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Keywords:

  • bone growth;
  • bone mineral density;
  • children;
  • modeling;
  • remodeling

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE AMOUNT OF MINERAL IN THE BONE MATRIX—MATERIAL MINERAL DENSITY
  5. THE AMOUNT OF MINERAL IN TRABECULAR AND CORTICAL TISSUE—COMPARTMENT MINERAL DENSITY
  6. THE AMOUNT OF MINERAL WITHIN THE PERIOSTEAL ENVELOPE—TOTAL BMD
  7. OUTLOOK
  8. References

Bone densitometry has great potential to improve our understanding of bone development. However, densitometric data in children rarely are interpreted in light of the biological processes they reflect. To strengthen the link between bone densitometry and the physiology of bone development, we review the literature on physiological mechanisms and structural changes determining bone mineral density (BMD). BMD (defined as mass of mineral per unit volume) is analyzed in three levels: in bone material (BMDmaterial), in a bone's trabecular and cortical tissue compartments (BMDcompartment), and in the entire bone (BMDtotal). BMDmaterial of the femoral midshaft cortex decreases after birth to a nadir in the first year of life and thereafter increases. In iliac trabecular bone, BMDmaterial also increases from infancy to adulthood, reflecting the decrease in bone turnover. BMDmaterial cannot be determined with current noninvasive techniques because of insufficient spatial resolution. BMDcompartment of the femoral midshaft cortex decreases in the first months after birth followed by a rapid increase during the next 2 years and slower changes thereafter, reflecting changes in both relative bone volume and BMDmaterial. Trabecular BMDcompartment increases in vertebral bodies but not at the distal radius. Quantitative computed tomography (QCT) allows for the determination of both trabecular and cortical BMDcompartment, whereas projectional techniques such as dual-energy X-ray absorptiometry (DXA) can be used only to assess cortical BMDcompartment of long bone diaphyses. BMDtotal of long bones decreases by about 30% in the first months after birth, reflecting a redistribution of bone tissue from the endocortical to the periosteal surface. In children of school age and in adolescents, changes in BMDtotal are site-specific. There is a marked rise in BMDtotal at locations where relative cortical area increases (metacarpal bones, phalanges, and forearm), but little change at the femoral neck and midshaft. BMDtotal can be measured by QCT at any site of the skeleton, regardless of bone shape. DXA allows the estimation of BMDtotal at skeletal sites, which have an approximately circular cross-section. The system presented here may help to interpret densitometric results in growing subjects on a physiological basis.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE AMOUNT OF MINERAL IN THE BONE MATRIX—MATERIAL MINERAL DENSITY
  5. THE AMOUNT OF MINERAL IN TRABECULAR AND CORTICAL TISSUE—COMPARTMENT MINERAL DENSITY
  6. THE AMOUNT OF MINERAL WITHIN THE PERIOSTEAL ENVELOPE—TOTAL BMD
  7. OUTLOOK
  8. References

BONE DEVELOPMENT is one of the key processes characterizing childhood and adolescence. Understanding this process is not only important for physicians treating pediatric bone disorders, but also for clinicians and researchers dealing with postmenopausal and senile osteoporosis.(1) Bone densitometry has great potential to enhance our understanding of bone development.(2) However, various authors recently have deplored that densitometry presently is not fulfilling this potential.(3–5)

The frequent neglect of the differences between bone size, bone mass, and bone density especially affects the interpretation of densitometric results in growing children and adolescents.(5,6) But even when these size-related problems are accounted for, densitometric data rarely are interpreted in light of the biological processes that they reflect. For example, increases in “bone density” during growth often are attributed uniformly to “bone mineralization,” regardless of whether this represents greater cortical thickness, thicker trabeculae, or incorporation of additional mineral into existing bone matrix. Only the latter process represents mineralization in its physiological sense.(7,8) Certainly, it would increase the usefulness of densitometry in children and adolescents, if bone's physiological mechanisms and structural features were given more consideration in the design and interpretation of densitometric studies.(3–5)

The aim of this contribution is to strengthen the link between bone densitometry and the physiology of bone development. The available literature is evaluated as to what is known about the physiological mechanisms and structural changes leading to variations in bone density during normal human bone development. To take bone's multilevel biological organization into account,(9,10) bone density is analyzed in three levels: in bone material, in a bone's tissue compartments, and in the entire bone.

