Osteomalacia risk factors
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
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Overview
Risk Factors
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[3]
Risk factors for osteomalacia are best understood at the individual patient level and separated into modifiable and non-modifiable factors. Most risk factors relate to nutritional (calcipenic) osteomalacia caused by vitamin D and/or calcium insufficiency; other factors predispose to phosphopenic or hereditary forms. Vitamin D deficiency is substantially more common than osteomalacia and therefore represents a predisposition rather than establishing the diagnosis. [1][2]
Non-modifiable risk factors
- Darker skin pigmentation. Increased melanin reduces cutaneous vitamin D synthesis for a given ultraviolet-B exposure and is associated with lower 25-hydroxyvitamin D concentrations. [1]
- Older age. Cutaneous vitamin D synthesis and vitamin D/calcium handling decline with age, while reduced outdoor exposure is common in older adults. [2]
- Hereditary predisposition. Genetic disorders such as X-linked hypophosphatemia and vitamin D–dependent rickets predispose to phosphopenic or calcipenic mineralization defects. [3]
Modifiable nutritional and behavioral risk factors
- Limited effective sun exposure. Indoor or housebound lifestyle, institutionalization, high-latitude winter exposure, concealing clothing, and sun avoidance reduce cutaneous vitamin D synthesis. [1]
- Low dietary vitamin D intake. Inadequate dietary intake increases the risk of vitamin D deficiency, particularly when endogenous cutaneous synthesis is also limited. [2]
- Low dietary calcium intake. Chronic calcium deficiency can produce osteomalacia even when vitamin D status is adequate and is particularly relevant in populations with low calcium intake. Histomorphometric studies demonstrate mineralization defects in association with vitamin D and calcium deficiency. [4]
- Obesity. Higher body mass index is associated with lower circulating 25-hydroxyvitamin D concentrations, partly related to sequestration of vitamin D in adipose tissue. [1]
Life-stage risk factors
- Pregnancy and lactation. Increased maternal and infant calcium and vitamin D requirements can increase susceptibility to deficiency-related mineralization disorders, particularly when dietary intake and vitamin D status are inadequate. [2]
- Infancy and early childhood. These are high-risk life stages for the rickets end of the rickets–osteomalacia spectrum, particularly in the setting of inadequate vitamin D or calcium intake. [5]
- Advanced age with institutionalization or limited mobility. Reduced sun exposure and dietary insufficiency may compound the age-related reduction in vitamin D synthesis. [5]
Medical comorbidities
- Malabsorptive gastrointestinal disease. Celiac disease, inflammatory bowel disease, pancreatic insufficiency, and cholestatic or hepatobiliary disease can impair vitamin D and/or calcium absorption. [6]
- Bariatric surgery. Malabsorptive procedures, particularly Roux-en-Y gastric bypass and biliopancreatic diversion/duodenal switch, increase the risk of persistent vitamin D and calcium deficiency and metabolic bone disease. Risk varies by procedure and may persist long term. Malabsorptive procedures have been associated with approximately 21–47% higher fracture risk depending on the procedure and comparator population. [7][8][9]
- Chronic kidney disease. Impaired renal vitamin D activation and altered phosphate/FGF23 handling increase susceptibility to defective mineralization. [3]
- Chronic liver disease. Impaired vitamin D metabolism and associated malabsorption can contribute to calcipenic osteomalacia. [6]
Medication-related risk factors
- Enzyme-inducing anticonvulsants. Phenytoin, phenobarbital, primidone, and carbamazepine induce cytochrome P450 enzymes and accelerate vitamin D catabolism, historically contributing to osteomalacia in institutionalized patients. The mechanism is not solely vitamin D–related: low vitamin D is not found in all studies, the vitamin D–bone mineral density correlation is inconsistent, and additional effects on bone turnover, hypocalcemia, and secondary hyperparathyroidism may contribute. Valproate and some non-inducing agents have also been associated with adverse skeletal effects. [10][11][12]
- Drugs causing proximal tubular phosphate wasting. Tenofovir disoproxil fumarate (TDF), adefovir, ifosfamide, and other agents capable of producing Fanconi-type proximal tubulopathy can cause hypophosphatemic osteomalacia. Risk is substantially more established with TDF than with tenofovir alafenamide, which has a more favorable renal and bone safety profile. [13][14]
- Aluminum-containing antacids or phosphate binders and sucralfate. These agents can promote phosphate depletion or interfere with mineralization when exposure is substantial or prolonged. [5]
- Intravenous iron, particularly ferric carboxymaltose. Ferric carboxymaltose can cause FGF23-mediated renal phosphate wasting and carries an FDA boxed warning for severe, prolonged hypophosphatemia associated with osteomalacia and fractures. This can occur even in patients with normal baseline phosphate and without apparent risk factors. In the PHOSPHARE-IDA randomized trials, ferric carboxymaltose was the only consistent treatment-associated risk factor for hypophosphatemia compared with ferric derisomaltose; severe or persistent hypophosphatemia occurred predominantly after ferric carboxymaltose. [15][16]
Clinical risk recognition
- Risk factors should be interpreted as predisposition rather than diagnosis. Vitamin D deficiency is common and does not by itself establish osteomalacia. [4][2]
- In an adult with suspected osteomalacia but a normal 25-hydroxyvitamin D concentration, consider phosphate-wasting disorders and drug-induced proximal tubular dysfunction rather than excluding osteomalacia solely on the basis of vitamin D status. [13]
- Proposed non-invasive case-finding features for nutritional osteomalacia include combinations of elevated alkaline phosphatase or PTH, low 25-hydroxyvitamin D, and low dietary calcium intake; detailed thresholds belong in the Screening and Laboratory Findings microchapters. [17]
References
- ↑ 1.0 1.1 1.2 1.3 Kechichian E, Ezzedine K (2018). "Vitamin D and the Skin: An Update for Dermatologists". American Journal of Clinical Dermatology. 19 (2): 223–235. doi:10.1007/s40257-017-0323-8.
