First Edition published by American Society for Bone and Mineral Research © 1990 American Society for Bone and Mineral Research Second Edition published by Raven Press, Ltd. Third Edition published by Lippincott-Raven Publishers © 1996 American Society for Bone and Mineral Research Fourth Edition published by Lippincott Williams & Wilkins © 1999 American Society for Bone and Mineral Research.
Contributors
Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA. Division of Oncology, Medicine and Pharmacology, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Hussein, PhD
Departments of Genetics and Genomics, Boston Children's Hospital; and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA Mara J. Department of Endocrinology and Diabetes, The Children's Hospital of Philadelphia; and Department of Pediatrics, Perelman School of the University of Pennsylvania.
McCloskey, MD, FRCPI
Department of Orthopedic Surgery; and Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, California, USA. University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA.
New, MD
Nguyen, DSc, PhD
Plotkin, PhD
David Roodman, MD, PhD
Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA. Division of Endocrinology, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York,.
Neale Weitzmann, PhD
Section of Endocrinology and Metabolism, Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA. Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA.
Liang Zeng, MD
Menzies Institute of Medical Research, University of Tasmania; and Faculty of Public Health, University of Tasmania, Hobart, Tasmania, Australia. The Mount Sinai Bone Program, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Preface to the Ninth Edition of the Primer
President’s Preface
About the Companion Website
Molecular and Cellular Determinants of Bone Structure and Function
INTRODUCTION
EARLY SKELETAL PATTERNING
Early Skeletal Morphogenesis in Embryonic Development
A signaling feedback loop between Fgf10 in the limb mesoderm and Fgf8 in the AER is required to direct P-D limb outgrowth. D-V pattern of the limb is determined by Wnt7a and BMP signaling through the regulation of the expression of Lmx1b in the limb mesenchyme.
EMBRYONIC CARTILAGE AND BONE FORMATION
Embryonic cartilage and bone formation 7 expression patterns of Sox9 in wild type and in . .
CONCLUSION
In the Wnt5a−/− mutant limb, the cartilage forms a ball-like structure and Vangl2 is symmetrically distributed on the cell membrane (Fig. 1.4). PCP mutations in the WNT5a and O2 genes have been found in skeletal malformations such as the Robinow syndrome and brachydactyly type B1, both of which exhibit short-limbed dwarfism [61–65].
ACKNOWLEDGMENT
For the first time, it was found with a definitive molecular marker, Vangl2 protein, a key regulatory component in the PCP pathway. Vangl2 protein is asymmetrically localized to the proximal side of Sox9-positive chondrocytes, not in Sox9-negative interdigital mesenchymal cells [60].
Role of dHAND in the anterior-posterior polarization of the limb bud: implications for the Sonic hedgehog pathway. During skeletal development, these specialized cells are derived from a common mesenchymal progenitor of either neural crest origin in the craniofacial region or mesodermal origin for bones formed elsewhere in the body.
CHONDROGENESIS AND CHONDROCYTE HYPERTROPHY DURING ENDOCHONDRAL
Intramembranous ossification is responsible for the formation of specific areas of the skull and clavicle, causing mesenchymal progenitor cells to differentiate. In contrast, endochondral ossification, the process responsible for generating most of the skeleton, requires a cartilage intermediate before bone is formed.
Endochondral Ossification
Hypertrophic chondrocytes express transcriptional regulators and a host of growth factors that not only coordinate the hypertrophic chondrocyte differentiation process, but also induce osteoblast differentiation of surrounding perichondrial cells and promote vascularization of the calcified cartilage through surrounding blood vessels. As cartilage growth and renewal in the postnatal or adult skeleton declines, cartilage's contribution to bone formation decreases dramatically, ultimately terminating the process of endochondral ossification.
MOLECULAR MEDIATORS OF CARTILAGE DEVELOPMENT
Indian hedgehog (IHH) and PTHrP form a critical negative feedback loop for the coordination of chondrocyte hypertrophy and endochondral ossification. Antagonistic to the IHH/PTHrP pathway, BMP and WNT signaling promote chondrocyte hypertrophy (Fig. 2.2).
OSTEOBLAST DIFFERENTIATION AND BONE FORMATION
Homozygous deletion of Osx in mice results in a thickened perichondrium at the diaphysis due to a failure of osteoblast differentiation. The WNT pathway similarly promotes osteoblast differentiation, but functions downstream of IHH (Fig. 2.2) (see also Chapter 9).
