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 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]

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]

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]

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 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]

• 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.

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]

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]

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 (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]

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]

• 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]

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]

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 (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]

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]

• 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]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[3]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[3]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S. 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]

 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]  Associate Editor(s)-in-Chief:   Ibrahim Elkhayat, M.B.B.Ch.[4]

Osteomalacia should be distinguished from disorders that present with low bone mineral density (BMD), diffuse bone pain, proximal weakness, fractures, or multifocal skeletal abnormalities. The most important diagnostic distinction is from osteoporosis, because both conditions may have reduced BMD but require different evaluation and management. Other clinically relevant mimics include rheumatologic and neuromuscular disorders, Paget disease of bone, renal osteodystrophy, metastatic bone disease, multiple myeloma, and hypophosphatasia.^[2][21]

The distinction from osteoporosis is particularly important because low BMD alone does not establish osteoporosis. Osteomalacia can reduce measured BMD because inadequate mineralization reduces measured bone mass, and DXA therefore cannot reliably distinguish osteomalacia from osteoporosis. Diffuse bone pain, proximal muscle weakness, abnormal mineral biochemistry, or pseudofractures should prompt evaluation for osteomalacia rather than attributing the findings to osteoporosis alone.^[2][22]

Looser zones and other pseudofractures can produce focal or multifocal abnormalities on radiography, CT, MRI, or bone scintigraphy and may be mistaken for metastatic disease or inflammatory skeletal disorders. Bilateral or symmetric lesions at characteristic sites support osteomalacia, particularly when accompanied by compatible mineral abnormalities.^[24]

Multiple myeloma should remain in the differential diagnosis of otherwise unexplained hypophosphatemic osteomalacia. Monoclonal light chains can cause proximal tubular dysfunction and acquired Fanconi syndrome, resulting in renal phosphate wasting and osteomalacia. Light-chain proximal tubulopathy is predominantly kappa (κ)-restricted, and PTH and FGF23 may remain normal. Osteomalacia may precede overt myeloma and can be the presenting manifestation.^[25][26][27]

• Do not diagnose osteoporosis from low BMD alone. Osteomalacia can also reduce BMD, and DXA does not reliably distinguish the two disorders.^[2][22]
• Do not interpret low BMD as proof of osteoporosis when mineral biochemistry is abnormal. Calcium, phosphate, ALP, 25-OHD, and PTH abnormalities should prompt consideration of osteomalacia or another metabolic bone disorder.^[21]
• A low ALP changes the differential. In a patient thought to have osteomalacia, unexpectedly low ALP should raise suspicion for hypophosphatasia.^[28]
• Do not assume multifocal bone-scan uptake represents metastases. Symmetric uptake at typical pseudofracture sites may reflect osteomalacia.^[24]
• Do not exclude myeloma-associated osteomalacia solely because the skeletal presentation is metabolic. Light-chain proximal tubulopathy can produce hypophosphatemic osteomalacia as the presenting manifestation of multiple myeloma.^[25]

The true prevalence of osteomalacia is uncertain because clinically apparent disease is often nonspecific or underrecognized, and there is no universally validated non-invasive case definition. Most osteomalacia is nutritional (calcipenic), whereas phosphopenic and hereditary forms are comparatively rare.^[3][29]

• In an autopsy study of 675 adults from northern Europe, histomorphometric osteomalacia, defined by osteoid volume/bone volume >2%, was present in approximately 26% of iliac-crest biopsies. Mineralization defects occurred in both sexes and across age groups.^[30]
• Among adults older than 45 years presenting with low-energy hip fractures, histologic osteomalacia was identified in 26.7% (19/72) of patients. Biochemical criteria identified substantially higher proportions, approximately 41.7–75%, depending on the criteria used.^[31]
• In contrast to histologic and biochemical estimates, clinically confirmed osteomalacia was identified in only 29 of 25,379 adults undergoing vitamin D testing in a North-East Scotland cohort, illustrating the substantial gap between clinically overt disease and broader histologic or biochemical definitions.^[10]
• Vitamin D deficiency is substantially more common than osteomalacia and should not be used as a direct surrogate for osteomalacia prevalence.^[3]

