, as well as hypercalcemia of malignancy. Table 3 lists the available bisphosphonates.
|Generic Name||Trade Name|
* Not available in the United States.
Alendronate is shown to increase BMD in the spine, femoral neck, and greater trochanter area and to decrease the risk of vertebral fracture at dose of 10 mg/day in postmenopausal women,18 even if they have already had a vertebral fracture or are older than 75 years. The BMD is maintained in those continuing alendronate, and BMD decreased in those switched to placebo. Alendronate is used for osteoporosis treatment (10 mg/day and 70 mg/week orally) and prevention (5 mg/day or 35 mg/week orally).19
Although rare, pill-induced esophagitis and ulcers can occur, and can be severe enough to warrant hospitalization and cause esophageal stricture. Hence, alendronate should not be given to patients with active upper GI disease, and it should be stopped if patients develop any symptoms of esophagitis. Alendronate should be taken on empty stomach with a glass of water (240 mL) while standing or sitting to facilitate passage of the pill from esophagus to stomach. The patient should stay upright for 30 minutes after taking the pill and not eat anything so as to improve absorption of the drug and prevent reflux.
Risedronate is safe and effective in preventing bone loss caused by corticosteroids and in postmenopausal women with normal bone density.20 The gastrointestinal side effects of risedronate may be less severe than with alendronate as demonstrated by a lower incidence of gastric ulcers (4.1% vs. 13.2%) after 2 weeks of daily therapy. Daily, weekly, and monthly oral dosing is available.
Ibandronate in a daily or monthly oral regimen or by IV every 3 months is also approved for treating postmenopausal osteoporosis.
Pamidronate given by IV infusion is not approved by the FDA but has been used to treat postmenopausal and corticosteroid-induced osteoporosis and to prevent postmenopausal osteoporosis.
Zoledronate is administered once a year as an infusion of 5 mg in 15 minutes. It powerfully increases BMD and reduces fractures. It avoids GI side effects and is well tolerated. Flulike illness is main side effect, and that can be mitigated by administration of acetaminophen or other NSAID before infusion.
The one rare complication common to all bisphosphonates is jaw osteonecrosis. Unfortunately, definition of this disorder is not clear and many patients in whom jaw osteonecrosis is diagnosed had other dental conditions when they were evaluated by experts.
Calcitonin is used in injection form (SC or IM) and as intranasal spray. Calcitonin injections are shown to increase BMD in the spine and reduce vertebral fracture better than calcium alone. Calcitonin has a significant analgesic effect on bone pain by an unknown mechanism,21 and it might have potential for reducing the pain of vertebral fracture in the acute setting.
Recombinant human PTH (hrPTH) is anabolic therapy. Given as a once-daily SC injection in humans, it has demonstrated a marked increase of BMD of the lumbar spine and hip. Vertebral fractures were reduced about 70% and nonvertebral fractures were reduced about 50% in studies.22 hrPTH is approved for use up to 24 months.
Treating and preventing osteoporosis has a goal of preventing fracture. Raloxifene has a demonstrated ability to reduce vertebral fracture risk in postmenopausal women who have osteoporosis regardless of the presence of prevalent vertebral fracture, reducing the risk to 0.45 if there is no prevalent fracture and to 0.70 if prevalent fracture is present. The same study could not demonstrate an effect of therapy on nonvertebral fractures.
Alendronate is quite effective in reducing the incidence of new vertebral fractures in patients with or without prevalent vertebral fracture (48%), as well as hip fractures (51%) and wrist fractures (48%).23
Risedronate has been shown to reduce vertebral fractures by 41% and 49% in patients with and without prevalent vertebral fractures, respectively.24 These studies also demonstrated reduction in nonvertebral fractures by 33% to 39%. Significant reduction in hip fractures has been shown. A significant effect on fracture risk is seen after only 1 year of treatment.