Determining density as defined by physics—weight divided by volume—should form the “golden standard” of densitometry. For each level of biological organization, we therefore present data based on such directly determined densities and compare results of indirect (absorptiometric) studies. The discussion focuses on bone mineral density (BMD), that is, the mass of inorganic (mineral) matter per unit volume.

THE AMOUNT OF MINERAL IN THE BONE MATRIX—MATERIAL MINERAL DENSITY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE AMOUNT OF MINERAL IN THE BONE MATRIX—MATERIAL MINERAL DENSITY
  5. THE AMOUNT OF MINERAL IN TRABECULAR AND CORTICAL TISSUE—COMPARTMENT MINERAL DENSITY
  6. THE AMOUNT OF MINERAL WITHIN THE PERIOSTEAL ENVELOPE—TOTAL BMD
  7. OUTLOOK
  8. References

Background

Bone as a material can be defined as extracellular bone matrix, whether mineralized or not.(9) Therefore, the relevant volume to calculate material density is the volume occupied by bone matrix and does not include marrow spaces, osteonal canals, lacunae, and canaliculi (Fig. 1). This has been called “true bone density,”(5,9) but the more descriptive term “material BMD” (BMDmaterial) may be preferable, because a variety of densities have been labeled “true.”

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Figure FIG. 1.. Definitions of the various types of mineral density. BMDmaterial and BMDcompartment (A and B) in trabecular and (C and D) in cortical bone. The mass of mineral (in gray) determining BMDmaterial and BMDcompartment is identical (mass 1 = mass 2), but the volume (encircled by black lines) differs (volume 2 > volume 1). Therefore, BMDmaterial is higher than BMDcompartment. (E) BMDtotal is defined as the mass of mineral divided by the volume enclosed by the periosteal envelope. This definition can be applied to the entire bone, part of the bone (e.g., the distal or proximal end), or a section through the bone, as shown.

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BMDmaterial reflects the degree of mineralization of organic bone matrix. The degree of matrix mineralization varies widely in any single piece of bone, and, therefore, BMDmaterial always is the average of a continuum of density values. Bone matrix has a mineral density of zero when it is released from the osteoblast, and mineralization starts only about 2 weeks later at a typical remodeling site.(10,11) Within a few days after the start of mineralization, inorganic material has filled 75% of the matrix volume originally occupied by water molecules (“primary mineralization,” not to be confused with “primary bone,” see the following paragraph).(7,10,12) During the following 6 months, mineral continues to be incorporated slowly into the matrix (“secondary mineralization”). Because of this time-dependent increase, recently deposited bone matrix has a lower mineral density than “old” matrix. From this, it follows that BMDmaterial is related inversely to bone remodeling activity: When remodeling activity is high, there will be more unmineralized osteoid and there will be more “young” bone matrix, which has not yet completed secondary mineralization.(13)

These considerations refer to secondary (remodeled) bone. Primary (unremodeled) bone, which osteoblasts add on the periosteal surface during growth, is denser than secondary bone, although it is younger.(14) Therefore, when there is rapid periosteal expansion and little intracortical remodeling, cortical BMDmaterial will be high. The functional mechanisms influencing BMDmaterial and the structural components reflected by BMDmaterial are summarized in Table 1.

Table Table 1.. Factors Determining BMDmaterial
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Direct studies on cortical BMDmaterial

BMDmaterial can be assessed by measuring the relative mineral (or ash) weight of dried bone samples, defined as ash weight divided by total dry bone weight. As shown in Fig. 2A, relative ash weight of the femoral midshaft cortex decreases after birth to a nadir in the first year of life and thereafter increases.(15–17)

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Figure FIG. 2.. Mineral density of long bone diaphyses on the three levels of biological organization. Variation with age from birth to 40 years. Note that age is shown on a logarithmic scale. (A) BMDmaterial. Relative ash weight of dried femoral midshaft cortex from individuals who had died after acute illnesses or accidents. Open circles indicate data from Vinz(15); closed circles are results from Currey and Butler.(16) The data represented by gray filled boxes were derived from calcium content as given in a report by Dickerson(14) by dividing calcium content by 0.39 (calcium constitutes 39% of ash weight(60)). (B) BMDcompartment. Cortical BMDcompartment at the femoral midshaft. Data derived from Vinz.(15,27) Cortical BMDcompartment values were calculated from percent water content of fresh bone, percent ash content of dried bone, and density of fresh bone using the equation: cortical BMDcompartment = [100 − (percent water content of fresh bone)] × (percent ash content of dry bone) × (density of fresh bone)/100. (C) BMDtotal. Dry total density (mineral mass plus mass of organic matter divided by external volume) of the humerus shaft in black girls. Results from Trotter et al.(39,40)

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Direct studies on trabecular BMDmaterial

In adults, the relative ash weight of trabecular bone is a few percent lower than of cortical bone.(18,19) This probably reflects the fact that the turnover of trabecular bone is higher than that of cortical bone.(10) As trabecular bone turnover decreases from childhood to adulthood,(11,20,21) BMDmaterial should increase during bone development. In fact, BMDmaterial of trabecular iliac bone shows such a trend between the first and the fourth decade of life(13,22) (Fig. 3).

