A Structural Approach to Renal Bone Disease

WHILE NO ONE WOULD DENY that there has been great progress made in our understanding of metabolic bone disease and our ability to evaluate these disorders in affected subjects, the accompanying editorial by Dr. Michael Parfitt provides undeniable evidence that we must recognize that progress has mixed benefits. Indeed, he points out what we have lost by reducing the use of bone biopsy and standard radiographies while relying on dual-energy X-ray absorptiometry of the central skeleton. His insights are extraordinarily relevant to the clinical decision making in patients with the bone abnormalities typically encountered in chronic renal failure. Clearly this article is essential reading for nephrologists, endocrinologists, rheumatologists, orthopedists, and bone basic scientists. Moreover, insights provided are a tribute to the gifted perspective that Dr. Parfitt brings to the bone and mineral community. Marc Drezner, M.D. Editor-in-Chief THE BONES ARE ORGANS composed of bone, which is a hard and rigid tissue. The primary function of the bones is to resist the mechanical forces applied to them by muscle contraction and gravity, so that the parts of the body can move without breaking.1 To carry out this function, each bone has a species-specific size, shape, and internal structure, the outcome of both evolutionary adaptation in the population and physiologic adaptation in the individual during growth.2,3 The precise three-dimensional location of each element of a bone is critical to its mechanical function, but much less important for subsidiary functions such as support of hematopoiesis and participation in mineral homeostasis.4 Endocrinologists and nephrologists have always been more interested in such nonmechanical functions and so have paid more attention to bone as a tissue than to bones as organs. The recent widespread recognition that increased susceptibility to fracture is the most important clinical manifestation of all metabolic bone disorders should logically have redirected attention to bones, but two aspects of current medical practice have counteracted this change in emphasis. First, most physicians no longer look at bone radiographs themselves, and so no longer observe directly the structural consequences of metabolic bone disease. Second, the ready availability of bone densitometry, with its misleading and often frankly erroneous terminology and units, has encouraged physicians to make diagnostic and therapeutic decisions on the basis of an abstract set of numbers that are completely divorced from the underlying structural reality which the numbers purport to represent. In each bone, the solid portion is enclosed between an outer periosteal envelope, which includes articular cartilage as well as periosteum, and an inner endosteal envelope, which surrounds the bone marrow and its extensions and includes the cancellous, endocortical, and intracortical subdivisions which are in continuity.5 The volume of matrix in a bone is defined by the precise three-dimensional locations of these envelopes. Since bone, unlike cartilage, is incapable of interstitial growth, primary changes in these locations underlie all changes in the size, shape, and orientation of a bone and of its internal structural elements. When bone is added, regions of bone surface usually become further apart, and when bone is lost, they usually become closer together. These changes in surface location are the result of cellular activity that takes place exclusively on surfaces, either internal or external. Bone is hard, rigid, and radiopaque because the matrix is impregnated with apatite-like mineral, which accumulates at the expense of water so that matrix volume does not change. The density, which is mass per unit volume, of unmineralized bone matrix is about 1.10 g/cm3; this increases to about 2.35 g/cm3 when all free matrix water has been replaced by mineral.6 Such complete mineralization is normally prevented by some property of living osteocytes,7 so that density does not ordinarily increase much above 2.05 g/cm3.6 For greatest accuracy, the volume to which mass is referred should exclude osteocyte lacunae and canaliculae, but in practice this refinement is usually disregarded. True bone density, as just defined, decreases if bone turnover is high and mean bone age is low, or if mineralization is impaired, and increases if bone turnover is low and mean bone age high, or if there is extensive osteocyte death.8 True bone density, the density of bone as a substance or material, must be distinguished from apparent bone density, which is the density of a whole bone as an organ, representing mass divided by external volume.8 Unlike true bone density, which changes little with age and may even increase, apparent bone density falls progressively with age because external volume either does not change or increases slightly, but matrix and mineral mass decline as bone substance is lost. Because true bone density is approximately constant in most circumstances, mineral mass, which is amenable to measurement in vivo, is a reasonable surrogate for bone matrix volume and bone mass. Apparent bone density—the bone within the bone9—is highly correlated with various measures of bone strength10 and would be an excellent index of the biologic phenomenon of age-related bone loss and of clinical fracture risk. Unfortunately, apparent bone density cannot be measured in vivo because, although