European Nuclear Medicine Guide
Osteoporosis is one of the most prevalent metabolic bone diseases worldwide with a large variety of incidence in the different European countries[88,89]. Osteoporosis is characterized by low bone mass and deterioration of the microarchitecture of bone tissue. This leads to low bone mass, enhances bone fragility and consecutively increases fracture risk.
A fracture caused by an inadequate trauma (e.g. a fall of a person from normal upright position or while walking) at a typical skeletal site suggests increased bone fragility and allows the diagnosis of an osteoporotic fracture. Thus, osteoporosis can be diagnosed based solely on clinical criteria.
Clinical assessment is able to capture determinants of fracture risk. A range of risk factors such as gender, age, hormonal and nutritional status, smoking, and alcohol etc. promote the development of osteoporosis. Furthermore, a previous fracture increases the risk for future fractures. Many risk factors have direct impact on bone density, which itself is a major risk factor for osteoporosis.
Since bone density itself does have a strong relationship to fracture incidence, it is reasonable to measure bone density to predict fracture risk. Dual X-ray absorptiometry (DXA / DEXA) is the preferred method to assess bone mass and density. At present the assessment of bone mass is the only aspect that can be readily measured in clinical practice. Therefore, it is recognized as a cornerstone for the general management of osteoporosis being used for diagnosis, risk prediction, and monitoring of patients on treatment.
In 1994 and 2008, the WHO published diagnostic criteria for osteoporosis in postmenopausal women based bone mineral density (BMD;[90]). Based on these criteria, osteoporosis is defined as a value for BMD 2.5 standard deviations (SD) or more below the young female adult mean (T-score less than or equal to −2.5 SD). Therefore, it is possible to make the diagnosis in clinically silent patients or in population using DXA as screening tool[88]. In this paper, we focus on the standards of DXA methods recommended by the ISCD (see also ISCD Official Positions www.iscd.org).
Various methods are used to assess fracture risk of an individual patient. Early methods to assess bone density used conventional x-rays of a hand and compared it to standardized attenuating material. However, this approach was not good enough to estimate the risk of osteoporotic fracture.
Based on conventional radiographs, radiogrammetry was developed to assess morphologic criteria at different sites of the skeleton (hand, hip, spine) and recently digital X-ray radiogrammetry became more popular. Digital X-ray radiogrammetry enables detailed analysis of the cortical part of metacarpal bones[91]. Due to its high precision, it is possible to measure changes of bone mineral density over time. This technique is promising to assess fracture risk in high-risk populations, although not yet established as tool in clinical routine.
Since the first efforts to assess bone density using conventional x-rays were not ideal, single photon absorptiometry (SPA) was introduced in the early 1960s. With SPA and dual photon absorptiometry (DPA) it became possible to measure bone density at the forearm (SPA with the forearm in a water bath) and at the central skeleton (i.e. lumbar spine and hip). The measurement of bone density at the lumbar spine was a breakthrough, since measurements were acquired at one of the sites where fragility fractures may occur (typical sites of fragility fractures are the vertebral spine, hip and distal forearm). These earlier methods needed radioactive sources (125I for SPA, t1/2 59.4 d and 153Gd for DPA, t1/2 240.4 d). Therefore, bone densitometry has long been part of nuclear medicine. However, there were limitations of these techniques, such as the decay of radioactive sources, a relatively low photon flux and high costs.
Radiographic techniques using an X-ray tube replaced these earlier methods and DXA became the standard method to assess bone density. With DXA it is possible to measure the vertebral column (i.e. lumbar spine from L1 to L4), the hip (of the non-dominant leg) and the forearm (of the non-dominant hand). Recent developments allow measuring the whole spine in the lateral view to assess the shape of vertebral bodies and osteoporotic fractures (Vertebral Fracture Assessment, VFA).
There are further X-ray methods to measure central and peripheral bone mass and density. Measurements in the periphery (i.e. forearm, heel etc.) are acquired also with quantitative computed tomography (QCT) and peripheral QCT (pQCT), respectively.