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Figure FIG. 3.. Trabecular BMDmaterial between birth and 40 years of age according to Mueller et al.(21) Full circles represent results in females and crosses represent results in males. In the original publication these results were shown in a chart but not analyzed quantitatively. Conversion of the data points into numerical values reveals that the association with age is highly significant (r = 0.47; p < 0.001; regression equation: BMDmaterial [mg/cm3] = 991 + 1.42 × age [years]). As calculated from this regression equation, trabecular BMDmaterial rises from 991 mg/cm3 at birth to 1048 mg/cm3 at the age of 40 years—an increase of 5.8%. Gender differences are not significant (p = 0.78, U-test).

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Absorptiometric studies of BMDmaterial

BMDmaterial cannot be determined with currently available noninvasive densitometric techniques, because the spatial resolution does not allow for the determination of the volumes of the marrow (in trabecular bone) or osteonal canals (in cortical bone). However, BMDmaterial can be assessed in bone biopsy specimens, for example, by using backscattered electron microscopy.(23,24)

THE AMOUNT OF MINERAL IN TRABECULAR AND CORTICAL TISSUE—COMPARTMENT MINERAL DENSITY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE AMOUNT OF MINERAL IN THE BONE MATRIX—MATERIAL MINERAL DENSITY
  5. THE AMOUNT OF MINERAL IN TRABECULAR AND CORTICAL TISSUE—COMPARTMENT MINERAL DENSITY
  6. THE AMOUNT OF MINERAL WITHIN THE PERIOSTEAL ENVELOPE—TOTAL BMD
  7. OUTLOOK
  8. References

Background

The trabecular compartment is defined as the space within the endocortical surface.(9) The cortical compartment is delimited by the periosteal and endocortical surfaces. Both compartments do not only contain bone matrix, but also nonbone tissue (Fig. 1). In trabecular bone, this is mainly hemopoietic and fat marrow. In cortical bone, the nonbone composites are blood vessels and the connective tissue within osteonal (Haversian) and Volkmann's canals. In this review we use the term “compartment BMD” (BMDcompartment) to denote the mass of mineral per unit volume of the trabecular or cortical compartment. In the densitometric literature trabecular BMDcompartment has been called “cancellous bone density”(25) or “volumetric trabecular apparent BMD.”(3) The cortical BMDcompartment has been referred to as “true cortical bone density”(26) or “material density of cortical bone.”(27)

BMDcompartment depends on BMDmaterial and relative bone volume, which is the relative amount of space occupied by bone matrix (Fig. 1).(9) The relationship between BMDcompartment, BMDmaterial, and relative bone volume is

  • equation image

This relationship is true for both cortical and trabecular bone, but relative bone volume is very different in these two types of bone—typically, between 90% and 97% in cortical bone and between 10% and 30% in trabecular bone.(10)

Structural features and functional mechanisms reflected by BMDcompartment are listed in Table 2. In cortical bone, relative bone volume depends on number and mean size of osteonal canals (Fig. 1). During remodeling, osteonal canals are transiently much larger than in quiescent osteons (“remodeling space”).(10) Therefore, relative cortical bone volume is smaller when intracortical remodeling activity is high. In trabecular bone, BMDcompartment depends on trabecular number (defined as the number of trabeculae that an imaginary line through the bone would hit per millimeter of its length) and mean trabecular thickness.(9) The mechanisms determining trabecular number during growth have not been well characterized. Trabecular thickness depends on remodeling activity (through variations in remodeling space) and on remodeling balance.(20)

Table Table 2.. Factors (Other than BMDmaterial) Determining BMDcompartment
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Direct studies on cortical BMDcompartment

BMDcompartment of the femoral midshaft decreases in the first months after birth and then increases until adulthood(16,28) (Fig. 2B). The increase in BMDcompartment between the age of 3–5 months and adulthood amounts to 36%, but most of this increase occurs in early childhood. Consequently, the difference between the age group of 4–13 years and young adults was only about 6% in the studies shown in Fig. 2B. These variations in cortical BMDcompartment appear to be more pronounced than the corresponding changes in relative ash weight.(16,28) Thus, the changes in cortical BMDcompartment probably are caused by variations in both BMDmaterial and relative bone volume.

