The Founder’s Lecture 2009: advances in imaging of osteoporosis and osteoarthritis
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- Link, T.M. Skeletal Radiol (2010) 39: 943. doi:10.1007/s00256-010-0987-0
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The objective of this review article is to provide an update on new developments in imaging of osteoporosis and osteoarthritis over the past three decades. A literature review is presented that summarizes the highlights in the development of bone mineral density measurements, bone structure imaging, and vertebral fracture assessment in osteoporosis as well as MR-based semiquantitative assessment of osteoarthritis and quantitative cartilage matrix imaging. This review focuses on techniques that have impacted patient management and therapeutic decision making or that potentially will affect patient care in the near future. Results of pertinent studies are presented and used for illustration. In summary, novel developments have significantly impacted imaging of osteoporosis and osteoarthritis over the past three decades.
Radiology still is mostly considered a medical science based on the morphological evaluation of anatomy and macroscopic pathology. Purely qualitative analysis, however, has limitations in quantifying disease processes, which is of considerable significance for patient management and scientific research studies. In particular, for analyses of the effects of novel techniques and their impact on or use for therapeutic decision making, quantitative measurements are required. Bone mineral density measurements were among the first quantitative measurements in musculoskeletal radiology and have gained tremendous importance in diagnosing and treating osteoporosis as well as in monitoring therapy effects. In osteoarthritis also there have been increasing efforts to implement quantitative or semi-quantitative measurements, in particular using MR-based techniques. The following article reviews the developments and advances in osteoporosis and osteoarthritis imaging over the past three decades.
Osteoporosis—from bone mineral density to structure imaging
Dual X-ray absorptiometry (DXA) [11, 12] was developed in parallel to QCT and, given that the technique did not require expensive CT equipment but used a dedicated scanner that was cheaper and had lower operating costs, DXA overtook QCT and is currently the standard for bone densitometry measurements. In addition DXA has a high precision and DXA T-scores have been established to define osteoporosis and osteopenia according to WHO guidelines . DXA has been used in multiple cross-sectional and longitudinal studies to differentiate individuals with and without fractures, assess fracture risk, and analyze therapy effects; thus the fund of knowledge for DXA is currently superior to QCT [14–18]. Though DXA only assesses areal BMD of the lumbar spine, proximal femur, and distal radius, which includes cortical and trabecular bone, and has limitations in patients with degenerative disease, it has been shown to be robust and a good technique to determine fracture risk and measure response to therapy.
Because bone mass measured with DXA only accounts for 60–70% of the variation in bone strength , researchers have been motivated to better characterize in vivo bone strength in osteoporosis. In 1993 the NIH osteoporosis consensus panel defined osteoporosis as a disease characterized by fragility fractures due to low bone mass and deterioration of bone architecture ; in 2001 the bone quality concept was introduced, which also included bone architecture . Given these new concepts and advances in radiology that allowed high resolution imaging of bone, research efforts increasingly focused on visualization of trabecular bone architecture and later also on cortical bone structure imaging.
Early studies used radiographs to assess trabecular bone structure and found significant correlations between biomechanically determined fracture load and structure measures [22–24]. In vivo radiographs of the spine, the calcaneus, and the distal radius were used with good results to discriminate patients with and without osteoporotic fractures [25–29]. Today as structure analysis techniques are getting more sophisticated, there is renewed interest in using low cost radiographs to assess trabecular bone architecture . However, a limitation of radiographs is that they represent an overall projection of the bone structure and do not demonstrate individual trabeculae; also the reproducible evaluation of bone structure is highly dependent on surrounding soft tissues, which significantly offsets clinical applicability.
One of the main limitations associated with extending the MD-CT technology to imaging trabecular bone structure in patients lies in the trade off between radiation exposure and spatial resolution. The higher the spatial resolution of images required, the greater the exposure to radiation, which greatly limits clinical applicability for imaging of the axial skeleton (spine and hip). While DXA has an effective dose of 0.01–0.05 mSv in adults and QCT has an effective dose of 0.06–0.3 mSv, the referenced studies showed that protocols to examine vertebral microstructure using high resolution MD-CT subject patients to an effective dose of about 3 mSv.
One of the early longitudinal studies using MRI showed that salmon calcitonin nasal spray had therapeutic benefit compared with placebo in maintaining trabecular microarchitecture at multiple skeletal sites and supported the use of MRI technology for assessment of trabecular microarchitecture in clinical research trials . Another longitudinal study in hypogonadal men suggested that testosterone replacement improves trabecular architecture . Interestingly it was also noted that structure parameters obtained from hr-pQCT were not directly comparable with those determined in high resolution MR studies . Kazakia et al. found that MRI and hr-pQCT provided statistically different values of structure parameters (P < 0.0001), with trabecular bone fraction and trabecular thickness exhibiting the largest discrepancies (MR/hr-pQCT = 3–4); differences in trabecular number values were also statistically significant, but the mean differences were on the order of the reproducibility measurements .