mineral mass can be measured with high precision, volume can only be estimated quite crudely.11 Most measurements of so-called bone density are in fact measurements of bone mineral mass partly normalized by some index of bone size. The semantic confusion is so great that one editorialist12 referred to apparent bone density as “true” (meaning three-dimensional) bone density! It has even been suggested13 that the use of the term “bone density” be abandoned! This bizarre situation—people who claim to measure bone density not even knowing what density is—persists because the use that physicians make of numbers depends not on their names, units, or scientific meaning but on how they relate to a reference range. The structural changes that occur in bone as a result of age itself and of age-related changes in muscular and hormonal function are sufficiently uniform that they can be captured by the numbers that are generated by bone “densitometry.” Relating such numbers to bone size is crucial to the understanding of skeletal growth14 but is of much less importance in the adult skeleton. Such numbers, whether or not they are corrected for bone size, provide useful information about bone strength and future fracture risk, although not as much information as when they are related more directly to mechanical properties.15 But the underlying assumptions, that true bone density does not change and that a particular fall in numerical value has the same structural significance in different persons, may no longer hold when the bones are affected by specific diseases as well as by aging. This possibility is greatest in the most complex and least predictable form of metabolic bone disease, that resulting from chronic renal failure.16 Retardation of growth and rickets-like deformities in children and rapidly progressive genu valgum in adolescents were noted more than a century ago and remained the most frequent skeletal manifestations of renal failure for many decades thereafter.17 More recently, radiographs revealed growth plate lesions resembling rickets, looser zones of osteomalacia, subperiosteal, subchondral, and subtendinous erosions, and cystic lesions due to osteitis fibrosa and osteosclerosis, especially in the endplates of the vertebral bodies.18 All these were noted in patients with end-stage renal failure before the availability of maintenance hemodialysis, which in addition to prolonging life led initially to a specific form of osteomalacia due to aluminum poisoning.19 Recognition of this disorder and its etiology required histologic examination of bone, an investigative tool first widely applied to renal bone disease by the Manchester group.20 The same tool revealed the decline in aluminum-related bone disease that followed appropriate preventive measures21 and the emergence of so-called aplastic or adynamic bone disease, in which bone formation is reduced but mineralization is not impaired.22 A variety of noninvasive tests have been tried, alone and in combination, to predict bone histology, and in many dialysis centers these have largely replaced bone biopsy as a guide to management, a trend that has been strongly criticized.23,24 The fall in use of bone biopsy has been accompanied by a rise in use of bone “densitometry.”25-28 The earliest in vivo structural study of bone was carried out by measurement of metacarpal cortical dimensions on hand radiographs. Although imprecise, this procedure had the unique advantage of surface specificity and established the most important facts about age-related bone loss as a biologic phenomenon.29,30 The earliest densitometric method was single-energy photon absorptiometry of the radius, a site of predominantly cortical bone. The development of dual-energy photon absorptiometry, and later dual-energy X-ray absorptiometry, allowed measurement of the spine and upper femur, sites with a higher proportion of cancellous bone and where (not necessarily as a result) the most important osteoporotic fractures occur. For these reasons, in the osteoporosis field, emphasis shifted strongly away from the peripheral toward the central skeleton.31 The same shift occurred in the study of renal bone disease, not because the central skeleton was the site of the most clinically significant loss of bone mineral, but simply because it was fashionable. By the time these methods were available, most nephrologists, like most endocrinologists, had either lost or never acquired the ability to think about bone in precise structural terms and so were unable to relate the results of “densitometry” to what was actually going on in the bones. The numbers, so readily obtained, were still just numbers. The histologic study of bone can open a window on its structure, but regrettably its practitioners have unnecessarily restricted their field of vision. Except for very limited use of the rib,32 bone samples were (and are) obtained from the ilium, a site preferred because it was accessible, safe, and representative of the central skeleton.33 The information that can be obtained from an iliac biopsy depends on the location and size of the sample. When obtained through the crest by Jamshidi needle or electric drill,34 only cancellous bone is obtained. Examination of such samples confirmed the high frequency of bone changes due to hyperparathyroidism, ranging from mild increase in turnover to severe osteitis fibrosa with dissecting resorption, abundant and more highly nucleated