Bone Scintigraphy: Part 3

Bone Scintigraphy: Part 3. Bone Scanning in Metabolic Bone Disease

I. Fogelman, B.D. Coffier and M.L. Brown

Department ofNuclear Medicine, Guy's Hospita!@London, U.K; Depanment ofNuclear Medicine, Milwaukee County Medical Complex Milwaukee, W&@consüz,,and Divirion ofNuclear Medicine, Unive,@cityofPittsbu,gh, Pittsbu,gh, Pemuylvania

the durationof the disease. The problem with diffuse in J Nuci Med 1993; 34:2247-2252 volvement of the skeleton is that recognition of increased uptake of tracer is subjective, unlike recognition of focal disease when metastases are present. This seems an ideal situationfor quantitationwhich has been shown to be help hereas radionucide bone scan appearances in van ful (6), but in practice is seldom performed except in re ous metabolic bone disorders have been extensively stud search protocols. Focal disease may be present in the met ied and reported upon, it is not widely performed in the abolic disordersbut is relatively uncommon and may arise routine evaluation of patients with classic metabolic bone with pseudofractures(7), brown tumors (8), ectopic calci diseases such as renal osteodystrophy and osteomalacia. fication (9) and chondrocalcinosis (10). It should be recog However, the bone scan is well established in Paget's dis nized that there is no routine role for the bone scan in the ease and there is increasing interest in osteoporosis, re diagnosis of these conditions (perhapswith the exception flecting the fact that this is an extremely common disease of renal osteodystrophy) and it is most helpful when an with high morbidity. In recent years, there have been sig swering specific questions such as in a case of osteomala nificant advances with regard to the treatment of Paget's cia, arepseudofracturesthe explanationfor localized pain? disease and the investigation and treatment of osteoporo sis. It seems opportune to review the role of radionuclide PAGEr'S DISEASE bone scanning in metabolic bone disease. Advances in bone density measurements and how they relate to osteo Inmany countries, Paget's disease is a common disorder porosis will also be examined. that is generallypolyostotic but may be monostotic in 20% of cases (11). However, there are wide geographicalvan RENAL OSTEODYSTROPHY, OSTEOMALACLAAND ations in incidence and even within a single country (12). PRIMARYHYPERPARAThYROIDISM While often grouped with the metabolic bone diseases, the cause is unknown, althoughcurrentlythoughtto be due to Metabolicbone disordersarecharacterizedby increased a viral infection (13,14). It is of interest that there is no tracer uptake throughout the skeleton and, in more severe correlation between an individual's age and the extent of cases, appearances are those of a “superscan―(1,2). In disease, suggesting that disease does not progress from addition,several individualmetabolic featuressuch as faint bone to bone during an individual's lifetime (15), but or absent kidney images, prominentcalvariaandmandible, progresses in involved bones which could be explained by beading of the costochondral junctions and a “tiester prior invasion of these bones by a virus with a long incu num―sign may be present (3). In general, renal osteodys bation period. There are occasional reports of disease oc trophy leads to the most striking appearances with early curring in previously unaffected bones, although this situ primary hyperparathyroidism at the other extreme where ation seems to be rare. From radiologicalevidence, bone scan findings are often normal (4,5). However, this will resorption progresses at a rate of 0.8 cm per year in an depend upon the severity of disease in individual cases. affected bone (16). Some patients with primary hyperparathyroidism can have The bone scan appearances in Paget's disease are well grossly abnormal scans, whereas mild renal osteodystro known and there are several reviews on the subject phy can appearnormal.These conditions have in common (17,18). The exquisite sensitivity of the bone scan and the excessive parathyroid hormone and the degree of abnor clear visualization of the whole skeleton make this the mality ofthe bone scan is directly related to its severity and imaging modality of choice. However, x-rays are neces sary whenever there is unexplained bone pain or other ReceivedJun. 22, 1993;revisionacoeptedJti. 18, 1993. suspicion of fractureor sarcomatouschange. Focal lesions Forcorrespondenceor reprIntscor*@ Dr.ManuelBrown,DM@onofNudear Medldne,Dept ofRadiology,Presbyte@an-UnWersftyHospftal,DeSotoat OHara may not always be apparent against a background of in Streets.Pittsburgh,PA 15213. tense tracer uptake. With the newer bisphosphonates,

