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 Primary osteoporosis represents bone mass loss unassociated with any other chronic illness and related to aging and loss of the gonadal function in females and the aging process in males.

Secondary osteoporosis results from a variety of chronic conditions that significantly contribute to bone mineral loss, or from effects of medications and nutritional deficiencies. Causes of secondary osteoporosis are listed in Table 1.

World Health Organization (WHO) defines osteoporosis as bone density (BD) that is 2.5 standard deviation (SD) or more below the young adult mean value (T-score < -2.5), while individuals with BD between 1 and 2.5 SD below average (T-score = -1 to -2.5) are said to have osteopenia.² Decreased BD imparts increased risk for bone fracture. Every 1 SD decrease in BD of the spine below the mean increases risk for new vertebral fracture by factor of 2.0 - 2.4.³

Osteoporosis is the most common metabolic bone disease in developed countries. Based on the WHO definition it was estimated that 54% of postmenopausal Caucasian females in the U.S. have osteopenia while 30% have osteoporosis. Men and non-white women who are at risk add to the number significantly (30 million to 54 million affected individuals in U.S.).

About 1.3 million osteoporotic fractures occur each year in the U.S. 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 fractures is considerably higher in whites than in blacks. Two factors contribute to this difference; higher peak bone mass (highest bone mass achieved by an individual in their lifetime); and slower postmenopausal bone loss in the blacks.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 represent a great burden on society and individuals that 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 living with the disease for years might be the greatest burden of osteoporosis.⁵

Osteoporosis in men has recently been recognized as an important health problem, as almost 30% of all hip fractures and up to 20% of symptomatic vertebral fractures occur in men.⁶

Basic mechanisms responsible for development of primary 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 Caucasians (and Asians), and higher in men than women, resulting in lower incidence of osteoporosis in these populations.

Approximately half the bone mass is accumulated during pubertal development.⁷ This accumulation is associated with 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), which results in achievement of peak bone mass during the third decade of life.

The main factor influencing peak bone mass is genotype. Studies in twins and mother-daughter pairs suggest that 40% to 80% of variability in bone mineral mass is determined by genetic factors.

None of these proposed genetic markers has been found in a majority of patients with osteoporosis. At this time, knowledge about genetic basis of osteoporosis is insufficient to affect patient management.

In contrast to peak bone mass, it appears that rate of bone loss in individuals is mostly determined by environmental factors (nutritional, behavioral, and medications) in males and females. However, genetic factors also play an important role, mostly acting on estrogen status of an individual.

Nutritional Factors
Nutritional factors include dietary calcium intake, Vitamin D status, protein and calorie intake. Other nutrients and trace minerals were also implicated but are less certainly associated with development of osteoporosis. These include phosphorus, vitamins C and K, copper, zinc, and manganese.

It has been shown that increasing dietary intake of milk during adolescence improves bone mineral acquisition. Low calcium intake during childhood increases risk of fracture later in the life.⁸ Calcium intake is also positively correlated with bone mineral mass at all ages, and supplementation is shown to reduce rate of bone loss and decrease fracture incidence in calcium-deficient elderly.

Optimal calcium intake varies among different age groups and is population-specific. Typical U.S. diet is sodium and protein rich, both of which increase urinary calcium excretion, thus increasing dietary requirements. Current recommendation for calcium and other nutrient intake will be discussed in the paragraph on therapy.

Vitamin D is essential for bone mineral metabolism through its role in calcium absorption and osteoclastic resorption. Supplementation with vitamin D reduces rate of all fractures in the elderly who are deficient in this vitamin.

Protein and caloric malnutrition predisposes to falls and diminishes soft tissue cover (eg, fat and muscle) over bony prominences. Protein intake is a major determinant of outcome after hip fracture, and serum albumin level is the single best predictor of survival in these patients. Eating disorders affect BMD in a profound manner. The body weight history of females with anorexia nervosa is the most important predictor for development of osteoporosis in these patients.

Behavioral Factors
Behavioral factors important in pathogenesis of osteoporosis include physical activity, smoking, and alcohol consumption.

