The radiological diagnosis of osteoporosis, osteomalacia and hyperparathyroidism

THE RADIOLOGICAL

DIAGNOSIS OF OSTEOPOROSIS, AND HYPERPARATHYROIDISM *

OSTEOMALACIA

G. A L A N ROSE, D.M., F.R.I.C.

Department of Medicine, The General Infirmary, Leeds OSTEOMALACIA, osteoporosis

and hyperparathyroidism are three quite distinct metabolic bone diseases. Each has its own distinctive aetiologies, clinical pictures, biochemical abnormalities, bone histology and treatment. Nowadays, when all the evidence from any given patient is assembled, it is usually possible to decide which of these diseases is present, although there are some notable difficulties. The radiologist, using as his diagnostic tool the x-ray pictures of bones, has a distinct role to play in contributing to the final diagnosis, and what follows is an attempt to define this role and to show some examples of when radiological evidence may be particularly helpful. It is stressed that this is not a complete review of metabolic bone disease, but concerned only with the three diseases already mentioned. In particular, there is practically no reference to the osteosclerosis which may accompany osteomalacia or hyperparathyroidism, but which is otherwise very poorly understood. When metabolic bone disease is either suspected or known to be present it is desirable on the one hand to take x-ray pictures of those bones which are most likely to reveal changes, but on the other hand to avoid unnecessary and superfluous taking of x-ray pictures. The present author follows the practice established over the last ten years by Professor C. E. Dent and Dr C. J. Hodson, at University College Hospital. An 'abbreviated skeleton' is requested, and this includes P.A. views of chest, renal areas, pelvis, knees and hands, and lateral views of skull and lumbar spine. With only these basic seven x-ray pictures all the information needed can usually be obtained, although obviously additional bones can be visualised when specific indications exist. How readily is loss of calcium from bone recognised on x-rays? Lachman (1955) reviewed the evidence of previous papers and concluded that there had to be a loss of at least 30 per cent, and possibly 50 to 60 per cent, of bone calcium before rarefaction would definitely be observed by eye on routine x-ray films. Not surprisingly, some workers have tried to improve upon these figures with specially standardised techniques. Thus, Schraer (1953) developed a sensitive system using an aluminium-zinc alloy calibration wedge, and

making x-ray films of selected areas with a high ratio of bone to other tissues. Nordin et al (1962) have compared x-ray density of vertebrae with the intervertebral spaces. These methods however either require special equipment or are not yet fully evaluated and certainly are not in general use. It must therefore be accepted that radiology as generally performed at present can provide only a crude estimate of the calcium content of bones. This means that if treatment of osteoporosis results in a gain of 10 or even 20 per cent in calcium content of the bones, this may go unrecognised radiologically. On the other hand, if a positive calcium balance of 300g of calcium is claimed, then this should be recognisable radiologically, since the normal skeletal calcium is about 1 kg. Is osteoporosis distinguishable from osteomalacia radiologically? Even when there is definite recognition radiologically of loss of bone calcium, the radiologist may still be unable to recognise the cause of the loss. In particular before the appearance of the specific hall-marks of osteomalacia or osteoporosis, which are described below, he may be quite unable to distinguish between these two conditions. This is of particular importance because despite the similarity in terminology the conditions are quite distinct biochemically, histologically and therapeutically. In osteomalacia, the bone matrix, the osteoid, is made without difficulty but there is an inability to calcify it; usually (but not necessarily in renal failure) there is a low calcium x phosphorus product in the plasma and plasma alkaline phosphatase is raised. In osteoporosis, there is loss of both mineral and organic matrix of the bone while the plasma calcium, phosphorus and alkaline phosphatase are normal. The treatments are different and, in general, osteomalacia responds well to treatment with vitamin D, but osteoporosis responds poorly to all treatments yet described. These distinctions are therefore of very real practical importance, and it is important to make the distinctions when this is possible. Figure 1 shows the x-ray of the lumbar spine of a lad of seventeen years with delayed puberty. There was nothing biochemically to suggest osteomalacia and it was concluded that he had