Population groups bearing a disproportionate burden of nutritional osteomalacia include:

• People with darker skin pigmentation, particularly immigrant and ethnic-minority populations living at higher latitudes, in whom vitamin D deficiency occurs at substantially higher rates than in background populations.^[29]
• People with limited effective ultraviolet exposure, including those living at high latitudes, people wearing extensive skin-covering clothing, institutionalized populations, and individuals with substantial sun avoidance.^[29]
• Older and institutionalized adults, particularly those presenting with low-energy fractures, in whom histologic osteomalacia is relatively common.^[31]
• Pregnant and lactating women, particularly dark-skinned immigrant populations living at high latitude. In a Swedish cohort of 123 pregnant or breastfeeding women, biochemical osteomalacia was identified in 20 participants, 19 of whom were Somali.^[32]
• Patients after malabsorptive bariatric surgery, in whom vitamin D deficiency is common; overt osteomalacia is an uncommon but recognized late complication.^[33]

• In higher-latitude regions, seasonal reduction in ultraviolet-B exposure contributes to vitamin D deficiency, with a disproportionate burden among dark-skinned residents and immigrants.^[29]
• In sunny, lower-latitude regions, including parts of the Indian subcontinent, Middle East, and Africa, nutritional osteomalacia may be driven by dietary calcium deficiency as well as vitamin D deficiency. Sun exposure does not eliminate risk, particularly where sun avoidance, concealing clothing, or dietary factors limit effective vitamin D or calcium availability.^[29]
• Reported severe vitamin D deficiency, defined as 25-OHD <30 nmol/L, is approximately 5.9% in the United States, 7.4% in Canada, and 13% in Europe, but exceeds 20% in several countries and regions of South Asia and the Middle East. These are vitamin D deficiency estimates, not osteomalacia prevalence.^[34]
• Population-level vitamin D deficiency estimates vary substantially by geography and study population and should not be interpreted as estimates of osteomalacia prevalence.^[34]

Histologic nutritional osteomalacia is not confined to women or older adults. In the large autopsy series, mineralization defects occurred in both sexes and across age groups, although specific populations such as older adults, institutionalized individuals, and pregnant or lactating women may carry a greater burden of nutritional disease.^[30]

Phosphopenic and hereditary osteomalacia are uncommon compared with nutritional disease.

• X-linked hypophosphatemia (XLH) is the most common form of hereditary hypophosphatemia, accounting for approximately 90% of hypophosphatemic rickets. Reported incidence is approximately 3.9 per 100,000 live births and prevalence approximately 1.7–4.8 per 100,000.^[35][4]
• Tumor-induced osteomalacia (TIO) is a rare acquired FGF23-mediated disorder that usually presents during adulthood, with a mean age at onset of approximately 40–45 years. Sex distribution is debated: several reviews describe approximately equal involvement of men and women, whereas the largest individual-patient-data systematic review, comprising 1,725 cases, found TIO to be more frequent, and more severe, in adult men. There is no established ethnic predilection, and population-level incidence data remain limited.^[36][37]

The epidemiologic burden of osteomalacia is difficult to quantify because reported prevalence varies according to whether histologic, biochemical, or clinical definitions are used. The discrepancy is particularly evident in low-energy hip-fracture cohorts, in which biochemical criteria identify substantially more patients than histologic criteria.^[3][31]

Underdiagnosis is particularly pronounced for TIO. A systematic clinical review of 895 cases reported diagnostic delays exceeding 2 years in more than 80% of patients, highlighting the substantial burden of delayed recognition.^[38]

A low 25-hydroxyvitamin D concentration is not synonymous with osteomalacia. Conversely, osteomalacia can occur in populations in which vitamin D deficiency is not the sole nutritional determinant, particularly where dietary calcium deficiency is prevalent.^[29]

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]

• 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]

• 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]

• 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]

• 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]

• 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]

• 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]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[3] There is no validated population screening test or program for osteomalacia itself. The closest available construct is screening for its principal upstream nutritional causes, particularly vitamin D deficiency, together with targeted biochemical case-finding in individuals at increased risk. Screening should be distinguished from diagnostic evaluation of patients with symptoms or clinical findings suggestive of osteomalacia.