Bone mass is higher in top-level (collegiate and professional-level) athletes than in non-athletes. This is particularly pronounced in athletes engaging in strength training. Mechanical loading is shown to increase bone mass. The relationship between load and bone density is curvilinear and much more pronounced at low levels of loads, best seen as a bone loss during immobilization. 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 bone mineral mass. This may explain relatively modest improvements in BMD (1-3% in lumbar spine) seen in exercise trials using either endurance or strength training.⁹

Chronic alcohol abuse 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 has been estimated at 28% to 52%.¹⁰ It is likely that other nutritional deficiencies associated with chronic alcohol abuse play an important role in development of osteoporosis in alcoholics. In addition, smoking is often associated with alcoholism and is an independent risk factor for low bone mass.

Optimal bone metabolism is result of hormonal, nutritional and mechanical harmony and deficit in one area is usually impossible to overcome by improvements in others.

Medications
Several medications show clear association with osteoporosis (Table 1). Glucocorticoids are the most important and cause loss of mostly trabecular bone. Consequently, fractures occur most commonly in vertebrae, ribs, and ends of the long bones. Bone loss occurs very rapidly and may be as high as 20-40% during the first year of steroid use. Incidence of osteoporotic fractures in patients taking corticosteroids for more than 6 months has been estimated to be 30% to 50%. Dose of steroid that is detrimental to BMD in most people appears to be more than 7.5 mg of prednisone daily, but risk for fracture may be seen with even lower doses.¹²

Endocrine regulation of bone mass is an aspect of bone metabolism that deserves separate consideration. Female sex hormones (estrogens) are essential for reaching peak bone mass and for maintenance of bone in females and males. Estrogen deficiency is considered a principal cause of postmenopausal osteoporosis, causing uncoupling of bone formation from resorption and, thus, accelerating bone loss.¹³ It may also play an important role in male osteoporosis. Risk factors for low bone mineral density are summarized in Table 2.

The clinical expression of osteoporosis is a skeletal fracture. Vertebral fracture is the most common type of fracture associated with osteoporosis. Up to two thirds remain asymptomatic after compressive vertebral fracture has occurred. These fractures are diagnosed as incidental findings on x-rays taken for other reasons.

Fracture usually occurs during routine daily activities such as bending of the body, coughing or lifting and are most common in lumbar spine and lower thoracic vertebrae. In fact, if fracture is above T-7, diagnosis other than osteoporosis should be considered. Fracture occurrence may be accompanied by acute onset of pain, which may disappear or become chronic dull back pain. Multiple fractures may lead to significant height loss and development of thoracic kyphosis (Dowager's hump). Patients notice abdomen protuberance, change in the way clothes fit, and loss of waist. This is caused by the loss of the vertical dimensions of abdominal cavity due to vertebral collapses and shifting of abdominal content anteriorly. Restrictive respiratory problems are seen because of diminished volume of thoracic cage, and poor expansion with breathing.

Hip fractures are another common consequence seen in osteoporotic individuals and affect about 15% of females and 5% of males 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 distal radius (Colles' fractures) occur more often in patients with osteoporosis and may be caused by falls on an outstretched hand, but also after minor trauma.

History and physical examination are important in screening for secondary causes of osteoporosis and recording behavioral risk factors, use of medications, and presence of sign and symptoms of osteoporotic complications.

Using risk factors to prescreen patients for further diagnostic procedures has been shown to be inefficient and fails to identify a substantial proportion of patients with osteoporosis.

Laboratory Evaluation
Laboratory evaluation of the patient should be aimed toward diagnosing secondary causes of osteoporosis. Exact tests used depend on the specific clinical situation. An overview appears in Table 3.

Assessment of bone turnover may yield useful information and guide management decisions in some cases.

Biohemical Markers of Bone Metabolism
During the bone synthesis, osteoblasts make collagen (predominantly type I) and a variety of other noncollagenous proteins that may be measured in serum and urine. In addition, during the bone resorption by osteoclasts a collagen breakdown product is released in circulation and excreted in urine where it can be measured and used to assess dynamic status of bone metabolism. These tests are non-invasive, widely available and inexpensive. They may indicate changes in bone metabolism much faster than measurements of BMD and can be repeated frequently. However, these tests are new and their role in patient management is still being defined. Table 4 lists the tests.