ACKNOWLEDGMENTS
The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. PERK-eIF2(alpha)-ATF4 pathway-mediated endoplasmic reticulum stress response is involved in BMP2-induced osteoblast differentiation.
Local and Circulating Osteoprogenitor Cells and Lineages
Once committed to the osteoblast lineage, osteoprogenitors further differentiate into matrix-producing osteoblasts characterized by abundant expression of the primary bone matrix component collagen type I (Col1), and then into mineralizing osteoblasts that typically express osteocal. A better understanding of the endogenous osteogenic progenitor cells present in the bone and BM environment and in the circulation will therefore be of vital importance for the development of osteoanabolic therapies for prevalent disorders of low bone mass, such as osteoporosis, and to intervene therapeutically in situations of compromised fracture healing.
IN SEARCH OF THE SKELETAL STEM CELL
The ultimate goal is to achieve a linear branching tree that defines the skeletal stem cell hierarchy to a similar extent as the organization of the well-defined hematopoie. These studies obtained a CD45-Ter 119-Tie2-AlphaV+Thy-6C3-CD105-CD200+ stem cell population [ 12 ] and so-called osteochondroreticular (OCR) cells expressing Gremlin (a BMP antagonist) [ 13 ].
OSTEOPROGENITOR CELLS IN BONE DEVELOPMENT, GROWTH,
Sacchetti and colleagues defined melanoma-associated cell adhesion molecule (MCAM/CD146) as a marker for stromal progenitors in human BM with the ability to self-renew, regenerate bone and stroma, and establish a hematopoietic microenvironment in vivo [ 10]. For mouse BM, stem cell biologists have used expression of stem cell antigen-1 (Sca-1) to define the MSPC population.
AND HOMEOSTASIS
Despite the possibility of widespread diffusion, the term MSC in the above sense has become a controversial topic. BMSCs or MSPCs in the BM are potential candidates to populate the osteogenic pool in the bone resorption cavity, as discussed in the next section.
PERIVASCULAR PROGENITORS WITH OSTEOGENIC POTENTIAL IN THE BM
PDGFRα+ Sca-1+ CD45−TER119− (PαS) non-hematopoietic mesenchymal progenitor cells in adult murine BM reside in the arterial perivascular space in vivo and are highly enriched for CFU-Fs [ 46 ]. During bone development, Osx+ cells originating in the fetal perichondrium contribute to stromal cells and mature osteoblasts inside the bone [24].
OSTEOPROGENITOR RECRUITMENT IN FRACTURE HEALING
Overall, the data suggest that labeling of Osx+ cells is mostly transient and that Osx+ pop. Interestingly, at least a fraction of Osx+ cells are pericytic during embryonic bone development, postnatal growth and fracture repair.
CIRCULATING OSTEOGENIC PRECURSOR CELLS
Molecular and cellular characterization of highly purified human bone marrow-derived stromal stem cells. Prospective identification, isolation and systemic transplantation of murine bone marrow multipotent mesenchymal stem cells.
CELL BIOLOGY OF OSTEOBLASTS
OSTEOBLAST FUNCTION
Osteoblasts: Function, Development, and Regulation
Bone is a dynamic tissue that is constantly remodeled by the coordinated actions of osteoblasts and osteoclasts in the bone remodeling unit [3]. Osteoblasts lining the bone surface generate an extracellular environment that both directly and indirectly supports non-skeletal hematopoietic cells [ 5 ].
DEVELOPMENT
The successive stages of osteoblastogenesis in vitro are characterized by the temporal expression of a number of well-characterized biomarkers that reflect the developmental steps required for bone formation in vivo. Hh is required for optional osteoblast function during intramembranous ossification and differentiation from perichondrial cells during endochondral ossification; however, Hh signaling is associated with age-related bone loss because it increases osteoclastogenesis by increasing the expression of RANKL [20].
REGULATION
The role of promoter CpG methylation in the epigenetic control of stem cell-related genes during differentiation. Histone H3 lysine 36 methyltransferase Whsc1 promotes the association of Runx2 and p300 in the activation of bone-related genes.
OSTEOCYTE ONTOGENY
Not only do these cells communicate with each other and with cells on the bone surface, but their dendritic processes can extend past the bone surface into the bone marrow and vascular spaces. The number of functions attributed to these cells is increasing [1] and includes the regulation of phosphate homeostasis; therefore the osteocyte network func.
