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Translational studies provide insights for the etiology and treatment of cortical bone osteoporosis

https://doi.org/10.1016/j.beem.2018.02.006Get rights and content

Abstract

Increasing attention is being focused on the important contributions of cortical bone to bone strength, fractures and osteoporosis therapies. Recent progress in human genome wide association studies in combination with high-throughput mouse gene knockout phenotyping efforts of multiple genes and advanced conditional gene inactivation in mouse models have successfully identified genes with crucial roles in cortical bone homeostasis. Particular attention in this review is given to genes, such as WNT16, POSTN and SFRP4, that differentially affect cortical and trabecular bone architecture. We propose that animal models of cortical bone metabolism will substantially contribute to developing anabolic osteoporosis therapies that improve cortical bone mass and reduce non-vertebral fracture risk.

Section snippets

Historical aspects

The interior structures of bone were examined beginning in the late 17th century, with Crisóstomo Martinez characterizing trabecular bone [1] and Clopton Havers discovering osteonal (Haversian) canals [2]. Studying dynamic aspects of bone metabolism became possible during the 1950s with autoradiography of bone-seeking radioisotopes [3] using undecalcified bone sections [4] and the fluorescent microscopy of tetracyclines [5], [6]. Development of techniques involving iliac crest biopsies examined

Importance of cortical bone in fracture prevention

Although attention was focused on trabecular bone loss for many years, several scientists emphasized the importance of maintaining cortical bone mass for preventing osteoporotic fractures [4], [11]. The laboratory of Jonathan Reeve described histological analyses of femoral neck bone and they concluded in 2001 that there is no difference in trabecular bone area between cases of hip fracture and age and sex-matched controls. Rather, a loss of cortical bone thickness and increased porosity is a

CT analyses of human and rodent cortical bone

Introduction of high resolution X-Ray Computed Tomography scanners after 2000 revolutionized examination and understanding of cortical bone dynamics [20]. Bones from rodent pharmacology studies and genetically-modified mouse models are now routinely analyzed by μCT for bone and marrow cavity areas, cortical thickness, cortical porosity, moments of inertia and tissue volumetric BMD. In addition to pure cortical bone sites, μCT analyses of rodent femoral neck and the vertebral body cortical shell

Underappreciated aspects of cortical bone development

With certain caveats, rodent bone biology mimics human skeletal genetic and metabolic bone diseases, including responses to therapies, and rodents are extensively employed as osteoporosis research models. Nonetheless, several aspects of cortical bone development in rodents are poorly understood by many researchers and appreciation of these bone modeling processes is helpful. The following paragraphs summarize knowledge of both longitudinal and radial growth, and formation of cortical bone at

Cortical Bone Heterogeneity

Reflecting the complex origins of its formation, cortical bone is structurally extremely heterogeneous. Bone viewed in histological sections under light or fluorescent microscopy, or from radiographic, DXA or CT X-ray images, generally appears homogeneous. Depending upon resolution, vascular canals and osteonal lacunae and canaliculi may be observed. However, little structural variability is observed in different quadrants and between periosteal and endocortical regions. In contrast, detailed

Genetic contributions to cortical bone structure

Twin and family studies have revealed that genetic factors can explain up to 85% of the variation in peak areal BMD as analyzed by 2-dimensional DXA [62], [63]. Since 2007, several genome-wide association studies (GWAS) for osteoporosis and related traits have identified multiple common variants associated with BMD, highlighting biologic pathways that influence areal BMD [64], [65], [66], [67], [68]. Although areal BMD is the most clinical useful measure for diagnosing bone fragility

Cortical bone dysregulation resulting from site-specific gene expression – WNT16

WNT signaling pathways, involving 19 secreted WNTs, LRP4,5,6 co-receptors and extracellular inhibitors SFRP4, DKK1 and sclerostin, have major roles in bone metabolism [75]. The GWAS identification of a genetic signal for both cortical bone thickness and the clinical fracture endpoint in the WNT16 locus was followed by translational functional validation studies in mice and thorough cellular and molecular studies, unravelling a completely new mechanism for the regulation of cortical bone

Cortical bone dysregulation resulting from site-specific gene expression - periostin

