The crush fracture syndrome in postmenopausal women

9 The Crush Fracture Syndrome in Postmenopausal Women J. C. G A L L A G H E R , J. AARON, A. HORSMAN, D. H. M A R S H A L L , R. W I L K I N S O N A N D B. E. C. N O R D I N

It is widely agreed that however osteoporosis may be defined and whatever the contribution of ageing or other causes may be, there is an unmistakable osteoporotic syndrome characterised by vertebral crush fractures with or without biconcavity which occurs predominantly in post-menopausal women. This syndrome, which was first clearly identified by Albright, Smith and Richardson in 1941, is generally easily recognised on lateral radiographs of the thoracic and lumbar spine, but its underlying cause and, therefore, the most effective form of treatment have yet to be defined. This chapter assembles the principal radiological, histological and metabolic data that we have collected over a period of years in a series of 58 postmenopausal women with vertebral crush fractures in whom none of the recognised causes of this condition, such as steroid therapy, hyperthyroidism, and realabsorption syndrome, were present. Although it has not been possible, even in the limited group, to identify a single pathogenic mechanism, we nonetheless believe that these cases have sufficient features in common to permit certain general conclusions on the causes and treatment of the condition. CLINICAL MATERIAL AND M E T H O D S The series consists of 58 post-menopausal women with one or more vertebral compression fractures, as shown in Table 1. Their ages ranged from 45 to 82 years and the age at menopause from 17 to 57 years; 49 of them had had a natural menopause; 7 had undergone bilateral oophorectomy; and in 2 cases the time of menopause could not be established owing to prior hysterectomy.

Radiology Vertebral compression was defined by an objective procedure which will be described in full elsewhere by one of us (A.H.). Briefly, the method involves measuring the angle subtended by the upper and lower endplates of the vertebrae on lateral films of the lumbar and thoracic spine and defining compression as being present when the angle subtended exceeds two standard Clinics in Endocrinology and Metabolism--Vol. 2, No. 2, July 1973.

293

Table 1, Initial data on 58 patients with crush fractures Case No.

Age

Age at menopause

2/105 2/009 2/0! 7 2/058 2/065 2/117 2/128 2/142 2/150 2/154 2/157 2/163 2/168 2/178 2/186 2/190 2/194 2/196 2/208 2/218 2/227 2/233 2/234 2/235 2/236 2/243 2/244 2/246 2/248 2/252 2/260 2/263 2/265 2/269 2/271 2/273 2/280 2/281 2/287 2/288 2/290 2/291 2/295 2/304 2/306 2/308 2/312 2/315 2/319 2/322 2/326 3/019 3/109 3/110 3/115 16/070

73 55 78 62 72 66 69 74 74 59 61 60 61 62 55 63 68 59 50 57 77 73 55 51 66 66 54 64 67 78 62 65 71 68 52 60 82 64 45 71 71 71 54 59 55 67 62 64 7l 71 56 60 53 71 74 51 59 64

57 36 50 40 50 44 22 52 50 52 49 56 50 21 50 17 41 45 52 47 46 50 42 32 46 51 50 44 50 46 48 44 45 49 50 50

16/123 16/131

*Hysterectomy only.

30 39 45 45 46 49 51 42 50 50 48 38 50 48 48 46 50 49 45 40

Artificial No. of crush (A) or fractures natural (N) N N N N N N A N N N N N N A N A A N H* N N N N N A N N N N N N N N N N N N H* A A N N N N N N N N N N N N N N N N N N

1 3 2 (C) 2 1 4 1 1 (C) 3 1 1 3 2 (C) 3 (C) 2 9 4 (C) 2 4 5 2 1 3 I 1 3 1 1 6 1 1 3 4 6 3 2 (C) 5 (C) 3 6 2 I 2 1 2 (C) 3 5 2 3 3 (C) 1 3 3 (C) 1 1 2 1 (C) 2 (C) 2

Vaginal smear ( ~ )

Metacarpal CA/TA

2 9 0 0 0 0 0 25 12 31 0 29 33 16 0 16 0 0 0 2 0 0 0 0 0 0 0 0 0 14 0 0 17 0 0 0 0 0 0 0 5 11 0 0 20