Osteomalacia generally evolves gradually from a biochemical and histologic mineralization defect to symptomatic skeletal and neuromuscular disease. In severe or prolonged disease, mechanically weak bone may develop pseudofractures, fractures, and skeletal deformity. The prognosis is generally favorable when the underlying cause is identified and corrected, although recovery of bone mass and skeletal microarchitecture may lag behind biochemical and symptomatic improvement.^[1][2][3]

Osteomalacia may remain clinically and radiographically occult during its early stages. In nutritional osteomalacia, compensatory secondary hyperparathyroidism and increased bone turnover may precede overt hypocalcemia or hypophosphatemia. Histologic abnormalities of osteoid accumulation and delayed mineralization may therefore precede characteristic abnormalities on plain radiographs.^[1][2][3]

The subsequent clinical course may include:

• Early/occult disease: Biochemical and histologic abnormalities without characteristic radiographic findings.
• Symptomatic disease: Progressive diffuse bone pain and tenderness, fatigue, and proximal muscle weakness with functional limitation and gait disturbance. Because these manifestations are nonspecific, osteomalacia may be mistaken for rheumatologic, neuromuscular, or other pain disorders.^[4]
• Advanced disease: Severe or prolonged mineralization defects may result in Looser zones (pseudofractures), pathological fractures, vertebral deformity, and other skeletal abnormalities.^[5][3]

In phosphopenic osteomalacia, including tumor-induced osteomalacia (TIO) and hereditary hypophosphatemic disorders, persistent renal phosphate wasting produces chronic hypophosphatemia and defective mineralization. Untreated TIO may progressively increase skeletal morbidity, particularly when diagnosis is delayed.^[6][7]

Diagnostic delay is an important contributor to skeletal morbidity in TIO. Reported delays from symptom onset to diagnosis may extend for several years, with substantial variation between patients, allowing potentially irreversible skeletal damage to accumulate.^[7]

The principal complications result from reduced mineralization and impaired mechanical strength of bone.

• Fragility and pathological fractures: Fractures may occur with minimal or no trauma and can involve the ribs, vertebrae, pelvis, and long bones. Patients with TIO may develop multiple fractures.^[5][8]
• Looser zones (pseudofractures): These incomplete fractures are characteristic of severe osteomalacia and may occur at the femoral neck, femoral shaft, pubic rami, ribs, scapula, clavicle, ulna, and metatarsals.^[5][3]
• Skeletal deformity: Long-standing severe disease may produce bowing of long bones, vertebral concavity (codfish vertebrae), and other structural deformities.^[5][3]
• Low or abnormal bone mineral density: DXA may demonstrate reduced BMD, but BMD findings are variable and do not establish or exclude osteomalacia. Normal or relatively high BMD can occur in some phosphopenic disorders, including XLH.^[3]

Proximal muscle weakness may cause difficulty rising from a chair, climbing stairs, or walking and may produce a waddling gait. Severe pain, weakness, and fractures can result in substantial functional limitation and impaired quality of life.^[4][9]

In severe calcipenic disease, hypocalcemia may produce neuromuscular irritability, tetany, or seizures. QT prolongation may occur with significant hypocalcemia. Severe deficiency in infancy within the rickets–osteomalacia spectrum may rarely be complicated by dilated cardiomyopathy and heart failure.^[1]

Chronic skeletal pain, fractures, proximal myopathy, and skeletal deformity may progressively impair mobility and quality of life. In TIO, prolonged phosphate wasting and diagnostic delay may result in substantial and potentially persistent musculoskeletal disability.^[8][7]

Osteomalacia is generally a highly reversible metabolic bone disorder when the underlying cause is recognized and corrected. Biochemical and clinical recovery commonly precede complete recovery of bone mass and skeletal microarchitecture.^[1][10]

