Osteomalacia
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Osteomalacia Microchapters |
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Osteomalacia On the Web |
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American Roentgen Ray Society Images of Osteomalacia |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[2]
Overview
Osteomalacia is a metabolic bone disease characterized by defective mineralization of newly formed osteoid, resulting in mechanically weak bone. The defect reflects inadequate availability of calcium and/or phosphate at the mineralization front or, less commonly, primary inhibition of the mineralization process.[1][2]
Osteomalacia versus rickets and osteoporosis
- Osteomalacia is impaired mineralization of the bone matrix (osteoid) and occurs predominantly after physeal closure.
- Rickets is impaired mineralization of the epiphyseal growth plate and therefore occurs in growing children. Osteomalacia and rickets may coexist in a growing child; after growth-plate closure, osteomalacia persists without rickets.[3][4]
- Osteoporosis is characterized primarily by reduced bone mass and deterioration of bone microarchitecture, without a primary defect in osteoid mineralization. A low DXA bone mineral density therefore does not by itself establish osteoporosis in a patient with suspected osteomalacia.[2]
Although osteomalacia is strictly a tissue-level histologic diagnosis, most patients can be diagnosed noninvasively using the combined clinical, biochemical, and radiographic findings. Bone biopsy is generally reserved for diagnostically inconclusive cases.[2]
Major causes
The major etiologic categories are:
- Calcipenic osteomalacia: vitamin D deficiency, inadequate calcium intake, gastrointestinal malabsorption, hepatic disease, anticonvulsant exposure, and vitamin D-dependent disorders. Secondary hyperparathyroidism is commonly present.[1]
- Phosphopenic osteomalacia: renal phosphate wasting, including FGF23-mediated disorders such as tumor-induced osteomalacia and hereditary hypophosphatemic disorders, as well as Fanconi syndrome and other causes of phosphate deficiency. FGF23 is a key unifying mediator of phosphate wasting in tumor-induced osteomalacia and several hereditary hypophosphatemic disorders.[5][6][4]
- Primary mineralization defects: hypophosphatasia and mineralization-inhibiting exposures such as aluminum and fluoride; chronic kidney disease–mineral and bone disorder may also produce defective mineralization. Hypophosphatasia is characteristically associated with a low serum alkaline phosphatase, in contrast to the elevated ALP commonly seen in calcipenic and phosphopenic osteomalacia.[7][1]
Clinical features
Adult osteomalacia commonly presents with nonspecific musculoskeletal manifestations, particularly:
- Diffuse bone pain and bone tenderness
- Proximal muscle weakness
- Difficulty walking or a waddling gait
- Fatigue and reduced physical function
- Fragility fractures or pseudofractures in established disease
Because these manifestations are nonspecific, osteomalacia may be mistaken for fibromyalgia, polymyalgia rheumatica, inflammatory musculoskeletal disease, myopathy, or functional disorders.[1]
Osteomalacia is frequently underdiagnosed because its symptoms are nonspecific and radiographic abnormalities may be insensitive, particularly early in the disease. A high index of suspicion is therefore required.[3][2]
Diagnostic approach
Biochemical evaluation is the practical cornerstone of diagnosis. Common findings in nutritional osteomalacia include elevated alkaline phosphatase, secondary elevation of parathyroid hormone, and low or low-normal calcium and/or phosphate, with reduced 25-hydroxyvitamin D when vitamin D deficiency is the underlying cause. The biochemical picture is heterogeneous, however: in biopsy-proven series, ALP is elevated in the large majority, whereas low calcium, low phosphate, and elevated PTH are each present in only a minority; therefore, no single biochemical pattern is pathognomonic.[8][2]
In patients with unexplained musculoskeletal symptoms, fasting morning serum phosphate should be considered. Persistent hypophosphatemia should prompt evaluation for renal phosphate wasting and, when clinically appropriate, FGF23-mediated disorders such as tumor-induced osteomalacia.[6]
A proposed biochemical framework for nutritional osteomalacia combines elevated ALP and PTH with low dietary calcium intake and/or markedly reduced 25-hydroxyvitamin D. These criteria are proposed rather than universally validated diagnostic criteria.[3]
A markedly reduced 25-hydroxyvitamin D concentration supports nutritional osteomalacia when accompanied by compatible clinical and biochemical findings, but a mildly reduced 25(OH)D concentration in the commonly termed "insufficient" range does not by itself establish osteomalacia. Available evidence suggests that established histologic and biochemical osteomalacia is generally associated with profound and persistent vitamin D deficiency, although an exact universal 25(OH)D diagnostic threshold has not been established.[9][10]
Imaging may demonstrate generalized osteopenia and, in established disease, characteristic Looser zones (pseudofractures). DXA may show reduced bone mineral density but is nonspecific and should not be used alone to distinguish osteomalacia from osteoporosis.[2]
Bone biopsy with double tetracycline labeling and quantitative histomorphometry remains the reference standard when the diagnosis cannot be established from the clinical and biochemical evaluation.[2][8]
Treatment principle
Treatment is cause-directed and consists of correcting the underlying disorder and restoring the deficient mineral substrate.