Osteocytes
These cells are removed regularly. distributed throughout the mineralized matrix, connected to each other and cells on the bone surface by pine. drical processes that typically radiate to the bone surface and blood supply. Note the caniculi connecting the lacunae to the bone surface at the bottom of the image.
OSTEOCYTES AS ORCHESTRATORS OF BONE (RE)MODELING
CapG and dextrin have been shown to be more strongly expressed in embedded osteocytes than in osteoblasts [10]. Collagen type 1-GFP is highly expressed in osteoblasts and osteocytes, osteocalcin-GFP is expressed in a few osteoblastic cells lining the endosteal bone surface and in scattered osteocytes, and an osteocyte-selective tracer, the 8 kilobase (kb) DMP1 promoter, which drives GFP has shown selective expression in early osteocytes [11].
OSTEOCYTE CELL DEATH AND APOPTOSIS
OSTEOCYTE MODIFICATION OF THEIR MICROENVIRONMENT
Glucocorticoids, in addition to effects on osteocyte apoptosis/autophagy, appear to compromise osteocyte metabolism and function, causing them to enlarge their lacunae and remove mineral from the perilacunar space, thereby causing gen. Enlargement of the lacunae and canaliculi would reduce the bone fluid flow shear stress and thereby reduce the mechanical stress on the osteocyte.
MECHANOSENSATION AND TRANSDUCTION
Glucocorticoid may therefore alter or compromise the metabolism and function of the osteocyte, not simply induce cell death. The surface area of the osteocyte-lacuno-canalicular system is several orders of magnitude greater than the bone surface area; therefore, removal of only a few angstrom minerals would have significant effects on systemic ion lev.
ROLE OF GAP JUNCTIONS AND HEMICHANNELS IN OSTEOCYTE
Therefore, changes in lacunar size and matrix properties can have dramatic effects on bone properties and quality in addition to osteocyte function. Gap junction channels are formed by proteins known as connexins, and Cx43 is the primary linker in bone cells.
THE POTENTIAL ROLE OF OSTEOCYTES IN BONE DISEASE
The role of the wnt/beta-catenin signaling pathway in the formation and maintenance of bones and teeth. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
CELL BIOLOGY OF THE OSTEOCLAST
Osteoclast Biology and Bone Resorption
Evidence of the crucial role that ανβ3 has in the resorptive process came with the generation of the β3-integrin knockout mouse, which develops a progressive increase in bone mass due to osteoclast dysfunction [3,9] . Consistent with the substitution of the actin ring for stress fibers in osteoclasts, these cells form podosomes instead of focal adhesions.
SIGNALS THAT REGULATE OSTEOCLAST FUNCTION
SIGNALS THAT REGULATE OSTEOCLAST DIFFERENTIATION
Shortly after RANKL stimulation, NF-κB induces the initial induction of the nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), the master regulator of osteoclast differentiation [22]. NFATc1 is continuously activated by calcium oscillation during osteoclastogenesis and binds to its own promoter with AP-1 complex, resulting in the robust induction of NFATc1 (autoamplification of NFATc1) [23].
FACTORS REGULATING OSTEOCLAST FORMATION AND/OR FUNCTION
Modulation of osteoclast differentiation and function by novel members of the tumor necrosis factor receptor and ligand families. Induction and activation of the transcription factor NFATc1 (NFAT2) integrates RANKL signaling in osteoclast terminal differentiation.
RUNX2 AND OSTERIX TRANSCRIPTION FACTORS
BMP SIGNALING
Signal Transduction Cascades Controlling Osteoblast Differentiation
However, upon binding to its specific type I and type II receptors, TGF-β induces activation of Smad2 and -3 [10]. As is the case for Smad1 and ‐5, Runx2 also interacts with Smad3 and cooperates in regulating TGF‐β‐induced transcription [ 11 ].
WNT SIGNALING
Interestingly, this mutation allows the receptor to induce Smad1, ‐5 and ‐8 signaling and enhanced heterotopic ossification in response to activins, a different subgroup of the TGF‐β superfamily that normally inhibits bone formation [ 9 ]. Interestingly, TGF-β can have both positive and negative effects on bone formation, depending on the context and concentration [10,11].