Markers of Bone Formation
Terminal portions of the type I collagen molecules are cleaved of the procollagen during collagen assembly. Their serum concentration may be used as a measure of bone formation. Several assays can measure these cleaved carboxy-terminal or amino-terminal peptides in serum, but other tissues also produce type I collagen (particularly skin), and current assays are not able to distinguish between peptides of different origin.

Osteocalcin is small noncollagenous protein of osteoblastic origin that circulates in the several forms. Assays detecting either intact molecule or large amino-terminal fragment (residues 1-43) have been shown to be reliable bone formation markers.

Bone-specific alkaline phosphatase is produced by osteoblasts and is essential for proper mineralization of the skeleton. Newer assays using specific antibodies against bone-specific alkaline phosphatase have been developed and have cross-reactivity with alkaline phosphatase of other origin (liver) of 10% to 20%.

Markers of Bone Resorption
During the resorption of bone, type I collagen is degraded and degradation products are released into circulation and eventually excreted from the body via the kidneys. These promise to be the most useful bone mineral metabolism markers. Collagen fibrils in the matrix are bound together covalently by cross-links. These are derivatives of 3-hydroxypyridinium and bridge several collagen molecules stabilizing the collagen superstructure. There are two forms; pyridinoline cross-links (more abundant) and deoxypyridinoline cross-links (more bone-specific). Cross-links may be released into circulation as free or peptide bound, and are excreted into the urine. Both forms can be measured by immunoassays in urine, but gold standard remains to be a high-performance liquid chromatography (HLPC).

Hydroxyproline and hydroxylysine are amino acids formed inside the osteoblasts during the posttranslational processing of collagen. When bone is degraded they are released into circulation, metabolized in the liver and excreted in the urine where they can be measured by HPLC. Hydroxyproline is not specific for bone but is also produced in the skin. Accurate hydroxyproline measurements require collagen-free diet since dietary collagen can interfere with measured value. In contrast, hydroxylysine measurements are not influenced by dietary factors. The main disadvantage of these measurements is a lack of convenient immunoassay and need for HPLC.

Collagen molecules are cross-linked in specific places along the molecule. These regions are known as aminoterminal and carboxyterminal telopeptides. Several assays are developed for measurement of these telopeptides as they are released to circulation and into the urine after degradation of the type I collagen.

Tartrate-resistant (originating in bone) acid phosphatase and bone sialoprotein are other markers of bone resorption that are occasionally used.

Clinical use of the bone metabolism markers measured in the urine has been limited by the need to collect 24-hour urine or 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.

Long-term variability of bone metabolism markers in clinically stable individuals has been 20% to 30% for urinary measurements, and 10% to 15% for serum measurements. Consequently, large changes in the levels of bone metabolism markers are required to be of clinical significance. After initiation of successful antiresorptive therapy there is a marked decrease in levels of bone mineral resorption markers within 4 to 6 weeks, and bone mineral formation markers in 2 to 3 months.¹⁴ These levels should remain reduced for the duration of therapy.

Bone Density Measurements
Diagnosis of clinical osteoporosis is made from history of fractures or radiological evidence of the same, but diagnosis of asymptomatic, early osteoporosis requires measurement of BMD. American Association of Clinical Endocrinologists lists indications for BMD determination:

• Perimenopausal or postmenopausal women who are willing to accept therapeutic or preventive interventions if osteoporosis is diagnosed.
• Individuals whose x-ray findings suggest osteoporosis.
• Individuals starting or receiving long-term glucocorticoid therapy if therapeutic or preventive intervention is acceptable.
• Individuals with asymptomatic primary hyperparathyroidism in whom evidence of bone mineral loss would result in parathyroidectomy.
• Individuals treated for osteoporosis as a tool for monitoring response to therapy.