Correction of vitamin D and calcium deficiency generally improves biochemical abnormalities, bone pain, and muscle weakness and reduces ongoing skeletal morbidity. Recovery occurs over weeks to months, although the duration depends on disease severity, duration, and the underlying cause.^[1][10]

Long-standing disease may leave residual skeletal deformity or fracture-related disability despite correction of the mineralization defect.^[3][10]

Complete resection of a causative phosphaturic mesenchymal tumor is typically curative. Intact FGF23 generally normalizes within approximately 24 hours, and serum phosphate typically normalizes within approximately 5 days; in a large postoperative cohort, normalization occurred within 7 days in approximately 83% of cured patients. Alkaline phosphatase and skeletal mineralization recover more gradually, with skeletal healing potentially continuing for approximately 1 year.^[11][12][13]

Hungry bone syndrome may occur after successful TIO tumor resection during rapid skeletal remineralization. It is characterized by secondary hyperparathyroidism with variable hypocalcemia, hypophosphatemia, and hypomagnesemia and may require calcium and vitamin D supplementation during the postoperative period.^[11]

Bone mineral density can improve substantially after successful treatment, particularly at the spine and hip, although recovery at peripheral skeletal sites may be slower. Long-standing fractures, vertebral deformities, and other structural damage may not completely reverse.^[8][12]

Persistent or recurrent TIO remains an important prognostic concern. In a large review, initial surgery was successful in approximately 59% of patients and overall successful resection was approximately 67%; these estimates include patients in whom the tumor could not necessarily be localized or completely resected. By contrast, a systematic review of more than 1,725 cases reported surgery to be successful in more than 90% of patients in whom the causative tumor was localized, illustrating the importance of the denominator used when reporting surgical success.^[14][15]

In a 230-patient cohort, approximately 18% had refractory disease, defined by nonremission or recurrence, with a median time to recurrence of approximately 33 months.^[16]

Bone-derived tumors, spinal location, malignant histology, lower preoperative serum phosphate, and higher preoperative FGF23 have been associated with a less favorable course.^[16][11][12]

In a retrospective cohort, non-localizing TIO was associated with significantly lower survival than localizing disease. An FGF23 level greater than 20 times the upper limit of normal in the presence of normal renal function, together with recurrence after initial cure, was associated with malignancy.^[17]

For nonlocalizable, unresectable, or recurrent TIO, conventional therapy with oral phosphate plus active vitamin D and burosumab, an anti-FGF23 monoclonal antibody, can improve phosphate homeostasis and osteomalacia-related manifestations. Detailed dosing and monitoring are addressed in the Medical therapy microchapter.^[11][18]

• The prognosis of osteomalacia depends primarily on identifying and correcting the underlying mineralization defect rather than on the BMD value at diagnosis.^[3]
• Biochemical and symptomatic recovery may occur before complete skeletal recovery; patients with severe or long-standing disease may therefore require prolonged follow-up.^[10][8]
• After successful TIO resection, early postoperative changes in phosphate and calcium metabolism should be recognized, including possible hungry bone syndrome.^[11]
• Patients treated for TIO require long-term surveillance for persistent or recurrent phosphate wasting, particularly when complete tumor resection is not achieved.^[11][16]

The true population burden and long-term prognosis of nutritional osteomalacia remain incompletely defined because the disease is frequently underrecognized.^[2]

The extent to which structural skeletal damage and quality-of-life impairment are completely reversible after prolonged TIO remains incompletely characterized, particularly in patients with longstanding fractures or deformity.^[8][12]

History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | X Ray | CT | MRI | Echocardiography or Ultrasound | Other Imaging Findings | Other Diagnostic Studies

Osteomalacia should be considered in adults with diffuse bone pain, proximal muscle weakness, fatigue, waddling gait, low-trauma or insufficiency fractures, or unexplained low bone mineral density accompanied by abnormalities of mineral metabolism.^[1][3]

The diagnostic approach is stepwise:

1. Targeted history and physical examination to identify the clinical phenotype and potential underlying cause.
2. Biochemical evaluation with a core mineral panel, with particular attention to serum phosphate.
3. Mechanistic classification as predominantly calcipenic or phosphopenic.
4. Imaging to identify skeletal manifestations such as Looser zones and, when tumor-induced osteomalacia (TIO) is suspected, to localize a causative tumor.
5. Bone biopsy only when the diagnosis remains uncertain despite clinical, biochemical, and imaging evaluation.^[4]

A fasting morning serum phosphate should be included in the evaluation of unexplained musculoskeletal symptoms or low-trauma fractures, interpreted using age-specific reference ranges. In adults, hypophosphatemia is generally defined as serum phosphate below 0.8 mmol/L (2.5 mg/dL). Chronic hypophosphatemia is confirmed by two values below the reference range on at least two occasions ≥2 weeks apart, rather than a single isolated value.^[4][3]

The core biochemical evaluation includes:

• Serum calcium, albumin, phosphate, and creatinine
• Total or bone-specific alkaline phosphatase (ALP)
• Parathyroid hormone (PTH)
• 25-hydroxyvitamin D (25OHD)
• 1,25-dihydroxyvitamin D (1,25(OH)₂D)
• Urinary phosphate and creatinine when renal phosphate wasting is suspected
• Intact FGF23 when hypophosphatemia with renal phosphate wasting has been established

Two broad biochemical patterns help distinguish the major mechanisms:

• Calcipenic osteomalacia: typically characterized by low or low-normal calcium, hypophosphatemia, elevated ALP, secondary hyperparathyroidism, and low 25OHD.^[5]
• Phosphopenic osteomalacia due to renal phosphate wasting: characterized by hypophosphatemia with inappropriate renal phosphate loss and elevated or inappropriately normal FGF23 in FGF23-mediated disease; 1,25(OH)₂D may be low or inappropriately normal and ALP is commonly elevated.^[6]

Renal phosphate handling can be assessed using tubular maximum reabsorption of phosphate per GFR (TmP/GFR) or tubular reabsorption of phosphate (TRP), calculated from paired serum and urine phosphate and creatinine measurements. Vitamin D deficiency and secondary hyperparathyroidism can confound interpretation and should be considered when interpreting renal phosphate-handling indices.^[7]

An inappropriately normal or elevated intact FGF23 in the setting of hypophosphatemia and renal phosphate wasting supports FGF23-mediated hypophosphatemia.^[8]

Plain radiographs may be normal in early osteomalacia. With established disease, findings may include generalized osteopenia, cortical thinning, biconcave vertebral bodies, and Looser zones (pseudofractures). Looser zones are narrow radiolucent lines with sclerotic margins and commonly involve the femoral neck or shaft, pubic rami, ribs, scapula, and ulna.^[3][9]

DXA is neither sensitive nor specific for osteomalacia. Bone mineral density may be reduced, normal, or relatively increased depending on the underlying disorder; therefore, DXA should not be used alone to establish or exclude osteomalacia.^[1]

When TIO is biochemically established, functional imaging is used to localize the causative tumor. Somatostatin-receptor PET/CT is the preferred first-line functional imaging modality where available, using tracers such as ⁶⁸Ga-DOTATATE, ⁶⁸Ga-DOTANOC, or ⁶⁸Ga-DOTATOC. Meta-analyses have reported pooled sensitivities of approximately 86–90% for Ga-68 DOTA-SSTR PET/CT, compared with approximately 67–73% for FDG-PET/CT.^[10][11][12]

Whole-body functional imaging is required because culprit tumors may arise at skeletal or soft-tissue sites throughout the body. MRI or CT can then provide anatomic characterization of candidate lesions. Selective venous sampling for FGF23 may help discriminate among multiple candidate lesions when imaging identifies more than one potential source.^[11][12][4]

Transiliac bone biopsy after double tetracycline labeling remains the definitive histological diagnostic test. Osteomalacia is characterized by increased osteoid accumulation and impaired mineralization; reported histomorphometric diagnostic parameters include osteoid thickness >12.5 µm and mineralization lag time >100 days.^[1]

