The Definition, Diagnosis, and Classification of Osteoporosis

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OSTEOPOROSIS

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THE DEFINITION, DIAGNOSIS, AND CLASSIFICATION OF OSTEOPOROSIS B. E. Christopher Nordin, MD, FRCP, FRACP, DSc, Barry E. Chatterton, MBBS, FRACP, Allan G. Need, MD, FRACP, FRCPA, and Michael Horowitz, MBBS, PhD

Osteoporosis is the most common bone disease in humans at the present time-at least in the western world. Its prevalence in the past is unknown. The dominant metabolic bone disease in earlier times was rickets, which was the subject of a monograph as early as 1650,24came to public attention after the industrial revolution, and was not really brought under control until World War 11. Since then, increasing longevity and improved technology have brought osteoporosis into prominence, particularly among women, although rickets has still not been entirely eliminated even in the West.3,l4 THE DEFINITION OF OSTEOPOROSIS

It is difficult to improve on Albright's original definition of osteoporosis as a condition in which there is "too little bone in the bone."' Confusion often arises because the word "bone" is used in two different senses, to define a tissue and to define an organ; however, the term bone in the bone indicates that it is the volume of bone tissue in a given volume of bone organ which is the relevant variable. The volume of From the Division of Clinical Biochemistry, Institute of Medical and Veterinary Science (BECN, AGN); Department of Pathology, The University of Adelaide (BECN); and the Departments of Nuclear Medicine and Medicine, Royal Adelaide Hospital (BEC, MH), Adelaide, Australia

PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA VOLUME 6 . NUMBER 3 AUGUST 1995

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bone in the bone is known as apparent density to distinguish it from the true density of bone tissue, for example, the weight:volume ratio of solid apparent he density of a bone may bone, which is about 2.0 g / ~ m ~ . ~ V vary from 0.25 in a vertebral body up to perhaps 0.75 in a cross-section through the midshaft of the radius. The apparent density of a bone is a function of the bone mineral density (BMD) determined by densitometry which denotes the amount of bone mineral (and by implication bone tissue) in a given area or volume of a bone organ. The use of this variable as a measure of osteoporosis is justified by the relative rarity of osteomalacia in the western world, which allows the assumption that the amount of bone (tissue) in any given bone (organ) is directly proportional to the amount of bone mineral. On that assumption, bone mineral content (BMC) is a measure of bone mass and BMD is a measure of apparent bone density. The only densitometric technique that measures true BMD is quantitative computed tomography (QCT) which can be applied to the vertebral body8 or the forearm78and is expressed in grams of bone mineral per unit volume of the bone organ (g/cm3).Conventional dual-energy x-ray absorptiometry (DEXA) scans the bones in two dimensions only and yields values for BMC (in grams of mineral) and area (in cm2)from which an areal density (g/cm2) can be calculated. With a linear scan across the long axis of a bone (e.g., the radius), BMC denotes bone mineral mass per unit length of bone (g/cm), which can be divided by bone width to yield BMD, again in g/cm2. In each case, the areal density that is derived takes no account of the depth of the bone under the scan; the correction for bone size is therefore incomplete. As the scan embraces a defined anatomical area (e.g., a vertebra in anteroposterior projection), there will be some correlation between the planar area scanned and the volume of the bone; but as the scan area is arbitrary (e.g., in Ward's triangle), there is no correlation between scan area and bone size. It follows that areal density is more valid in some regions than others but theoretically inferior to volume density in discriminating between osteoporotic and normal subjects. This is borne out in practice. With QCT, the mean bone vertebral density in women over 70 years is 38% lower than in young women, whereas with DEXA of the spine the difference is only 21% (Table 1). The diagnostic accuracy of DEXA of the spine can be improved by performing the scan in anterior and lateral projections and calculating a true volume density13 that comes close to that obtained by QCT but is not standard practice.

