Osteomalacia historical perspective
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[2]
Overview
Historical Perspective
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3] Associate Editor(s)-in-Chief:
The historical understanding of osteomalacia evolved from early descriptions of skeletal softening to recognition of nutritional, hereditary, and acquired disorders of bone mineralization. Major advances included identification of the sunlight–vitamin D axis, characterization of vitamin D as an endocrine system, recognition of phosphate-wasting disorders, and discovery of fibroblast growth factor 23 (FGF23) as a central regulator of phosphate homeostasis.
Early descriptions and the emergence of rickets
Descriptions compatible with skeletal softening and deformity appear in historical medical writings, although it is uncertain whether these early observations represented vitamin D deficiency or other skeletal disorders. During the 17th century, Daniel Whistler described rickets in 1645, followed by Francis Glisson's detailed account in De Rachitide in 1650. The priority of the earliest description and the origin of the term rickets have remained subjects of historical discussion.[1]
Industrialization, sunlight, and rickets
During the industrial era, rickets became highly prevalent in children living in polluted, densely populated cities with limited exposure to sunlight. In 1822, Jędrzej Śniadecki proposed a relationship between sunlight exposure and prevention of rickets. Armand Trousseau subsequently emphasized the roles of sunlight and nutrition and advocated cod-liver oil. In 1890, Theobald Palm demonstrated a geographic association between latitude and the prevalence of rickets.[1]
In 1919, Kurt Huldschinsky demonstrated that artificial ultraviolet radiation could cure rickets in infants, providing an important experimental link between ultraviolet exposure and antirachitic effects before vitamin D had been chemically identified.[2]
Discovery of vitamin D
The early 20th century established the nutritional and environmental basis of rickets. In 1916, Alfred Hess and colleagues demonstrated the antirachitic effects of cod-liver oil and sunlight. Edward Mellanby subsequently demonstrated the antirachitic properties of a dietary factor, and in 1922 Elmer McCollum and colleagues identified and named vitamin D.[1]
In 1924, Harry Steenbock and Alfred Hess independently demonstrated that ultraviolet irradiation could confer antirachitic activity on foods. These observations established the basis for vitamin D fortification. In 1932, Adolf Windaus and colleagues clarified the chemical nature of vitamin D, including the distinction between vitamin D2 and vitamin D3.[1]
The combination of dietary supplementation, food fortification, and improved understanding of sunlight exposure substantially reduced nutritional rickets and osteomalacia in many populations.[3]
Development of the vitamin D endocrine system
Subsequent research established that vitamin D acts through an endocrine pathway rather than solely as a dietary nutrient. Work on parathyroid hormone and vitamin D metabolites clarified the regulation of calcium and phosphate homeostasis. During the early 1970s, the biologically active metabolite 1,25-dihydroxyvitamin D (calcitriol) was identified.[4]
The identification of vitamin D hydroxylation pathways and subsequent molecular characterization of the vitamin D receptor (VDR) in the late 20th century established vitamin D as a hormone-like regulator of mineral metabolism. These discoveries provided the foundation for the modern biochemical understanding of calcipenic osteomalacia.[4]
Recognition of phosphate-wasting disorders
X-linked hypophosphatemic rickets (XLH) was first described by Fuller Albright in 1937 as a form of childhood rickets refractory to vitamin D doses effective for nutritional rickets. Subsequent genetic studies in the 1990s identified PHEX as the causative gene.[5][4]
Recognition of hereditary and acquired phosphate-wasting disorders established that defective mineralization could result from abnormalities in phosphate homeostasis rather than isolated vitamin D deficiency.[4]
Tumor-induced osteomalacia and the FGF23 era
Tumor-induced osteomalacia (TIO) was first described by Robert McCance in 1947. In 1959, Andrea Prader reported tumor-associated phosphate wasting and proposed the existence of a tumor-secreted "rachitogenic" substance. This work established the historical foundation for the concept of a circulating phosphaturic factor causing acquired hypophosphatemic osteomalacia.[6]
The discovery of FGF23 in 2000 provided a unifying explanation for several hereditary and acquired hypophosphatemic disorders. FGF23 was identified through complementary investigations of hereditary hypophosphatemia and tumor-induced osteomalacia.[4][7][8]