- Nutritional osteomalacia is treated with adequate vitamin D repletion together with sufficient calcium intake.
- Malabsorption and other underlying gastrointestinal or hepatic disorders should be addressed.
- Phosphate-wasting osteomalacia requires correction of the phosphate abnormality and, depending on the cause, active vitamin D therapy or targeted FGF23 therapy.
- In tumor-induced osteomalacia, localization and definitive treatment of the causative tumor may correct the phosphate-wasting disorder.[11][12]
Key clinical points
- Consider osteomalacia in an adult with diffuse bone pain, proximal weakness, and elevated ALP, while recognizing that hypophosphatasia is an important exception characterized by low ALP.
- A low 25-hydroxyvitamin D level does not by itself establish nutritional osteomalacia and does not exclude a concurrent phosphate-wasting disorder.
- Serum phosphate should not be omitted when evaluating unexplained musculoskeletal symptoms, particularly when the biochemical pattern is not typical for nutritional disease.
- Osteomalacia is frequently clinically underrecognized because symptoms are nonspecific and imaging may be insensitive early in the disease.
- True nutritional osteomalacia is generally associated with profound, persistent vitamin D deficiency; mild 25(OH)D reduction alone should not be equated with osteomalacia.
- Do not diagnose osteoporosis from a low DXA result alone when the clinical or biochemical picture suggests defective mineralization.
- The treatment strategy depends on identifying and correcting the underlying cause.
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.[13]
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.[13]
The combination of dietary supplementation, food fortification, and improved understanding of sunlight exposure substantially reduced nutritional rickets and osteomalacia in many populations.[14]
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.[15]
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.[15]
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.[4][15]
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.[15]
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.[16]
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.[15][17][18]
Recognition of FGF23 as a major phosphaturic hormone established a common biological framework linking hereditary hypophosphatemic disorders with TIO.[17][18]
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.[5][19]
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.[14][17]
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.[14][15]
Key historical milestones
- 1645: Daniel Whistler described rickets.[13]
- 1650: Francis Glisson published De Rachitide, an early detailed description of rickets.[13]
- 1822: Jędrzej Śniadecki proposed a relationship between sunlight and rickets.[13]
- 1861–1862: Armand Trousseau emphasized sunlight, nutrition, and cod-liver oil in the prevention and treatment of rickets.[13]
- 1890: Theobald Palm demonstrated a geographic association between latitude and rickets.[13]
- 1919: Kurt Huldschinsky demonstrated the antirachitic effect of artificial ultraviolet radiation.[20]
- 1922: Elmer McCollum and colleagues identified and named vitamin D.[13]
- 1924: Steenbock and Hess demonstrated that ultraviolet irradiation could confer antirachitic activity on foods.[13]
- 1932: Adolf Windaus and colleagues clarified the chemistry of vitamin D2 and vitamin D3.[13]
- 1937: Fuller Albright described vitamin D–refractory hereditary hypophosphatemic rickets.[4]
- 1947: Robert McCance described tumor-induced osteomalacia.[16]
- 1959: Andrea Prader proposed a tumor-secreted phosphaturic ("rachitogenic") substance in tumor-associated hypophosphatemic disease.[16]
- 1970s: Calcitriol was identified as the biologically active vitamin D metabolite.[15]
- 1990s: Molecular studies established PHEX as the gene responsible for XLH.[15]
- 2000–2001: FGF23 was identified through studies of hereditary hypophosphatemia and as a causative factor in tumor-induced osteomalacia.[17][18]
- 21st century: Targeted anti-FGF23 therapy translated the FGF23 discovery into treatment for selected FGF23-mediated disorders.[5][19]
Diagnosis
History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | X Ray | CT | MRI | Echocardiography or Ultrasound | Other Imaging Findings | Other Diagnostic Studies
Treatment
Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies
References
- ↑ 1.0 1.1 1.2 1.3 Abi-Ghanem AS, Chouairy CJ, Meguerian Z, Azar L. A 49-Year-Old Man With Debilitating Aches and Pains and a Mysterious Culprit. Arthritis Care & Research. 2020;72(1):1-8. doi:10.1002/acr.23807.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Jha S, Chapman M, Roszko K. When Low Bone Mineral Density and Fractures Is Not Osteoporosis. Current Osteoporosis Reports. 2019;17(5):324-332. doi:10.1007/s11914-019-00529-7.