Table 1. MEAN VERTEBRAL DENSITY IN YOUNG AND OLD WOMEN DETERMINED BY QCT AND DEXA Method -

-

QCT DEXA (Lunar) DEXA (Hologic)

Units -

g/cm3 g/cmZ g/cm2

Young Adults 0.16 1.22 1.04

% Loss with Age

Old Adults

-

-

0.10 0.96 0.82

38 21 21

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Although BMC and BMD are quite distinct variables, there is a tendency for the two terms to be used interchangeably. It is not uncommon for the term BMC to appear in the title of a scientific paper or presentation, or in the legend to a figure,4O when the data are in fact BMD values (and vice versa). This loose use of terminology may be superficially justified in comparisons between normal and osteoporotic populations of the same mean skeletal size, when the difference in BMD is the same as the difference in BMC. If subjects of different skeletal size are being compared (as is often the case), however, then differences in bone mass due to differences in bone size may either obscure or falsely enhance a real difference in bone density between normal and osteoporotic subjects. Correction of bone mass for bone size is, strictly speaking, only necessary or appropriate in populations where these two variables are related. By analogy, the definition of obesity is not based on body weight but on body mass index (BMI) because, in reference populations, weight and height are so strongly related. A man weighing 12 stone would not be regarded as obese if he was 6 foot tall but would be obese if his height were 5 foot 6 inches. However, the range of weights over the entire normal and obese populations (say 8 stone to 20 stone) is much greater than the range of heights (say 5' 6" to 6' 2") so that body weight can be used to define obesity at the extremes. Taking height into account allows much more precise descrimination between normal and obese subjects than using weight alone. The same is true of bone mass and density. In normal subjects, bone mass and bone size are strongly related, even within one sex (Fig. 1). This relationship would be maintained during aging if all subjects lost bone at the same rate but because the rates of change in bone mass vary

Area (cm*) Figure 1. The relation between bone mass and bone size in 100 premenopausal women.

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from -4% to + 1%per a n n ~ m , 6whereas ~ bone size changes very little, the relationship between the two is progressively lost, and in osteoporosis it disappears (Table 2). Correction of mass for size therefore reduces the variance and improves discrimination between normal and osteoporotic young subjects but has less effect on discrimination between normal and osteoporotic old subjects because in them the dependence of bone mass on size has been lost. This is not to deny that bone size may make a positive contribution to bone strength and therefore to fracture risk, but osteoporosis is not defined by bone strength although it is related to it. The breaking strength of a tubular bone is a function of its cross-sectional area as well as its mass. The difference in fracture rates between elderly men and women reflects not only the difference in bone density between them but the difference in bone size. Though we know of no direct evidence, it may be true that small-boned (commonly called petite) women are more liable to fracture than large-boned women; however, there is certainly no basis for the common statement that small-boned subjects are more liable to osteoporosis than large-boned subjects. Bone density is the major, but not the only, determinant of fracture risk. Other factors involved in fracture risk include bone size and the liability to falls. DIAGNOSIS Radiology

Before the advent of densitometry, the diagnosis of osteoporosis was generally based on a lateral spine radiograph showing biconcavity or compression of one or more vertebral bodies as seen in a spine radiograph. These features were described by Albright and colleagues in 19392and by the gastroenterologist MeulengrachV9at about the same time, although the latter attributed this vertebral morphology to osteomalacia. Albright's recognition of the connection between osteoporosis and vertebral deformation represented a turning point in diagnosis, but it was not until 20 years later that an attempt was made to quantitate the deformation by actual measurement of vertebral dimensions: a

Table 2. THE RELATION BETWEEN FOREARM BONE AREA AND BONE MASS (BMC glcm) IN YOUNG AND OLD NORMAL AND OSTEOPOROTIC WOMEN

Group

n

Normal premenopausal Normal postmenopausal 560 years Normal postmenopausal >60 years Osteoporotic >60 years