Techniques of measurement include quantitative ultrasound (US) measuring the speed of sound and attenuation of the ultrasonic beam in the bone. Results of these measurements correlate with bone density and strength¹⁵ and can predict hip fracture. Further confirmation of these findings may make US techniques an attractive alternative to DEXA because of lower cost, portability and lack of radiation exposure. Ultrasound measurements are limited to peripheral bone (usually calcaneus) and are very precise (coefficient of variation < 1%). These properties make quantitative US an attractive screening test for osteoporosis. Currently, US results suggestive of osteoporosis should be confirmed by measurement using DEXA.

Dual x-ray absorptiometry is widely accepted as a standard technique for BMD measurements. The x-ray tube is capable of producing two distinct radiation energies and, thus, allowing simultaneous measurements of two tissue types (bone and soft tissue, or lean tissue and fat tissue). This method may also be used as a precise instrument for body composition analysis.

The standard DEXA measurement consists of spine and hip imaging in anterior-posterior projection. Spinal measurements in lateral projection are also possible but are not standardized. Interpretation of the spinal DEXA measurements in the elderly may be difficult because of common arthritic changes. In individuals younger than 65 this is seldom seen and measurements are more reliable. Hip area is rarely affected by such difficulties and some authors recommend using it at all ages.¹⁶ Approximately 15% of patients may have high bone density at one site, and low at another and measurements at multiple sites may be desirable. Measurements of total body bone mineral content and density are also possible with DEXA and are useful for assessment of bone mineral accumulation during growth and development, and for body composition analysis.
It is important to realize that all of the above methods measure apparent bone density (g/cm²) calculated as bone mineral content per unit of projected area, rather than true, volumetric bone density (g/cm³).

Quantitative computed tomography (QCT) is the only method able to measure true (volumetric) bone density. This is achieved by comparing density of a desired area on the CT image with the densities of the standard (series of tubes filled with different concentrations of calcium solution) included in the field of view of the CT apparatus. Ability to measure BMD of the trabecular bone, on which structural strength mostly depends, may allow for slightly better prediction of vertebral fracture risk than with DEXA. 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 and at any age to optimize bone mass and preserve skeletal integrity. Ensuring adequate dietary calcium intake is one of the mainstays. This is particularly important in children and adolescents. Recommended daily calcium intake is presented in Table 5. These needs may be met either through diet rich in calcium (milk, dairy products, Ca fortified fruit juices etc), or by use of calcium supplements. Patients with untreated renal stones or hypercalciuria should only receive calcium supplementation under supervision of their medical condition.

Adequate Vitamin D supplementation should be prescribed whenever there is suspicion of inadequate intake and particularly in elderly patients. About 800 IU per day is considered sufficient intake but tests of serum and urinary vitamin D and calcium can more accurately determine the necessary amount.

Good general nutrition with adequate caloric and protein intake should also be promoted. Use of tobacco should be strongly discouraged, as well as excessive use of alcohol. Regular weight-bearing exercise is integral for development of skeleton during growth and development and might slow bone loss in elderly. In addition, it promotes agility, flexibility and strength, possibly preventing falls.

Hormonal replacement therapy (HRT) was considered standard of care for prevention and treatment of postmenopausal bone loss. Recently a doubt was raised about efficacy of HRT in fracture prevention in population not selected for osteoporosis. The HERS (Heart Estrogen/progestin Replacement Study) data showed no evidence of reduction in fracture incidence with HRT in older women.¹⁷ In addition, the latest data on excess risk from HRT therapy regarding the incidence of breast and endometrial cancer as well as incidence of stroke, coronary artery disease and other thrombotic incidents derived form the FHI (Female Health Initiative) study will force us to rethink it's role for therapy of osteoporosis. Table 6 lists available preparations for HRT.

Selective estrogen receptor modulators (SERM) are newer medications that may be free of undesirable effects on reproductive tissues.¹⁸ Raloxifene is tissue-selective receptor agonist, that has both estrogen agonist and antagonist properties. Raloxifene has estrogen-like activity on estrogen receptor in bone and cardiovascular tissue, but not in endometrium and breast. Raloxifene preserves bone density and decreases serum total cholesterol level. It does not cause endometrial hyperplasia or breast tissue hyperplasia.