HEDGEHOG SIGNALING
The effects of TGF-β/Smad3 signaling on Runx2 function are cell type and promoter context dependent [ 11 ]. Interestingly, only TGF-β2-deficient mice, but not those lacking TGF-β1 or TGF-β3, show severe skeletal abnormalities [ 13 ].
NOTCH SIGNALING
Inhibition of the canonical Hh-Gli signaling and a subsequent up-regulation of the non-canonical Hh-RhoA signaling pathway in osteoprogenitor cells have been found to lead to growth retardation and osteopenia by impairing osteoblast differentiation [ 24 ].
OTHER SIGNALING PATHWAYS
TGF-beta and BMP signaling in osteoblasts, skeletal development and bone formation, homeostasis and disease. The relative contributions of Smad-mediated and noncanonical pathways to the effects of TGF-β/activin and BMP signaling in skeletal tissues are poorly understood.
The TGF‐ β Superfamily in Bone Formation and Maintenance
These studies also highlight the highly context-dependent contribution of TGF-β superfamily members to the skeletal system (Fig. 8.1). It has been reported that in humans, some polymorphisms in the gene encoding TGF-β1 (TGFB1) are associated with an osteoporotic pathology.
TGF AND BONE MAINTENANCE TGF and coupling
An increase in chondrogenesis in the mutant embryos suggests that TGFβRII limits chondrogenesis in the interzone, and that activity is required for phalangeal joint formation [7]. Mutations in the pro-region of TGF-β1 have been reported to be causes of Camurati-Engelmann disease, an autosomal dominant bone dysplasia [9].
BMPS AND BONE DEVELOPMENT TG/KO phenotypes of ligands
In addition, bone mass is reduced in mutant mice in association with compromised osteoblastic differentiation of bone marrow mesenchymal progenitors [35]. Mice with double mutations of Bmpr1b and Bmp7 show severe skeletal defects in the forelimbs and hindlimbs [34].
BMPS AND BONE MAINTENANCE BMPs and coupling
The mouse short ear skeletal morphogenesis locus is associated with defects in a bone morphogenetic member of the TGF beta superfamily. Activating and deactivating mutations at the GDF5 receptor interaction site result in symphalangism or brachydactyly type A2.
WNT/ Β ‐CATENIN SIGNALING CORE PATHWAY
Our knowledge of Wnt signaling continues to expand, with recent work identifying several mechanisms by which the pathway is fine-tuned at multiple levels, including the activity of Wnt as a ligand and the regulation of Wnt receptor protein levels. We are becoming more and more aware of the complexity of Wnt regulation of bone homeostasis, and we are trying to manipulate this pathway to cure human skeletal diseases.
REGULATION OF WNT PRODUCTION AND SECRETION
Wnt/β-catenin signaling plays a variety of key roles in the regulation of embryogenesis, organogenesis, cell fate determination, and differentiation.
Recent Developments in Understanding the Role of Wnt Signaling in Skeletal
Development and Disease
During Wnt ligand biogenesis in “Wnt-secreting cells,” the endoplasmic reticulum (ER) localized Porcupine adds palmitoleic acid to Wnts. Wnt signaling can also be repressed by posttranslational regulation of the ligand (via inhibitors that include sFRP, Notum, and Tiki1) or via the availability or levels of receptors (by SOST, DKK, RNF43/ZNRF3, and others).
WNT GENE MUTATIONS AND SKELETAL DISEASE
On the other hand, Wnt5a can activate canonical Wnt signaling in the presence of Frizzled4 (Fzd4) and Lrp5 (not Lrp6), similar to how Norrin stabilizes β-catenin [ 5 ]. Changes in the LRP5 gene, which encodes a Wnt coreceptor, were identified as being associated with low or high bone mass in humans in the early 2000s [25].
REGULATION OF FRIZZLED RECEPTOR STABILITY AT THE CELL SURFACE
Jumpy receptors in a family comprising seven transmembranes were first identified as Wnt receptors in but their specific roles in skeletal development have not been studied in as much detail as Lrp5/6. Bone-specific Fzd deletions will provide more compelling evidence for further characterization of the function of each Frizzled in bone.
SUMMARY
Osteoblast-specific overexpression of human WNT16 increases cortical and trabecular bone mass and structure in mice. Albers J, Schulze J, Beil FT, et al., Control of bone formation by the serpentin receptor Frizzled‐9.