100 81 60 123

Age (Years, SD) 39 54 67 69

(18-58) (32-60) (61-79) (61-84)

r

P

0.68 0.48 0.29 0.14

<0.001 <0.001 (0.05 ns

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procedure that has since been enormously developed and refined.18,44 There is now fairly general agreement that if anterior vertebral height is 15% (some would say 20%) below posterior height, the vertebra is to be regarded as "wedged" and if the posterior height is more than 15% (some would say 20%) below the height of the nearest vertebra above or below (or by comparison with vertebral height from a reference series), that vertebra should be regarded as "crushed." (Note that posterior compression rarely occurs without anterior compression and then only in the lumbar spine.) In practice, these measurements are seldom used for diagnostic purposes because experienced clinicians and radiologists are satisfied that they can detect significant vertebral deformation with the eye alone, and it is true that there is generally quite good agreement between the recognition of vertebral deformity by simple visual assessment and by measurement. However, when it comes to longitudinal observations, particularly in prospective drug trials, something more precise than visual assessment is required and it is in this context that vertebral morphometry is proving important. Whether vertebral deformation is recognized by morphometry or by visual assessment, it is undoubtedly a useful indicator of the presence of osteoporosis of rather severe degree, assuming that secondary cancer, myeloma, and severe trauma have been excluded. However, it is a diagnostic sign with high specificity but low sensitivity because vertebral fracture generally indicates rather severe disease. Vertebral fracture is therefore unlike peripheral fracture in that the latter is almost invariably associated with trauma and may therefore occur before very significant bone loss has taken place. Whereas the mean bone density T scores (standard deviations below the young mean) in spine and hip fracture cases are between -3 and -4, the mean T score in postmenopausal women with peripheral fractures (of which 30% occur at the wrist) is only about -1.8 (Figs. 2 and 3). Although the number of deformed vertebrae is inversely related to the density of (nonfractured) vertebrae as determined by QCT68 (Fig. 4), there are many women with low vertebral density and no vertebral deformation. Nonetheless, the mean vertebral density in women with even only one wedged vertebra is significantly lower than in those without, and even lower in those with, one crushed vertebra (Fig. 4). This confirms the clinical observation that wedging of a vertebra is frequently the first stage in the collapse of that vertebra; even a single-wedged vertebra should not be treated lightly because it may be the first indication of progressive disease and disability. The prevalence of one vertebral fracture (however defined) is reported to increase the risk of future vertebral fracture by a factor of 5." Unfortunately, vertebral fracture is essentially irreversible; the slight reexpansion of vertebrae reported during treatmenP6 is probably within the range of measurement error. This is why the early diagnosis of osteoporosis by densitometry has become so important. Before leaving this section on the radiology of osteoporosis, mention must be made of radiogrammetry-the measurement of cortical thickness on bone radiographs. This has been applied most commonly to the

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YSM

5

60

65

1

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10

15

20

70

75

25

Figure 2. Forearm bone mineral density (BMD) as a function of age (mean and range) in normal postmenopausal women. The mean and standard error in three fracture groups are indicated.

50

Age

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55

60

65

70

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Figure 3. Vertebral BMD (determined by quantitative computed tomography (QCT)) as a function of age (mean and range) in normal postmenopausal women. The mean and standard errors in three fracture groups are indicated.

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Number of wedged or crushed vertebrae Figure 4. Mean vertebral BMD (determined by QCT) in postmenopausal women with increasing numbers of wedged or compressed vertebrae.

midpoint of the second metacarpal of the right hand6*21 but has also and other sites. These the calcar fem~rale?~ been applied to the measurements undoubtedly can be useful if densitometry is not available, and they are known to correlate with bone mass and density.84 However, they are not as effective as bone densitometry partly because they take no account of trabecular bone or of intracortical bone resorption. Densitometry

It is clear that the diagnosis of osteoporosis on the basis of fracture, whether in the spine or elsewhere, is inadequate and that x-ray morpho-