Direct studies on trabecular BMDcompartment

In sagittal sections of vertebral bodies, directly determined trabecular BMDcompartment increases from about 120 mg/cm3 to approximately 170 mg/cm3 between 2 and 20 years of age.(13) This 40% increase is the combined effect of the rise in BMDmaterial discussed previously and an increase in trabecular thickness.(13) These two factors are sufficient to explain the increase in trabecular BMDcompartment. Thus, the number of trabeculae per millimeter cross-section probably remains constant in vertebral bodies, similar to iliac bone.(11,20)

Absorptiometric studies of BMDcompartment

Both trabecular and cortical BMDcompartment can be measured by quantitative computed tomography (QCT).(2,29,30) Trabecular BMDcompartment cannot be determined by projectional densitometric methods such as dual-energy X-ray absorptiometry (DXA) because the effect of the overlying cortex cannot be separated. However, algorithms have been devised that allow for the estimation of cortical BMDcompartment of long bone diaphyses by DXA when a circular bone shape is assumed.(26,29)

A QCT study that was restricted to prepubertal children in the narrow age range from 8.3 to 12.8 years did not detect a variation with age in femoral midshaft cortical BMDcompartment.(31) Using DXA and comprising a larger age range, Bass et al. found an increase of about 10% between the ages of 9.7 and 16.5 years in girls.(26)

In a QCT study analyzing transverse sections of vertebral bodies, Gilsanz and coworkers found an increase of about 21% in trabecular BMDcompartment between the ages of 2 and 18 years.(32) In contrast, trabecular BMDcompartment at the distal metaphysis of the radius does not appear to increase with age in females and increases very little in males.(33–35)

THE AMOUNT OF MINERAL WITHIN THE PERIOSTEAL ENVELOPE—TOTAL BMD

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE AMOUNT OF MINERAL IN THE BONE MATRIX—MATERIAL MINERAL DENSITY
  5. THE AMOUNT OF MINERAL IN TRABECULAR AND CORTICAL TISSUE—COMPARTMENT MINERAL DENSITY
  6. THE AMOUNT OF MINERAL WITHIN THE PERIOSTEAL ENVELOPE—TOTAL BMD
  7. OUTLOOK
  8. References

Background

The volume to determine total BMD (BMDtotal) is enclosed by the bone's periosteal envelope and articular surfaces (Fig. 1). Terms used in the literature to denote BMDtotal include “bone mineral apparent density,”(36) “volumetric bone density,”(26) and “true bone density.”(37)

BMDtotal is determined by trabecular and cortical BMDcompartment and by the relative volumes of the two compartments (Fig. 1). Because the sum of these relative volumes is one, BMDtotal can be calculated as follows:

  • equation image

The relative volume of the cortical compartment corresponds to relative cortical area, when a bone's cross-section is analyzed. This is shown in Fig. 4. The relative volume of the cortical compartment is determined by periosteal expansion and endocortical resorption or apposition (Table 3). During growth, these processes are a function of bone modeling rather than remodeling.(38,39)

Table Table 3.. Factors (Other Than BMDcompartment) Determining BMDtotal
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Figure FIG. 4.. Relationship between BMDtotal, relative cortical area, and trabecular and cortical BMDcompartment in a thin cross-sectional slice of a bone.

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Direct studies on BMDtotal

The dry total density of long bones (i.e., mineral plus organic mass divided by external bone volume) decreases by about 30% in the first few months after birth (Fig. 2C).(40–42) This is followed by a rapid increase until about 2 years of age and a slower increase thereafter. Radiogrammetry studies found a similar time course for the postnatal changes in relative cortical area at the diaphyses of the second metacarpal and the tibia (Fig. 5).(14,43) Thus, the postnatal drop in BMDtotal partly is caused by decreasing relative cortical area. The simultaneous decline in cortical BMDmaterial and BMDcompartment, as outlined previously, also will contribute to lower BMDtotal in early infancy.