0.68 0"72 0.68 0'79 0"78 0.81 0"73 0"71 0.81 0 "73 0.78 0.77 0"79 0"66 0"85 0"6~5 0"76 0.70 0"91 0.78 0"67 0'68 0"83 0"81 0"75 0"83 0"78 0'80 0"76 0"74 0'75 0"74 0"75 0"73 0"80 0.79 0.57 0,59 0,82 0.68 0.68 0.78 0-77 0.70 0.68 0'73 0"71 0.76 0.79 0'72 0.64 0"75 0'77 0.83 0.73

(C) signifies lower forearm fracture (Colles')

THE CRUSH FRACTURESYNDROMEIN POSTMENOPAUSALWOMEN

295

deviations above the mean for normal individuals of the same age and sex. H a n d radiographs of all patients were taken by a standard procedure using a non-screen film and a film focus distance of 40 inches. The total diameter and medullary width of the second metacarpal of the right hand at its midpoint were measured with calipers, as described by Nordin and Smith (1965), and rounded to the nearest 0-1 mm. The cortical and total areas were calculated on the assumption that the metacarpal is cylindrical and the results expressed as the cortical area/total area (CA/TA) ratio to allow for inter-individual differences in bone size. We have found that the coefficient of variation of the CA/TA ratio in pre-menopausal women is 7.9 per cent whereas the coefficient of variation of cortical area alone in the same women is 12.2 per cent. In a limited number of cases, repeated observations over periods up to five years permitted the evaluation of sequential changes in individuals. For this purpose, metacarpal measurements were made on the second, third, and fourth metacarpals of each hand and the mean cortical area calculated (Horsman and Nordin, 1973). The mean measurement error on this value is +_ 0.005 cm 2. In sequential studies, correction for total area is not required.

Histology Iliac crest biopsies were obtained from a point lin. behind the anterior superior spine in 16 cases, using the Sacker-Nordin trephine (Sacker and Nordin, 1954). The biopsies were fixed in formaldehyde-glutaraldehyde, embedded for at least four weeks in 9:1 methyl:butylmethacrylate, and cut into 40 serial sections. Quantitative measurements were then made on 64 fields from 16 sections for the evaluation of bone volume and other parameters by the method of Bordier et al (1964). Vaginal smears Vaginal smears were obtained in 45 cases, stained with a Papanicolaou stain, and assessed by the method of Stone et al (1967) in which all cell types are given a score. 200 cells are counted and expressed as a maturation value which in pre-menopausal women generally varies between 60 and 100 per cent. Urinary oestrogen Twenty-four hour total urinary oestrogens were measured by the method of Brown et al (1968) in 18 cases,

Plasma and urine biochemistry Plasma and urine calcium, phosphate, creatinine, and urine hydroxyproline were measured by standard Auto-Analyzer methods on fasting plasma and urine samples. Radiocalcium absorption Radiocalcium absorption was determined in 54 cases by the administration in the fasting state of 5 gCi of 45Ca or 47Ca in 20 mg of calcium as calcium chloride in 250 ml of water. Blood samples were taken at 15, 30, 45, 60, 90 and 120 minutes to permit the calculation of the rate of radiocalcium absorption by the method of Bullamore et al (1970a).

296

J . C . GALLAGHER ET AL

Calcium balances

Calcium balances were performed by a daily balance technique using polyethylene glycol 4000 (PEG) as a non-absorbable faecal marker (Wilkinson, 1971). The patients were given a constant calcium intake which was also gelatin free, and 500 mg P E G three times a day with meals. Equilibration was carried out for a period of seven days, after which daily faecal and urine collections were made for a further seven days, faecal calcium being marker corrected, and urine calcium corrected to mean dailycreatinine output to reduce the day-to-day variation (Bullamore et al, 1970b). All results are based on the mean of the seven daily balances. Net absorption is defined as the difference between dietary and faecal calcium. The normal relation between calcium intake and net absorption has been calculated from the 92 normal balances of Nordin (1960a) and is shown in Figure 1. Bone turnover

10 IxCi of 47Ca was administered intravenously on the morning of day 8 of the balance, which was day 1 of the collection week. Plasma, faecal and urinary activities of 47Ca were determined by standard techniques for 7 days.

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Figure 1. The relationship between calcium intake and net calcium absorption in 92 normal balances (Nordin, 1960a). The mean line is represented by the equation and the 95 per cent limits are also shown. Bone mineralisation rate was calculated by the method of Burkinshaw et al (1968), and bone resorption rate from the difference between the balance and the mineralisation rate.