OSTEOGENIC MECHANICAL STIMULI
One of the most important factors determining bone shape, strength, architecture, and overall quality is the type, duration, and magnitude of mechanical loads placed on the skeleton. The detection of mechanical stimuli and the transformation of mechanical signals into biochemical reactions is made possible by the extensive network of cytoplas.
Mechanotransduction in Bone Formation and Maintenance
For years the strongest argument favoring the osteocyte network as the primary mechanosensory system in bone was based on these characteristics. Although tissue strains produced by bone matrix bending can induce mechanical signals detected by osteocytes, the extensive array of osteocyte cytoplasmic processes positions these cells to sense fluid flow.
MOLECULAR BASIS FOR
MECHANOTRANSDUCTION IN BONE
DNA-binding proteins localized in adhesion molecule-associated complexes translocate to the nucleus in response to mechanical stress, thereby transmitting mechanical information from the adhesion com. In vitro studies, together with early evidence showing the existence of gap junctions between osteocytes and osteoblasts on the bone surface [23], led to the hypothesis that Cx43 is required for the response to mechanical stimulation in vivo.
BIOCHEMICAL RESPONSES TO MECHANICAL STIMULI
Mechanical stimulation
Upon mechanical stimulation of bone (exercise/loading), sclerostin is reduced and Sost expression levels are correlated with areas of high stress in bone [38]. In conclusion, the mechanical loads placed on the skeleton have a critical role in bone remodeling throughout life.
BONE AS A COMPOSITE
Information on the gene and protein structure and potential function of bone ECM components has exploded over the past decades. This chapter summarizes the composition of bone and the salient features of the classes of bone matrix proteins.
The Composition of Bone
For example, the deletion of the biglycan gene leads to a significant decrease in the development of trabecular bone, indicating that it is a positive regulator of bone formation. One of the hallmarks of bone formation is the synthesis of high levels of alkaline phosphatase (Table 11.4).
OTHER COMPONENTS
Association of specific proteolytic processing of bone sialoprotein and bone acid glycoprotein-75 with mineralization within biomineralization foci. Together, these tools can provide a comprehensive view of bone density, structure, and quality to provide insight into treatment and targeted signaling pathways that influence fracture resistance.
Assessment of Bone Mass, Structure, and Quality in Rodents
Moreover, the organization of bone at the macroscale, microscale, and nanoscale is similar in rodents and humans: bone shapes of the appendicular and axial skeleton are homologous despite the difference in movement; trabeculae are located at the ends of long bones and the center of vertebrae; and at the ultrastructural level of organization, bone matrix is composed of hydrated type I collagen organized into fibrils with noncollagenous proteins and nanocrystals of calcium phosphate (hydroxyapatite with carbonate substitutions) existing inside and outside the fibrils [1,2]. Following the gold standard assessment of bone mass in patients, DXA scanners can longitudinally measure areal bone mineral density (aBMD) for specific bones or the whole skeleton of rodents.
DUAL‐ENERGY X‐RAY ABSORPTIOMETRY
MICRO‐COMPUTED TOMOGRAPHY
This is to ensure that the image cross-section (XY plane) matches the orientation of the bone when loaded in compression or in bending. This obviously requires weekly calibration tests against the hydroxyapatite phantom and occasional recalibration as the spectrum of the x-ray source deviates.
COMPRESSION TESTS OF VERTEBRAL BODIES
If properties related to bone geometry are sought for biomechanical analysis, the rodent bone (L6 vertebra, femur, etc.) must be axially aligned with the long axis of the test tube or orthogonal to the x-rays. By aligning the long axis of the femur with the scanner axis, the correct cross-sectional features can be determined without having to adjust the image stack.
BENDING TESTS OF LONG BONES
Unlike the point of crack initiation, Kc calculated at peak load provides a more comprehensive measure of bone resistance to fracture [44] and has a smaller standard deviation (assuming consistent notching) compared to initiation or other methods of determining bone fragility, including strength tests [ 39]. Changes in bone fracture resistance with progression of type 2 diabetes in ZDSD rats.
PROCESS OF SKELETAL HEALING Cellular contribution to healing tissues
Overall, research efforts have led to a general understanding of the molecular and genetic control of the inflammatory, cellular and tissue processes necessary for healing, which are generally conserved across species and similar in structurally distinct skeletal elements. This chapter provides a concise and up-to-date overview of our understanding of the skeletal healing process at the cellular and molecular levels, a discussion of a few key situations that complicate healing, and an overview of therapeutic modalities that are either in development or employed clinically to enhance repair or facilitate healing in unrelated situations.