Through the use of MRI at higher field strength (3.0 T), visualization of trabecular bone architecture can be substantially improved as demonstrated by Phan et al. . These investigators showed in an in vitro study that MR imaging at 3.0 T provided a better measure of the trabecular bone structure than did MR imaging at 1.5 T using microCT measures as a standard of reference.
In addition to high resolution MRI, researchers also focused on quantitative MR techniques to assess water content of the cortical bone as a potential parameter to assess bone strength. This ultra-short echo time (UTE) imaging technique allows the detection of signal components with T2 relaxation times on the order of only a few hundred microseconds. These components are found in highly ordered tissues such as cortical bone and tendons and can not be detected with conventional imaging techniques, where TE is limited to 1–2 ms . Techawiboonwong et al.  recently reported UTE imaging with radial MR pulse sequences to characterize cortical bone water. These investigators validated the technique in adult sheep and human tibia specimens using an isotope exchange experiment and studied the right tibial midshaft in pre- and postmenopausal females and patients on hemodialysis. The quantitative analysis showed that bone water content was 135% higher in the patients on maintenance dialysis than in the premenopausal women and 43% higher than in the postmenopausal women. Interestingly no significant differences were found in tibial volumetric BMD between patients on hemodialysis and pre- and postmenopausal normal controls.
Osteoporosis—vertebral fracture assessment
Previous studies have found a circa 10% prevalence of vertebral fractures in women in their 50s and 25–45% in women in their 80s [58, 59]. A large number of vertebral fractures do not come to clinical attention, although osteoporosis-related vertebral fractures have important health consequences for older women, including disability and increased mortality [60, 61]. Also it should be noted that the presence of one vertebral fracture increases the risk of any subsequent vertebral fracture fivefold  and that 20% of the women with a diagnosed vertebral fracture will sustain a new fracture within the next 12 months . Because further fractures can be prevented with appropriate medications, recognition and treatment of these high-risk patients is warranted.
In 2000, a cross-sectional study raised substantial concern that vertebral fractures may be underreported by radiologists . In this survey Gehlbach et al.  reviewed PA and lateral chest radiographs that had been performed in 934 women aged 60 years and older who had been hospitalized. Moderate or severe vertebral fractures were identified in 132 (14.1%) study subjects, but only 50% of the radiology reports identified a fracture as present, and only 17 (1.8%) of the 934 patients had a discharge diagnosis of vertebral fracture. As a consequence, relatively few of these patients with vertebral fractures received appropriate osteoporosis-specific medications to prevent further fractures. Another study published by Kim et al.  analyzed PA and lateral chest radiographs of 100 randomly selected patients 60 years or older who presented to the emergency department of a tertiary care hospital. A clinically important vertebral fracture was defined as one that was at least moderate to severe (loss of height ≥ 25%). The mean age of the population was 75 years, and 47% were women. According to a reference radiologist, the prevalence of moderate to severe vertebral fractures was 22% in this population. However, only 55% (12/22) of these vertebral fractures were mentioned in the official radiology reports.
Recent efforts have focused on using standard MD-CT as a tool to diagnose osteoporotic vertebral fractures [71, 72] using routine sagittal reconstructions, as these are missed on axial sections. In a recent study, Muller et al.  analyzed routine abdominal or thoracoabdominal MD-CTs in 112 postmenopausal women. Axial images and sagittal reformations were analyzed separately by two radiologists in consensus and compared to the official radiology reports. In 27 patients osteoporotic vertebral deformities were found on the sagittal reformations, but only 6 of these were shown in the axial images and none of these were diagnosed in the official radiology report. The authors concluded that sagittal reformations of standard MD-CT images provide important additional information on osteoporotic vertebral deformities and should be part of standard CT analyses. In a similar study, Williams et al.  found that 38 of 192 (19.8%) patients had moderate to severe vertebral fractures and in only 5 (13%) patients were these correctly reported in the initial CT reports. Consequently they stated that incidental osteoporotic vertebral fractures are underreported on CT and that sagittal reformations are strongly recommended to improve the detection rate.
In addition, recent publications have provided evidence that what was previously defined as spontaneous osteonecrosis of the knee (SONC) is in fact an insufficiency fracture [75, 76]; this new concept again may alter patient management as it has been shown that osteoporosis-specific therapies will reduce the number of future insufficiency fractures. Similar findings were also presented for the hip, questioning the diagnosis of avascular necrosis in older patients and demonstrating histological signs of insufficiency fractures instead [77–79].
Osteoarthritis—from WORMS to cartilage matrix imaging
Conventional radiographs were the standard for diagnosing osteoarthritis (OA) over many years, and the radiograph-based Kellgren-Lawrence Scale is still a standard of reference for grading osteoarthritis . In 2003, however, a study assessing MR findings in OA  demonstrated that MRI gives substantial information beyond radiographs as it also demonstrates degenerative changes in the cartilage, menisci, ligaments, bone marrow, and synovial tissue. In particular, morphological evaluation of the cartilage has subsequently gained substantial significance as a biomarker for the evaluation of osteoarthritis.