Based on a paper delivered to the Faculty of Radiologists, Leeds, 6th October 1962. 75

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FIG. 1 Fro. 2 FIG. 3 FIG. 4 FIG. 1--Lateral lumbar spine showing mild osteoporosis due to delayed puberty. Increase in vertical striations. FIG. 2--Lateral lumbar spine in more advanced osteoporosis, but without any shape changes. 'Outline vertebrae' with distinct outlines but little visible structure, FIG. 3--Lateral lumbar spine in immobilisation osteoporosis showing typical irregular vertebral collapse. FIG. 4 - Lateral thoracic spine in osteoporosis from cortisone-like drugs showing typical irregular vertebral collapse.

osteoporosis due to hypogonadism. Note the increase in striatal markings, especially the vertical striations, due to loss of the cortex which would normally mask these striations. Such loss of cortex (which may also be observed in long bones) can occur both in osteoporosis and osteomalacia, so that the radiologist can only report this as 'somewhat rarefied' and cannot be sure of which disease is present. At a more advanced stage of calcium loss the trabecular pattern may be lost, leaving 'outline vertebrae' as in Figure 2. Such an appearance is usually indicative of osteoporosis, although the author is not convinced that this cannot occur in osteomalacia. Osteoporotic bones are brittle bones, since they are normal in composition, but there is not enough bone present to provide the normal strength. They therefore fracture readily, and indeed it is the fractures which provide the hall-mark of osteoporosis and permit its diagnosis radiologically. The fractures occur with very little trauma and in weight-bearing areas especially. The vertebral bodies are often affected and crush fractures develop in a somewhat sporadic fashion except that the lumbar vertebrae tend to be affected somewhat more than the thoracic or cervical vertebrae. The fractures usually develop one at a time so that a

quite characteristic picture of irregular vertebral collapse is seen. Such vertebrae are seen in Figure 3 where the aetiology was immobilisation, and Figure 4 where the aetiology was cortisone therapy, and indeed any cause of osteoporosis can give the same sort of appearances, which, however, are quite different from the shape changes seen in osteomalacic vertebrae (see below). Another characteristic of osteoporosis is the Schmorl's node due to herniation of the nucleus pulposus of the intervertebral disc into the body of the vertebra itself. Figure 5 shows changes similar to those of Figures 3 and 4 and this patient was at first diagnosed as having senile osteoporosis, but x-rays of the pelvis (Fig. 6) revealed that this was not the true diagnosis and she proved to have multiple myelomatosis. Thus, the x-rays of the spine in osteoporosis may be indistinguishable from those due to neoplastic infiltrations. In contrast, diffusely osteomalacic bones are abnormal in composition containing a lot of uncalcified osteoid tissue which lacks strength, and will slowly bend rather than fracture. The vertebral bodies do not fracture as in osteoporosis, but all being equally malleable, they all become equally deformed and assume a biconcave (codfish vertebra) appearance. Each vertebral body has the same

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FIG. 5 FIG. 6 FI6. 5--Lateral lumbar spine in multiple myelomatosis showing irregular vertebral collapse. FIG. 6--Pelvis of same patient as Figure 5 showing multiple round radio-translucent areas.

FIG. 7 Fto. 8 FIG. 9 FIG. 7 Lateral lumbar spine in long-standing osteomalacia from renal tubular acidosis, which had also caused renal calculi and uraemia. Note the remarkable regularity of the vertebral collapse, giving 'cod-fish' biconcave vertebral bodies. The sclerosis is probably attributable to azotaemic osteodystrophy but this is not discussed here. FiG. 8--Lateral lumbar spine in osteomalacia of long standing and probably due to a vitamin D-deficient diet. Note the regularity of the vertebral collapse. FiG. 9--Lateral lumbar spine of an osteoporotic boy of fourteen years. Cause of osteoporosis was 'idiopathic'. Note the remarkable regularity of the vertebral collapse. A patient of Professor C. E. Dent by whose courtesy this picture appears.

