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Osteomalacia is a metabolic bone disorder characterized by defective mineralization of the osteoid matrix in mature bone due to insufficient calcium, phosphate, or vitamin D.

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• In children, the analogous condition is rickets (affecting growth plates).

Anatomy

Functional anatomy of the growth plate:

![The architecture of the growth plates. The growth plates, or physis, are highly organized cartilage tissues located between the epiphysis and metaphysis of the long bones. They are composed of chondrocytes embedded in an extracellular matrix and contain three distinct zones: resting, proliferative, and hypertrophic. Vasculature from the epiphysis and metaphysis provide nutrients to cells in the resting and hypertrophic zones. Figure created with BioRender.com.

Tiffany AS, Harley B a. C. Growing Pains: The need for engineered platforms to study growth plate biology. Advanced Healthcare Materials. 2022;11(19). doi:10.1002/adhm.202200471](attachment:f5c2b875-42f8-4149-9935-615becb25dd5:image.png)

The architecture of the growth plates. The growth plates, or physis, are highly organized cartilage tissues located between the epiphysis and metaphysis of the long bones. They are composed of chondrocytes embedded in an extracellular matrix and contain three distinct zones: resting, proliferative, and hypertrophic. Vasculature from the epiphysis and metaphysis provide nutrients to cells in the resting and hypertrophic zones. Figure created with BioRender.com.

Tiffany AS, Harley B a. C. Growing Pains: The need for engineered platforms to study growth plate biology. Advanced Healthcare Materials. 2022;11(19). doi:10.1002/adhm.202200471

Histopathology:

https://www.youtube.com/watch?v=y7iA0_jkOTI

![Morphology of the growth plate in rickets: a,b | Morphology of a healthy, human growth plate (physis). The growth plate is characterized by maturation of chondrocytes (cartilage cells) occurring progressively from the epiphysis to the metaphysis. The border between the metaphysis and the growth plate is marked by a provisional zone of calcification of the cartilage matrix (red-pink staining) that undergoes resorption and replacement with mineralized bone (turquoise staining).  c | A rachitic growth plate showing the marked increase in longitudinal width marked by the persistence of the zone of hypertrophic chondrocytes that lose their columnar arrangement. The growth plate abnormalities are the consequence of impaired chondrocyte apoptosis and impaired mineralization of the cartilage matrix surrounding the apoptotic chondrocytes. Apoptosis of hypertrophic chondrocytes is induced by extracellular phosphate via phosphorylation of mitogen-activated protein kinase (MAPK) pathway intermediates and downstream inhibition of the caspase 9-dependent mitochondrial apoptotic pathway. Thus, reduction in ambient phosphate availability to the chondrocyte, which is common to all forms of rickets, seems to be central to the impaired apoptosis. The ligand 1,25-dihydroxyvitamin D (1,25(OH)2D) and its receptor might be involved as well. Finally, expansion of the hypertrophic chondrocyte zone can be induced by impaired vascularization, influenced by vascular endothelial growth factor, which is regulated by MAPK pathway intermediates.

Parts b and c courtesy of F. H. Glorieux. Carpenter, T., Shaw, N., Portale, A. et al. Rickets. Nat Rev Dis Primers 3, 17101 (2017). https://doi.org/10.1038/nrdp.2017.101 ](attachment:cf672d1d-b5bd-4620-97a2-0ca1c19cda17:image.png)

Morphology of the growth plate in rickets: a,b | Morphology of a healthy, human growth plate (physis). The growth plate is characterized by maturation of chondrocytes (cartilage cells) occurring progressively from the epiphysis to the metaphysis. The border between the metaphysis and the growth plate is marked by a provisional zone of calcification of the cartilage matrix (red-pink staining) that undergoes resorption and replacement with mineralized bone (turquoise staining).  c | A rachitic growth plate showing the marked increase in longitudinal width marked by the persistence of the zone of hypertrophic chondrocytes that lose their columnar arrangement. The growth plate abnormalities are the consequence of impaired chondrocyte apoptosis and impaired mineralization of the cartilage matrix surrounding the apoptotic chondrocytes. Apoptosis of hypertrophic chondrocytes is induced by extracellular phosphate via phosphorylation of mitogen-activated protein kinase (MAPK) pathway intermediates and downstream inhibition of the caspase 9-dependent mitochondrial apoptotic pathway. Thus, reduction in ambient phosphate availability to the chondrocyte, which is common to all forms of rickets, seems to be central to the impaired apoptosis. The ligand 1,25-dihydroxyvitamin D (1,25(OH)2D) and its receptor might be involved as well. Finally, expansion of the hypertrophic chondrocyte zone can be induced by impaired vascularization, influenced by vascular endothelial growth factor, which is regulated by MAPK pathway intermediates.