In 2008 an additional score, the Boston Leeds Osteoarthritis Score (BLOKS), was established to grade MRI studies of the knee  and demonstrated good reliability. It was also shown that BLOKS may have superior validity for one of the components compared to WORMS, as Hunter et al.  found that maximum bone marrow lesion size on the BLOKS scale had a positive linear relation with visual analogue scale pain while the WORMS scale did not and that the association between baseline bone marrow lesion score with cartilage loss was stronger for the BLOKS than for the WORMS scale.
However, it should be noted that these grading systems focus on morphological abnormalities associated with relatively advanced disease. Given the fact that cartilage does not regenerate and the degenerative cartilage defects will not heal, diagnosis of degeneration should be made before irreversible cartilage loss has occurred. Efforts have therefore been undertaken to use MR techniques to diagnose cartilage degeneration at the biochemical/molecular level before morphological damage is evident. Three techniques have been developed that serve as surrogate markers for cartilage biochemical composition: delayed gadolinium-enhanced MRI of cartilage (dGEMRIC), and T1rho and T2 relaxation time measurements.
Cartilage consists of approximately 70% water and the remainder predominantly of type II collagen fibers and glycosaminoglycans (GAG). These GAG macromolecules contain negative charges that attract sodium ions (NA+). One of the most frequently used MRI contrast agents, Gd-DTPA2−(Magnevist, Bayer Healthcare), also has negative charges and will therefore not penetrate cartilage in areas of high GAG concentrations. In fact it will be distributed in higher concentrations in areas with lower GAG concentration and thus pathologic cartilage composition. Gd-DTPA2−concentrations in cartilage can be quantified, and this technique has been defined as delayed gadolinium-enhanced MRI of cartilage (dGEMRIC). Initial studies have shown that the dGEMRIC measurement of GAG corresponds to the true GAG concentration as measured with biochemistry and histology [84–86]. This technique has also been used in a number of clinical studies, and variations of this measurement have been shown in patients with osteoarthritis, trials of autologous chondrocyte implants, and subjects with sedentary lifestyle versus those taking regular exercise [87–90]. Williams et al. examined 31 patients with knee OA with a dGEMRIC protocol at 1.5 T and full-limb knee radiographs to assess alignment . These authors found that compartments of the knee joint without joint space narrowing had a higher dGEMRIC index than those with any level of narrowing (mean 408 vs. 365 ms; P = 0.001). In knees with one unnarrowed (spared) and one narrowed (diseased) compartment, the dGEMRIC index was greater in the spared versus the diseased compartment (mean 395 vs. 369 ms; P = 0.001). Valgus-aligned knees tended to have lower dGEMRIC values laterally, and varus-aligned knees tended to have lower dGEMRIC values medially. The authors concluded that these quantitative findings may have an important role in evaluating early osteoarthritis.
T2 relaxation time measurements
The third parameter that has been proposed to measure cartilage biochemical composition is T1rho-relaxation mapping. T(1rho) describes the spin-lattice relaxation in the rotating frame, and changes in the extracellular matrix of cartilage, such as the loss of GAG, may be reflected in measurements of T1rho due to less restricted motion of water protons. Preliminary results have demonstrated the in vivo feasibility of quantifying early biochemical changes in symptomatic osteoarthritis subjects employing T1rho-weighted MRI on a 1.5 T clinical scanner [98, 99]. In an early clinical study, Li et al. examined 10 healthy volunteers, and 9 osteoarthritis patients at 3 T and found a significant difference (P = 0.002) in the average T1rho within patellar and femoral cartilage between controls (45.04 ± 2.59 ms) and osteoarthritis patients (53.06 ± 4.60 ms) . A significant correlation was found between T1rho and T2 relaxation measurements; however, the difference in T2 was not significant between controls and osteoarthritis patients. These initial results suggested that T1rho relaxation times may be a promising clinical tool for osteoarthritis detection and treatment monitoring.
A review of the literature of the last three decades indicates that substantial progress in diagnostic techniques to diagnose and monitor osteoporosis and osteoarthritis has been made. We have moved from qualitative techniques increasingly to quantitative techniques, and we have achieved higher spatial resolutions to quantify bone structure while also developing new imaging techniques to quantify the biochemical composition of bone and cartilage. These techniques have impacted and will in the future increasingly impact patient management to prevent, treat, and monitor osteoporosis and osteoarthritis.
The Founders Medal of the International Skeletal Society (ISS) was awarded to Harry K. Genant, Professor Emeritus, UCSF, San Francisco, CA, USA at the ISS annual meeting in Washington DC, USA in 2009. The recipient was honored for contributions made to the ISS and in advancing the field of musculoskeletal science particularly in the field of imaging of osteoporosis and osteoarthritis. This review is largely based on the lecture of the same title given in honor of the 2009 Founders Medal recipient. The International Skeletal Society was founded 37 years ago.
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