Skeletal Healing: Cellular and Molecular Determinants
As mentioned, the better the fracture is fixed (minimizing instability), the greater the ratio of intramembranous to endochondral ossification in the overall healing process. Above this is the genetic profile of osteoblast differentiation that occurs during the formation of intramembranous bone and in the process of conversion of cartilaginous callus to woven bone.
CONDITIONS THAT IMPAIR FRACTURE HEALING AND THERAPEUTIC MODALITIES
While COX‐2–/– mice develop normally, bone repair is impaired in knockout mice grown after fracture [ 25 ]. Recent work has determined the function of COX-2 in specific cell populations during fracture healing in a mouse model.
MOLECULAR THERAPIES TO ENHANCE BONE HEALING
Effects of blood glucose control on fracture healing in BB Wistar rats with diabetes mellitus. Tobacco extract, but not nicotine, impairs the mechanical strength of fracture healing in rats.
BIOMECHANICAL ASSESSMENT OF FRACTURE HEALING
This chapter presents a biomechanical description of fracture healing, focusing on methods to assess the extent of healing. We also note that this chapter does not include a discussion of the biomechanics of fracture fixation, as this topic has been extensively discussed elsewhere [1–3].
Biomechanics of Fracture Healing
Fracture healing is often classified as either primary or secondary fracture healing, where the former is characterized by direct cortical reconstitution and the latter involves significant periosteal callus formation. The techniques for assessing healing presented in this chapter apply equally well to primary and secondary healing; however, the reviews of the biomechanical stages of fracture healing and the mechanobiology of fracture healing are largely specific to secondary healing.
BIOMECHANICAL STAGES OF FRACTURE HEALING
NONINVASIVE ASSESSMENT OF FRACTURE HEALING
While previous scoring systems were based on various combinations of the presence of callus, callus bridging, bone formation, visibility of fracture lines and/or remodeling, RUST assigns points to each of the four cortices visible on anterior-posterior and lateral. radiographs, substantiating that cortical continuity is correlated to callus strength. However, a comparison of these scores with biomechanical properties of fracture toughness has not yet been published.
MECHANOBIOLOGY OF FRACTURE HEALING
Biomechanical analyzes of fracture healing are thus crucial for a thorough assessment of the repair process. Influence of the size and stability of the osteotomy gap on the success of fracture healing.
Skeletal Physiology
However, direct studies of human bone development are still invaluable, as pathological and genetic findings on human bone diseases have been extremely important to generat. In this chapter, we will focus on human data related to the physiology of fetal and neonatal bone development.
PHYSIOLOGY OF FETAL AND NEONATAL BONE DEVELOPMENT
Our understanding of human bone development, particularly that which occurs in utero, has been greatly advanced through analysis of animal models.
Human Fetal and Neonatal Bone Development
The primary hormone responsible for the active transport of minerals through the placenta to the fetus is PTHrP [11]. PTH is important in fetal bone mineralization, but not in active calcium transport across the placenta.
EXTRINSIC FACTORS THAT AFFECT FETAL/
The transport of phosphorus across the placenta is less well understood, but NaPi-IIb, a sodium-dependent inorganic phosphorus transporter, is believed to play an important role in transplacental phosphorus transport [10]. Calcitonin, on the other hand, may not play an important role in fetal bone development, as evidenced by calcitonin or calci.
NEONATAL BONE DEVELOPMENT Nutritional influences
Rats with uncontrolled diabetes have been shown to have decreased calbindin mRNA in the placenta, and this could explain decreased calcium transport across the placenta [26]. Seasonal variation has been shown to affect newborn BMC, possibly due to the effect on maternal vitamin D levels.
INHERITED FETAL/NEONATAL BONE DISORDERS
VARIANCES IN BONE TRAIT ARE ESTABLISHED EARLY IN LIFE
Skeletal Growth: a Major Determinant of Bone’s Structural Diversity
The proportion of 412 fetal femurs whose length remained within the same quartile during pregnancy was 13% (n = 54). The numbers to the right of the bars give examples of the range of femur length of individuals by their baseline quartile location during pregnancy.
