Workup consists of appropriate laboratory studies to establish baseline values and to look for potential secondary causes of osteoporosis, along with measurement of bone mineral density (BMD) to assess bone loss and estimate the risk of fracture. Bone biopsy may be indicated in specific situations.
Conventional radiography is used for the qualitative and semiquantitative evaluation of osteoporosis; morphometry assesses the presence of fractures.  Quantitative imaging methods commonly used are dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT) scanning.  In the United States, current diagnostic and treatment criteria for osteoporosis are based solely on QCT hip and DXA spine or hip T-score measurements. [95, 96]
BMD should be measured at both the posteroanterior (PA) spine and hip in all patients undergoing DXA.  Forearm BMD should be measured under the following circumstances:
Hip and/or spine cannot be measured or interpreted
Very obese patients (over the weight limit for DXA table)
For information on American College of Radiology (ACR) recommendations for evaluating the appropriateness of BMD measurement tests for osteoporosis in patients at risk of developing this condition, see ACR Appropriateness Criteria for osteoporosis and bone mineral density.
Children and adolescents
The official position of the International Society for Clinical Densitometry (ISCD) is that “fracture prediction should primarily identify children at risk of clinically significant fractures” (eg, fracture of lower-extremity long bones, vertebral compression fractures, or two or more upper-extremity long-bone fractures).  However, densitometric criteria alone should not be used to diagnose osteoporosis in children and adolescents. Rather, such a diagnosis in this population must be based on a low bone mineral content (BMC) or BMD in conjunction with a clinically significant fracture history. Fractures are considered clinically significant  if one or more of the following are present:
Lower-extremity long-bone fracture
Vertebral compression fracture
Two or more upper-extremity long-bone fractures
Low BMC or BMD, defined as a BMC or areal BMD Z-score that is –2.0 or less, adjusted for age, sex, and body size, as appropriate
Laboratory studies are used to establish baseline conditions or to exclude secondary causes of osteoporosis. They are summarized in Tables 5 and 6, below.
Table 5. Baseline Studies for Baseline Conditions in Osteoporosis (Open Table in a new window)
|Complete blood count (CBC)||CBC results may reveal anemia, as in sickle cell disease (patients with anemia, particularly those older than 60 years, should also be evaluated for multiple myeloma), and may raise the suspicion for alcohol abuse (in conjunction with results from serum chemistry tests and liver function tests)|
|Serum chemistry levels||
Calcium levels can reflect underlying disease states (eg, severe hypercalcemia may reflect underlying malignancy or hyperparathyroidism; hypocalcemia can contribute to osteoporosis)
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
levels of serum calcium, phosphate, alkaline phosphatase, and 25(OH) vitamin D may be obtained to assess osteomalacia
Creatinine levels may decrease with increasing parathyroid hormone (PTH) levels or may be elevated in patients with multiple myeloma
Creatinine levels are also used to estimate creatinine clearance, which may indicate reduced renal function in elderly patients
Magnesium is very important in calcium homeostasis  ; decreased levels of magnesium may affect calcium absorption and metabolism
|Liver function tests||Increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), bilirubin, and alkaline phosphatase may indicate alcohol abuse|
|Thyroid-stimulating hormone (TSH) level||Thyroid dysfunction has been associated with osteoporosis and should therefore be ruled out |
|25-Hydroxyvitamin D level||This test assesses for vitamin D insufficiency; inadequate vitamin D levels can predispose persons to osteoporosis|
An important study by Tannenbaum evaluated 173 healthy women (ages 46-87 years) for secondary causes of osteoporosis and found that 55 (32%) had a previously undiagnosed disorder of bone or mineral metabolism.  Given that occult disorders are so common in patients with osteoporosis, minimal laboratory screening is indicated in all patients who present with decreased bone mass.