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F~6. 11

shape as the one above and the one below, although there is a trend towards increasing deformity from the top downwards. These changes can be seen in long-standing osteomalacia due to renal tubular acidosis (Fig. 7) or vitamin D deficiency (Fig. 8) or any other cause. It thus appears that when there are shape changes in the vertebral bodies it is possible radiologically to distinguish osteomalacia from osteoporosis. Two notable exceptions must be mentioned however. First, children with osteoporosis may develop radiological appearances similar to Figure 8, with the vertebrae severely but uniformly biconcave. An example of this is Figure 9. Second, the combination of osteoporosis and osteomalacia may cause confusion (see below), since there is nothing to prevent both diseases being present at the same time. In long-standing osteomalacia, many other bones besides the vertebrae may be affected and malleable and give rise to the well-known deformities from either weight-bearing as in Figure 10, or muscular pull as in Figure 11. There is, however, a further characteristic lesion in osteomalacia, the Looser zone (Looser 1920) or pseudo-fracture. These are

ribbon-like radio-translucent zones of uncalcified osteoid tissue. They appear in certain characteristic sites and often in bone which otherwise looks normal. The development and appearances of these zones were well described by Dent and Hodson (1954). They may be regarded as hall-marks of osteomalacia, although exceptionally, similar looking zones are seen in other conditions (Dent and Hodson 1954). If, as in Paget's disease, the translucent zones develop in bone obviously affected by a recognisable disease, differentiation from osteomalacia is quite clear radiologically. But at other times the bone may otherwise look normal, and differentiation from osteomalacia can then only be made biochemically or histologically. Looser zones often occur when osteomalacia has developed in an adult with previously normal bones. These conditions are provided by post-gastrectomy osteomalacia, and Figure 12 shows a Looser zone from such a patient. The patient of Figure 13 developed osteomalacia at sixty years. She had had an illness that may well have been rickets in childhood, but was normal from twenty to sixty years when she developed hypophosphataemic osteomalacia.

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Flo. 13

These differences between long-standing and recent osteomalacia may thus enable the radiologist to say something about the age of onset of osteomalacia. He is less likely to be able to say what is the cause of the osteomalacia. This is because the cause of the osteomalacia (steatorrhoea or renal failure) does not itself cause any specific changes in the bones other than those due to the osteomalacia, and the latter are largely independent of the cause (Rose, Dent and Lumb 1957). Thus, the radiologist cannot recognise a cause of osteomalacia on x-ray pictures of bones themselves, but must depend on views of the kidneys or of the small intestine to have renal failure or steatorrhoea suggested to him. We may therefore conclude that once bone fractures or deformities have appeared, it is usually possible for the radiologist to say with reasonable confidence whether he has been looking at osteoporotic or osteomalacic bones, but he may be quite unable to say what is the cause of either the osteoporosis or osteomalacia.

Can osteomalacia

and osteoporosis

co-exist?

Osteoporosis may occur in a limb that has been immobilised (Gurd 1938) or in the whole skeleton if the individual is immobilised (Deitrick et al 1945). Such osteoporosis may give rise to special radiological signs which permit its recognition. Figure 14 shows the typical sub-articular osteoporosis of

immobilisation. The patient was a woman of thirty-seven years who 'sprained' her ankle two months before this x-ray was taken. During these two months she limped around as best she could but did not go to bed. After this x-ray she was rested in bed for five months on account of oedema and pregnancy. At the end of the period her ankles were as in Figure 15 which shows gross loss of calcium, but again affecting the sub-articular areas maximally as in Sudeck's atrophy. Figure 16, from a different patient, shows a similar sub-articular loss of calcium, and in addition there is especially well seen around the hip-joints (Fig. 17) a 'raindrop' pattern of decalcification, which in this case was also thought to be explicable by the osteoporosis (Brailsford 1948). This patient, however, had hypophosphataemic osteomalacia with raised plasma alkaline phosphatase, and many Looser zones. He was a tough farmer who had suddenly become completely immobilised in bed with severe and diffuse bone pain from osteomalacia that he developed for the first time at about fifty years of age. It does not seem at all surprising that he should have developed immobilisation osteoporosis superimposed upon his osteomalacia. He did well on vitamin D therapy and needed no treatment to combat the osteoporosis. We are thus led to the important conclusion that the co-existence of osteomalacia and osteoporosis

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FIG. 14 FIG. 15 FIG. 14--Sub-articular osteoporosis in a thirty-seven-year-old woman after partial immobilisation for two months. FIG. 15--Same patient as Figure 14, but after a further five months with complete immobilisation.