BONE SIZE, SHAPE,
AND MICROARCHITECTURE
The same amount of bone is assembled as a larger cross-section with mainly cortical bone along the femoral shaft, and most of this is distributed inferiorly. Cortical bone predominates along the femoral shaft and varies in thickness around a cross section, being thickest inferiorly.
PUBERTY AND THE APPEARANCE OF SEX DIFFERENCES IN BONE MORPHOLOGY
In bones with a smaller cross-sectional area, the risk of fracture due to slenderness is offset by more periosteal attachment relative to their initial cross-sectional size and excavation of a smaller medullary canal and lower cortical porosity, so vBMD is higher. So a high peak vBMD is not the result of increased bone formation (mass has a high energy cost), it is the result of reduced bone resorption. (The resorption is not followed by formation and is modeling, not remodeling.) Similarly, a lower vBMD is the result of more bone resorption and not less bone formation.
GROWTH OF METAPHYSES
AND FRACTURES IN CHILDHOOD
EFFECT OF ILLNESSES ON BONE MORPHOLOGY IS MATURATIONAL
Peak bone mass, along with macro and microstructure, is reached by the end of the second or third decade of life [1]. Racial differences in the rate of growth of the axial and appendicular skeleton and differences in the age of onset of puberty and duration of pubertal growth contribute to the racial differences in axial and appendicular morphology and the risk of fractures during the pre- and peripubertal years, as well as determining racial differences in fracture risk in advanced age [2-5].
RACIAL DIFFERENCES IN FRACTURE RATES IN CHILDHOOD AND ADOLESCENCE
Childhood and adolescence are important critical periods in the creation of peak bone mass, macro‐. This chapter addresses some of these issues and highlights the value of studying racial dimorphism as a tool for understanding bone fragility.
RACIAL DIFFERENCES IN FRACTURE RATES IN ADULTHOOD
Racial Differences in the Acquisition and Age‐related Loss of Bone Strength
RACIAL DIFFERENCES IN BONE MASS AND GEOMETRY IN CHILDREN
RACIAL DIFFERENCES IN BONE MASS AND GEOMETRY IN ADULTHOOD
Americans have less bone with relatively thicker and denser cortical bone (due to lower porosity and higher matrix mineral density) and more trabecular plates [37]. Similarly, more robust microstructural properties measured by HRpQCT have been reported in Australian-Chinese versus white women [38] and Hong Kong Chinese women.
RACIAL DIFFERENCES IN BONE LOSS AND REMODELING IMBALANCE
Differences in bone size and bone mass between black and white 10-year-old South African children. Pre- and postmenopausal differences in bone microstructure and mechanical competence in Chinese-American and white women.
CALCIUM
BMD in later life is a function of peak bone mass and the rate of subsequent bone loss [1]. Furthermore, low BMD in childhood is a risk factor for fracture in childhood [3], suggesting that optimizing age-appropriate bone mass may also have a more direct benefit on fracture rates in childhood.
Calcium, Vitamin D, and Other Nutrients During Growth
The short-term benefits of supplementing Gambian toddlers (12 to 18 months) for distal forearm BMD for 18 months (5% to 6% greater gains) also disappeared within 12 months of discontinuing supplementation [15].
VITAMIN D
FRUIT AND VEGETABLES
DIET IN PREGNANCY
Maternal folic acid intake at 32 weeks was positively associated with spinal SA-BMC after adjusting for infant weight and height [39] in 9. LS BMD was also positively associated with maternal milk intake and calcium and phosphorus density.
BREASTFEEDING
In another cohort, first-trimester maternal protein intake was positively and carbohydrate intake negatively associated with TB BMC at age 6 years [ 43 ] with no association. Similarly, in a cohort of rural Indian mother-child pairs, all dairy products, legumes, and fruit intake were positively associated with spine BMD in children aged 6 years [ 40 ].
SALT
However, in a retrospective study, premenopausal women who had breastfed for >3 months had greater cortical thickness. Importantly, breastfeeding was protective against childhood fractures in a longitudinal study of prepubertal children [54] and in a case-control study of children aged 4 to 15 years [8], although this was not observed in a longi.
SOFT DRINKS AND MILK AVOIDANCE
Carbonated soft drink consumption and bone mineral density in adolescence: the Northern Ireland Young Hearts project.