Table 6. Tests for Secondary Causes of Osteoporosis (Open Table in a new window)
|Tests for Secondary Causes of Osteoporosis||Disorder|
|24-Hour urine calcium level||This study assesses for hypercalciuria and hypocalciuria|
|Parathyroid hormone (PTH) level||An intact PTH result is essential in ruling out hyperparathyroidism; an elevated PTH level may be present in benign familial hypocalciuric hypercalcemia|
|Thyrotropin level (if on thyroid replacement)||Experts are divided on whether to include thyrotropin testing, regardless of a history of thyroid disease or replacement; however, one study showed reduced femoral neck bone mineral density (BMD) in women with subclinical hypothyroidism and hyperthyroidism |
|Testosterone and gonadotropin levels in younger men with low bone densities||These tests may help evaluate a sex hormone deficiency as a secondary cause of osteoporosis|
|Urinary free cortisol level and tests for adrenal hypersecretion||These tests are used to exclude Cushing syndrome, which, although uncommon, can lead to rapidly progressive osteoporosis when the condition is present; a urine free cortisol value or overnight dexamethasone suppression test should be ordered in suspected cases|
|Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP)||These are used to identify multiple myeloma|
|Antigliadin and antiendomysial antibodies||These tests can help identify celiac disease|
|Serum tryptase and urine N-methylhistamine||These tests help identify mastocytosis|
|Bone marrow biopsy||This study is obtained when a hematologic disorder is suspected|
Biochemical Markers of Bone Turnover
Biochemical markers of bone turnover reflect bone formation or bone resorption. These markers (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.
Currently available serum markers of bone formation (osteoblast products) include the following:
Bone-specific alkaline phosphatase (BSAP)
Carboxyterminal propeptide of type I collagen (PICP)
Aminoterminal propeptide of type I collagen (PINP)
Currently available urinary markers of bone resorption (osteoclast products) include the following:
Free and total pyridinolines (Pyd)
Free and total deoxypyridinolines (Dpd)
N-telopeptide of collagen cross-links (NTx) (also available as a serum marker)
C-telopeptide of collagen cross-links (CTx) (also available as a serum marker)
Currently available serum markers of bone resorption include cross-linked C-telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase, as well as NTx and CTx. Of all the biochemical markers of bone turnover mentioned above, the ones most commonly used in clinical practice are BSAP, OC, urinary NTx, and serum CTx.
BSAP can be mildly elevated in patients with fractures. In addition, patients with hyperparathyroidism, Paget disease, or osteomalacia can have elevations of BSAP. Serum OC levels, if high, indicate a high-turnover type of osteoporosis.  Elevation of urinary NTx (>40 nmol bone collagen equivalent per mmol urinary creatine) indicates a high turnover state.
Significant controversy exists regarding the use of these biochemical markers, and concerns have been raised about intra-assay and interassay variability. Further study is needed to determine the clinical utility of these markers in osteoporosis management.
For more information, see the Medscape Reference article Bone Markers in Osteoporosis.
Plain radiography is recommended to assess overall skeletal integrity. In particular, in the workup for osteoporosis, plain radiography may be indicated if a fracture is already suspected or if patients have lost more than 1.5 inches of height (see the following image).
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 (see the following image). A scoliosis series is useful for detecting occult vertebral fractures.
Radiographic findings can suggest the presence of osteopenia, or bone loss, but cannot be used to diagnose osteoporosis. Osteopenia is suggested by a cortical width that is less than the medullary width. Radiographs may also show fractures or other conditions, such as osteoarthritis, disk disease, or spondylolisthesis.
Plain radiography is not as accurate as BMD testing. Because osteoporosis predominantly affects trabecular bone rather than cortical bone, radiography does not reveal osteoporotic changes until they affect the cortical bone. Cortical bone is not affected by osteoporosis until more than 30% of bone loss has occurred. Approximately 30-80% of bone mineral must be lost before radiographic lucency becomes apparent on radiographs.  Thus, plain radiography is an insensitive tool for diagnosing osteoporosis.
Dual-Energy X-Ray Absorptiometry (DXA)
Several large prospective studies have shown that BMD measurements of the distal and proximal femur and the vertebral bodies can predict the development of the major types of osteoporotic fractures. BMD has been shown to be the best indicator of fracture risk. According to the National Osteoporosis Foundation (NOF), evaluating BMD on a periodic basis is the best way to monitor bone mass and future fracture risk, [2, 4] although there is controversy about how frequently to measure this. 
DXA is currently the criterion standard for the evaluation of BMD. [3, 4] Compared with other screening tools (eg, calcaneal quantitative ultrasonography, the Simple Calculated Osteoporosis Risk Estimation [SCORE]), DXA has been found to be efficacious and cost-effective.  DXA is not as sensitive as quantitative computed tomography (QCT) scanning for detecting early trabecular bone loss, but it provides comparable costs,  it is done on an outpatient basis,  and there are no special requirements for performing it. Also, radiation exposure is kept to a minimum.
DXA is used to calculate BMD at the lumbar spine, hip, and proximal femur (see the images below). 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.  Peripheral DXA is used to measure BMD at the wrist; it may be most useful in identifying patients at very low fracture risk who require no further workup.