Although periostin (Postn) is a widely expressed extracellular matrix protein with multiple activities, the highest expression is observed in cortical bone and periosteal tissue [87]. A crucial role of periostin in cortical bone is supported by observations that Postn knockout mice have low cortical bone mass resulting from reduced periosteal bone formation *[85], *[87], [88]. An effect of periostin in cortical but not trabecular bone homeostasis is further indicated by the finding that

Distinct cortical/trabecular bone dysregulation with SFRP4 inactivating mutations

Secreted frizzled related protein 4 (SFRP4) is a secreted Frizzled decoy receptor that binds WNTs to prevent their activation of Frizzled receptors. SFRP4 mutations cause Pyle's disease (OMIM 265900) [95], [96], *[97], with radiographs showing thin cortices in long bones, elevated trabecular bone mass, and wide metaphyseal bone (Erlenmeyer Flask deformity, EFD). The identical phenotypes occur in Sfrp4 KO mice *[85], *[97], [98] while overexpression of Sfrp4 results in low trabecular bone mass

Distinct cortical/trabecular bone dysregulation with parathyroid hormone receptor activating mutations

Patients with Jansens's metaphyseal chondrodysplasia (OMIM 156400), resulting from ligand-independent activating mutations in the parathyroid hormone 1 receptor (PTH1R), suffer from hypercalcemia, hypophosphatemia, low circulating PTH levels, cortical bone erosion, and rickets-like metaphyseal dysplasia involving growth plate defects leading to dwarfism [101], [102]. Knockout of mouse Pth1r results in embryonic lethality [103] but a transgenic mouse model with expression of the constitutively

What are some known unknowns that influence cortical bone?

Advances in whole genome and whole exome sequencing continue to identify genes responsible for human genetic skeletal diseases and an update to the 2015 Skeletal Nosology database [106] is expected during 2018. Extremely high bone mass in humans can result from unidentified mutations [107], [108] and the genes responsible are likely to be identified during the next few years.

Summary

Great progress has been made during the past decade understanding the important contributions of cortical bone structure to skeletal strength and fracture resistance [109], [110], [111] and the genes involved in the growth (modeling), turnover (remodeling), microarchitecture and biomechanics of cortical bone. Continued advances are expected this next decade.

Funding

This study was supported by funding from the Swedish Research Council (grant 2016-01001), ALF/LUA research grant from the Sahlgrenska University Hospital, Lundberg Foundation, Torsten and Ragnar Söderberg's Foundation, Novo Nordisk Foundation, Knut and Alice Wallenberg Foundation.

Research Agenda

  • Human genetic studies on HR-pQCT derived specific cortical and trabecular bone parameters will likely identify novel osteoporosis drug targets.

  • Further technical improvements, including higher spatial

References (111)

  • A.M. Parfitt et al.

    Structural and cellular changes during bone growth in healthy children

    Bone

    (2000)
  • F. Rauch et al.

    The bone formation defect in idiopathic juvenile osteoporosis is surface-specific

    Bone

    (2002)
  • W. Sontag

    Quantitative measurements of periosteal and cortical-endosteal bone formation and resorption in the midshaft of male rat femur

    Bone

    (1986)
  • W. Sontag

    Quantitative measurement of periosteal and cortical-endosteal bone formation and resorption in the midshaft of female rat femur

    Bone

    (1986)
  • A.R. Altman et al.

    Quantification of skeletal growth, modeling, and remodeling by in vivo micro computed tomography

    Bone

    (2015)
  • J.B. Richards et al.

    Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study

    Lancet

    (2008)
  • R. van Amerongen et al.

    Knockout mouse models to study Wnt signal transduction

    Trends Genet

    (2006)
  • X. Tu et al.

    Noncanonical Wnt signaling through G protein-linked PKCdelta activation promotes bone formation

    Dev Cell

    (2007)
  • N. Bonnet et al.

    Periostin action in bone

    Mol Cell Endocrinol

    (2016)
  • H.Y. Cho et al.

    Transgenic mice overexpressing secreted frizzled-related proteins (sFRP)4 under the control of serum amyloid P promoter exhibit low bone mass but did not result in disturbed phosphate homeostasis

    Bone

    (2010)
  • S. Gomez

    Crisostomo Martinez, 1638-1694: the discoverer of trabecular bone

    Endocrine

    (2002)
  • J. Dobson

    Pioneers of osteogeny: Clopton Havers

    J Bone Jt Surg Br

    (1952)
  • J. Jowsey et al.

