Clinical manifestations, diagnosis, and treatment of osteomalacia in adults

INTRODUCTION — Osteomalacia is a bone disorder characterized by decreased mineralization of newly formed osteoid at sites of bone turnover. Osteomalacia can result from different etiologies via mechanisms that result in hypocalcemia, hypophosphatemia, or direct inhibition of the mineralization process. In adults, nutritional osteomalacia due to vitamin D deficiency is the most common etiology.

This topic review will present an overview of the clinical manifestations, diagnosis, and treatment of adults with osteomalacia. The clinical manifestations, diagnosis, and treatment of nutritional rickets in children, as well as rickets due to hereditary vitamin D resistance, 1-alpha-hydroxylase deficiency, and hereditary hypophosphatemic disorders that present before adulthood are discussed separately. (See "Etiology and treatment of calcipenic rickets in children" and "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia".)

The epidemiology and causes of osteomalacia also are reviewed separately. (See "Epidemiology and etiology of osteomalacia".)

CLINICAL FEATURES

Clinical findings — In early stages, osteomalacia is often asymptomatic. With progression, it can produce characteristic symptoms that are not specific to the underlying cause. These include diffuse bone and joint pain, muscle weakness, and difficulty walking [1-3]. Symptoms may be insidious in onset. Many symptoms of osteomalacia can mimic other skeletal, rheumatologic, and systemic illnesses; diagnosis is often delayed and requires a high degree of clinical suspicion.

●Bone pain – Bone pain is usually most pronounced in the lower spine, pelvis, and lower extremities, as well as where fractures have occurred, and may be associated with tenderness to palpation. The pain is characterized as dull and aching and is aggravated by activity and weight bearing. Bone pain is not a feature of osteoporosis; bone pain in a patient with a history of fragility fracture(s) should raise concern that the underlying process is osteomalacia rather than osteoporosis.

●Muscle weakness – Muscle weakness is usually proximal and may be associated with muscle wasting, hypotonia, and discomfort with movement [1]. Muscle weakness may lead to a waddling gait and is a frequent finding in osteomalacia due to vitamin D deficiency or disorders of phosphorus metabolism.

●Fractures – Fractures may occur with little or no trauma and typically involve the ribs, vertebrae, pelvis, and long bones. Hypophosphatasia can present with a different fracture pattern that is generally nonvertebral and often includes slow healing metatarsal or other lower extremity fractures [4]. Atypical femur fractures may occur in adults with hypophosphatasia, both in untreated patients and in those inappropriately treated with antiresorptive therapy for osteoporosis [5].

●Bone deformity – Abnormal spinal curvature or deformity of the thorax or pelvis appears only in severe osteomalacia of long duration [1].

Additional findings may be present depending on the underlying etiology. For example, etiologies that lead to hypocalcemia may present with muscle cramps, paresthesias, and physical examination findings of neuromuscular irritability (eg, Trousseau's sign, Chvostek's sign). Osteomalacia secondary to hypophosphatasia, caused by mutations in the ALPL gene, may be associated with chondrocalcinosis and premature loss of teeth during childhood and adulthood [6]. (See "Epidemiology and etiology of osteomalacia", section on 'Hypophosphatasia'.)

In a report of 17 patients with osteomalacia on bone biopsy, the following findings were observed [7]:

●Bone pain and muscle weakness in 16 (94 percent)

●Bone tenderness in 15 (88 percent)

●Fracture in 13 (76 percent)

●Difficulty walking and waddling gait in four (24 percent)

●Muscle spasms, cramps, a positive Chvostek's sign, tingling/numbness, and inability to ambulate in one to two (6 to 12 percent)

Laboratory findings — Laboratory abnormalities in patients with osteomalacia largely depend on the underlying cause (table 1 and algorithm 1). The interpretation of laboratory tests in the evaluation of osteomalacia is discussed below. (See 'Laboratory tests' below.)

In retrospective reviews of patients with biopsy-proven nutritional osteomalacia, the following laboratory abnormalities were observed [7,8]:

●Alkaline phosphatase elevated in 95 to 100 percent

●Serum calcium and phosphorus reduced in 27 to 38 percent

●Urinary calcium low in 87 percent

●25-hydroxyvitamin D (25[OH]D, calcidiol) <15 ng/mL (37 nmol/L) in 100 percent

●PTH elevated in 100 percent

Most patients (40 of 43) in these reviews had nutritional osteomalacia from either gastrointestinal malabsorption or suboptimal nutrition and inadequate sun exposure. In these cases, 25(OH)D levels were very low (almost uniformly <12 ng/mL [30 nmol/L] and all <15 ng/mL [37.5 nmol/L]), which is generally not the case in other causes of osteomalacia, such as the renal phosphate wasting syndromes. (See 'Severe vitamin D deficiency' below and 'Alternative etiology suspected' below.)