Bone biopsy is generally reserved for diagnostically challenging cases in which the clinical, biochemical, and imaging findings remain discordant or insufficient for diagnosis.^[1]

Osteoporosis and osteomalacia can both present with low bone mineral density and fractures, but they represent fundamentally different skeletal disorders. Osteoporosis is characterized by reduced bone mass with preserved mineralization, whereas osteomalacia results from defective mineralization of newly formed osteoid.^[1]

The distinction is clinically important because a low BMD measurement alone does not establish osteoporosis. Mineral abnormalities, particularly abnormalities involving phosphate, ALP, calcium, or PTH, should prompt evaluation for osteomalacia before attributing low BMD or fractures to primary osteoporosis.^[1]

• Normal radiographs do not exclude osteomalacia. Biochemical and histological abnormalities may precede characteristic radiographic findings.^[2][3]
• Do not rely on DXA alone. BMD abnormalities are neither sufficiently sensitive nor specific for osteomalacia.^[1]
• Do not omit serum phosphate from the initial mineral evaluation. Persistent hypophosphatemia should prompt assessment for renal phosphate wasting and, when appropriate, FGF23-mediated disease.^[4][6]
• Do not assume vitamin D deficiency explains all hypophosphatemia. FGF23-mediated phosphate wasting can coexist with vitamin D deficiency.^[4]
• Reserve bone biopsy for unresolved cases. Most patients can be diagnosed without invasive histological confirmation when the clinical, biochemical, and imaging findings are concordant.^[1]

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

The treatment strategy follows the mechanistic classification established during diagnosis:

• Calcipenic osteomalacia: replace vitamin D and calcium and correct the underlying cause of deficiency or impaired vitamin D metabolism.^[1][3]
• Phosphopenic osteomalacia: correct renal phosphate wasting with appropriate phosphate and active vitamin D therapy or, when indicated, FGF23-directed treatment.^[2][4]
• Tumor-induced osteomalacia (TIO): localize and completely resect the causative tumor whenever feasible; medical therapy is used when the tumor cannot be localized, cannot be completely resected, or disease persists or recurs.^[4][5]
• Underlying cause: correct reversible contributors such as malabsorption, renal or hepatic disease, or an offending medication whenever possible.^[6]

Nutritional vitamin D deficiency is treated with vitamin D repletion together with adequate calcium intake, followed by maintenance therapy. The specific regimen should be individualized according to the severity and duration of deficiency, the underlying cause, absorption, adherence, and response to treatment.^[1][3]

Patients with impaired vitamin D activation may require an active vitamin D metabolite such as calcitriol or alfacalcidol rather than relying solely on parent vitamin D.^[2][6]

Detailed vitamin D and calcium dosing, indications for active metabolites, and safety monitoring are covered in the Medical Therapy microchapter.

Hereditary and acquired renal phosphate-wasting disorders generally require oral phosphate in divided doses together with an active vitamin D metabolite when conventional therapy is used; phosphate should not be given as monotherapy, because phosphate loading stimulates PTH secretion and may lead to secondary or tertiary hyperparathyroidism while providing inadequate correction of the underlying disorder.^[4][7]

Burosumab, an anti-FGF23 monoclonal antibody, provides mechanism-directed therapy for selected FGF23-mediated disorders, including X-linked hypophosphatemia and tumor-induced osteomalacia that is not amenable to curative surgery.^[7][4]

When burosumab is initiated, oral phosphate and active vitamin D analogs must be discontinued at least 1 week before the first dose; burosumab should not be co-administered with oral phosphate because of the risk of hyperphosphatemia.^[8][7]

Drug-induced phosphate wasting should prompt withdrawal or substitution of the offending medication when clinically feasible, together with correction of the resulting mineral abnormalities.^[6]

Detailed phosphate, active vitamin D, and burosumab dosing and monitoring are covered in the Medical Therapy microchapter.

