Osteomalacia causes
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.
Overview
Osteomalacia is the softening of the bones caused by deactivated bone mineralization primarily due to inadequate levels of available phosphate and calcium, or because of resorption of calcium. Osteomalacia in children is known as rickets, and because of this, use of the term "osteomalacia" is often restricted to the milder, adult form of the disease. Signs and symptoms can include diffuse body pains, muscle weakness, and fragility of the bones.
Causes
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[3] Osteomalacia results from inadequate delivery of calcium or phosphate to mineralizing bone, or from impaired bone mineralization. Causes are most usefully grouped as calcipenic, phosphopenic (FGF23-mediated or FGF23-independent), and inhibitor/matrix disorders. Nutritional vitamin D and/or calcium deficiency remains the leading global cause of nutritional osteomalacia.[1]
Calcipenic causes
Vitamin D and calcium deficiency
- Nutritional vitamin D deficiency — the leading global cause of nutritional osteomalacia.
- Dietary calcium deficiency — may cause osteomalacia even when vitamin D status is adequate, particularly with chronically low calcium intake.[1]
Malabsorptive and hepatobiliary disorders
- Malabsorption — including celiac disease, inflammatory bowel disease, pancreatic insufficiency, and cholestatic/hepatobiliary disease.
- Bariatric surgery — particularly malabsorptive procedures such as Roux-en-Y gastric bypass and biliopancreatic diversion.
- Chronic liver disease — may contribute through impaired vitamin D metabolism and fat-soluble vitamin malabsorption.[2]
Hereditary defects of vitamin D metabolism or action
- Vitamin D-dependent rickets type 1A (VDDR1A) — CYP27B1 deficiency.
- VDDR1B — CYP2R1 deficiency.
- VDDR2A — vitamin D receptor dysfunction.
- VDDR2B — impaired interaction of the vitamin D receptor with vitamin D response elements.
- VDDR3 — gain-of-function CYP3A4 variants, including I301T, accelerate inactivation of 25-(OH)D and 1,25-(OH)₂D to low-activity metabolites.[3][4]
Phosphopenic causes
Chronic hypophosphatemia caused by renal phosphate wasting can produce osteomalacia despite adequate calcium and vitamin D. Phosphopenic disorders can be divided into FGF23-mediated and FGF23-independent forms.[5]
FGF23-mediated phosphate wasting
- X-linked hypophosphatemia (XLH) — PHEX-related inherited FGF23 excess.
- Autosomal dominant hypophosphatemic rickets (ADHR) — associated with cleavage-resistant FGF23.
- Autosomal recessive hypophosphatemic rickets (ARHR) — including DMP1- and ENPP1-related disease.
- Tumor-induced osteomalacia (TIO) — usually caused by FGF23-secreting phosphaturic mesenchymal tumors.
- Fibrous dysplasia/McCune-Albright syndrome — GNAS-mutant skeletal lesions can overproduce FGF23; renal phosphate wasting occurs in approximately half of affected patients and frank hypophosphatemia in a smaller subset, with phosphate abnormalities correlating with skeletal disease burden.[6][7]
- Cadmium toxicity (Itai-itai disease) — chronic exposure causes proximal tubular atrophy with renal phosphate wasting and increases intact FGF23 by enhancing FGF23 glycosylation through GalNAc-T3 and suppressing furin-mediated proteolytic cleavage; direct osteotoxicity may also contribute.[8][9][10]
- Iron-infusion-associated phosphate wasting — particularly with ferric carboxymaltose, which increases intact FGF23 and causes renal phosphate wasting. Head-to-head randomized trials found hypophosphatemia in approximately 74–75% of patients receiving ferric carboxymaltose versus approximately 8% with ferric derisomaltose, with severe hypophosphatemia occurring predominantly with ferric carboxymaltose.[11][12][13]
FGF23-independent phosphate wasting
- Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) — SLC34A3-related renal phosphate wasting.
- Fanconi syndrome — generalized proximal tubular dysfunction, which may be inherited (e.g., cystinosis, Wilson disease, Dent disease) or acquired (e.g., multiple myeloma, tenofovir disoproxil fumarate, ifosfamide, or heavy-metal exposure).
- Renal tubular acidosis — proximal RTA, usually as part of Fanconi syndrome, causes phosphate wasting. Distal (type 1) RTA may contribute to metabolic bone disease through chronic acidosis, impaired calcitriol synthesis, and hypercalciuria; histomorphometrically it is better characterized as a low-turnover lesion with suppressed bone formation and a variable, usually mild, mineralization defect rather than frank osteomalacia. Skeletal disease is largely reversible with correction of acidosis.[14][15][16]
Inhibitor and matrix causes
These disorders impair mineralization despite adequate systemic mineral availability.
- Hypophosphatasia — ALPL loss of function with accumulation of inorganic pyrophosphate; characteristically associated with low serum alkaline phosphatase.