FIG. 16 FJG. 17 FIG. 16--Sub-articular osteoporosis in a man who suddenly became completely immobilised in bed from pain due to osteomalacia. FIG. 17--'Rain-drop' osteoporosis in upper femoral shaft and neck of patient with osteomalacia (same patient as Figure 16). A Looser zone is present on the lateral aspect of the left symphysis pubis.

may be recognised radiologically. Perhaps, in those rare cases when the vertebral bodies of an osteomalacic patient show irregular collapse, this is in fact the explanation. Does osteoporosis occur in primary hyperparathyroidism? The radiological signs of primary hyperparathyroidism have been well described by others. They include the large osteoclastomata described by Hunter and Turnbull (1931) and which can occur in almost any bone and are illustrated here in the tibia in Figure 18. Multiple cyst formation may occur and be similar to those

of Figure 20. Sub-periosteal erosions of the phalanges of the hands were described by Pugh (1951) and are shown in Figure 19. Dent and Hodson (1954) illustrated these erosions at other sites as well, and also drew attention to the granularity of the calvarium shown in Figure 20. The loss of lamina dura of the teeth although a wellknown sign of hyperparathyroidism, is an unreliable sign in the opinions of Dent (1960), Keating (1961), Gordan et al (1962) and the present author. Diffuse loss of calcium was alleged to be a radiological sign by Albright and Reifenstein (1948) and by Nordin

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FIG. 18

(1958), but this has been disputed by Dent (1959) and Dent and Harper (1962). The present author believes that radiological osteoporosis as described above is not a sign of primary hyperparathyroidism. This is not to say, however, that patients with this condition cannot have diffuse osteoporosis and irregular vertebral collapse but rather that if such signs are seen they indicate co-existent osteoporosis due to either immobilisation or senility, Cushing's syndrome (polyglandular syndrome) hyperthyroidism, hypogonadism or any of the other known causes of osteoporosis. What is secondary hyperparathyroidism? It is now generally accepted that the prime function of the parathyroid glands is maintenance of the plasma ionised calcium within normal limits (Copp and Davidson 1961). When the plasma calcium drops below normal, and the parathyroids are present, they may respond with an increased secretion of parathyroid hormone, and this is secondary hyperparathyroidism. The recognition of this condition is fraught with difficulties, however, because of our inability at present to measure parathyroid hormone in body fluids. At autopsy, or at operation, it may be possible to view the parathyroids and assess function from the size of the glands, but this method is obviously of F(16)

F~o. 20 Diffuse granularity of the calvarium in a patient with primary hyperparathyroidism. Note the absent lamina dura.

very limited value. Biopsy of bone may reveal osteitis fibrosa cystica, and so indicate excess parathyroid hormone secretion, but a far easier way of obtaining the same information is by recognition of hyperparathyroidism radiologically. Secondary hyperparathyroidism has been well demonstrated in renal failure (Dent et al 1961,

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FIG. 21 FIG. 22 Fro. 21--Multiple bone cysts due to secondary hyperparathyroidism. The patient had gluten sensitive steatorrhoea, and osteomalacia with Looser zones (not shown). Sclerosis is also present and probably due to healing of the bone disease at a stage several years earlier. The lesion in the upper right pubis is from a bone biopsy which confirmed osteitis fibrosa cystica. Fro. 22--Osteoclastoma in the rib in secondary hyperparathyroidism. Same patient as Figure 21.