Complete surgical resection of the causative phosphaturic mesenchymal tumor is the definitive curative treatment when the tumor can be localized and safely resected. A systematic review reported successful surgery in more than 90% of patients in whom the causative tumor was localized.^[5]

In TIO, conventional therapy with phosphate plus active vitamin D should be initiated as soon as the biochemical diagnosis is established, in parallel with tumor localization and in preparation for surgery, to treat the osteomalacia and minimize postoperative hungry bone syndrome.^[4]

For nonlocalizable, unresectable, or recurrent tumors, long-term medical therapy with conventional phosphate plus active vitamin D or burosumab may be required.^[4][7]

Percutaneous tumor ablation may provide an alternative local treatment for selected accessible tumors when conventional surgery is not feasible.^[2]

Detailed indications, perioperative management, tumor resection, and ablation are covered in the Surgery microchapter.

Treatment response should be assessed using the biochemical abnormalities that established the diagnosis, together with improvement in skeletal and functional manifestations. Monitoring intensity should be individualized according to the underlying cause, treatment used, disease severity, and changes in therapy.^[1][2]

Particular attention should be paid to:

• Serum calcium and phosphate
• Alkaline phosphatase and PTH
• 25-hydroxyvitamin D or active vitamin D measurements when clinically appropriate
• Urinary calcium in patients receiving calcium, phosphate, or active vitamin D therapy
• Renal function and evidence of nephrocalcinosis when prolonged phosphate or active vitamin D therapy is used

Biochemical improvement generally precedes complete skeletal recovery; persistent symptoms, fractures, or biochemical abnormalities should prompt reassessment of adherence, absorption, treatment adequacy, and the underlying cause.^[1][2]

After successful TIO resection, rapid restoration of phosphate metabolism may be followed by hungry bone syndrome, with secondary hyperparathyroidism and variable hypocalcemia, hypophosphatemia, and hypomagnesemia. Postoperative calcium and vitamin D supplementation may be required.^[4]

Treatment should balance correction of the mineralization defect against the risks of overtreatment, particularly hypercalcemia, hypercalciuria, nephrocalcinosis, and treatment-induced hyperparathyroidism.^[1][4]

Prevention of nutritional osteomalacia and prevention of recurrence after treatment are addressed separately in the Primary Prevention and Secondary Prevention microchapters.

Economic considerations, including high-cost biologic therapy and population-level prevention strategies, are addressed in the Cost-Effectiveness of Therapy microchapter.

Emerging or investigational treatments are addressed in the Future or Investigational Therapies microchapter.

Presentation. An adult presents with chronic low back pain, morning stiffness, diffuse bone pain, and proximal muscle weakness causing difficulty rising from a chair and a waddling gait. Limited sun exposure and low dietary calcium intake are present. An initial diagnosis of seronegative spondyloarthropathy may be made because of back pain, stiffness, and apparent sacroiliitis on pelvic imaging.^[1][2]

Workup. Typical findings include low 25-hydroxyvitamin D, low or low-normal calcium, low or low-normal phosphate, elevated alkaline phosphatase (ALP), and elevated PTH consistent with secondary hyperparathyroidism.^[3]

Diagnosis. Calcipenic osteomalacia due to vitamin D/calcium deficiency. Proposed non-invasive diagnostic criteria include elevated ALP, elevated PTH, low dietary calcium intake (<300 mg/day) and/or low serum 25-hydroxyvitamin D (<30 nmol/L), with compatible symptoms or Looser zones. Bone biopsy is rarely required when the clinical and biochemical findings are concordant.^[3]

Management and course. Vitamin D and calcium repletion followed by maintenance therapy corrects the mineralization defect in nutritional osteomalacia. Detailed treatment is covered in the Medical Therapy microchapter.^[4]

Teaching points.