Bone Scanning in MetabolicBone Disease •Fogelman at al. 2247 osteoporosis, which is best defined as the established dis ease, i.e., with fractures (23). In recent years, a variety of “deformation―indices have been used to document changes in spinal vertebrae on x-ray, e.g., a reduction of FIGURE 1. Peg 20%(24,25) or a reduction of three or four standarddcvi ers dIsease. Bone scan offemur6 mo ations in height when compared with normal vertebrae after sbc weeldy, (25,26). This provides an objective measure of change and 30-mg Infusionsof is used extensively in pharmaceutical studies. However, APD. Note nonh@ the clinical relevance of such changes is uncertainbecause mogeneftyof trecer patients are often asymptomatic and the affected vertebrae uptake with focal defects. It unaware may not be positive on a bone scan. This is quite different of treatment,there from fractures at any other site in the skeleton and there would be concern must be doubt as to what exactly is being measured. We about the possI@ll suggest that if clinically indicated, the bone scan should be ltyofsarcomatous used in such situations to confirmfracture. Change. The typical bone scan appearanceof a vertebralfracture is intense linearly increased tracer uptake that gradually there is an effective treatmentfor Paget's disease and pro resolves over the following 6 to 24 mo (27). However, longed remissions can be expected (19). However, after appearances can resolve more rapidly and complete reso treatment some unusual and bizarre bone scan appear lution of multiple lesions over a three-month interval has ances can be seen when reactivation of disease occurs, and been reported (28). The bone scan can be of particular it is important to be aware that the patient has received value in the evaluation of a patientwith known osteoporo therapy (Fig. 1)(1$20). While treatment is often perceived sis who presents with back pain to clarifywhether further as being highly successful, this evaluation is generally fracture has occurred or some other explanation for pain based on an assessment of biochemical parameters. Even should be sought. In some cases, patients have lost 6—9in. with second generation bisphosphonate therapy, it has in height with multiple fractures, thus identifyingnew pa been found that only 10% of bone scan lesions completely thology becomes difficult. Bone scans clearly identify the resolve, 65% improve and the remainder are essentially recent fracturesites. On occasion, the bone scan will iden unchanged (21). There was no significantdifference in re tify coexistent disease such as a rib fracture or metastases sponse between various bony sites throughout the skele that may be the cause of, or contribute to, symptoms. It ton, but less active lesions are more likely to resolve com should always be remembered that even when scan ap pletely. Thus, while many lesions improve, complete pearances are typical of a vertebral fracture, the findings resolution is uncommon and the clinical significance of are not specffic to osteoporosis and a coexistent lesion lesions which remain metabolically active is uncertain. In cannot be excluded. However, when multiple vertebral the past, usually only patients with symptomatic Paget's fractures are present, particularly when showing different disease received treatment. Currently, with successful stages ofresolution, osteoporosis is the probable diagnosis. therapy available, it is much more likely that patients will Occasionally a disease which causes generalized deminer receive treatmentat an earlierstage of disease with a view alization such as myeloma can mimic this situation. to preventingprogression and the development of compli Recently, it has been found that back pain in osteopo cations. rosis may often be due to coexistent degenerative disease A poor quality bone scan in patients receiving bisphos that can be unrelated to the site of fracture (29). This is phonate therapy has been reported (22). There is contro generally due to facet joint arthritis. SPED.' provides in versy as to what extent bisphosphonate loading can affect creased sensitivity for diagnosis and localization of lesions the quality of a bisphosphonate bone scan (18). There are a largenumberofpotential bindingsites in the skeleton and this is essentially not a problem in clinical practice, partic ularly with oral therapy. However, if parenteral bisphos phonate is given in high dosage and a bone scan obtained shortly thereafter, then a study with poor tracer uptake by ‘F the skeleton and high backgroundactivity may result. OSTEOPOROSIS r The radionucide bone scan has no role in the initial diagnosis of osteoporosis and in cases of suspected frac 1, tare an x-ray should be obtained. The definition of osteo porosis is contentious at best. The term osteopema is pre FIGURE 2. Transwdal SPECT image shows focal, increased ferred for patients with low bone density who are at risk of treceruptakeinfacetjointdue to arthrItis(arrow).