297

T H E C R U S H F R A C T U R E SYNDROME IN POSTMENOPAUSAL W O M E N

RESULTS

Radiology All the patients presented with backache of varying duration with the exception of three who presented with a fractured neck of femur. The number of compression fractures observed in each case is shown in Table 1, and a frequency distribution histogram of the sites of fracture is given in Figure 2. The commonest fractures occurred at the 7th, 8th and 12th thoracic vertebrae. No less than 12 of the 58 cases had also suffered a fracture of the distal radius and ulna (Colles' fracture).

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Metacarpal CA/TA ratios are shown in Figure 3. Although more than half the values fall below the normal mean for the patient's age the majority lie within one standard deviation of the mean and it is clear that the CA/TA ratio is of little diagnostic value in spinal osteoporosis. (This is also true of simple cortical thickness and cortical area.) In our experience, lower forearm densitometry, using either x-rays or y-rays, offers no diagnostic advantage in this respect. These data do not suggest that the patients reached the menopause with a reduced amount of bone as Newton-John and Morgan (1970) have suggested.

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Figure 4 T h e c h a n g e in m e a n metacarpal cortical area calculated f r o m sequential h a n d r a d i o g r a p h s in 13 u n t r e a t e d a n d 30 treated c r u s h fracture c a s e s N i n e cases c o m m o n to the g r o u p s are joined by lines. T h e n o r m a l m e a n a n d range are derived f r o m observations in 46 p o s t m e n o p a u s a l w o m e n N o t e that in 8 o u t o f 9 cases, the rate o f loss was reduced by treatment, a n d that m a n y o f the treated cases lost little or n o bone during t r e a t m e n t

299

THE CRUSH FRACTURE SYNDROME IN POSTMENOPAUSAL WOMEN

Sequential observations of mean metacarpal cortical area (CA) in 18 of the cases followed for periods of up to five years yielded the changes in CA shown in Figure 4. The mean and 2 S.D. range of the changes in 46 postmenopausal women (23 natural menopause and 23 artificial) is indicated. It will be seen that the untreated crush fracture patients generally lose bone much faster than the average rate for postmenopausal women. However, the loss is greatly reduced in the patients on treatment, which has generally consisted in vitamin D for those with malabsorption of calcium; phosphate or oestrogens for those with a high urine calcium, and calcium supplements in the remainder. The one case with excessive bone loss was on a large dose of vitamin D (20 000 units daily) and this may represent a manifestation of vitamin D overdosage. o Normal • Crush fracture 40

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Figure 5. The relationship between age and the volume of bony tissue, expressed as a percentage of the total volume of bone, in the iliac crest of 16 crush fracture patients and 54 post-mortem controls.

Bone histology The area of bony tissue, expressed as a percentage of the total biopsy area, in 16 crush fracture cases and in 54 post-mortem controls is shown in Figure 5. It can be seen that the amount of trabecular bone in the iliac crest of crush fractt~re cases is low both in absolute terms (less than 15 per cent of total bone area) and relative to normal individuals of the same age, particularly in the younger cases. No consistent abnormality of osteoid-covered surfaces, resorbing surfaces or calcification fronts was observed in these biopsies. N o r was there any relation between the area of bone in the biopsy and the number of crush fractures. An example of an iliae crest biopsy in a crush fracture is shown in Figure 6.

300

J . C . GALLAGHER ET AL

Figure 6. Iliac crest biopsy (× 16) in a 70-y~ar-old female control patient (left) and a 75-year-old female crush fracture patient (right). In the control patient the volume of bony tissue was 19 per cent, and in the crush fracture patient 8 per cent of the total bone volume.

Oestrogenic activity Vaginal smears were performed in 45 cases and the majority showed no oestrogenic activity (Table 1). Although comparable low values are frequently found in postmenopausal women, such values are relatively more common in crush fractures as shown in Table 2. This difference is just significant (p < 0.05). Twenty-four hour total urinary oestrogen excretion was estimated in 18 cases which are compared with 37 controls covering the same age range in Table 3. Urinary oestrogen was generally below 2 lag/24 hours in the crush fracture cases and 2 Ixg or more in the control urines. This difference is just significant (p < 0.05).

Plasma parathyroid hormone (PTH) Plasma P T H levels were measured by radioimmunoassay in 14 untreated crush fracture cases by M. Peacock. All the values fell within his normal range of 0.5 to 1.5 ng/ml.