Furthermore, quantitative ultrasound is available (QUS, with a range of devices for the measurement at different bone sites). Recent developments established techniques without radiation, such as ultrasound of the heel or the fingers. These techniques show promising results regarding the non-invasive assessment of bone structure and the prediction of fractures at the vertebral spine or hip, i.e. even in the central skeleton when measuring at a peripheral site.
Nevertheless, the main important technique remains DXA to measure bone mass and BMD of the lumbar spine, hip and forearm, since the world health organisation (WHO) recommends central DXA as the standard method.
DXA technology is based on the fact that two different energies of radiation will be absorbed differently depending on the density of the tissue they penetrate, i.e. between bone and soft tissues. DXA scanners generate two energies either by switching from a lower energy (35 – 50 kV, usually around 45 kV) to a higher energy (more than 70 keV, usually around 100 kV) in the tube. Alternatively, two energy peaks are created by filtering a radiation beam. A broad range of different scanner configurations is available. Pencil beam systems have the advantage of a very low radiation exposure, but it takes more time for scanning than fan beam systems. Modern systems usually work with fan beam technology (with a range from narrow to wide fan beams). They are usually somewhat more expensive (more detectors) and may cause a higher radiation burden to the patient. They can scan faster and the quality of the image is better (which is important e.g. for vertebral fracture assessment). However, as detector technology advances it is possible to generate better images with lower radiation exposure. Manufacturers have different preferences for the design of their devices. Such differences may lead to variations of radiation exposure and differences in measured BMD values, which limits comparability of measurements acquired on different devices (see the quality control section). Nevertheless, all DXA machines relay on the use of two distinct radiation energies to calculate radiation absorption in tissues.
Typical effective dose to patients from DXA procedures are in the range of 1-10 Sv[92]. While this is a small number compared to most nuclear medicine examinations, the use of DXA must still be justified and optimised at patient level. The exposure to staff performing the examinations in a properly designed, busy examination room can be kept well below 1 mSv per year.
Bone mineral density (BMD) can be a problem in all age groups from babies to geriatric patients, in females and males and in recent years increasingly in transgender and gender non-conforming individuals. Originally, the increased fracture risk in postmenopausal women was the most important indication for DXA. However, any person with risk factors associated with a low bone mass or increased bone loss, as well as patients taking medication that causes bone loss should receive DXA, particularly those who suffered a fragility fracture.
In children and adolescents, the diagnosis of osteoporosis should not be made on the basis of densitometric criteria alone. However, also younger patients may have an elevated risk of a clinically significant fracture due to primary or secondary bone diseases.
Therefore, DXA measurement is part of a comprehensive skeletal health assessment in younger patients with increased risk of fracture (see also ISCD, paediatric official positions). In this population Z-Score should be used instead of the T-Score (see below).
The WHO recommends BMD measuring of the hip and lumbar spine (in ap projection in the supine patient) to assess bone density in all patients. Measurement of the distal forearm is helpful when the hip and/or the spine cannot be measured or interpreted. Additionally, in patients with hyperparathyroidism, since there is a high content of trabecular bone in the distal forearm showing high turnover of the bone faster than other sites. There might be obese patients over the limit of the DXA table and then only a measurement of the forearm is possible, because this measurement can be done when the patient sits on a chair besides the device.
At the spine, all vertebrae from L1 to L4 should be scanned and for the measurement, the vertebrae with adequate quality (i.e. without structural change or artefact) should be selected. It is best to use information of all four lumbar vertebrae, but at least two lumbar vertebrae should be analysed to diagnose Osteopenia or Osteoporosis. Do not base your BMD diagnosis on only one vertebra. If a lumbar vertebra is abnormal, e.g. after a fracture, it is non-assessable. If a vertebra shows a bone density which is more than 1.0 T-score higher or lower than the adjacent lumbar vertebra, it also has to be excluded from interpretation. The mean BMD value of all suitable lumbar vertebrae is used for interpretation. If the quality of spinal DXA is too bad for interpretation, the diagnosis has to be based on another measuring site.