2248 TheJournalof NuclearMedicine•Vol.34 •No. 12 •December1993 (Fig. 2). Such findings have potentially importantimplica rosis Foundationhas suggested four clinical indicationsfor tions for therapy (30). measurementof bone density (45): The bone scan is of value in confirmingsuspected frac 1. The estrogen-deficientfemalewho may needtreat tures when initial x-rays are negative at sites such as fore ment with estrogen. arms or hips. Bone scans may also provide diagnostic 2. Vertebralabnormalitiesidentifiedon x-ray. information in other less common situations such as osteo 3. Patientsreceivinglong-termsteroid therapy. porosis of pregnancy, transientregional osteoporosis (31— 4. Asymptomaticprimary hyperparathyroidismin which 33), reflex sympathetic dystrophy syndrome (34—37)and an abnormalresult may influence the decision to pro the detection of microfracturesin patients receiving fluo ceed with surgery. ride therapy (3839). Measurement of bone density is likely to arise in one of two situations: (1) to assess whether bone density for an BONE DENSITY MEASUREMENTS individual is in the normal range or (2) as part of a research While there has been considerable research interest in protocol to monitor the effect of a drug on the skeleton. In the measurementofbone density, it is only in recent years, this context, it should be noted that much recent informa with the advent of dual x-ray absorptiometry(DXA), that tion pertainingto pharmacologicaleffects in the skeleton such measurements have become established in routine could not have been obtained without the benefit of such clinical practice (40-42). DXA utilizes an x-ray tube as the measurements, e.g., effectiveness of cyclical etidronate radiation source rather than ‘53Gdwhich is used in dual therapy in osteoporosis (46,47), tamoxifen protecting the photon absorptiometry (DPA). This has the attraction of skeleton (48;49) and fluoride, although it leads to a sub eliminating difficulties relating to calibration with a contin stantialincrease in bone density in the spine, causing bone uously declining source strength due to radioactive decay loss in the femur in some cases (50,51). The major potential and providingsignificantsavings on the isotope purchases. areafor bone density measurements is in identifyingthose The majoradvantages of DXA are its practicalitybecause individuals who are at risk for developing osteoporosis scan time is reduced from 20 to 40 mm with DPA to 2 to 5 (52). Once established, osteoporosis is difficultto treat and min. Further, the greater photon flux means higher preci it is generallyagreedthatprevention of bone loss is impor sion, approximately 1% compared to 2%—4%with DPA tant. There is now no doubt that bone density measure (4Z43). There is also improved resolution and image qual ments provide the best, albeit not perfect, means of iden ity is greatly enhanced. In addition, there have been im tifying those at risk of fracture. This has been confirmed in provements in software, in particularthe “compare―fad several prospective studies (53—57).A clinical profile of ity for serial studies, which ensures that regions of interest risk factors does not contribute to the evaluation of risk in (ROIs) around bone and soft tissue can be accurately re this situation (5859). In many cases, an individual may be produced. concerned about osteoporosis, e.g., a menopausalwoman The standard DXA examination includes the lumbar whose mother had osteoporosis, patients with early meno spine and the proximal femur. In the elderly, DXA mea pause, patientsreceivingsteroids, patientswith a historyof surements of the spine may not accurately reflect bone prolongedamenorrhoea,patientswho have sustained after density because of confounding factors such as degenera trivialtraumaandpatients inwhom anx-ray has suggested tive disease, vertebralfracturesandaorticcalcificationthat osteopenia. In these situations, bone density measure may be apparenton x-ray. There are no technical difficul ments will help to resolve the problem and patients can be ties in measuring spinal bone density. The femur is more reassured that all is well or be given precise information problematic, however, and results can be affected by pa about the severity of the problem. tient positioningandsubsequent analysis ofthe study, e.g., The issue is how to define normalbone density. In prac ROI placement (44). Rigorous quality control, appropriate tice, an individual'sresults are generally compared to nor training of technicians and review of scans by an experi mal age-relatedcurves provided by individualmanufactur enced observer is important,particularlyfor research pro ers. There is some discussion as to whether it is better to tocols and serial studies where clinical decisions could be relate results to age-matched controls or to values cx affected. Until recently, there have been relatively limited pected for young normals. In practice, both sets of data are dataon the femurwhen comparedwith the spine, andwhat provided as the Z or T scores, respectively. There is at data are available generally relate to the femoral neck. least a theoretical problem with Z scores since these as Routine DXA analysis provides data for the femoral neck, sume a normal distribution for the reference population. trochanterandWard's triangle.Ward's triangleis the most The assumption is also made by manufacturerswhen pre sensitive site for the detection of trabecularchange in the senting reference ranges that the standard deviations for proximal femur. Although theoretically attractive as a various age groups do not alter with advancing age. This is means of detecting postmenopausal bone loss, its clinical unlikely to be the case. The use of percentiles resolves use is limitedby relatively poor precision of approximately some of these issues (52) and are also much simpler to 3%(44). comprehend, e.g., a patientis in the lowest 30th percentile The Scientific Advisory Board of the National Osteopo for her age rather than this information being given as