In clinical trials raloxifene caused modest increase in BMD in all tested skeletal sites (2.4% in lumbar spine and 2.0% for whole body) over two years. These changes persisted during the third year, and markers of bone turnover were suppressed to the normal premenopausal range in raloxifene-treated females. It appears (but is not yet proven) that an antagonistic effect on breast tissue has protective effect on incidence of breast cancer in women treated with raloxifene. There was no increase in endometrial cancer, but increased incidence of thromboembolic disease is observed and comparable to the risk with estrogen. Raloxifene is FDA approved for osteoporosis prevention, and treatment.

Bisphosphonates are medications that inhibit bone resorption and have minimal side effects. After administration they attach to the bony surfaces and are released during the remodeling process to prevent osteoclast-mediated bone resorption.¹⁹

Bisphosphonates are widely used for prevention and treatment of osteoporosis. Table 7 lists available bisphosphonates.

Alendronate was the first such drug approved for treatment and prevention. It increases BMD in the spine, femoral neck and greater trochanter area, and decreases risk of vertebral and non-vertebral fractures at 10 mg/d in postmenopausal women²⁰ even if they already had vertebral fracture or are older than 75. Alendronate is used for osteoporosis treatment (10 mg per day orally) and prevention (5 mg per day orally). Recently, the FDA approved alendronate use in once weekly dosing schedule for treatment (70 mg) and prevention (35 mg) of osteoporosis, which is shown to be of similar efficacy as 1 mg and 5 mg daily dosing and had lower incidence of gastrointestinal (GI) side effects.²¹ It is also used in steroid induced osteoporosis. Incidence of upper GI problems in patients receiving alendronate in clinical trials is no different than with placebo, but pill-induced esophagitis and ulcer can occur, and be severe enough to warrant hospitalization and sometimes lead to esophageal stricture. Because of these complications, alendronate should not be given to patients with active upper GI disease, and should be stopped if patients develop any symptoms of esophagitis. Alendronate should be taken on empty stomach with water (240 ml) while standing or sitting to facilitate passage of the pill from esophagus to stomach. Patient should stay upright for 30 minutes after taking the pill and not eat anything to improve absorption of the drug and prevent reflux.

Risedronate is safe and effective in preventing bone loss caused by corticosteroids and in postmenopausal females with normal bone density.²² A daily 5 mg dose is taken in the same way as alendronate. It appears that gastrointestinal side effects of risedronate may be less severe than with alendronate as demonstrated by lower incidence of gastric ulcers (4.1% vs. 13.2%) in an endoscopic study after 2 weeks of therapy. Risedronate is FDA approved for prevention and treatment of steroid induced osteoporosis. It increases spinal and hip density and prevents vertebrae and hip fractures. A weekly 35 mg dose is now available.

Etidronate is given cyclically (usually 400 mg/d for two weeks every 15 weeks) and has demonstrated effectiveness in treatment of vertebral osteoporosis and reducing vertebral fractures in postmenopausal women,²³ and in patients taking glucocorticoids. It is approved in Canada and Europe, but not currently approved in the U.S. for treatment of osteoporosis.

Pamidronate is approved by FDA to treat hypercalcemia of malignancy and Paget's disease. It has been used off label to treat postmenopausal²⁴ and corticosteroid-induced osteoporosis, and prevent postmenopausal osteoporosis. It is administered intravenously in most cases with initial dose of 90 mg and subsequently 30 mg every 3 months over 1 hour. It is given to patients intolerant to other oral drugs.
Ibandronate, clodronate, tiludronate, and zoledronate are currently not approved for use in osteoporosis.
Calcitonin is used in injection form (subcutaneously and intramuscularly) and as intranasal spray. Injections (50-10 IU daily or every other day) are shown to increase BMD in spine and reduce vertebral fracture better than calcium alone. The metered nasal spray has replaced the injectable form. It stabilizes bones, prevents loss, and decreases vertebral fractures (<20%). Calcitonin is shown to have significant analgesic effect on bone pain by unknown mechanism²⁵ and may reduce pain of vertebral fracture.