At the hip the measurements include a total hip region of interest (ROI) and the femoral neck ROI. Years ago, additional ROIs were used such as the Ward Triangle (where the bone mass is the lowest) or the trochanteric ROI. These ROIs are not recommended for diagnosis, anymore, but might still be in use in certain settings. For diagnosis the lowest T-score either of the femoral neck or the total hip ROI is taken. It is sufficient to scan only one hip (usually the non-dominant hip). At the forearm only the 33% ROI (i.e. the 1/3 ROI) of the radius of the non-dominant arm is used for diagnosis.
For follow-up examination, the same information is used at the lumbar spine. Therefore, defining the suitability these lumbar vertebrae for interpreting the mean BMD is important. Sometimes it is necessary to re-evaluate a former measurement in order to correctly compare it to the actual examination. However, for follow-up of hip BMD the value of total hip ROI and for the forearm the value of the total radius ROI may be preferred.
Measured values are given as bone mineral content (in g) or as bone mineral density (in g/cm2). Density is therefore weight per area. It corresponds to the sum of slices acquired in the region of interest and not to a volume of the measured bone. The size of the measured bone is also given with the measurement. However, the size (i.e. the area) can change in serial BMD testing for example when a fragility fracture occurred and the affected vertebral body becomes smaller.
In order to perform correct DXA measurements a range of quality control procedures have to be respected. Quality control procedures have to adhere to manufacturer guidelines for system maintenance. Furthermore, daily and / or weekly quality controls include measurements of a phantom as an independent assessment of system calibration. Each DXA facility should determine its own precision error and calculate the least significant change (LSC;[93]). It is clear, that every facility has to comply with regulatory requirements (radiation surveys, specifications defined by government agencies).
However, to perform adequate quality control is not a trivial thing. Because the precision error supplied by the manufacturer of a device should not be used, precision error needs to be assessed by each facility itself regarding the performance of the device and including the performance of the technologist, who takes the measurement. Primarily, each technologist has to perform adequate training to gain scanning skills before working in a routine patient setting. If more than one technologist works in the same unit with the same DXA device an average precision error can be calculated for the whole group. To fulfil the quality requirements every technologist has to measure patients and document these measurements. The in vivo precision assessment requires measurement of the same patient several times by the same technologist [93–95]. The data is used to define the precision error of each technologist and of the DXA facility as a whole. It serves to control an established range of acceptable performance. If the skill level of a technologist has changed or a new DXA device is installed, the whole procedure has to be repeated.
To note, that also each DXA device is a rather individual system and has its own range of acceptable performance. If a DXA system is changed, it is important to make a cross-calibration between the old system and the new system in order to be able to provide correct follow-up examinations in patients. The same is true if BMD measurements shall be compared between different devices (from different providers, but also from the same manufacturer and even when using the same model of DXA device from different sites). Cross-calibration between different systems or when changing hardware can be done using a spine phantom.
All phantom measurements are recorded and plotted to create control tables and charts. This allows to control system performance over time. Typically, a Shewhart control chart is designed where the values of each measurement are plotted against the known bone density value of the phantom within limits of ±1.5%. Another commonly used method are cumulative sum charts (CUSUM charts) which are employed by many professional densitometry quality control centres. Nowadays, all manufacturers have automated quality control procedures and calibration standards are contained within the device. Furthermore, a continuous internal calibration is performed within the device during the scan of a patient on each point of measurement by a rotating disk with densities equivalent to air (i.e. a whole in the disk), soft tissue and bone. The external calibration of the device is done by daily measurement of a phantom with known soft tissue and bone density equivalents.
Usually, control procedure is automatically performed including internal calibration and external phantom scanning every morning before the device can be used for patient scanning. The type of plots / documentation may differ between manufacturers. It is important to strictly comply with these quality measurements to detect changes over time and to track machine performance. When values of measurements fall outside the control limits (i.e. a sudden shift of values or a drift over time) an alarm is triggered and further clearly specified procedures take place to reset the quality of the DXA device by additional phantom measurements. If more than 2% variation of measurements is found the manufacturer should be contacted for service (for example when an X-ray tube starts to fail and values decline over time, i.e. drift of measurements).