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metry has limitations. Osteoporosis therefore needs to be defined and diagnosed in terms of bone density. The difficulty lies in defining the cutoff point-the dividing line between normal and osteoporotic bone. There are some who include a fracture of some kind, any kind, in the definition of the osteoporotic as though a patient had to suffer a stroke before he or she could be diagnosed as hypertensive. Others argue that osteoporosis is present when the bone density falls below the "fracture threshold." This is an implausible definition because there is no fracture threshold; fracture risk is a continuous inverse function of bone density (even within the normal range) increasing by a factor of about two for each standard deviation (SD) reduction in bone density9,l1 (Fig. 5). The mean bone density of young women suffering wrist fractures is lower than that of age-matched controls, but most of the readings are within the young normal range.30

Bone Density (sd units) Figure 5. Relative fracture risk as a function of forearm BMD derived from retrospective and prospective data on 492 postmenopausal volunteers.

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It is therefore simplest, and most closely in accord with current practice in other branches of medicine, to use the normal range of BMD in young adults as the reference range and to regard values falling below this range (defined in the same sex and at the same site) as osteop~rotic.~~ It might be said that T scores between -1 and -2 represent "incipient" osteoporosis; values between - 2 and - 3 "mild" osteoporosis; values below - 3 "moderate" osteoporosis; and values below - 4 "severe" osteoporosis. These degrees of severity correspond to the progressive shading shown in Figures 2 and 3. A variant on this theme is the suggestion that osteoporosis should be diagnosed at T scores below -2.5 SD and described as severe if a fracture is present.39This definition seems to be quite arbitrary and also implies that an individual may have mild osteoporosis on the day before a fracture but severe osteoporosis on the day after. Whatever cut-off point is adopted, the diagnosis of osteoporosis would be reasonably straightforward if bone density was always determined by the same instrument at the same site or if all densitometers and all sites yielded the same density values. This is far from the case as illustrated in Figure 6. It is clear that different readings are obtained from different machines at the same site and by the same machine at different sites. These differences between instruments and sites are aggravated by the different reference standards used by the manufacturers of bone densitometers. Not only do the absolute values differ from instrument to instrument and site to site, but the reference populations differ as well. In normal premenopausal and postmenopausal women and cases of simple postmenopausal osteoporosis, the internal correlations between the measurement sites are very high (r values of the order of 0.7 to 0.8) (Fig. 7), but the T and Z scores derived from the manufacturer's reference lines may be very different at different sites in the same subject on the same machine or at the same site on different machines. Although it may be true that there is accelerated loss of bone from the spine in subjects on corticosteroid therapy54and accelerated loss from the periphery in cases of primary hyperparathyroidism,31osteoporosis in the aging population is generally a systemic disease affecting the whole skeleton; major discrepancies in T and Z scores between different sites in the same subject are more often because of differences between the reference lines than between the bones themselves. This is particularly obvious on inspection of the three measurements normally made on the proximal femur (femoral neck, trochanter, and Ward's triangle) which may yield different T and Z scores within the same individual which makes little biological sense. Another consideration that weakens the validity of the manufacturers' reference values is their failure to take the menopause into account, with the result that this major determinant of bone density in women is obscured by age. The importance of this can be seen in Figure 8 in which the same forearm BMD data are plotted on age and on years since menopause. In the former plot (Fig. 8A), there is a significant

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Spine (L) 86%

Spine (H) 77% F.Neck (L) 84% F.Troch (L) 92% F.Neck (H) 74%

F.Troch (H) 78%

Age group Figure 6. Mean BMD as a function of age at different sites derived from hologic (H) and lunar (L) reference data.

decrease in BMD with age before age 50 years, whereas in the latter (Fig. 8B) the very slight decrease is not significant. Because the mean age at menopause is about 49 years, 50% of women must experience it before this age and the inclusion of these women in the young normal reference groups creates the impression of a decrease in bone density before the menopause which is largely spurious and yields reference lines that produce quite misleading T and Z scores. Which Bone to Measure? A recent Consensus Development Conferenceloconcluded that any skeletal site could be used for the prediction of fracture in general, but