Bone Scanning in MetabOliCBone Disease •Fogelman at al. 2249 either a multiple or a fraction of a standard deviation. There is also the concept of a “fracturethreshold,―i.e., a value below which an individualis at risk of fracture(60). While this is somewhat artfficial, it is nevertheless useful when consideringrisk. The “fracturethreshold―has either been defined as two standarddeviations below the value for a young normal(61) or as the 90th percentile of values taken from a population who has sustained osteoporotic fractures (62). In practice, the two definitions agree well. The concept of mass screening of the female population to identify those at risk of osteoporosis remains conten tious and there is no case to be made for this at the present time. However, this is not because bone density measure ments are not of clinical value, but because there is no consensus as to how to manage an abnormal result. If, after full discussion of the issues with an individualpatient, she states that if she is at risk she wishes to take hormone replacement therapy (HRT), then clearly bone density measurements will be important in influencing this dcci sion. However, it is apparentthat the majorityof women are not preparedto take long-termHRT (63). Advances in FiGURE 3. Morphometrlc HRT are occurring with several bleed-free regimens and DXA scan shows markers for progestogens, which have a lower incidence of side effects. measuringanteiior,midand pos It is probablethat compliance with HRT will improve, but tenor vertebral heights. (Image providedDr.Stelger,Hologk@) there remains the long-term safety issues, particularly, concerns about associations with breast cancer (64,65). Screening is only a concept that applies to younger This has led to a significant reduction in scanning time; it is women because it is apparentthatvirtuallyallwomen over now possible to obtain an adequate spinal measurementin 75 who have never received hormone replacement therapy 5 sec (77). will have bone density values which place them at risk of There is furtherimprovement in precision, particularly fractures (62). Should there be a suitable safe treatment for for lateral spine studies (75,78). With this methodology, it osteoporosis, it is likely that bone density measurements is now possible to obtain a true volumetric analysis of will be used not only to decide who to treat, but also to vertebrae (79). The most importantpotentialuse for lateral determine the duration of therapy. In the future, there may DXA is evaluation of vertebral morphometry (80), an area be sets of tables to assist a physician in making a decision of active interest and research. 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2252 TheJournalof NudearMedicine•Vol.34 •No. 12 •December1993