Anderson et al 1961, and Stanbury and Lumb 1962) where a good correlation has been found, although admittedly only in small numbers of patients, between parathyroid size, bone histology and radiology of bones. Davies et al (1956) demonstrated radiological hyperparathyroidism secondary to steatorrhoea, a condition long known to cause enlargement of the parathyroids. It therefore seems that the finding of radiological hyperparathyroidism in either chronic renal failure or steatorrhoea truly indicates excess parathyroid activity even though more complete studies are needed to confirm this. The radiological signs of secondary hyperparathyroidism are identical with those of primary hyperparathyroidism. Usually there are subperiosteal erosions of the middle phalanges of the hands, but there may be multiple bone cysts (Fig. 21) or osteoclastomata (Fig. 22). This patient had occult gluten-sensitive steatorrhoea, Looser zones and biochemical osteomalacia, and bone biopsy showed evidence of both osteomalacia and hyperparathyroidism. The finding of radiological hyperparathyroidism therefore cannot itself indicate whether this is primary or secondary. This distinction rests upon the plasma calcium level which is raised in the former, and not raised in the latter. If, however, the radiologist also observes radiological osteomalacia (Looser zones, etc.), then it is extremely likely that the hyperparathyroidism is

secondary to renal failure, steatorrhoea or perhaps some other cause of osteomalacia. Davies et al (1956) however, described a case of steatorrhoea followed by primary hyperparathyroidism and they supposed that long-standing secondary hyperparathyroidism bad been followed by adenoma formation in two of the parathyroids. Similar sequences of events may perhaps explain some of those cases where primary hyperparathyroidism has appeared to have caused rickets (Wood and Robinson 1958) or osteomalacia (Lichwitz et al 1956, Stanbury 1962). Does secondary hyperparathyroidism occur in hypophosphataemic osteomalacia? In hypophosphataemic rickets or osteomalacia (Winters et al 1958), also known as 'phosphate diabetes' (Fanconi and Girardet 1952), and as renal tubular osteomalacia (Dent 1952) the plasma calcium is always normal and it is the plasma phosphate that is low. The latter has been attributed by the Albright school to secondary hyperparathyroidism that in turn is due to a 'tendency to a low serum calcium' (Albright and Reifenstein 1948). On the other hand a school in this country, led principally by Dent (1952) have considered that there is a basic defect in renal tubular handling of phosphate not attributable to secondary hyperparathyroidism. The arguments on both sides are extensive and cannot be reviewed here. It is stressed, however, that not only is the plasma calcium almost invariably

D I A G N O S I S OF OSTEOPOROSIS, OSTEOMALACIA AND / - i Y P E R P A R A T H Y R 0 i D I S M

normal, but fnrthermore the radiological signs of hyperparathyroidism are almost never seen. The situation is thus quite different from both steatorrhoea and renal failure, both of which are frequently accompanied by both low plasma calcium and by radiological hyperparathyroidism. Whether or not secondary hyperparathyroidism is present in hypophosphataemic osteomalacia must remain uncertain perhaps until parathyroid hormone can be measured in biological fluids. Meanwhile, the radiological interpretation must be that secondary hyperparathyroidism is not present. It will be of great interest to see in due course if this interpretation is correct.

G E N E R A L CONCLUSIONS The radiological diagnosis of metabolic bone disease is subject to very substantial limitations. The radiologist can never rule out the existence of metabolic bone disease. Osteomalacia and primary hyperparathyroidism may both be present without radiological changes and in any case are much more accurately diagnosed by biochemical investigations. Osteoporosis is not readily diagnosed biochemically but even here, the radiological evidence is of conclusive value only in advanced cases. On the other hand, when radiological changes are seen in the bones, these provide a useful, even if crude, evaluation of the extent of the disease, and of effects of therapy. Furthermore, when a combination of two or more of the conditions of osteoporosis, osteomalacia and hyperparathyroidism co-exist in a single patient, then radiological examination of the bones may provide a particularly valuable way of demonstrating this.