osteoclasts, para- and intratrabecular fibrosis, and in extreme cases, woven bone formation.23,35 Small samples of cancellous bone are also satisfactory for the recognition of osteomalacia and the detection of aluminum deposition. Bone structure is better preserved in transiliac specimens with cortex at each end,33-35 but the cortical bone is generally regarded more as protection for the cancellous bone than as worthy of examination in its own right. Thus, in the current study of renal bone disease, invasive as well as noninvasive methods focus on cancellous bone to the virtual exclusion of cortical bone. Cortical bone, or compacta, forms the almost solid outer wall of all bones. Most mechanical load bearing in the skeleton is carried out by cortical bone, which bears the immediate burden of all skeletal muscle contraction, because all muscles are attached, directly or indirectly, to periosteum. Even at sites with the highest proportion of cancellous bone, such as the long bone metaphyses and vertebral bodies, fractures began in cortical bone.36 In the skeleton as a whole, cortical bone provides about 75% of the volume and mass but only about 25% of the surface,5 but in the ilium, representative of the central skeleton, the proportions are closer to two-thirds and one-third, respectively.37 The relative loss of bone with age is greater for cancellous than for cortical bone, because of its higher surface-to-volume ratio, but the absolute amount of bone lost is greater in cortical bone. This is because the volume of bone lost per unit of surface is greater for the endocortical than for the intracortical and cancellous subdivisions of the endosteal envelope.38 Furthermore, thinning of vertebral cortices with age contributes substantially to loss of compressive strength of the vertebral bodies,39 and much of the strength of the spinal column as a functional unit is provided by the neural arches and their spinous processes, which consist primarily of cortical bone. The usual reason given for the examination of cancellous rather than cortical bone is that because of its higher turnover, changes due to disease occur sooner and are of larger magnitude.33 The literature is replete with unqualified statements that bone turnover is higher in cancellous than in cortical bone, but the reality is not so simple. Bone turnover, which is fractional volume replacement per unit time (usually expressed as percentage per year), depends on two unrelated factors. These are a geometric factor-surface to volume ratio (BS/BV) and a cellular factor-bone formation rate per unit of surface (BFR/BS). BS/BV is invariably higher in cancellous than in cortical bone, although for both types there is some variability between sites. In the ilium of healthy young women, the ratio is about 4:1.37 In the same subjects, BFR/BS was about 50% higher on the intracortical and endocortical surfaces than on the cancellous surface, so that bone turnover in the ilium was only 2.5–3 times higher in cancellous bone (about 15%/year) than in cortical bone (about 5–6%/year).38 Remodeling in cancellous bone is much lower adjacent to yellow than to red marrow, so that turnover is higher in central cortical bone than in peripheral cancellous bone.40 Nevertheless, when compared at the same sites, osteoid accumulation in disease is substantially greater in cancellous than in cortical bone.41 The structure of cortical bone can be economically described by two features: thickness, which varies substantially from <1 mm to >10 mm at different skeletal sites, and porosity, which is usually in the range of 2–8% and varies much less between sites. Cortical thickness at skeletal maturity depends mainly on the magnitude of combined periosteal and endocortical net apposition during the adolescent growth spurt.3 Cortical thinning with age reflects the balance between very slow periosteal expansion and much more rapid net endocortical resorption.13,29 The cellular is that during each of are than at an This has been at both biopsy sites, and and there is no reason to that it is a of age-related cortical bone bone surfaces in with marrow, the basic which is the of bone the surface a slow cortical the are most because of and are rapid cortical as the the surface, the of the to expansion and of and of the inner of the cortex to a In the of this cortical increases but in the cortical bone that increases only with age a increase in cortical increase in bone in cortical bone due to hyperparathyroidism, whether primary or to and on its mild to the of age and are in a changes occur that are In the bone turnover is increased about to which of change are are more sites on the endocortical and intracortical surfaces because each basic unit further its The on the endocortical not surfaces are because the of and on the of are at this a of the inner cortex is more the rate of endocortical bone loss is and cortical thickness a increase in net periosteal Cortical is increased as in of high bone with primary have lost cortical bone but are no longer it than This a of inner cortical bone that is lost more in the same location as the bone that was during the growth The changes of severe are referred to as osteitis an but useful The most of osteitis fibrosa in cortical bone is most readily in the periosteum, where is just on high radiographs of the But in severe hyperparathyroidism, the are much and more and are with a of tissue and woven bone, both and also on all subdivisions of