Recognition of FGF23 as a major phosphaturic hormone established a common biological framework linking hereditary hypophosphatemic disorders with TIO.[7][8]
The FGF23 era subsequently provided the biological basis for targeted anti-FGF23 therapy. The development of burosumab, a humanized monoclonal antibody targeting FGF23, represented the translation of this historical discovery into targeted treatment for selected FGF23-mediated disorders.[9][10]
Contemporary perspective
The historical evolution of osteomalacia has therefore progressed from a predominantly nutritional and environmental disorder to a heterogeneous group of mineralization disorders caused by abnormalities in vitamin D metabolism, calcium and phosphate homeostasis, and FGF23-mediated phosphate regulation.[3][7]
Despite major advances in prevention and treatment, nutritional rickets and osteomalacia continue to occur in vulnerable populations, while hereditary and acquired phosphate-wasting disorders remain important causes of hypophosphatemic osteomalacia.[3][4]
Key historical milestones
- 1645: Daniel Whistler described rickets.[1]
- 1650: Francis Glisson published De Rachitide, an early detailed description of rickets.[1]
- 1822: Jędrzej Śniadecki proposed a relationship between sunlight and rickets.[1]
- 1861–1862: Armand Trousseau emphasized sunlight, nutrition, and cod-liver oil in the prevention and treatment of rickets.[1]
- 1890: Theobald Palm demonstrated a geographic association between latitude and rickets.[1]
- 1919: Kurt Huldschinsky demonstrated the antirachitic effect of artificial ultraviolet radiation.[2]
- 1922: Elmer McCollum and colleagues identified and named vitamin D.[1]
- 1924: Steenbock and Hess demonstrated that ultraviolet irradiation could confer antirachitic activity on foods.[1]
- 1932: Adolf Windaus and colleagues clarified the chemistry of vitamin D2 and vitamin D3.[1]
- 1937: Fuller Albright described vitamin D–refractory hereditary hypophosphatemic rickets.[5]
- 1947: Robert McCance described tumor-induced osteomalacia.[6]
- 1959: Andrea Prader proposed a tumor-secreted phosphaturic ("rachitogenic") substance in tumor-associated hypophosphatemic disease.[6]
- 1970s: Calcitriol was identified as the biologically active vitamin D metabolite.[4]
- 1990s: Molecular studies established PHEX as the gene responsible for XLH.[4]
- 2000–2001: FGF23 was identified through studies of hereditary hypophosphatemia and as a causative factor in tumor-induced osteomalacia.[7][8]
- 21st century: Targeted anti-FGF23 therapy translated the FGF23 discovery into treatment for selected FGF23-mediated disorders.[9][10]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 Rajakumar K (2003). "Vitamin D, Cod-Liver Oil, Sunlight, and Rickets: A Historical Perspective". Pediatrics. 112 (2): e132–e135. doi:10.1542/peds.112.2.e132.
- ↑ 2.0 2.1 Rajakumar K, Thomas SB (2005). "Reemerging Nutritional Rickets: A Historical Perspective". Archives of Pediatrics & Adolescent Medicine. 159 (4): 335–341. doi:10.1001/archpedi.159.4.335.
- ↑ 3.0 3.1 3.2 Bouillon R, Antonio L (2020). "Nutritional Rickets: Historic Overview and Plan for Worldwide Eradication". Journal of Steroid Biochemistry and Molecular Biology. 198: 105563. doi:10.1016/j.jsbmb.2019.105563.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Miller WL, Imel EA (2022). "Rickets, Vitamin D, and Ca/P Metabolism". Hormone Research in Paediatrics. 95 (6): 579–592. doi:10.1159/000527011.
- ↑ 5.0 5.1 Kamenický P, Briot K, Munns CF, Linglart A (2024). "X-Linked Hypophosphataemia". Lancet. 404 (10455): 887–901. doi:10.1016/S0140-6736(24)01305-9.
- ↑ 6.0 6.1 6.2 Hacisahinogullari H, Tekin S, Tanrikulu S; et al. (2023). "Diagnosis and management of tumor-induced osteomalacia: a single center experience". Endocrine. 82 (2): 427–434. doi:10.1007/s12020-023-03450-3.
- ↑ 7.0 7.1 7.2 7.3 Fukumoto S (2026). "FGF23 – A hormone produced by bone and has many faces –". Reviews in Endocrine & Metabolic Disorders. doi:10.1007/s11154-026-10079-w.
- ↑ 8.0 8.1 8.2 Shimada T, Mizutani S, Muto T; et al. (2001). "Cloning and Characterization of FGF23 as a Causative Factor of Tumor-Induced Osteomalacia". Proceedings of the National Academy of Sciences of the United States of America. 98 (11): 6500–6505. doi:10.1073/pnas.101545198.
- ↑ 9.0 9.1 Kinoshita Y, Fukumoto S (2018). "X-Linked Hypophosphatemia and FGF23-Related Hypophosphatemic Diseases: Prospect for New Treatment". Endocrine Reviews. 39 (3): 274–291. doi:10.1210/er.2017-00220.
- ↑ 10.0 10.1 Michigami T (2022). "Advances in Understanding of Phosphate Homeostasis and Related Disorders". Endocrine Journal. 69 (8): 881–896. doi:10.1507/endocrj.EJ22-0239.