SUMMARY Although the early changes in osteoporosis may not be radiologically distinguishable from those of osteomalacia, the more advanced changes are readily distinguishable. The radiological changes of primary and secondary hyperparathyroidism are similar to each other and quite distinct from those of osteomalacia or osteoporosis. Radiologieal osteoporosis and osteomalacia may co-exist in the same patient. Primary hyperparathyroidism does not cause radiological osteoporosis and if the two conditions co-exist in a given patient then the osteoporosis must have a cause other than hyperparathyroidism.

3

Secondary hyperparathyroidism cannot be recognised radiologically in patients with hypophosphataemic (renal tubular, types 1 and 2) osteomalacia. This is thought to mean that secondary hyperparathyroidism is not present in these diseases. Aeknowledgement.--I am grateful to Professor C. E. Dent for Figure 9, and for reading the manuscript and making some helpful suggestions. REFERENCES ALBRmHT, F. & REIrENSTEIN, E. C. (1948). Parathyroid glands and metabolic bone disease. Baltimore: Williams & Wilkins. ANDERSON, C. K , HODGKINSON,A. & PYRAH, L. N. (1961). Brit. J. Surg. 48, 498. BRAILSFORD,J. F. (1948). The radiology o f bones and joints, p. 195. London: Churchill. Cope, D. H. & DAVlDSON, G. F. (1961). Proc. Soc. exp. Biol. (N. Y.), 107, 342. DAVIES, D. R., DENT, C. E. & W1LLCOX, A. (1956). Brit. reed. J. 2~ 1133. DEITRICK, J. E., WHEDON, G. D., SHORR, E. & BARR, D. P. (1945). Trans. ninth meeting o f conference on metabolic aspects o f convalescence, p. 62. New York: Macy Foundation. DENT, C. E. (1952). J. Bone Jr. Surg. 34b, 266. D~NT, C. E. (1959). Proe. R. Soc. Med. 52, 993. DENT, C. E. (1960). Personal communication. DENT, C. E. & HARPER, C. M. (1962). Lancet, 1, 559. DENT, C. E., HARPER, C. M. & PHILPOT, G. R. (1961). Quart. J. Med. 30, 1. DENT, C. E. & HODSON, C. J. (1954). Brit. J. Radiol. 27, 605. FANCOM, G. & GmARDET, P. (1952). Helv. paediat. Acta, 7, 14. GORDAN, G. S., EISENBERG,E., LOKEN, H. F., GARDNER, B. & HAYSHIDA,T. (1962). Recent Progr. Hormone Res. 18, 297. GURD, F. B. (1938). Surg. Gynec. Obstet. 66, 489. HUNTER, D. & TURNBULL, H. M. (1931). Brit. J. Surg. 19, 203. KEAXlNG, F. R. (1961). J. Amer. reed. Ass. 178, 547. LACHMAN, E. (1955). Amer. J. Roentgenol. 74, 712. L1CHWITZ, A., DE SEZE, S., HOtCO, D., BORDIER, P. & MAZABRAUD,A. (1956). Presse m&l. 88, 2031. LOOSER, E. (1920). Dtsch. Z. Chit. 152, 210. NORDIN, B. E. C. (1958). Advanc. intern. Med. 9, 81. NORDIN, B. E. C., BARNETT, E., MACGREGOR,J. d~; NISBET, J. (1962). Lancet, 2, 1793. PUGH, D. G. (1951). Amer. J. Roentgenol. 66, 577. ROSE, G. A , LUMB, F. H. & DENT, C. E. (1957). Proc. R. Soc. Med. 50, 371. SC~RAER, H. (1953). J. Paediat. 52, 416. STANBURY,S. W. & LUMB,G. A. (1962). Medicine (Baltimore), 41, 1. WINTERS, R. W., GRAHAM,J. B., WILUAMS,T. F., MCFALLS, V. W. & BURN~TT, C. H. (1958). Medicine (Baltimore), 37, 97. WOOD, B. S. B. & ROBINSON, A. W. (1958). Arch. Dis. Childh. 167, 139.