Calcium absorption RADIOACTIVE CALCIUM. T h e hourly rates of radiocalcium absorption in 52 crush fracture cases are shown in Figure 7. The great majority of cases (about 80 per cent) fall below the normal mean for women under the age of

THE CRUSH FRACTURE SYNDROME IN POSTMENOPAUSAL WOMEN

301

Table 2. Maturation value of vaginal smear in crush fracture and control patients Maturation value

Crush fractures

Postmenopausal normals

30 15

25 34

0 >0 Chi Squared 5.11 p < 0-05

Table 3. Twenty-four, hour total urine oestrogens in crush fracture and control patients Urine oestrogens ~tg/24 hrs

Crush fractures

Postmenopausal normals

4 14

22 15

2 <2 Chi Squared 5.33 p < 0-05

60, b u t owing to the fall o f calcium a b s o r p t i o n with age in n o r m a l subjects, this distinction is lost in the older cases. STABLE CALCIUM. N e t calcium a b s o r p t i o n d e t e r m i n e d b y the calcium b a l a n c e technique in 34 crush fracture cases is shown in F i g u r e 8. The n o r m a l m e a n a n d range are indicated, a n d it is clear t h a t the great m a j o r i t y o f the crush fracture cases fall b e l o w the m e a n t h o u g h m a n y o f these are within the r a t h e r wide n o r m a l range relative to intake. I n general, faecal calcium a p p r o x i m a t e s to calcium i n t a k e in these patients. I n 15 o f the 34 cases, net a b s o r p t i o n is zero or less, a n d in 8 o f these severe m a l a b s o r p t i o n is present. Post menopausal • Crush Fractures.

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Figure 7. The relationship between the hourly rate of calcium absorption and ago in 52 crush fracture patients. The hatched area represents the mean + 1 S.D, for normal female controls (Bullarnore et al, 1970a).

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Figure 8. The relationship between net calcium absorption and dietary intake of calcium in 34 balances on untreated crush fracture patients. Values are expressed as mg Ca/kg/day. The lines represent the mean and 95 per cent limit calculated for 92 normal balances (Nordin, 1960a) given by the equation shown in Figure 1.

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Figure 9. The relationship between net calcium absorption determined by the balance technique and the hourly rate of calcium absorption determined by the radiocalcium absorption test in 34 patients with crush fractures. The stable calcium absorption is expressed as a percentage deviation from the normal mean calcium absorption at the appropriate intakes derived from Figure 1.

303

THE CRUSH FRACTURE SYNDROME IN POSTMENOPAUSAL WOMEN

The relation between the radiocalcium and the stable calcium absorption (the latter expressed as a percentage deviation from the normal mean at the appropriate intake derived from Figure 1) is shown in Figure 9. The coefficient of correlation is 0.74 (p < 0"001). Thus, there is agreement between these two procedures, both of which indicate reduced calcium absorption in crush fracture cases. Calcium balance The relation between calcium intake and calcium output in the 34 balances is shown in Figure 10. Over a wide range of dietary calcium, calcium output is almost invariably greater than calcium intake, and usually higher relative to intake than it is in normal subjects. Urine calcium

The relation between dietary and urinary calcium in the 34 balance studies is shown in Figure 11. The normal relation with 95 per cent limits is given by the equation' y = 0-056x + 2.09 +_ 1-95 mg/kg/day where y is urinary calcium and x is dietary calcium. Virtually all the cases fall within the normal range, and most of them below the normal mean, indicating that the high output relative to intake shown in Figure 10 must be attributable to realabsorption of calcium rather than to hypercalciuria. //

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Figure 10. The relationship between calcium intake and calcium output (urine ÷ faeces) in 34 balances on untreated crush fracture patients. All values expressed as mg Ca/kg/day. The solid lines represent the mean + 2 S.D. for 92 normal balances given by the equation y = 0,74x q- 2.4 _+ 2,1 mg/kg/day (Nordin, 1960a). The broken line is the 45 degree line of equality.

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Figure 12. The relationship between urine calcium and net absorption of 'calcium in 34 balances on untreated crush fracture patients. All values are expressed as mg Ca/kg/day. The solid lines represent the mean ± 2 S.D. for 92 normal balances (Nordin, 1960a) given by the equation y = 0.25x ÷ 1.92 + 1-34 mg/kg/day. The broken line is the 45 degree line of equality.