    Microradiographs and autoradiographs of cortical bone from monkeys injected with 90Sr

    Br J Exp Pathol

    (1953)
  • J.S. Arnold

    A method for embedding undecalcified bone for histologic sectioning, and its application to radioautography

    Science

    (1951)
  • H.M. Frost et al.

    Measurement of bone formation in a 57 year old man by means of tetracyclines

    Henry Ford Hosp Med Bull

    (1960)
  • R.A. Milch et al.

    Fluorescence of tetracycline antibiotics in bone

    J Bone Joint Surg Am

    (1958)
  • B.L. Riggs et al.

    A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men

    J Bone Miner Res

    (1998)
  • S.C. Manolagas

    From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis

    Endocr Rev

    (2010)
  • S. Khosla et al.

    The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed?

    J Bone Miner Res

    (2011)
  • J.M. Zanelli et al.

    Methods for the histological study of femoral neck bone remodelling in patients with fractured neck of femur

    Bone

    (1993)
  • N. Crabtree et al.

    Intracapsular hip fracture and the region-specific loss of cortical bone: analysis by peripheral quantitative computed tomography

    J Bone Miner Res

    (2001)
  • J. Power et al.

    Bone remodeling at the endocortical surface of the human femoral neck: a mechanism for regional cortical thinning in cases of hip fracture

    J Bone Miner Res

    (2003)
  • K.L. Bell et al.

    Super-osteons (remodeling clusters) in the cortex of the femoral shaft: influence of age and gender

    Anat Rec

    (2001)
  • J. Reeve

    Role of cortical bone in hip fracture

    Bonekey Rep

    (2017)
  • F. Cosman et al.

    Effect of teriparatide on bone formation in the human femoral neck

    J Clin Endocrinol Metab

    (2016)
  • N. Doyle et al.

    Abaloparatide, a novel PTH receptor agonist, increased bone mass and strength in ovariectomized cynomolgus monkeys by increasing bone formation without increasing bone resorption

    Osteoporos Int

    (2017)
  • S. Boutroy et al.

    In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed tomography

    J Clin Endocrinol Metab

    (2005)
  • A.M. Agnew et al.

    Brief communication: reevaluating osteoporosis in human ribs: the role of intracortical porosity

    Am J Phys Anthropol

    (2012)
  • P. Szulc et al.

    Cortical bone status is associated with serum osteoprotegerin concentration in men: the STRAMBO study

    J Clin Endocrinol Metab

    (2011)
  • L. Vandenput et al.

    Serum estradiol levels are inversely associated with cortical porosity in older men

    J Clin Endocrinol Metab

    (2014)
  • R. Shigdel et al.

    Determinants of transitional zone area and porosity of the proximal femur quantified in vivo in postmenopausal women

    J Bone Miner Res

    (2016)
  • A. Bjornerem et al.

    Menopause-related appendicular bone loss is mainly cortical and results in increased cortical porosity

    J Bone Miner Res

    (2018)
  • R. Zebaze et al.

    Denosumab reduces cortical porosity of the proximal femoral shaft in postmenopausal women with osteoporosis

    J Bone Miner Res

    (2016)
  • E. Lespessailles et al.

    Osteoporosis drug effects on cortical and trabecular bone microstructure: a review of HR-pQCT analyses

    Bonekey Rep

    (2016)
  • C. Ohlsson et al.

    Cortical bone area predicts incident fractures independently of areal bone mineral density in older men

    J Clin Endocrinol Metab

    (2017)
  • L.A. Ahmed et al.

    Measurement of cortical porosity of the proximal femur improves identification of women with nonvertebral fragility fractures

    Osteoporos Int

    (2015)
  • D. Sundh et al.

    Increased cortical porosity in older men with fracture

    J Bone Miner Res

    (2015)
  • S.H. Kilborn et al.

    Review of growth plate closure compared with age at sexual maturity and lifespan in laboratory animals

    Contemp Top Lab Anim Sci

    (2002)
  • L.I. Hansson et al.

    Rate of normal longitudinal bone growth in the rat

    Calcif Tissue Res

    (1972)
  • B.P. Halloran et al.

    Changes in bone structure and mass with advancing age in the male C57BL/6J mouse

    J Bone Miner Res

    (2002)
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