- Aluminum toxicity — historically associated with aluminum-containing phosphate binders and dialysate, particularly in patients with chronic kidney disease.
- Fluoride exposure — can alter bone mineral composition and mechanical properties and has been associated with osteomalacia and skeletal fluorosis.[17]
- High-dose or prolonged etidronate — a classic iatrogenic inhibitor of bone mineralization; this mechanism is not characteristic of modern nitrogen-containing bisphosphonates at standard doses.
- Axial osteomalacia — rare osteomalacia predominantly affecting the axial skeleton, with incompletely defined pathogenesis.[18]
- Fibrogenesis imperfecta ossium — rare collagen/matrix disorder associated with defective bone mineralization; its association with monoclonal gammopathy has been reported but is not established as a universal mechanism.[19]
Drug-induced osteomalacia
- Antiretroviral therapy, particularly tenofovir disoproxil fumarate, can cause proximal tubular phosphate wasting and Fanconi syndrome and is frequently reported in pharmacovigilance data for drug-associated osteomalacia.[20]
- Enzyme-inducing antiepileptics — phenytoin, phenobarbital, primidone, and carbamazepine can accelerate vitamin D catabolism through PXR-mediated induction of CYP3A4 and CYP24A1.[21][22]
- Antacids and phosphate binders containing aluminum hydroxide and/or magnesium hydroxide, and sucralfate, can cause hypophosphatemic osteomalacia through intestinal phosphate binding with chronic heavy use, including in patients with normal renal function.[23][24]
- Ferric carboxymaltose — see the FGF23-mediated phosphate-wasting section above.
Chronic kidney disease
Chronic kidney disease can produce CKD-mineral and bone disorder through impaired vitamin D activation, phosphate retention, secondary hyperparathyroidism, altered FGF23 signaling, and abnormalities of bone turnover and mineralization. Osteomalacia represents a mineralization-defect pattern within the broader spectrum of renal osteodystrophy; detailed CKD-MBD classification belongs in the relevant classification and diagnostic chapters.[25]
References
- ↑ 1.0 1.1 Uday S, Högler W (2020). "Nutritional Rickets & Osteomalacia: A Practical Approach to Management". Indian Journal of Medical Research. 152 (4): 356–367. doi:10.4103/ijmr.IJMR_1961_19. PMID 33380700 Check
|pmid=value (help). - ↑ Bami H, Lau AN, Adachi JD (2019). Metabolic Bone Disease in Gastrointestinal Disorders (4th ed.).
- ↑ Roizen JD, Li D, O'Lear L; et al. (2018). "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3". Journal of Clinical Investigation. 128 (5): 1913–1918. doi:10.1172/JCI98680. PMID 29461981.
- ↑ Uday S, Högler W (2025). "Differential Diagnosis of Heritable and Acquired Osteomalacia in Children: Biochemical and Biomaterial Signatures". Calcified Tissue International. 116 (1): 91. doi:10.1007/s00223-025-01398-2. PMID 40586907 Check
|pmid=value (help). - ↑ Trombetti A, Al-Daghri N, Brandi ML; et al. (2022). "Interdisciplinary management of FGF23-related phosphate wasting syndromes: a Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia". Nature Reviews Endocrinology. 18 (6): 366–384. doi:10.1038/s41574-022-00662-x.
- ↑ Riminucci M, Collins MT, Fedarko NS; et al. (2003). "FGF-23 in Fibrous Dysplasia of Bone and Its Relationship to Renal Phosphate Wasting". Journal of Clinical Investigation. 112 (5): 683–692. doi:10.1172/JCI18399. PMID 12952917.
- ↑ Gun ZH, Osamor C, Taylor J; et al. (2024). "Serum Phosphorus as a Driver of Skeletal Morbidity in Fibrous Dysplasia". The Journal of Clinical Endocrinology and Metabolism. 109 (5): 1334–1340. doi:10.1210/clinem/dgad671. PMID 37975816 Check
|pmid=value (help). - ↑ Takebayashi S, Jimi S, Segawa M, Kiyoshi Y (2000). "Cadmium Induces Osteomalacia Mediated by Proximal Tubular Atrophy and Disturbances of Phosphate Reabsorption. A Study of 11 Autopsies". Pathology, Research and Practice. 196 (9): 653–663. doi:10.1016/S0344-0338(00)80010-2. PMID 10997741.
- ↑ Kido S, Fujihara M, Nomura K; et al. (2014). "Molecular Mechanisms of Cadmium-Induced Fibroblast Growth Factor 23 Upregulation in Osteoblast-Like Cells". Toxicological Sciences. 139 (2): 301–316. doi:10.1093/toxsci/kfu043. PMID 24614234.
- ↑ Fukumoto S (2024). "Regulation of FGF23 Production in Osteocytes". Current Osteoporosis Reports. 22 (2): 273–279. doi:10.1007/s11914-024-00860-8.