Calcitonin has been shown to modestly reduce the risk of hip fracture if given by injection, in comparison with the patient's taking only calcium (relative risk, 0.69 and 0.75, respectively). It reduces the risk of vertebral fractures if given as nasal spray.25
The hrPTH has reduced vertebral fracture between 66% and 69% and has reduced nonvertebral fractures by 53%. Benefit was apparent after 8 months of treatment.22
In light of presented information I propose the following guidelines for testing and treatment of patients with suspected or established osteoporosis.
A careful history should be taken to assess for risk factors for osteoporosis (see Box 2) and falling in each patient. Patients should be educated about osteoporosis and the importance of prevention and treatment. Instructions for adequate nutrient intake, especially calcium, vitamin D, and protein should be provided. Benefits of engaging in physical regular activities should be emphasized. Patients should be educated about the detrimental effects of alcohol and tobacco abuse. Willingness of the patient to accept preventive measures and medications for osteoporosis should be established.
Patients perceived to be at higher risk include those with a history of hip or vertebral fracture in first-degree relative, patients with low body weight (<127 lbs in women), all women ages 20 to 55 years with a history of fracture not caused by significant trauma, patients with history of falling, patients with medical conditions that cause secondary osteoporosis, patients taking medications detrimental to bone health, and women 65 years old or older.
The evaluation should consist of laboratory testing and BMD measurements. Laboratory testing includes serum calcium, phosphorus, 25(OH) vitamin D, alkaline phosphatase, liver enzymes, indices of renal function, total protein and albumin, and 24-hour urinary calcium excretion. Tests aimed at secondary causes of osteoporosis should be performed in patients with clinical suspicion of these conditions (see Table 1). BMD measurement should be performed on the nondominant hip and an AP scan should be made of the spine using DEXA at the facility where it will be possible for patient to have subsequent BMD measurements performed (to ensure use of the same DEXA machine). Patients who are suspected of having osteoporosis based on quantitative ultrasound should have the diagnosis confirmed by DEXA.
Based on the results of the evaluation, patients should be advised about preventive measures against osteoporosis and falling, offered treatment, or referred to an osteoporosis specialist.
Preventive measures consist of adequate nutrition (calcium, vitamin D, protein), regular physical exercise, cessation of smoking, and fall prevention (adequate lightning, hand rails, anchored rugs, and adequate shoes). Prevention only, without further intervention, should be implemented by patients with normal BMD at all measured sites (T-score no less than −1), those with BMD T-score between −1 and −2.5 at any site and without risk factors, patients taking medications that may increase propensity to fall, and patients not willing to accept any other form of treatment.
Treatments of osteoporosis available to primary care physician include alendronate, risedronate, zoledronate, ibandronate raloxifene, calcitonin, and rhPTH in addition to preventive measures. Candidates for treatment include patients with BMD T-score less than −2.5, patients with BMD T-scores less than −1.5 and presence of one or more risk factors for osteoporosis, patients with demonstrated bone loss despite adequate prevention measures, and patients with low-trauma bone fracture and BMD T-score less than −1.0.
Osteoporosis specialist should be consulted for further management of exceptional patients:
Patients who are evaluated for osteoporosis should be re-evaluated on a yearly basis to assess their adherence to the recommended prevention and therapeutic measures and to seek new signs or symptoms suggesting osteoporotic complications. These patients should have serial BMD measurements performed on the same DEXA machine.
Patients with unusually high BMD might not need further measurements. Patients with normal BMD may have repeated measurements at 3- to 5-year intervals. Patients who are implementing an osteoporosis prevention program and who ahve borderline BMD (T-score between −1 and −2.5) should have BMD measurements at intervals of 1 to 2 years until BMD is stabilized and then at 2 to 3-year intervals. Patients treated for established osteoporosis should have BMD measurements every year until stable BMD is demonstrated, and then every 2 years after that. However, insurance companies and government regulations might limit the number and frequency of serial BMD measurements.