Although measurement of BMD 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 BMD determination include spinal fractures, osteophytosis, scoliosis, and extraspinal (eg, aortic) calcification.
Bone density data from a DXA are reported as T-scores and Z-scores. The T-score is the value compared to that of control subjects who are at their peak BMD, whereas the Z-score reflects a value compared to that of patients matched for age and sex. [5, 6, 7, 8]
NOF, ISCD, and USPSTF recommendations
The NOF,  the International Society for Clinical Densitometry (ISCD),  and the US Preventive Services Task Force (USPSTF)  have issued recommendations on BMD measurement.
The 2014 NOF guidelines recommend BMD measurement in the following patients  :
Women age 65 years and older and men age 70 years and older, regardless of clinical risk factors
Younger postmenopausal women and women in menopausal transition with clinical risk factors for fracture
Men age 50-69 years with clinical risk factors for fracture
Adults who have a condition associated with low bone mass or bone loss (eg, rheumatoid arthritis)
Adults who take a medication associated with low bone mass or bone loss (eg, glucocorticoids, ≥5 mg of prednisone daily for ≥3 mo)
The 2013 ISCD Official Positions recommend bone density testing in the following patients  :
Women aged 65 and older
Post-menopausal women younger than age 65: a bone density test is indicated if they have a risk factor for low bone mass (eg, low body weight, prior fracture, high-risk medication use, disease or condition associated with bone loss)
Women during the menopausal transition with clinical risk factors for fracture (eg, low body weight, prior fracture, high-risk medication use)
Men age 70 years and older
Men younger than 70 years who have a risk factor for low bone mass (eg, low body weight, prior fracture, high-risk medication use, disease or condition associated with bone loss)
Adults with a fragility fracture
Adults with a disease or condition associated with low bone mass or bone loss
Adults taking medications associated with low bone mass or bone loss
Anyone being considered for pharmacologic therapy
Anyone being treated, to monitor treatment effect
Anyone not receiving therapy in whom evidence of bone loss would lead to treatment
Women discontinuing estrogen should be considered for bone density testing according to the indications listed above.
The USPSTF recommends measuring BMD in the following patients  :
Women age 65 years and older without previous known fractures or secondary causes of osteoporosis
Women younger than 65 years whose 10-year fracture risk is equal to or greater than that of a 65-year-old white woman without additional risk factors
These recommendations do not contradict the NOF recommendations for screening in women. However, in contradiction to the NOF recommendation, the USPSTF makes no recommendation for screening men without risk factors. For men without previous known fractures or secondary causes of osteoporosis, the USPSTF has determined that current evidence is insufficient to assess the balance of benefits and harms of screening.
WHO T-score and Z-score criteria
World Health Organization (WHO) criteria define a normal T-score value as within 1 standard deviation (SD) of the mean BMD value in a healthy young adult. Values lying farther from the mean are stratified as follows  :
T-score of –1 to –2.5 SD indicates osteopenia
T-score of less than –2.5 SD indicates osteoporosis
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. Of note, about half of osteoporotic fractures occur in women with a T-score greater than –2.5, and the other half occur in those with a T-score lower than –2.5, the WHO’s cutoff for DXA-based diagnosis of osteoporosis.
This diagnostic classification should not be applied to premenopausal women, men younger than 50 years, or children. Instead, Z-scores adjusted for ethnicity or race should be used, with values of –2.0 SD or lower defined as "below the expected range for age" and those above –2.0 SD being "within the expected range for age." The diagnosis of osteoporosis in these groups should not be based on densitometric criteria alone.
International Society of Clinical Densitometry (ISCD) positions
The following are the official positions of the ISCD on peripheral DXA (pDXA)  :
pDXA can be used in postmenopausal women for fracture risk assessment (vertebral and global fragility fracture risk), although its vertebral fracture predictive ability is weaker than central DXA and heel quantitative ultrasonography (QUS); evidence for use in men is insufficient
The WHO diagnostic classification can be applied only to DXA a the femur neck, total femur, lumbar spine, and the 33% radius region of interest (located in the distal forearm) measured by DXA or pDXA devices utilizing a validated young-adult reference database
If central DXA cannot be done, radius pDXA measurements can be used to identify patients in whom pharmacologic treatment should be initiated; the fracture probability, based on both device-specific thresholds and clinical risk factors, should be high in those patients
pDXA cannot be used to monitor the effects of osteoporosis treatments
Measurements of bone strength
Measurements of bone strength that can be obtained by DXA, with appropriate software, include hip structural analysis (HSA) and trabecular bone scores (TBS). An additional technique for measurement of bone strength, finite element analysis (FEA), can be based on either computed tomography (CT) or DXA .