THE CRUSH FRACTURE SYNDROME IN POSTMENOPAUSAL WOMEN

305

Another way of looking at this is to relate urinary calcium to net absorbed calcium. In the 92 balances on 39 normal subjects already referred to (Nordin, 1960a), the relation between urinary calcium, y, and net absorbed calcium, x, with the 95 per cent limits can be expressed by the equation: y = 0.25x + 1.92 _+ 1-34 mg/kg/day Thus, urinary calcium is more closely related to net absorbed calcium (slope 0-25) than it is to dietary calcium (slope 0.056), and normal subjects are in negative calcium balance when their absorbed calcium falls below about 2.5 mg/kg/day. The same is true of crush fracture patients (Figure 12) who are neither more nor less able than normals to adapt to a low level of absorbed calcium. The fasting urine calcium was normal (Ca/Cr below 0.15) in two-thirds of the crush fracture cases at the time they were first seen but in about one-third of them it was raised (Figure 13). This suggests an increased rate of bone resorption in these cases since fasting urine calcium is presumed to come from bone (Nordin, 1971).

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Mineralisation rates in 34 crush fracture cases are shown in Figure 14 and compared with measurements in nine normal women. It is clear that the crush fracture series includes patients with high, normal, and low mineralisation rates. We have not enough normal data to be certain what the lower normal limit of this value should be, but the application of our calculation to the mean radiocalcium data collected and reported by Heaney et al (1965)

306

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Figure 15. The relationship between urinary hydroxyproline and the calculated bone resorption rate in 34 untreated crush fracture patients (p < 0.001). Bone resorption is calculated from the difference between mineralisation rate and the balance.

THE CRUSH FRACTURE SYNDROMEIN POSTMENOPAUSALWOMEN

307

yields a mean mineralisation rate of 6 mg/kg/day. (It is not possible to calculate a range from their data.) It therefore seems possible that a proportion of crush fracture patients have significantly reduced mineralisation rates. There was no relation between the mineralisation rate and the amount of bone in the iliac crest, the metacarpal CA/TA ratio, or the measurements of oestrogenic activity. Resorption, of course, is calculated from the difference between the mineralisation rate and the calcium balance, and in absolute terms may be high, normal, or low according to the relation between these two parameters. However, urinary hydroxyproline provides an independent measure of resorption rate, and this value is compared with the resorption rate in the 34 balance studies in Figure 15. They are significantly related (p < 0.001). We regard the upper limit of the normal range for hydroxyproline as 0.40 mg/kg/day, on which basis nearly half the crush fracture patients have an increased urinary hydroxyproline. Treatment

VITAMIN D. The effect of vitamin D on radiocalcium absorption is shown in Figure 16. Our routine practice has been to start patients with malabsorption on 1000 units vitamin D daily, to measure their radiocalcium absorption after six weeks and to increase the dose if satisfactory improvement in absorption has not occurred. In this way the dose has been progressively increased to 10 000, 20 000 and, finally, 40 000 units in those few patients who have not responded to lower doses. Figure 16 shows the initial absorption

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308

J . C . GALLAGHER ET AL

value and the final value achieved to date in 26 cases. Three cases responded to 1000 units daily and the dose was not increased beyond that level. In 3 more cases, satisfactory absorption was achieved with 10 000 units. In 7 cases adequate absorption was obtained with 20 000 units, and in 3 cases high absorption was achieved with 40 000 units. Four patients have completely failed to respond even to 40 000 units, and 4 have shown partial improvement on this dose. (However, we have some preliminary evidence that this dose of vitamin D may increase bone resorption, and we suggest that vitamin D at this dose level should be used with great caution.) It appears, therefore, that the malabsorption of calcium in crush fracture cases generally responds to vitamin D in large doses. The cases that fail to respond tend to be the oldest patients in the series. The effect of vitamin D on net calcium absorption measured by the balance technique in 9 crush fracture cases is shown in Figure 17. In each the initial balance is shown as a solid circle, and the final balance by an arrow. Improved absorption is indicated by movement of the arrow towards the mean normal net absorption line. It will be seen that in 8 of the 9 cases net absorption

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THE CRUSH FRACTURE SYNDROME IN POSTMENOPAUSALWOMEN

309

was improved by vitamin D in doses of 20 000 to 40 000 units. In general, the improvement in net absorption determined by the balance procedure agreed with the improvement determined with the radiocalcium test.