At first sight all these measurements seem to be exaggerated. However, considering that there is (1) only a little amount of calcium in the measured ROI of an osteoporotic bone, that (2) measurement are performed with low radiation exposure (low photon flux) and that (3) physiologic changes of (healthy) bone are only sparse, it becomes clear that precision of machine performance and of technologists’ work is of paramount importance.
To practice interpretation of DXA examinations the interpreter should have a valid certification in bone densitometry (at least one per facility, 7). DXA measurement in an individual person is compared to a reference database. In contrast to earlier recommendations, to date, comparisons are usually based on a uniform Caucasian population of young women and not to populations of different ethnic groups. All manufacturers use the NHANES III database as the reference standard for measurement of the hip (i.e. femoral neck and total hip T-score) but still shall use their own database as the reference standard for lumbar spine T-scores. However, other guidelines recommend the use of a gender matched reference population (i.e. a male reference to compare with men; DachverbandOsteologie, DVO)
Osteopenia and osteoporosis are widely used terms to describe the category in which the measured bone mass of patient falls. However, the term ‘low bone mass’ or ‘low bone density’ is preferred to the term ‘osteopenia’. To note that a person with a low bone mass / density is not necessarily at high fracture risk. It is possible that a healthy person has a bone density that is far higher than the normal range or far lower (i.e. even having an 'osteoporotic value') without having a bone disease. In a normal population of young adults (in the reference data base) already 15% of young healthy individuals have BMD values -1.0 and less and 0.6% have a BMD of -2.5 or less. Remember, we look at relative differences and report T-score values in relation to young female adults who reached their peak bone mass (according to the reference NHANES III, white females aged 20 – 29 years).
The WHO international reference standard for osteoporosis diagnosis is a T-score of -2.5 or less at the femoral neck. Osteoporosis may be diagnosed in postmenopausal women and men age 50 or older if the T-score is -2.5 or less as measured at the lumbar spine, total hip or femoral neck. In postmenopausal women and men age 50 and older T-scores are preferentially reported. For each patient a single diagnosis is reported and not a different diagnosis for each skeletal site. Only in certain circumstances the 33% radius (also called 1/3 radius) may be utilized.
Usually, other regions of interest (Ward’s area or trochanteric region at the hip and other regions at the forearm) shall not be used for diagnosis (local recommendations may differ).
Low bone mass is defined as a bone density of between -1.1 and -2.4. A T-score value of -1.0 is still normal and a T-score value of -2.4 corresponds to low bone mass (there is no ‘almost osteopenia’ or almost osteoporosis’, do not report ‘severe osteopenia’ with a T-score value of -2.4). To note, that by using these terms we classify patients into a diagnostic group. A T-score value of -2.5 and less denotes the population where most individuals will suffer from a fracture in the future. A T-score value of -1.1 to -2.4 defines a population where a high proportion of individuals will develop osteoporosis. These patients do not necessarily have an increased fracture risk (it depends on several risk factors).
A distinction is made between diagnostic classification and the use of BMD for fracture risk assessment. Remember, fracture risk assessment can also be done using other techniques and depends on the clinical situation (see also FRAX Tool, University of Sheffield).
It is important to consider clinical information of the patient to correctly report and interpret results. For example, it is helpful to know if a patient lost height during recent years or developed hyperkyphosis. Therefore, many DXA facilities measure the weight and height of a patient in order to have this information ready for serial tests. However, to determine whether treatment should be initiated, usually, a range of information is required.
Follow-up BMD testing should be done in all patients where the result is likely to influence further patient management, e.g. when treatment options have changed.
When reporting in females prior to menopause and in males younger than age 50, Z-scores are preferred (instead of T-scores). In contrast to T-scores, Z-scores should be population specific where adequate reference data exist (usually, a reference of the manufacturer is available). For the purpose of Z-score calculation, the patient’s self-reported ethnicity should be used. Reporting of Z-scores is particularly important in children and young people who did not yet reach their peak bone mass.