the endosteal envelope, with larger intracortical even more extensive of the inner and dissecting intratrabecular with of the The amount of cancellous bone is often increased because of and is and in extreme lost In mild hyperparathyroidism, in to cortical bone, the age-related changes in cancellous bone are not but rather with and greater of Thus, mild and have on bone turnover the skeleton, and structural on cortical bone, but structural on cancellous The of chronic renal failure with the for bone is very in the when abnormalities in bone and mineral are or and the patients are The of is and not be More important to is its by the time has of some is almost In such the of the bones should be the same as in mild primary but has been on cortical thinning can be but as as can only one study has been carried out in and the obtained hand on to a medical in who had a of but no clinical evidence of renal failure. In such metacarpal in between and increases in both outer and inner and a significant in mean combined cortical thickness of mm or about with a in relative cortical of about was not but metacarpal cortical thickness with and no is of the patients had which higher than the endocortical Because of this the two surfaces can For of by or renal may to but cortical thinning to radiographs are to the study of renal bone disease, not only and endocortical changes but metacarpal increased cortical porosity, a of increased intracortical By the time dialysis is many patients have changes on all surfaces of cortical but the endocortical changes are the most representing the of bone and unlike the periosteal and intracortical are Cortical thinning is much the of the low for single-energy photon absorptiometry at the of dialysis at both and although the magnitude of the is less if is and if dialysis is cortical thinning can be prevented by an appropriate of which an is the most important In cortical bone loss can not only be but partly by Unlike both and on cortical and cancellous bone are although in structural has generally on cortical bone and generally on cancellous bone. This for primary hyperparathyroidism, is even more for with has long been as a of renal bone and evidence was that as a was more and more severe than in primary hyperparathyroidism, partly because are higher and partly because of the of to Cortical mainly the skeleton and cancellous mainly the skeleton a of skeletal with little change in body or skeletal The bone of is more established and its better on to increase as with there is both bone formation at bone surfaces and of by an increase in wall these are restricted to cancellous bone surfaces is less in current than in of renal bone It may be less because to and are more but it is also less well radiographs are and even more by is on densitometric methods such as dual-energy photon absorptiometry or dual-energy X-ray absorptiometry, which in the spine the mainly cancellous bone of the vertebral and the mainly cortical bone of the vertebral and so the most structural the results have been quite with mean that are higher the same most lower in The most is a of with a higher than usual proportion of both high and low In the upper femur, the results have been generally lower than in the especially in a predominantly cortical but with Such have very either to the understanding of or to the of individual but have in the of different More have been with which can measure apparent density in a of cancellous bone in the of a vertebral The results highly with bone volume in tissue volume in iliac bone patients with The mean value was increased in patients with histologic evidence of osteitis the of The mean value was in patients with low turnover which includes both and osteomalacia as well as aplastic bone Most of the individual were in the lower of the It is that much of the mineral unmineralized in aplastic bone disease iliac is from of the of aplastic bone disease in clinical significance is also still although the of function to the and increased vertebral at vertebral deformities have been on but whether their is higher in dialysis patients than in and subjects, or is related to histologic of renal not most because, before renal replacement available, patients with renal failure not long for increase in fracture to become there were of by through cystic lesions of osteitis More recently, fractures have occurred through regions of although only dialysis for at least But fractures in significant numbers were first in with aluminum-related the most The of these fractures were not but complete fractures through zones have long been to occur in and replacement of a amount of bone by osteoid would be to bone Nevertheless, when all tissue in an iliac biopsy is cortical thinning much the to bone even in patients with severe aluminum-related of fractures in dialysis patients have been but there has been only one on fracture is increased to in patients with end-stage renal disease, of or The relative was highest to in the to age but the absolute or was highest in the to age fracture may be related to the of or to and but such a increase in fracture would some the dialysis population as a on the the most such is cortical which is severe before the of dialysis and the of bone strength of and of the histologic or the disorder of bone that may be at the time the fracture Although of may be during dialysis is and of much in the disease the of reducing fracture in patients with chronic renal