Anabolic agent teriparatide (human recombinant PTH 1-34) increases bone density more (about twice as much) than antiresorptive therapies. It is given as daily subcutaneous injection at 20 µg per dose. This results in short lasting peak of serum PTH concentration that far exceeds normal level and stimulates bone formation while bone resorption is not significantly increased (as is seen with continuous infusion or in patients with primary hyperparathyroidism). Teriparatide therapy increases bone density of the spine after only 3 months²⁶ while hip BMD increases after 6-12 months.²⁷ Increase is first seen in trabecular bone, while cortical bone stays stable or even decreases slightly (1%-2%) in the first year of therapy and then starts to increase.

Combination therapy trials showed additive effect of estrogen with etidronate and alendronate²⁸ on BMD. Effect is modest and there is no data showing further decrease in fracture rate on combination therapy. Use of combination may be justified in patients who continue to lose bone mass on monotherapy. Combining anabolic therapy with rhPTH and antiresorptive therapy with bisophosphonate alendronate showed diminished BMD gains in men when compared to rhPTH alone.²⁹

Data show that estrogen reduces vertebral fracture rate by 50% or more in females taking it for 7 to 10 years.³⁰ Elderly individuals (over 75) may still experience senile bone loss and efficacy of estrogen may be less in this age group. Compiled data from literature suggest relative fracture risk of 0.7 in estrogen users versus non-users.

Raloxifene demonstrated ability to reduce vertebral fracture risk in postmenopausal women with osteoporosis regardless of presence of prevalent vertebral fracture, reducing the risk to 0.45 if there were no evidence of prevalent fracture and 0.70 if prevalent fracture was present.

Alendronate is quite effective in reducing incidence of new vertebral fractures in patients with or without prevalent vertebral fracture (48%), as well as hip fractures (51%) and wrist fractures (48%).³¹ In Fracture Intervention Trial (FIT), therapy with alendronate was associated with reduction of bed days and days of decreased activity, suggesting beneficial effect on quality of life.

Risedronate has been shown to reduce vertebral fractures by 41% and 49%, respectively, in patients with and without prevalent vertebral fractures.³² These studies also demonstrated reduction in non-vertebral fractures by 33% to 39%. Most recently, significant reduction in hip fractures has been shown. Significant effect on fracture risk is seen after only one year of risedronate treatment.³³

Nasal spray calcitonin has shown a small reduction in vertebral fractures (<20%) but no fracture reduction in the hip.³⁴

Therapy with hPTH-(1-34) for 18 months in osteoporotic postmenopausal women who had at least one previous vertebral fracture reduced the risk of new vertebral fracture by 65%, severe vertebral fracture by 90%, and nonvertebral fracture fragility fractures by 54%.³⁵

• Measures recommended for average risk patients:
• Take careful history to assess for osteoporosis risk factors (Table 2) and falling in each patient.
• Educate patients about osteoporosis and importance of prevention and treatment.
• Instruct for adequate nutrient intake, especially calcium, vitamin D, and protein.
• Emphasize benefits of regular physical activity.
• Educate about detrimental effects of alcohol and tobacco abuse.
• Establish patient willingness to accept preventive measures and medications for osteoporosis.

Patients perceived to be at higher risk include:

• Individuals with a history of hip or vertebral fracture in a first-degree relative
• Individuals with low body weight (less than 127 lbs in females)
• All women with history of fracture between age 20 and 55 not caused by significant trauma
• Patients with a history of falling
• Patients with medical conditions that cause secondary osteoporosis (Table 1)
• Patients taking medications detrimental to bone health (Table 1)
• Women 65 years old or older

The evaluation should consist of laboratory testing and BMD measurements:

• Serum calcium, phosphorus, 25(OH) vitamin-D, alkaline phosphatase, liver enzymes, indices of renal function, total protein and albumin
• 24-hour urinary calcium excretion
• Tests aimed at secondary causes of osteoporosis in patients with clinical suspicion of these conditions (Table 3).
• BMD measurement of nondominant hip and AP scan of the spine using DEXA at the facility where it will be possible for patient to have subsequent BMD measurements performed (to assure use of the same DEXA machine
• Patients who are suspected of having osteoporosis based on quantitative US should have 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 lighting, hand rails, anchored rugs, and adequate shoes). Prevention only, without further intervention, should be implemented by the individuals with:

• Normal BMD at all measured sites (T-score no less than -1)
• BMD T-score between -1 and -2.5 at any site and without risk factors
• Patients taking medications that may increase propensity to fall
• Patients not willing to accept any other form of treatment

Treatment available to primary care physicians include alendronate, risedronate, raloxifene, and calcitonin in addition to the preventive measures. Candidates for treatment include:

• Patients with BMD T-score of less than -2.5
• Patients with BMD T-scores of less than -1.5 and presence of one or more risk factors for osteoporosis
• Patients with demonstrated bone loss despite adequate prevention measures
• Patients with low-trauma bone fracture and BMD T-score of less than -1.0
  

Osteoporosis specialists should be consulted for further management of patients with:

• Unusually severe osteoporosis (BMD T-score less than -3.0)
• Osteoporosis at a young age (premenopausal women, or man younger than 60)
• Fractures despite normal or low normal BMD
• Transplanted organs
• Secondary causes of osteoporosis
• No response to treatment (fractures or continuing bone loss while on therapy).
• Inability to tolerate FDA-approved treatment

Patients evaluated for osteoporosis should be reevaluated yearly to assess adherence to recommended prevention and therapeutic measures, and to detect any new signs or symptoms suggestive of osteoporotic complications. These patients should have serial BMD measurements performed on the same DEXA machine:

• Individuals with unusually high BMD may not need further measurements.
• Individuals with normal BMD may have repeated measurements in the intervals of 3 to 5 years.
• Patients implementing osteoporosis prevention program and with borderline BMD (T-score -1 and -2.5) should have BMD measurements in intervals of 1 to 2 years until BMD is stabilized and than in 2-to-3-year intervals.
• Patients treated for established osteoporosis should have BMD measurements every year until stable BMD is demonstrated, and every 2 years after that.

1. Heaney RP. Pathophysiology of osteoporosis. Endocrin Metabol Clin North Am. 1998;27:255-65.
   
   
2. Kanis JA, Melton LJ III, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res. 1994;9:1137-41.
   
   
3. Wasnich R. Bone mass measurement: prediction of risk. Am J Med. 1993;95:65-105.
   
   
4. Meier D, Luckey M, Wallenstein S, Lapinski RH, Catherwood B. Racial differences in pre- and postmenopausal bone homeostasis: association with bone density. J Bone Miner Res. 1992; 7:1181-1189.
   
   
5. Farmer ME, White LR, Brody JA, Bailey KR. Race and sex differences in hip fracture incidence. Am J Public Health. 1984;74:1374-1380.
   
   
6. Pande I, Francis RM. Osteoporosis in men. Best Practice & Research Clinical Rheumatology. 2001;15:415-427.
   
   
7. Bonjour JP, Theintz G, Buchs B, Slosman D, Rizzoli R. Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence. J Clin Endocrin Met. 1991;73:555-563.
   
   
8. Matkovic V, Kostial K, Simonovic I, Buzina R, Brodarec A, Nordin BE. Bone status and fracture rates in two regions of Yugoslavia. Am J Clin Nutr. 1979;32:540-549.
   
   
9. Cummings SR, Nevitt MC, Browner WS, at al. Study of Osteoporotic Fractures Research Group; Risk factors for hip fracture in white women. N Engl J Med. 1995;332:767-773.
   
   
10. Harding A, Dunlap J, Mattalina A, Azar F, O'Brien M, Kester M. Osteoporotic correlates of alcoholism in young males. Orthopedics. 1988;11:279-282.
    
    
11. Mazess R, Barden H. Bone mineral density in premenopausal women: Effects of age, dietary intake, physical activity, smoking and birth control pills. Am J Clin Nutr. 1991;53:132-142.
    