Parts b and c courtesy of F. H. Glorieux. Carpenter, T., Shaw, N., Portale, A. et al. Rickets. Nat Rev Dis Primers 3, 17101 (2017). https://doi.org/10.1038/nrdp.2017.101

![Histological characteristics of osteomalacia: Goldner's trichrome staining of undecalcified iliac crest bone samples showing mineralized bone in turquoise and unmineralized bone matrix (osteoid) in red-pink. Compared with a control sample (part a), a sample obtained from a child with X-linked hypophosphataemic rickets (part b) shows a marked increase in the amount and thickness of osteoid (arrows) covering mineralized bone in the bone cortex or outer shell (*) and the trabecular area, which is a typical feature of osteomalacia. Part c depicts abnormal accumulation of osteoid surrounding the osteocytes (the intercommunicating osteogenic lineage cells that are embedded throughout the bone matrix), which is another characteristic of osteomalacia in patients with X-linked hypophosphataemic rickets known as peri-osteocytic lesions.

Parts a and b courtesy of F. H. Glorieux. Part c is from Feng, J. Q. et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat. Genet. 38, 1310–1315 (2006). Carpenter, T., Shaw, N., Portale, A. et al. Rickets. Nat Rev Dis Primers 3, 17101 (2017). https://doi.org/10.1038/nrdp.2017.101](attachment:9893c46c-47a0-4ec4-aeed-174751fd55f2:image.png)

Histological characteristics of osteomalacia: Goldner's trichrome staining of undecalcified iliac crest bone samples showing mineralized bone in turquoise and unmineralized bone matrix (osteoid) in red-pink. Compared with a control sample (part a), a sample obtained from a child with X-linked hypophosphataemic rickets (part b) shows a marked increase in the amount and thickness of osteoid (arrows) covering mineralized bone in the bone cortex or outer shell (*) and the trabecular area, which is a typical feature of osteomalacia. Part c depicts abnormal accumulation of osteoid surrounding the osteocytes (the intercommunicating osteogenic lineage cells that are embedded throughout the bone matrix), which is another characteristic of osteomalacia in patients with X-linked hypophosphataemic rickets known as peri-osteocytic lesions.

Parts a and b courtesy of F. H. Glorieux. Part c is from Feng, J. Q. et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat. Genet. 38, 1310–1315 (2006). Carpenter, T., Shaw, N., Portale, A. et al. Rickets. Nat Rev Dis Primers 3, 17101 (2017). https://doi.org/10.1038/nrdp.2017.101

Etiology

Pathophysiology

• Osteoid is laid down by osteoblasts but fails to mineralize due to low calcium or phosphate availability.
• This results in soft, pliable bones that are prone to pain, deformity, and fractures.

Clinical Features:

![Spectrum of clinical presentation of nutritional rickets and osteomalacia from conception to old age. Clinically evident symptoms of rickets as well as osteomalacia only represent the tip of the iceberg. The iceberg’s hidden part (widespread solar vitamin D and dietary calcium deficiency) in the majority remains undiagnosed.

Suma Uday, Wolfgang Högler. Spot the silent sufferers: A call for clinical diagnostic criteria for solar and nutritional osteomalacia. The Journal of Steroid Biochemistry and Molecular Biology. 2019;188:141-146. doi:https://doi.org/10.1016/j.jsbmb.2019.01.004](attachment:86e215bc-80e8-46b1-994b-056b28c1115e:1-s2.0-S0960076018305429-gr1_lrg.jpg)

Spectrum of clinical presentation of nutritional rickets and osteomalacia from conception to old age. Clinically evident symptoms of rickets as well as osteomalacia only represent the tip of the iceberg. The iceberg’s hidden part (widespread solar vitamin D and dietary calcium deficiency) in the majority remains undiagnosed.

Suma Uday, Wolfgang Högler. Spot the silent sufferers: A call for clinical diagnostic criteria for solar and nutritional osteomalacia. The Journal of Steroid Biochemistry and Molecular Biology. 2019;188:141-146. doi:https://doi.org/10.1016/j.jsbmb.2019.01.004

Biochemical Features:

![Stages of calcium deprivation, secondary to vitamin D and/or dietary calcium deficiency, that lead to osteomalacia in at risk individuals of all age groups.

Uday S, Högler W. Nutritional Rickets and Osteomalacia in the Twenty-first Century: Revised Concepts, Public Health, and Prevention Strategies. Curr Osteoporos Rep. 2017;15(4):293–302 in accordance with Creative Commons license (http://creativecommons.org/licenses/by/4.0/))](attachment:0fd03d1d-e930-4fa0-9aba-5c0b8dd13229:1-s2.0-S0960076018305429-gr2_lrg.jpg)

Stages of calcium deprivation, secondary to vitamin D and/or dietary calcium deficiency, that lead to osteomalacia in at risk individuals of all age groups.

Uday S, Högler W. Nutritional Rickets and Osteomalacia in the Twenty-first Century: Revised Concepts, Public Health, and Prevention Strategies. Curr Osteoporos Rep. 2017;15(4):293–302 in accordance with Creative Commons license (http://creativecommons.org/licenses/by/4.0/))

Radiology