- ↑ 3.0 3.1 3.2 Uday S, Högler W. 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:10.1016/j.jsbmb.2019.01.004.
- ↑ 4.0 4.1 4.2 4.3 Kamenický P, Briot K, Munns CF, Linglart A. X-Linked Hypophosphataemia. Lancet. 2024;404(10455):887-901. doi:10.1016/S0140-6736(24)01305-9.
- ↑ 5.0 5.1 5.2 Kinoshita Y, Fukumoto S. X-Linked Hypophosphatemia and FGF23-Related Hypophosphatemic Diseases: Prospect for New Treatment. Endocrine Reviews. 2018;39(3):274-291. doi:10.1210/er.2017-00220.
- ↑ 6.0 6.1 Jan de Beur SM. Tumor-Induced Osteomalacia. JAMA. 2005;294(10):1260-1267. doi:10.1001/jama.294.10.1260.
- ↑ Lin EL, Gottesman GS, McAlister WH, et al. Healing of Vitamin D Deficiency Rickets Complicating Hypophosphatasia Suggests a Role Beyond Circulating Mineral Sufficiency for Vitamin D in Musculoskeletal Health. Bone. 2020;136:115322. doi:10.1016/j.bone.2020.115322.
- ↑ 8.0 8.1 Bingham CT, Fitzpatrick LA. Noninvasive Testing in the Diagnosis of Osteomalacia. The American Journal of Medicine. 1993;95(5):519-523. doi:10.1016/0002-9343(93)90335-M.
- ↑ Bolland MJ, Avenell A, Grey A. Prevalence of biochemical osteomalacia in adults undergoing vitamin D testing. Clinical Endocrinology. 2021;95(1):74-83. doi:10.1111/cen.14483.
- ↑ Macleod AD, Bolland MJ, Balfour A, et al. Biochemical osteomalacia in adults undergoing vitamin D testing in the North-East of Scotland. Annals of Clinical Biochemistry. 2025;62(4):303-311. doi:10.1177/00045632251315671.
- ↑ Amir Sam A, Meeran K, Hill N. Osteomalacia. Endocrinology and Diabetes. 2023.
- ↑ Slouma M, Bettaieb H, Rahmouni S, Cheour E, Lamloum M. Personalized Treatment Pathways for Adult Osteomalacia. Journal of Clinical Densitometry. 2026;29(2):101685. doi:10.1016/j.jocd.2026.101685.
- ↑ 13.00 13.01 13.02 13.03 13.04 13.05 13.06 13.07 13.08 13.09 Invalid
<ref>tag; no text was provided for refs namedRajakumar2003 - ↑ 14.0 14.1 14.2 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.
- ↑ 15.0 15.1 15.2 15.3 15.4 15.5 15.6 15.7 Miller WL, Imel EA (2022). "Rickets, Vitamin D, and Ca/P Metabolism". Hormone Research in Paediatrics. 95 (6): 579–592. doi:10.1159/000527011.
- ↑ 16.0 16.1 16.2 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.
- ↑ 17.0 17.1 17.2 17.3 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.
- ↑ 18.0 18.1 18.2 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.
- ↑ 19.0 19.1 Michigami T (2022). "Advances in Understanding of Phosphate Homeostasis and Related Disorders". Endocrine Journal. 69 (8): 881–896. doi:10.1507/endocrj.EJ22-0239.
- ↑ Invalid
<ref>tag; no text was provided for refs namedRajakumarThomas2005