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Figure FIG. 5.. Relative cortical area of the second metacarpal from 3 months to 11 years of age in Swiss girls.(42)

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The decrease in cortical thickness during the first months of life has been dubbed “physiological osteoporosis of infancy” a century ago.(44) However, in growing children, a decrease in cortical thickness and BMDtotal is not necessarily a sign of bone loss. This is exemplified in Fig. 6, which summarizes studies on femoral midshaft development during the first 6 months of postnatal life.(16,28,42,45,46) In healthy babies, the decline in BMDtotal reflects a redistribution of bone tissue from the endocortical to the periosteal surface rather than bone loss.(14) Therefore, bone mineral mass increases considerably during the first months of life despite the precipitous drop in BMDtotal (Fig. 6).(42,43)

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Figure FIG. 6.. A model of bone development at the femoral midshaft from birth to 6 months of age. At birth, the external bone diameter is about 6.0 mm and cortical thickness is 2.15 mm.(44) Thus, 92% of the cross-section is cortical bone.(44) At 6 months of age, BMDtotal has dropped by 30%,(41) and cortical thickness has decreased. However, the external bone diameter has increased to 9.0 mm.(45) Therefore, the mineral mass in a 2-mm-thick slice of bone has increased by 58%. The data for cortical BMDcompartment are derived from Vinz, as discussed previously.(15,27)

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Absorptiometric studies of BMDtotal

BMDtotal can be measured by QCT at any site of the skeleton, regardless of bone shape.(2,29,30) Also, it is possible to obtain measures of BMDtotal from standard X-rays when a calibration device is X-rayed at the same time, a method called radiographic absorptiometry.(29,47,48) Algorithms have been developed to estimate BMDtotal based on data obtained by DXA.(36,49,50) At locations with a simple geometry, like the femoral midshaft, these mathematically derived results for BMDtotal appear to be in good agreement with directly determined values.(16,26,28,50) However, at sites with a complex structure such as the lumbar spine, the physiological meaning of these values is uncertain. The posterior vertebral processes add to the mass but not to the volume that is calculated from the anteroposterior projection image of the vertebrae.(36) The result therefore not only reflects vertebral body BMDtotal, but also is determined by the size and BMDtotal of the posterior processes.(26)

As expected from Eq. (2), BMDtotal increases markedly with age at sites where relative cortical area increases, such as metacarpal bones,(48,51) phalanges,(47,52) radius, and ulna.(33,53) The age variation within BMDtotal is less or not detectable at the femoral neck(29,49,54) and femoral midshaft.(26,29)

Areal BMD

This is by far the most widely used densitometric parameter.(1,29) Areal BMD is defined as the mineral mass of a bone divided by its projection area.(29,30) Therefore, areal BMD reflects BMDtotal and also the mean length of the path that the radiation beam takes through the bone.(4,29,55) Both of these parameters undergo simultaneous changes during childhood and adolescence. For these reasons it is difficult to establish a link between the physiology of bone development and areal BMD data.(56)

OUTLOOK

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE AMOUNT OF MINERAL IN THE BONE MATRIX—MATERIAL MINERAL DENSITY
  5. THE AMOUNT OF MINERAL IN TRABECULAR AND CORTICAL TISSUE—COMPARTMENT MINERAL DENSITY
  6. THE AMOUNT OF MINERAL WITHIN THE PERIOSTEAL ENVELOPE—TOTAL BMD
  7. OUTLOOK
  8. References

Interpreting bone density in terms of the underlying biological organization does not only provide a better understanding of bone development but is helpful to reconcile seemingly contradictory results of densitometric studies in children with bone diseases. For example, in osteogenesis imperfecta BMD can be decreased, normal, and increased in the same bone. BMDmaterial is abnormally high both in trabecular and in cortical bone.(24) However, cortical BMDcompartment is normal,(57) presumably because cortical porosity is increased.(58) Trabecular BMDcompartment is even decreased,(59) because trabecular number and thickness are very low.(60) BMDtotal at the femoral midshaft is decreased because cortical thickness is decreased.(57) This example may serve as a reminder that the deceptively simple concept of BMD in fact is as complex as bone itself.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE AMOUNT OF MINERAL IN THE BONE MATRIX—MATERIAL MINERAL DENSITY
  5. THE AMOUNT OF MINERAL IN TRABECULAR AND CORTICAL TISSUE—COMPARTMENT MINERAL DENSITY
  6. THE AMOUNT OF MINERAL WITHIN THE PERIOSTEAL ENVELOPE—TOTAL BMD
  7. OUTLOOK
  8. References
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