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Femur Neck BMD (glcm*) Figure 7. The relation between BMD at the femoral neck and in the forearm in an unselected series of women measured in the Norland XR26 (Norland Corporation, Fort Atkinson, WI).

that specific sites were more powerful predictors of specific fractures, for example, that measurement at the hip was a better predictor of hip fracture than measurement elsewhere. This view relies heavily on a very large but rather short prospective study" which reported that the risk of hip fracture increased by a factor of 1.6 for each SD decrease in forearm BMD and increased by a factor of 2.6 for each SD decrease in BMD at the femoral neck. It is difficult to question a multicenter study based on such large numbers, but the validity of the result depends critically on the relative quality of the densitometry at the two sites which is hard to assess from the published paper. The conclusion is, however, difficult to reconcile with the high correlation between femoral neck and forearm BMD in Figure 7, in which the scatter around the line is largely accounted for by the errors on the measurements. CLASSIFICATION

Albrightl originally classified osteoporosis into three main types: postmenopausal, in women up to the age of 65 years; senile, when it occurred in either sex over the age of 65 years; and idiopathic, when neither menopause nor age nor any of the other causes that he identified (hyperadrenocorticism,hyperthyroidism, acromegaly, and disuse) were present. Riggs and M e l t ~ n subsequently ~~ modified this classification by introducing the concept of Type I and Type I1 osteoporosis. Type I was characterized by wrist or spine fracture and occurred in postmenopausal women up to the age of 65 years; Type I1 was characterized by hip fracture and occurred in women over 75 years old. In the decade of 66

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Forearm (normal controls)

Age group

A 500 -

"

2

450-

s E

400-

JYorearrn (nortnal controls)

V

n 5 m

350-

300-

25

20

42

19

154

>49

1-5

186

112

56

43

I

<30 30-39 40-49

B

Age

6-10 11-15 16-20 >20

YSM

Figure 8. A, Forearm BMD as a function of age in 657 pre- and postmenopausal volunteers. In the women below age 50 there is a significant negative correlation with age (r = -0.27; P = 0.003). 6,The same data replotted as a function of age in the premenopausal women and years since menopause in the postmenopausal women. BMD does not change significantly with age in the premenopausal group (r = -0.16; P = 0.096).

to 75 years, osteoporosis was of mixed type. However, classification categories need to be mutually exclusive to be useful and this is not the case with this particular classification. Many wrist and spine fracture cases go on to develop hip and it has recently been suggested that wrist fractures themselves should be divided into Type I when occurring before the age of 60 years and Type I1 in women over 60 years old.69This suggestion further weakens the value of the classification. Diseases and disorders can be classified in many ways. There was a time when nephritis was divided into Types I and I1 on the basis of