Hip structural analysis
HSA uses data obtained from DXA examinations to estimate structural properties of the femur. Specifically, estimated parameters such as femoral neck cross-sectional moment of inertia, hip axis length, and cross sectional area parameters can be combined with clinical characteristics (eg, age, weight, ethnicity) to calculate the femoral strength index, which is ultimately an estimate of how well the femur can withstand a direct impact to the greater trochanter. 
HSA measurements have been found to correlate well with other measures of bone density such as DXA-derived BMD and quantitative CT  but have not consistently demonstrated superiority.  Furthermore, the ability of HSA to determine bending strength is limited to the specific plane of the image; comparisons require consistent and correct positioning, which has proven a hindrance to widespread clinical use. [108, 109]
Trabecular bone scores
TBS are another DXA-derived measurement of bone strength. TBS uses “gray-level texture measurements” from two-dimensional DXA scans of the lumbar spine to derive bone strength parameters.  TBS may complement standard measures of BMD. 
Finite element analysis
Traditional methods of measuring bone density (eg, DXA), while inexpensive and easy to perform, do not account for all the material properties of bone. In fact, many females, and even more males, who sustain hip fractures have BMDs above the osteoporotic threshold.  FEA is a relatively new technique for measuring fracture risk that is emerging as a highly accurate tool to evaluate bone strength.
With FEA, three-dimensional renderings of bone created using CT images  or DXA  are subjected to computer-simulated loads until fracture. This technique for measuring bone strength is mostly used in research settings, but has the potential for future clinical use. 
Quantitative Computed Tomography
Quantitative computed tomography (QCT) is another method employed to measure spinal BMD. At the spine, it measures 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. QCT scanning of the spine is the most sensitive method for diagnosing osteoporosis, because it measures trabecular bone within the vertebral body. At the hip, QCT produces DXA-equivalent T-scores and BMD measures in g/cm2. [95, 96]
QCT scanning may be useful in identifying fractures. It can be used to identify not only the fracture line but also areas of callus formation and sclerosis, consistent with healing fracture. It may also be used for evaluation of metastatic bone disease.
Compared with DXA scanning, QCT has a comparable cost  and precision. [95, 116, 117, 118] In addition, as with DXA, no dye injection should be used.  QCT is a very sensitive technique when repeated measurements are needed to detect small changes in BMD, and modern three-dimensional (3D) QCT acquisition has a scan time less than 10 seconds for the lumbar spine or proximal femur, and there is no interference by osteophytes. [120, 121] However, QCT requires a higher radiation dose. 
Nonetheless, QCT scanning is less commonly used than DXA; based on Medicare data, about 5% of all BMD assessments are done with QCT scanning. Smaller, rural hospitals may favor QCT scanning, as they often already have a CT scanner for trauma cases and may not be able to afford a DXA machine as well.
International Society of Clinical Densitometry positions
The following are the official positions of the International Society of Clinical Densitometry (ISCD) on QCT of the lumbar spine (ref31)
When using single-slice QCT, L1-L3 should be scanned; with 3D QCT, L1-L2 should be scanned
QCT of the spine can be used to predict vertebral fractures in postmenopausal women, but there is insufficient evidence to recommend spine QCT for spinal fracture prediction in men or hip fracture prediction in both women and men
Peripheral QCT (pQCT) of the forearm at the ultra-distal radius predicts hip, but not spine, fragility fractures in postmenopausal women; there is lack of sufficient evidence to support this position for men
Because T-scores by QCT are not equivalent to T-scores based on DXA, the World Health Organization (WHO) diagnostic classification of osteoporosis cannot be used
If central DXA measurements cannot be obtained, QCT of the spine or pQCT of the radius can be used to identify patients who are appropriate candidates for pharmacologic treatment; fracture probability based on both device-specific thresholds and clinical risk factors should be high in those patients
QCT of the spine can be used to monitor age-, disease- and treatment-related BMD changes via trabecular BMD of the lumbar spine
The following are the official positions of the ISCD on pQCT of the radius  :
pQCT of the forearm at the ultra-distal radius cannot be used for fracture risk assessment of the spine, but does predict hip fragility fractures in postmenopausal women
There is insufficient evidence to recommend pQCT for fracture risk prediction in men
As with QCT of the spine, pQCT of the radius cannot be used to diagnose osteoporosis based on the WHO diagnostic classification
As with QCT of the spine, pQCT of the radius along with clinical risk factors can be used to initiate pharmacologic treatment if central DXA cannot be obtained
pQCT measurements of the trabecular and total BMD of the ultra-distal radius can be used to monitor age-related BMD changes
Single-Photon Emission CT
Single-photon emission computed tomography (SPECT) scanning represents a tomographic (CT-like) bone imaging technique that offers better image contrast and more accurate lesion localization than planar bone scanning. It increases the sensitivity and specificity of bone scanning for detection of lumbar spine lesions by 20-50% over planar techniques.