• Osteomalacia may mimic spondyloarthritis, polymyalgia rheumatica, myopathy, or fibromyalgia; in a matched comparative series, approximately two-thirds of patients with osteomalacia had previously been misdiagnosed as spondyloarthritis or ankylosing spondylitis.^[5]
• Abnormal mineral biochemistry should prompt reconsideration of a primary rheumatologic diagnosis.^[6]
• Low dietary calcium intake and/or low 25-hydroxyvitamin D in the setting of elevated ALP and PTH should prompt evaluation for calcipenic osteomalacia rather than osteoporosis or a primary rheumatologic disorder.^[3]

Presentation. A middle-aged adult presents with several years of progressive diffuse bone pain, proximal muscle weakness, difficulty walking, and low-trauma fractures. TIO is frequently diagnosed only after a prolonged diagnostic course.^[7][8]

Workup. Hypophosphatemia with renal phosphate wasting, elevated ALP, and an elevated or inappropriately normal intact FGF23 indicate FGF23-mediated phosphate wasting. In contrast to calcipenic osteomalacia, serum calcium is typically normal in TIO and 1,25-dihydroxyvitamin D is low or inappropriately normal; PTH is usually normal but may be elevated, reflecting secondary hyperparathyroidism in response to FGF23-mediated suppression of 1,25-dihydroxyvitamin D.^[9][10][11]

Whole-body functional imaging, particularly somatostatin-receptor PET/CT such as ⁶⁸Ga-DOTATATE or ⁶⁸Ga-DOTA-TOC PET/CT, can localize a small phosphaturic mesenchymal tumor.^[12][13]

Diagnosis. FGF23-mediated tumor-induced osteomalacia caused by a phosphaturic mesenchymal tumor.

Management and course. Complete surgical resection of the causative tumor is generally curative when the tumor can be localized and safely resected. Nonlocalizable, unresectable, or recurrent disease may require medical therapy with phosphate plus active vitamin D or burosumab.^[11]

Teaching points.

• Persistent hypophosphatemia with renal phosphate wasting should prompt consideration of TIO or another FGF23-mediated disorder.
• The combination of low phosphate, renal phosphate wasting, normal calcium, and low or inappropriately normal 1,25-dihydroxyvitamin D helps distinguish TIO from calcipenic osteomalacia; PTH may be normal or elevated.^[9][10]
• Somatostatin-receptor PET/CT is an important tumor-localization modality in suspected TIO.^[8][13]
• Closed (needle) biopsy of a suspected phosphaturic mesenchymal tumor is discouraged because tumor recurrence has been observed after prior closed biopsy, attributed to tumor-cell spillage.^[7]
• A suspected phosphaturic mesenchymal tumor should therefore be managed through an appropriate tumor-localization and surgical pathway rather than routine diagnostic biopsy.^[11]

Presentation. An adult presents with diffuse bone pain, proximal weakness, low-trauma fractures, or reduced bone mineral density, with or without prominent gastrointestinal symptoms. Celiac disease may be clinically subtle when skeletal manifestations are identified.^[14]

Workup. The biochemical pattern may include low 25-hydroxyvitamin D, low or low-normal calcium, hypophosphatemia, elevated ALP, and secondary hyperparathyroidism. Malabsorption from proximal small-bowel disease can impair calcium and vitamin D absorption. Positive celiac serology with confirmatory duodenal biopsy establishes the underlying enteropathy.^[15]

Diagnosis. Calcipenic osteomalacia secondary to malabsorption from celiac disease. Frank osteomalacia is less well characterized in celiac disease than the more commonly reported low bone mineral density and osteoporosis; the prevalence of osteomalacia specifically remains uncertain.^[16][17]

Management and course. Treatment requires correction of the underlying enteropathy together with vitamin D and calcium repletion. Patients with persistent malabsorption may require individualized replacement and long-term biochemical monitoring.^[15][4]

Teaching points.

• Osteomalacia may be the presenting skeletal manifestation of previously unrecognized celiac disease.
• Malabsorption should be investigated when nutritional osteomalacia occurs despite apparently adequate intake or responds inadequately to standard repletion.
• Low bone mineral density alone does not establish osteomalacia; biochemical evidence of defective mineralization should be sought when skeletal disease is suspected.^[18]
• Treating the underlying malabsorptive disorder is an essential component of long-term management.