Osteomalacia overview
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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]
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.
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 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.
- ↑ 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.