SPECT scanning is helpful when accurate localization of skeletal lesions within large and/or anatomically complex bony structures is required. This localization is possible because SPECT can visualize bony structures that would overlap on planar images (eg, separating vertebral body, facet and pars interarticularis lesions).
Quantitative ultrasonography (QUS) of the calcaneus is a low-cost portable screening tool. It has the advantage of not involving radiation, but it is not as accurate as other imaging methods. Ultrasonography cannot be used for monitoring skeletal changes over time, nor can it be used to monitor the response to treatment, because of its lack of precision.
International Society of Clinical Densitometry positions
The following are the official positions of the ISCD on QUS  :
Bone density measurements from QUS devices should be independently validated; measurements by different devices cannot be directly compared
The heel is the only validated skeletal site for the clinical use of QUS in osteoporosis management
Validated calcaneal QUS devices can be used in postmenopausal women to predict hip, vertebral, and global fracture risk ,and in men older than 65 years to predict hip and all nonvertebral fractures
The WHO diagnostic classification cannot be applied to T-scores from QUS measurements
If central DXA cannot be obtained, calcaneal QUS in combination with clinical risk factors can be used to identify patients in whom pharmacologic treatment should be initiated
Calcaneal QUS plus clinical risk factors can also be used to identify patients at very low fracture probability in whom no further diagnostic testing is necessary
QUS cannot be used to monitor the skeletal effects of treatments for osteoporosis
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) may be useful in identifying fractures and in the assessment of metabolic bone disease. Using fat-suppression sequences, marrow edema consistent with fracture may be noted as areas of hypointensity on T1-weighted images in association with corresponding areas of hyperintensity on T2-weighted images. MRI is a very sensitive modality and is believed by some to be the diagnostic imaging method of choice in the detection of acute fractures, such as sacral fractures.
MRI can be used to discriminate between acute and chronic fractures of the vertebrae and occult stress fractures of the proximal femur. These osteoporotic fractures demonstrate characteristic changes in the bone marrow that distinguish them from other uninvolved parts of the skeleton and the adjacent vertebrae.
Bone scanning assesses the function and tissue metabolism of organs by using a radionuclide (technetium-99m [99m Tc]) that emits radiation in proportion to its attachment to a target structure. This technique detects an increase in osteoblastic activity (as seen in compression fractures).
Images may be obtained in three phases of the bone scanning process (immediate-flow study, immediate static blood pool study, and delayed static study). Acute fractures are visible in all phases of bone scanning and may remain beyond the reference range for up to 2 years.
Bone Biopsy and Histologic Features
Bone biopsy can help to exclude underlying pathologic conditions, such as multiple myeloma, that may be responsible for presumed osteoporotic fracture. Typically, iliac crest biopsy is performed either in the minor procedure suite or in the operating room.
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, which may potentially indicate that too little bone formation or too much bone resorption is the cause of osteoporosis in a patient. Tetracycline labeling may also help clinicians to test potential therapy (ie, did the treatment slow bone resorption, increase bone formation, or both?) and study other metabolic bone responses.
One may also perform a vertebral body bone biopsy when performing a therapeutic procedure such as kyphoplasty (see the images below) or vertebroplasty for fixation of a vertebral compression fracture.
Histologic examination of osteoporotic bone may reveal generalized thinning of trabeculae and irregular perforation of trabeculae, reflecting unbalanced osteoclast-mediated bone resorption.  The following images are of histologic specimens from patients with osteoporosis.
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- Approach Considerations
- Laboratory Studies
- Biochemical Markers of Bone Turnover
- Plain Radiography
- Dual-Energy X-Ray Absorptiometry (DXA)
- Quantitative Computed Tomography
- Single-Photon Emission CT
- Quantitative Ultrasonography
- Magnetic Resonance Imaging
- Bone Scanning
- Bone Biopsy and Histologic Features
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