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renal pathology and clinical presentation.15 It soon became apparent, however, that the pathological and clinical components of this classification were discordant and it is now seldom used. Classification by etiology is common in the anemias (iron deficiency, vitamin B,, deficiency), but classifications by cell size (microcytic and macrocytic) or cell type (megaloblastosis) are also used. Hypertension has classically been divided into benign and malignant (or accelerated) categories, but each category may be primary (idiopathic) or secondary to an underlying cause. Osteoporosis was at one time divided into primary and secondary type~,6~ and this classification is still used occasionally but, with increasing understanding of the pathogenesis of osteoporosis, the primary category is shrinking and the secondary category growing. Osteoporosis had also been classified into trabecular and cortical types35(which led to the Types I and I1 described above), but densitometry does not clearly distinguish between these two types of osteoporosis (sometimes referred to as spinal and peripheral) and the difference between them is becoming increasingly blurred. The current tendency in disease classification is towards the concept of risk factors. Of course there are well recognized genetically determined diseases (e.g., cystinuria and phenylketonuria) in which the cause of the clinical syndrome is clearly defined, and there is little or no overlap of the relevant variable between affected and normal subjects. Likewise, bacterial and viral diseases exist in which the cause of the disorder can be identified and eliminated, though even in this area genetic or immunological factors clearly play a role. There are genetic factors in the pathogenesis of hypertension, diabetes, breast cancer, and other diseases, but in all of them is evidence of environmental factors that exert powerful or at least statistically significant effects. Thus the pathogenesis of the common disorders and diseases is multifactorial; the same is true of osteoporosis. There are many ways in which osteoporosis could be classified. It could be classified by bone turnover, or more precisely by the rates of bone formation and resorption (based on histology and biochemistry) because there must be an imbalance between these variables for osteoporosis to occur. There are no doubt cases (e.g., patients on corticosteroid therapy) where impaired bone formation is a significant contributory factor, but increased bone resorption is generally the main feature and classification on these lines would yield only a small number of categories. Classification by calcium intake, absorption, and excretion would also cause confusion because the relationship between these variables is more important than any one of them alone and there is still uncertainty as to whether or when a high urine calcium, or a low calcium absorption, is the cause or the result of the osteoporosis in any particular case. Nor is it useful or possible to classify osteoporosis into congenital and acquired forms. Although there is no doubt a genetic component in osteoporosis, as judged by studies on twins50,70, 8' and mothers and the suggestion that it is a genetically determined disease in the accepted sense52is incompatible with current knowledge about

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risk factors. No other clean classification based on etiology is possible because of the ever present likelihood that more than one cause is operating in any particular case. Corticosteroid therapy and hyperthyroidism are both recognized "causes" of osteoporosis, but they do not affect everyone equally and it is clear that other factors are involved in their final effect on the skeleton. This being the case, the most useful classification at the present state of knowledge is simply to list the main risk factors that contribute to the osteoporotic state, bearing in mind that frequently more than one of them will be operative. These risk factors are as follows and are almost certainly additive61: Genes Estrogen status Androgen status Body weight Dietary calcium Calcium absorption Calcium excretion Dietary sodium and protein Corticosteroid hormones Thyroid hormones Alcohol Smoking Caffeine Exercise Heparin Diuretics Rheumatoid arthritis Some of them influence the consolidation of bone during growth while others determine the rate of bone loss after the menopause in women and after age 55 in men; some affect both processes. It would be beyond the scope of this article to describe or discuss in any depth the way in which these risk factors operate but some comments may be appropriate. The contribution of genetic factors to peak bone density has already been mentioned and is reinforced by comparison between young black and white subjects? 22 but calcium intake and exercise are also important determinants of bone density in young women.27In one study, 40% of the variance on BMD at the spine and hip in young adults was accounted for by body weight, exercise, age, and smoking; in this study, calcium intake did not reach significan~e.~~ Estrogen must also be a factor in this phase, as judged by the low BMD in ovarian a g e n e ~ i and s ~ ~ the adverse effect of late After peak bone density has been achieved early in the third decade, ~ , in ~ ~men there is little change in BMD in women before m e n o p a u ~ e ' or before the age of about 55 years.32Little is known about the risk factors that determine bone loss (if any) in young adults; much more is known about the risk factors that influence the rate of bone loss after menopause