WHAT IS THE WINDOW OF OPPORTUNITY?
Determining whether an intervention in children can reduce skeletal fragility in adults will require understanding its effects on each mechanical determinant. No one is yet able to determine whether childhood adaptations translate into anti-fracture effectiveness in adults, but the latter variables do provide surrogates of bone strength.
Mechanical Loading
There is convincing evidence that growing bone has a greater capacity to respond to increased mechanical loading than the adult skeleton [2–9]. There is also evidence that the increase in estrogen levels in males and females during adolescence increases the amount of functional estrogen receptor alpha (ERα) available to facilitate stress-related responses in bone [28,29], explaining increased sensitivity to physical activity in early puberty.
CHARACTERISTICS OF AN EFFECTIVE LOADING PRESCRIPTION
By optimizing the osteogenic index, this program can achieve a modest but significant increase in bone parameters.
PEAK BONE MASS OR PEAK BONE STRENGTH?
PERSISTENCE OF CHILDHOOD BONE ADAPTATION
Erlandson MC, Kontulainen SA, Chilibeck PD, et al. Bone mineral accretion in 4- to 10-year-old precompetitive, recreational gymnasts: a 4-year longitudinal study. Warden SJ, Fuchs RK, Castillo AB, et al. Exercising at a young age provides lifelong benefits for bone structure and strength.
PREGNANCY
Pregnancy and Lactation
Most human studies have examined changes in biochemical markers of bone formation and resorption during pregnancy. Focal, transient osteoporosis of the hip is a rare, self-limited form of pregnancy-related osteoporosis [13].
LACTATION
The reduced estradiol levels of lactation are important, but are unlikely to be the sole explanation. The calcium content of milk appears to derive largely from skeletal resorption; consequently, low calcium intake does not alter the calcium content of breast milk nor accentuate maternal bone loss during lactation [ 41 - 44 ].
ADOLESCENT PREGNANCY AND LACTATION
During breastfeeding, 25OHD levels in the mother remain unchanged [39, 40] because very little vitamin D or 25OHD passes into breast milk. This is likely because maternal calcium homeostasis is dominated by skeletal resorption induced by estrogen deficiency and PTHrP.
IMPLICATIONS
Changes in bone mineral density and markers of bone remodeling during lactation and post-weaning in women on high calcium intake. Changes in cortical volumetric bone mineral density and thickness, and trabecular thickness in lactating women postpartum.
INTRODUCTION—BONE MODELING AND REMODELING
Menopause and Age‐related Bone Loss
SURFACE AREA/BONE MATRIX VOLUME CONFIGURATION
AGE‐RELATED BONE LOSS
MENOPAUSAL BONE LOSS
The cortices became thinner, but flexural strength remained unchanged despite bone loss and cortical thinning because periosteal apposition was still sufficient to displace the thinness. Bone loss resulting in osteoporosis is thought to occur through two different mechanisms and lead to type I (postmenopausal) or type II (age-related or involutional) osteoporosis [44].
Mineral Homeostasis
CALCIUM DISTRIBUTION Total body distribution
Regulation of Calcium Homeostasis
CALCIUM BALANCE
HORMONAL REGULATION OF CALCIUM HOMEOSTASIS
FGF23 is a powerful inhibitor of the renal 1α(OH)ase and can also stimulate the renal 24(OH)ase and thereby participate in the reduction of circu. Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo.
HYPOMAGNESEMIA
Serum ionized Mg2+ is maintained in a tight normal reference range through the effects of kidney, intestine and bone [6-9].
Magnesium Homeostasis
A number of drugs can result in hypomagnesemia by promoting renal excretion of magnesium, including diuretics, both thiazide and furosemide, antibiotics and antifungals (foscarnet, amphotericin B and aminoglycoside), anticancer drugs (i.e. platinum derivatives such as cisplatin, carboplatin), immunosuppressants ( rapa, mycin and calcineurin inhibitors such as tacrolimus and cyclosporine A), as well as EGF receptor inhibitors (cetuxi, mab).
HYPERMAGNESEMIA
MAGNESIUM ABSORPTION Intestinal magnesium absorption
Moreover, intracellular Mg2+ is involved in the activation of adenylate cyclase and in the intracellular signaling of cyclic AMP [37]. Although transepithelial magnesium transport in the DCT is still far from fully understood, molecular genetic research in patients shows that it has different forms of heredity.