Oestrogens In six postmenopausal women with crush fractures the administration of ethinyloestradiol, usually in a dose of 0-05 mg daily, produced a small fall in plasma calcium within 2 to 4 weeks and a substantial fall in fasting urine calcium (Figure 18), which has been maintained for as long as observation has continued, in some cases up to one year. This is associated with a fall in fasting urinary hydro×yproline, as indicated in Figure 19 which shows that fasting urinary calcium and hydroxyproline decline together. 0"4

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In four crush fracture cases, balance studies were repeated after 3 to 6 months on ethinyloestradiol and the fall in urine calcium has been very impressive (Table 4). It can be seen that oestrogen therapy had no consistent effect on absorption in these cases, and that the fall in urine calcium was therefore invariably associated with improvement in calcium balance. There was no consistent effect on the mineralisatior/rate, and the calculated rate of bone resorption therefore fell markedly, as did the urine hydroxyproline. One of these balances is illustrated in Figure 20 which shows the fall in urine calcium and the improvement in calcium balance on 0.05 mg ethinyloestradiol daily, and also shows that 0.025 mg daily had a similar effect which was, however, less marked.

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THE CRUSH FRACTURE SYNDROME IN POSTMENOPAUSAL WOMEN

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Calcium supplements Four crush fracture patients with normal calcium absorption have been studied before and on calcium supplements (calcium citrate in three, extra milk in one). The results are shown in Table 5. In all four cases there was an improvement in calcium balance, and a fall in urine hydroxyproline. In three cases resorption rate fell but in the other case there was a substantial rise in bone turnover so that both mineralisation and resorption rates rose, the latter less than the former. DISCUSSION No absolute morphometric or metabolic difference distinguishes crush fracture patients from the rest of the population, but a limited number of iliac crest biopsies suggests that the fractures occur in patients with a severely reduced amount of trabecular bone. As with all fractures, however, t r a u m a - or at least weight-bearing--must also be a factor, and it is presumably the unpredictability of this additional factor that accounts for some of the variability between the degree of bone loss and the presence of fractures. Clearly, traumatic fractures of the spine may occur in normal individuals; and equally clearly there may be subjects with osteoporotic vertebrae who have not been exposed to sufficient trauma or stress to cause fracture. On the whole, however, the vertebral crush fracture syndrome in postmenopausal women seems to be due to excessive loss of bone from the vertebral bodies which is reflected in the iliac crest. Presumably too there is excessive loss of trabecular bone from the lower forearm in view of the high incidence of lower forearm fractures in this series (12 out of 58 cases). Other bones are less affected, at least to judge from metacarpal cortical thickness, although there is a tendency for the metacarpal CA/TA ratio to lie below the mean for the age of the patient, and sometimes outside the normal range, particularly in younger patients. However, sequential observations suggest that cortical bone is not unaffected since it is being lost at a faster rate than normally occurs in postmenopausal women. Whether cortical thickness in a particular case falls within or below the normal range presumably depends upon the initial value, the rate of bone loss and the duration of the process. According to our data shown in Figure 3 and 4, cortical thickness in crush fracture cases must ultimately fall below the normal range if the patient lives long enough, unless the process is arrested. Thus the concept that this is a self-limiting-disease may be true of the spine, but is certainly not true of the metacarpal, where loss is continuing at an accelerated rate. It is particularly striking that the rate of bone loss is generally greatly reduced by treatments directed primarily at the reduction of negative calcium balance. With one exception, we have never seen further compression fractures occurring during medical treatment. However, the patient with the greatest metacarpal loss shown in Figure 4 has continued to compress her vertebrae while under treatment and this we now fear may be due to vitamin D overdosage--20 000 units daily. Neither our sequential nor our cross-sectional data suggest that crush fracture patients are those who reach middle age with less bone than the