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and during aging. For the first few years after menopause, peak bone density is of course the main determinant of BMD. Over any given 5year period, 90% of the variance on bone density is accounted for by the initial but with the passage of time the rate of change in bone density (which in normal postmenopausal women ranges from - 4 to + 1%per a n n ~ mbecomes ~~) increasingly dominant, and by 15 years after menopause the rate of change has become the main determinant of bone status.36,57 With the passage of time, therefore, the risk factors that determine rate of change in bone mass or density become the main determinants of osteoporosis. Of the risk factors influencing the rate of bone loss, estrogen deficiency (causing an increase in bone resorption) is the most important. It is most commonly due to menopause but it may result from anorexia nervosa, excessive physical exercise, or other causes. Androgen deficiency is an important cause of osteoporosis in men,16 probably mediated through reduced bone formation,17 and may also contribute to osteoporosis in women.63 Body weight is an important determinant of the rate of bone l0ss,6~ possibly due to the fat rather than the lean component72but not entirely accounted for by the role of fatty tissue in the conversion of androgens to estrogen.62The residual effect of weight is unexplained. Dietary calcium has already been mentioned as contributing to bone consolidation during growth, but it has also been related to changes in spinal density during young adult life4 and is increasingly regarded as a risk factor in postmenopausal bone Calcium absorption and obligatory calcium loss are risk factors that have been identified in case control studies.20,51, Malabsorption syndromes probably increase the risk of osteoporosis through their effect on calcium absorption. Dietary sodium (as judged by urine sodium) is an important determinant of urine calciumh5and is therefore likely to influence the rate of bone loss, as has been conclusively demonstrated in rats.26 Protein intake also influences the rate of calcium excretion79and is probably a risk factor for this reason. Both sodium and protein may be said to increase the calcium r e q ~ i r e m e n t . ~ ~ Corticosteroid therapy (like natural hyperadrenocorticism) is a risk 54 probably mainly because factor for osteoporosis at both ends of of depression of bone formation. Thyroid hormone excess increases bone resorption and may lead to osteopor~sis.~~ Parathyroid hormone excess increases bone resorption; osteoporosis is not uncommon in primary hyperparathyroidism31,71* 86 but it is still uncertain whether the effect on bone is selective (i.e., effecting cortical more than trabecular bone). Alcohol excess can undoubtedly lead to 0steoporosis,3~, but there is some evidence that quite a modest intake may have an adverse e f f e ~ t . ~ ~ , ~ ~ Alcohol probably depresses bone formation," but it may also have an

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independent action by increasing urine calcium,'jl just as it increases magnesium excretion.s2 Smoking is also a recognized risk factor for o~teoporosis~~ but its mechanism of action is unknown. It has been suggested that it depresses calcium ab~orption.~~ Caffeine has an adverse effect on calcium balance, possibly because it increases calcium e~cretion.~, 28 This may be secondary to an increase in glomerular filtration rate. Exercise (short of causing amenorrhea) has a positive effect on probably by stimulating bone formation. Immobilization has the reverse effect.43 High-dose, long-term heparin administration can lead to osteoporosis2" the mechanism is unknown. Loop diuretics tend to increase urinary calcium and therefore reprewhereas thiazide diuretics lower urinary sent an adverse risk calcium and probably represent a favorable factor.41 Rheumatoid arthritis is associated with osteoporosis not only in the peripheral skeleton but also in the spine25;the explanation is uncertain. Other risk factors for postmenopausal osteoporosis which have been invoked at various times include age at menopause, type of menopause, and parity, but we have not found any of them to be ~ignificant.~~ CONCLUSIONS

We conclude that osteoporosis is best defined in terms of apparent bone density and diagnosed by bone densitometry. However, absolute difference in density readings between densitometers, differences between reference lines, and apparent differences in density between skeletal regions are all impeding a standardized approach to diagnosis. The pathogenesis of osteoporosis is multifactorial and rigid classification by any criterion is impractical. At present, analysis by risk factors is the most useful classification. ACKNOWLEDGMENT The authors thank Anna Langen-Zueff for her artwork and Margaret Hilton for secretarial assistance.

References 1. Albright F, Reifenstein EC: The Parathyroid Glands and Metabolic Bone Disease. Baltimore, Williams & Wilkins, 1948 2. Albright F, Smith PH, Richardson AM: Postmenopausal osteoporosis; its clinical features. J Am Med Assoc 116:2465, 1941 3. Arneil GC, Crosbie JC: Infantile rickets returns to Glasgow. Lancet 2:423, 1963 4. Baran D, Sorensen A, Grimes J, et al: Dietary modification with dairy products for

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