A Z-score of -2.0 or lower is defined as ‚below the expected range for age’ and a Z-score above
-2.0 is ‚within the expected range for age’.
Therefore, it is not possible to diagnose osteoporosis in men under the age of 50 based on BMD alone. However, it is possible to apply the WHO diagnostic criteria to women in the menopausal transition.
For example, a male patient aged 48 years and a Z-score of -1.5 and a T-score of -1.1 has still a bone mass within the expected range. A female patient at the age of 48 with the same Z-score and T-score has also a bone mass within the expected range as long as she is premenopausal (T-score not allowed). If she is in the menopausal transition or postmenopausal the T-score interpretation is preferred, thus, reporting a ‘low bone density’ would be correct.
With DXA it is also possible to measure ‚whole body composition’ (WBC). There is no (official) reference population that was defined as normal for WBC. Therefore, it is mainly used in individuals for serial testing to assess changes in lean body mass (which correlates to muscle mass), calcium content of the whole skeleton (without the head) and fat content. It can be used e.g. to monitor treatment effects in younger patients including children with growth disturbances, malnourishment or medication that may influence bone metabolism and growth.
Densitometric spine imaging for detecting vertebral fractures is called ‘Vertebral Fracture Assessment’ (VFA). Morphometry of the vertebral spine allows to automatically assess the height of the vertebral bodies at the thoracic and lumbar spine by scanning the vertebral column from the lateral view. It is recommended for example when the T-score is less -1.0 or in patients with height loss of more than 4 cm (1.5 inches). Reporting of vertebral fractures should be done according the Genant visual semi-quantitative method[96].
As image quality constantly improves with better detectors, possible applications of DXA scanning broaden, e.g. by additionally measuring aortic plaques.
Furthermore, it is possible to measure defined regions of interest for example at the hip in patients with hip prosthesis and information can be given about hip geometry. Hip axis length can be derived from the DXA measurement and is associated with hip fracture risk in postmenopausal women. There are many geometry parameters that can be derived from DXA. However, they should not be used to assess hip fracture risk or to initiate treatment.
Trabecular bone score (TBS) is a measurement that can be acquired with DXA devices[97]. While BMD is a measure of bone quantity, TBS is a measure of bone quality. With DXA a two-dimensional texture analysis of the grey levels in a region of interest is acquired on the lumbar vertebral bodies. The level of density in each measured pixel of the ROI defines this grey level. This is correlated to the number of trabecula and microarchitecture and density of connective tissue. A high TBS describes bone with strong microarchitecture, a low one bone with higher fracture risk. Vertebral bodies can have the same BMD, but may have a high or a low TBS. Thus, TBS serves as an independent predictor of osteoporotic fractures in women and men. In contrast to BMD, TBS is independent of degenerative alterations of the vertebral body and independent from BMD, FRAX or clinical risk factors. Therefore, this measurement is a very useful adjunct when performing DXA and a statement about fracture risk can be improved with this additional information. However, TBS is not validated for monitoring anti-resorptive therapy.
| BMD | Bone mineral density |
| CUSUM Charts | Cumulative Sum Charts |
| DPA | Dual photon absorptiometry |
| DXA | Dual X-ray absorptiometry |
| LSC | Least Significant Change |
| pDXA | Peripheral DXA |
| pQCT | Peripheral QCT |
| QCT | Quantitative computed tomography |
| QUS | Quantitative ultrasound |
| SPA | Single photon absorptiometry |
| VFA | Vertebral Fracture Assessment |
| WBC | Whole Body Composition |
| TBS | Trabecular bone score |
International Osteoporosis Foundation (IOF) https://www.iofbonehealth.org/
International Society for Clinical Densitometry (ISCD) https://www.iscd.org/
International Osteoporosis Foundation https://www.iofbonehealth.org/
Dachverband Osteologie (DVO) http://www.dv-osteologie.org/