- ↑ Wolf M, Rubin J, Achebe M; et al. (2020). "Effects of Iron Isomaltoside vs Ferric Carboxymaltose on Hypophosphatemia in Iron-Deficiency Anemia: Two Randomized Clinical Trials". JAMA. 323 (5): 432–443. doi:10.1001/jama.2019.22450.
- ↑ Schaefer B, Tobiasch M, Viveiros A; et al. (2021). "Hypophosphataemia After Treatment of Iron Deficiency With Intravenous Ferric Carboxymaltose or Iron Isomaltoside-a Systematic Review and Meta-Analysis". British Journal of Clinical Pharmacology. 87 (5): 2256–2273. doi:10.1111/bcp.14643. PMID 33188534 Check
|pmid=value (help). - ↑ Schaefer B, Zoller H, Wolf M (2022). "Risk Factors for and Effects of Persistent and Severe Hypophosphatemia Following Ferric Carboxymaltose". The Journal of Clinical Endocrinology and Metabolism. 107 (4): 1009–1019. doi:10.1210/clinem/dgab852. PMID 34850000 Check
|pmid=value (help). - ↑ Domrongkitchaiporn S, Pongsakul C, Stitchantrakul W; et al. (2001). "Bone Mineral Density and Histology in Distal Renal Tubular Acidosis". Kidney International. 59 (3): 1086–1093. doi:10.1046/j.1523-1755.2001.0590031086.x. PMID 11231364.
- ↑ Domrongkitchaiporn S, Pongskul C, Sirikulchayanonta V; et al. (2002). "Bone Histology and Bone Mineral Density After Correction of Acidosis in Distal Renal Tubular Acidosis". Kidney International. 62 (6): 2160–2166. doi:10.1046/j.1523-1755.2002.00656.x. PMID 12427141.
- ↑ Wagner CA, Unwin R, Lopez-Garcia SC; et al. (2023). "The pathophysiology of distal renal tubular acidosis". Nature Reviews Nephrology. 19 (6): 384–400. doi:10.1038/s41581-023-00699-9.
- ↑ Collins MT, Marcucci G, Anders HJ; et al. (2022). "Skeletal and extraskeletal disorders of biomineralization". Nature Reviews Endocrinology. 18 (8): 473–489. doi:10.1038/s41574-022-00682-7.
- ↑ Whyte MP, Fallon MD, Murphy WA, Teitelbaum SL (1981). "Axial Osteomalacia. Clinical, Laboratory and Genetic Investigation of an Affected Mother and Son". The American Journal of Medicine. 71 (6): 1041–1049. doi:10.1016/0002-9343(81)90338-7.
- ↑ Bhadada SK, Dhaliwal R, Dhiman V, Rao SD (2019). "Fibrogenesis Imperfecta Ossium". Calcified Tissue International. 104 (5): 561–569. doi:10.1007/s00223-019-00547-8.
- ↑ Dardonville Q, Salguiero E, Rousseau V; et al. (2019). "Drug-Induced Osteoporosis/Osteomalacia: Analysis in the French and Spanish Pharmacovigilance Databases". European Journal of Clinical Pharmacology. 75 (12): 1705–1711. doi:10.1007/s00228-019-02743-9. PMID 31468068.
- ↑ Wang Z, Lin YS, Dickmann LJ; et al. (2013). "Enhancement of Hepatic 4-Hydroxylation of 25-Hydroxyvitamin D3 Through CYP3A4 Induction in Vitro and in Vivo: Implications for Drug-Induced Osteomalacia". Journal of Bone and Mineral Research. 28 (5): 1101–1116. doi:10.1002/jbmr.1839. PMID 23212742.
- ↑ Pascussi JM, Robert A, Nguyen M; et al. (2005). "Possible Involvement of Pregnane X Receptor-Enhanced CYP24 Expression in Drug-Induced Osteomalacia". Journal of Clinical Investigation. 115 (1): 177–186. doi:10.1172/JCI21867. PMID 15630458.
- ↑ Woodson GC (1998). "An Interesting Case of Osteomalacia Due to Antacid Use Associated With Stainable Bone Aluminum in a Patient With Normal Renal Function". Bone. 22 (6): 695–698. doi:10.1016/S8756-3282(98)00060-X. PMID 9626411.
- ↑ Chines A, Pacifici R (1990). "Antacid and Sucralfate-Induced Hypophosphatemic Osteomalacia: A Case Report and Review of the Literature". Calcified Tissue International. 47 (5): 291–295. doi:10.1007/BF02555911. PMID 2257522.
- ↑ Alexander AJ, Jahangir D, Lazarus M, Sprague SM (2017). "Imaging in Chronic Kidney Disease-Metabolic Bone Disease". Seminars in Dialysis. 30 (4): 361–368. doi:10.1111/sdi.12598.