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313

normal population (Newton-John and Morgan, 1970); they may even reach this point with more bone than their contemporaries, but they lose it faster, at least in the metacarpal. Since the vertebrae and iliac crest also contain a reduced amount of bone when the patients are seen, it seems likely that a phase of accelerated bone loss that has affected trabecular bone as well has preceded the fracture that brings the patient to the clinician, who may be seeing the patient at the stage when the vertebrae have reached or are reaching the limit of the amount of bone they can lose without disintegrating. It could even be that the accelerated bone loss from the metacarpal is the result of the end-stage reached in the vertebrae, i.e. that when trabecular bone is no longer available cortical bone is resorbed at an increased rate. In seeking to establish the abnormality, or combination of abnormalities, responsible for crush fractures, the most striking feature is the prevalence of the condition in postmenopausal women, originally noted by Albright et al (1941), and the increased proportion of patients in their and our series who have undergone oophorectomy (7 out of 58 cases). In the present series of crush fractures there was a significant reduction in oestrogenic activity (as judged by vaginal smears and urinary oestrogen excretion) among the patients, compared with postmenopausal women of similar age. We have reported elsewhere the rise in fasting plasma and urine calcium and 24-hour urine hydroxyproline which follows bilateral oophorectomy, and that this clearly reflects an increase in the rate of bone resorption (Gallagher, Young and Nordin, 1972). Previously, we have noted that oestrogens given to women who had a natural menopause produced a fall in fasting plasma and urine calcium (Young et al, 1968), and in the present series ethinyloestradiol has produced a significant fall in fasting plasma and urine calcium and urine hydroxyproline. It has also markedly improved calcium balance in all four crush fracture patients studied. These results leave little doubt that one of the factors involved in this accelerated bone loss is oestrogen insufficiency. Nonetheless, this cannot be the whole explanation since there are many postmenopausal women with low oestrogenic activity who do not develop crush fractures, and in seeking to identify the additional factors responsible for the accelerated bone loss the one most clearly implicated by our studies is malabsorption of calcium, which might be expected to produce osteoporosis in the same way that calcium deficiency does in experimental animals (Nordin, 1960b). Whether measured with radioactive calcium or by conventional balance techniques there is a marked tendency to malabsorption of calcium in this series, which is clearly apparent in the younger cases though less obvious in the older ones because malabsorption of calcium is common in normal women over 65 (Bullamore et al, 1970a). If it is legitimate to suggest that the cause of the condition is most likely to be apparent in the younger cases, then it seems clear that malabsorption of calcium is an important factor in addition to the increased bone resorption resulting from oestrogen deficiency. The nature of the absorptive defect is far from clear, though it appears to respond in many cases, particularly the younger ones, to vitamin D, albeit in larger doses than would be required if this were simply a correction of vitamin D deficiency. An alternative explanation would be that PTH

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activity is reduced in crush fracture cases owing to the increased sensitivity of the bone to PTH, and that this reduction in PTH levels is responsible for the reduced calcium absorption. Whatever the cause may be, it is clear from our balance studies that the calcium output of our crush fracture cases tends to be higher at arty given level of intake than in normal individuals, and in this sense their calcium requirement is increased. The majority of the balances reported in this paper were performed at a standard calcium intake of 500 mg daily, which is the dietary allowance recommended by the F.A.O. and W.H.O. (1962) and the British Department of Health and Social Security (1969). If our balance studies are correct, which we believe them to be, this is not an adequate calcium allowance for this group of cases, and we suspect that it is not an adequate allowance for postmenopausal women in general. Finally, although our bone turnover measurements in crush fracture cases cover the whole range of rates from zero to 10 mg/kg/day, we are impressed by the relatively large number with low mineralisation rates (below 3.0 mg/kg/day). However, we do not have enough measurements on normal women to be sure of the significance of this observation; it may be that women generally have a lower bone turnover than men. Clearly a low rate of new bone formation could predispose to bone loss since bone resorbed to meet the calcium requirements of the body could be less easily replaced. This mechanism, originally suggested by Albright et al (1941), cannot be the whole explanation of spinal osteoporosis since many of our cases have normal or even high rates of turnover, but it may be an important factor in some of them. In summary, although we have been describing a reasonably homogeneous group of cases in terms of age, sex and x-ray appearance, we are inclined to the conclusion that no single pathogenesis can account for all crush fractures. In fact art identical anatomical state can be produced in hyperthyroidism (see Chapter 11) and in hyperadrenocorticism (see Chapter 12) and therefore it seems probable that several pathways can lead to the same end result. Although we have identified low oestrogenic activity, reduced calcium absorption and low bone turnover as possible pathogenic factors, there may well be others that we have neither considered nor studied. As far as management of these cases is concerned, we are proceeding on an individual basis using a combination of oestrogen and/or vitamin D and/or calcium supplements as appears appropriate from the results of the metabolic studies in any given case. If urine calcium, particularly fasting urine calcium, is raised, oestrogens (or phosphate) are indicated. If calcium absorption is reduced, vitamin D is administered. When and if both these parameters are normal, calcium supplements are added. Balance studies suggest that this is the correct approach, and this is strongly supported by sequential measurements of metacarpal cortical thickness and by the rarity of new compression fractures in patients on treatment. However, a net gain of bone does not appear to occur in the metacarpal, and the bone loss--though reduced-does not generally cease completely.