    
12. Libanati CR, Baylink DJ. Prevention and treatment of glucocorticoid-induced osteoporosis. A pathogenetic perspective. Chest. 1992;102:1426-35.
    
    
13. Manolagas SC. The role of IL-6 type cytokines and their receptors in bone. Annals of the New York Academy of Sciences. 1998;840:194-204.
    
    
14. Garnero P, Shih WJ, Gineyts E, Karpf DB, Delmas PD. Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab. 1994;79:1693-1700.
    
    
15. Bauer DC, Gluer CC, Cauley JA, et al. Broadband ultrasound attenuation predicts fractures strongly and indenpedently of densitometry in older women. Arch Int Med. 1997;157:629-634.
    
    
16. Cummings SR, Black D. Bone mass measurements and risk of fracture in Caucasian women: A review of findings from prospective studies. Am J Med. 1995;98(Suppl 2A):24S.
    
    
17. Cauley JA, Black DM, Barrett-Connor E, et al. Effects of hormone replacement therapy on clinical fractures and height loss: The Heart and Estrogen/Progestin Replacement Study (HERS). Am J Med. 2001;110:442-450.
    
    
18. Khovidhunkit W, Shoback DM. Clinical effects of raloxifene hydrochloride in women. Ann Intern Med. 1999;130:431-439.
    
    
19. Rodan GA, Fleisch HA. Bisphosphonates: Mechanism of action. J Clin Invest. 1996;97:2692-2696.
    
    
20. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med. 1995;333:1437-1443.
    
    
21. Scnitzer T, Bone HG, Crepaldi G, et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in treatment of osteoporosis. Alendronate Once-Weekly Study Group. Aging (Milano) 2000;12:1-12.
    
    
22. Mortensen L, Charles P, Bekker PJ, Digennaro J, Johnston CC. Risedronate increases bone mass in an early postmenopausal population: two year of treatment plus one year of follow-up. J Clin Endocrinol Metab. 1998;83;396-402.
    
    
23. Miller PD, Watts NB, Licata AA, et al. Cyclical etidronate in the treatment of postmenopausal osteoporosis: efficacy and safety after seven years of treatment. Am J Med. 1997;103:468-476.
    
    
24. Peretz A, Body JJ, Dumon JC, et al. Cyclical pamidronate infusions in postmenopausal osteoporosis. Maturitas. 1996;25:69-75.
    
    
25. Sambrook P, Birmingham J, Kelly P, et al. Prevention of corticosteroid osteoporosis: A comparison of calcium, calcitriol and calcitonin. N Engl J Med. 1993;328:1747-1752.
    
    
26. Body JJ, Gaich GA, Scheele WH, et al. A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002;87:4528-35.
    
    
27. Finkelstein JS, Klibanski A, Schaefer EH, Hornstein MD, Schiff I, Neer RM. Parathyroid hormone for the prevention of bone loss induced by estrogen deficiency. N Engl J Med. 1994;331:1618-23.
    
    
28. Lindsay R, Cosman F, Lobo RA, et al. Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: a randomized, controlled clinical trial. J Clin Endocrinol Metab. 1999;84:3076-3081.
    
    
29. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med. 2003;349:1216-26.
    
    
30. Lindsay R, Tohme JF. Estrogen treatment of patients with established postmenopausal osteoporosis. Obstet Gynecol. 1990;76:290-295.
    
    
31. Cummings S, Black D, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280:2077-2082.
    
    
32. Watts NB. Risedronate for the prevention and treatment of postmenopausal osteoporosis: results from recent clinical trials. Osteoporosis Int. 2001;12 (Suppl 3):S17-22.
    
    
33. Reid DM, Adami S, Devogelaer JP, Chines AA. Risedronate increases bone density and reduces vertebral fracture risk within one year in men on corticosteroid therapy. Calcif Tissue Int. 2001;69(4):242-247.
    
    
34. Silverman SL. Calcitonin. Rheum Clin North Am. 2001;27:187-196.
    
    
35. Neer RM, Arnaud CD, Zancehtta JR, et al. Effect of parathyroid hormone (1-34) on fracture and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434-1441.

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