- ↑ 2.0 2.1 2.2 2.3 2.4 Demay MB, Pittas AG, Bikle DD; et al. (2024). "Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology and Metabolism. 109 (8): 1907–1947. doi:10.1210/clinem/dgae290.
- ↑ 3.0 3.1 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.
- ↑ 4.0 4.1 Priemel M, von Domarus C, Klatte TO; et al. (2010). "Bone Mineralization Defects and Vitamin D Deficiency: Histomorphometric Analysis of Iliac Crest Bone Biopsies and Circulating 25-Hydroxyvitamin D in 675 Patients". Journal of Bone and Mineral Research. 25 (2): 305–312. doi:10.1359/jbmr.090728.
- ↑ 5.0 5.1 5.2 Uday S, Högler W (2020). "Nutritional Rickets & Osteomalacia: A Practical Approach to Management". The Indian Journal of Medical Research. 152 (4): 356–367. doi:10.4103/ijmr.IJMR_1961_19.
- ↑ 6.0 6.1 Bami H, Lau AN, Adachi JD (2019). Metabolic Bone Disease in Gastrointestinal Disorders (4th ed.).
- ↑ Kim J, Nimeri A, Khorgami Z; et al. (2021). "Metabolic Bone Changes After Bariatric Surgery: 2020 Update, American Society for Metabolic and Bariatric Surgery Clinical Issues Committee Position Statement". Surgery for Obesity and Related Diseases. 17 (1): 1–8. doi:10.1016/j.soard.2020.09.031.
- ↑ Saad RK, Ghezzawi M, Habli D, Alami RS, Chakhtoura M (2022). "Fracture Risk Following Bariatric Surgery: A Systematic Review and Meta-Analysis". Osteoporosis International. 33 (3): 511–526. doi:10.1007/s00198-021-06206-9.
- ↑ Winckelmann LA, Gribsholt SB, Bødkergaard K; et al. (2024). "Risk of Fractures Following Bariatric Surgery With Roux-en-Y Gastric Bypass or Sleeve Gastrectomy: A Danish Population-Based Cohort Study". European Journal of Endocrinology. 191 (1): 1–8. doi:10.1093/ejendo/lvae068.
- ↑ van der Burgh AC, de Keyser CE, Zillikens MC, Stricker BH (2021). "The Effects of Osteoporotic and Non-osteoporotic Medications on Fracture Risk and Bone Mineral Density". Drugs. 81 (16): 1831–1858. doi:10.1007/s40265-021-01625-8.
- ↑ O'Sullivan S, Grey A (2015). "Adverse skeletal effects of drugs – beyond Glucocorticoids". Clinical Endocrinology. 82 (1): 12–22. doi:10.1111/cen.12549.
- ↑ Aghoram R, Nair S, Nair P; et al. (2024). "Pharmacological interventions for bone health in people with epilepsy". Cochrane Database of Systematic Reviews (1): CD013109. doi:10.1002/14651858.CD013109.pub2.
- ↑ 13.0 13.1 Cho J, Cheung PP (2018). "Osteomalacia Due to Drug-Induced Fanconi Syndrome". Arthritis & Rheumatology. 70 (7): 1168. doi:10.1002/art.40492.
- ↑ Barbieri AM, Chiodini I, Ragni E; et al. (2018). "Suppressive effects of tenofovir disoproxil fumarate, an antiretroviral prodrug, on mineralization and type II and type III sodium-dependent phosphate transporters expression in primary human osteoblasts". Journal of Cellular Biochemistry. 119 (6): 4855–4866. doi:10.1002/jcb.26696.
- ↑ "Ferric Carboxymaltose". Food and Drug Administration. 2026. Missing or empty
|url=(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). - ↑ Uday S, Högler W (2019). "Spot the Silent Sufferers: A Call for Clinical Diagnostic Criteria for Solar and Nutritional Osteomalacia". The Journal of Steroid Biochemistry and Molecular Biology. 188: 141–146. doi:10.1016/j.jsbmb.2019.01.004.