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REFERENCES Albright, F., Smith, P. H. & Richardson, A. M. (1941) Post-menopausal osteoporosis-its clinical features. Journal of the American Medical Association, 116, 2465-2474. Bordier, P., Matrajt, H., Miravet, L. & Hioco, D. (1964) Mesure histologique de la masse et de la resorption des travees osseuses. Pathologie et biologie, 12, 1238-t243. Brown, J. B., MacLeod, S. C., MacNaughton, C., Smith, M. A. & Smythe, B. (1968) A rapid method for estimating oestrogens in urine using a semi-automatic extractor. Journal of Endocrinology, 42, 5--15. Bullamore, J. R., Ga!lagher, J. C.,Wilkinson, R., Nordin, B. E. C. & Marshall, D. H. (1970a) Effect of age on calcium absorption. Lancet, ii, 535-537. Bullamore, J. R., Marshall, D. H., Nordin, B. E. C., Oldfield, W. A. & Wilkinson, R. (1970b). Measurement of calcium balance and bone turnover by new techniques. Calcified Tissue Research, 4 (Supplement), 93-94. Burkinshaw, L., Marshall, D. H., Oxby, C. B., Spiers, F. W., Nordin, B. E. C. & Young, M. M. (1969). Bone turnover model based on a continuously expanding exchangeable calcium pool. Nature, 222, 146-148. Department of Health and Social Security (1969) Recommended intakes of nutrients for the United Kingdom. Report on Public Health and Medical Subjects No. 120. London: Her Majesty's Stationery Office. Food and Agriculture Organisation and World Health Organisation (1962) Calcium requirements. Report of a joint FAO/WHO Expert Group. FAO Nutrition (Mtg) Report Service 30th Technical Report Service Worm Health Organisation 230. Gallagher, J. C., Young, M. M. & Nordin, B. E. C. (1972) Effects of artificial menopause on plasma and urine calcium and phosphate. Clinical Endocrinology, 1, 57-64. Heaney, R. P., Bauer, G. C. H., Bronner, F., Dymling, J. F., Lafferty, F. W., Nordin, B. E. C. & Rich, C. (1964). A normal reference standard for radiocalcium turnover and excretion in humans. Journal of Laboratory and Clinical Medicine, 64, 21-28. Horsman, A. & Nordin, B. E. C. (1973) The quantitative assessment of sequential changes in cortical bone geometry. In Proceedings of the 9th European Symposium of Calcified Tissues. (To be published.) Newton-John, H. F. & Morgan, D. B. (1970) The loss of bone with age, osteoporosis and fractures. Clinical Orthopaedics, 71, 229-252. Nordin, B. E. C. (1960a) Osteoporosis and calcium deficiency. In Bone as a Tissue, ed. F. Rodahl. London: McGraw Hill. Nordin, B. E. C. (1960b) Osteoporosis, osteomalacia and calcium deficiency. Clinical Orthopaedics, 17, 235-258. Nordin, B. E. C. (1971) Clinical significance and pathogenesis of osteoporosis. British Medical Journal, i, 571-576. Nordin, B. E. C. & Smith, D. (1965) Diagnostic Procedures in Disorders of Calcium Metabolism. London: Churchill. Sacker, L. & Nordin, B. E. C. (1954) A simple bone biopsy needle. Lancet, i, 347. Stone, D. F., Sedlis, A., Stone, M. L. & Turkel, W. L. (1967) Oestrogen-like effects inthe vaginal smears of post-menopausal women. Acta Cytologiea, 11, 349-352. Wilkinson, R. (1971) Polyethylene glycol 4000 as a continuously administered non-absorbable faecal marker for metabolic balance studies in human subjects. Gut, 12, 654-660. Young, M. M., Jasani, C., Smith, D. A. & Nordin, B. E. C. (1968) Some effects of ethinyl oestradiol on calcium and phosphorus metabolism. Clinical Science, 34, 411-417.