Imaging findings

●Radiographic findings – In adults with osteomalacia, radiographic evidence of reduced bone mineral density (BMD) with thinning of the cortex is the most common finding but is very nonspecific. More specific are changes in vertebral bodies and Looser zones. Infrequently, radiographic evidence of secondary hyperparathyroidism can be seen. These more specific findings are part of the diagnostic evaluation and discussed in detail below. (See 'Skeletal imaging for suspected osteomalacia' below.)

The radiographic abnormalities in adults with osteomalacia are less striking than those seen in children with rickets [9-13]. (See "Overview of rickets in children".)

●BMD – Depending on the underlying etiology of osteomalacia, BMD measured by dual-energy x-ray absorptiometry (DXA) may be decreased, normal, or increased. In patients with osteomalacia due to vitamin D deficiency, several studies have demonstrated markedly reduced spine, hip, and forearm BMD (as measured by DXA) [7,8]. In contrast, BMD may be normal or increased (especially at the lumbar spine) in adults with X-linked hypophosphatemia, axial osteomalacia, hypophosphatasia, fibrogenesis imperfecta, and skeletal fluorosis [14-16]. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'X-linked hypophosphatemia' and "Epidemiology and etiology of osteomalacia", section on 'Defective bone matrix'.)

DIAGNOSTIC AND ETIOLOGIC EVALUATION

Whom to evaluate — Osteomalacia may be difficult to diagnosis. It should be suspected in any adult with bone pain and tenderness. It also should be suspected in younger or middle-aged adults with low bone mineral density (BMD) or atraumatic fracture in the absence of a known secondary cause of bone loss (eg, glucocorticoid use). The diagnosis is supported by the presence of risk factors such as conditions associated with gastrointestinal malabsorption, chronic liver disease, or chronic kidney disease. (See 'Clinical history and physical examination' below.)

A high index of clinical suspicion for osteomalacia is important because symptoms are generally nonspecific, and a delay in diagnosis is common [7,17,18]. In one study of 33 women with osteomalacia, the mean duration of symptoms before diagnosis was 2.5 years [17]. Diagnoses considered prior to confirmation of osteomalacia included osteoporosis, Paget disease of bone, malignancy, pseudohypoparathyroidism, osteoarthritis, malabsorption, irritable bowel syndrome with depression, fibromyalgia, and somatization disorders. (See 'Differential diagnosis' below.)

Osteoporosis and osteomalacia may coexist. In a cross-sectional study of 72 older adults (mean age 70.4 years) presenting with low trauma hip fracture, approximately 30 percent of participants met histologic criteria for osteomalacia [19]. Mixed skeletal pathology with a component of osteomalacia also may be evident in individuals with chronic kidney disease. (See "Evaluation of renal osteodystrophy", section on 'Subtypes of renal osteodystrophy'.)

Approach to evaluation — The diagnosis of osteomalacia is based on clinical, radiographic, and laboratory findings. Laboratory findings are variable and specific to the underlying cause (table 1 and algorithm 1); thus, laboratory data help both verify the diagnosis and identify the underlying cause. (See 'Laboratory tests' below.)

Transiliac crest bone biopsy with double tetracycline labeling and histomorphometric assessment is the most accurate way to diagnose osteomalacia and is considered the gold standard. However, it is infrequently performed clinically because it is invasive, not widely available, and is rarely required to establish the diagnosis in patients with normal kidney function. Indications for bone biopsy are reviewed below. (See 'Bone biopsy if the diagnosis or etiology remains uncertain (rarely performed)' below.)

The diagnosis of genetic causes of osteomalacia and rickets that typically present before adulthood (eg, 1-alpha-hydroxylase deficiency, vitamin D resistance, X-linked hypophosphatemia) is discussed elsewhere. (See "Etiology and treatment of calcipenic rickets in children", section on 'Defects in vitamin D metabolism' and "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia".)

Clinical history and physical examination

●Clinical history – In adults with suspected osteomalacia, clinical history should elicit both bone-related symptoms and potential risk factors for specific etiologies. We assess for the following risk factors for osteomalacia:

•Nutritional risk factors

-History of bariatric surgery, cystic fibrosis, or gastrointestinal disease (eg, celiac disease, inflammatory bowel disease) suggest possible nutritional osteomalacia due to gastrointestinal malabsorption.

-General undernutrition and low intake of common food sources of calcium and vitamin D (table 2 and table 3) are risk factors for nutritional osteomalacia. Individuals with limited sun exposure (eg, homebound or hospitalized adults) are similarly at risk for vitamin D deficiency. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Groups at high risk'.)

•Kidney or liver dysfunction

-Chronic kidney disease leads to reduced 1,25-dihydroxyvitamin D (calcitriol) through diminished renal 1-alpha-hydroxylase activity. Treatment with aluminum or iron also may contribute to osteomalacia in the setting of chronic kidney disease. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Abnormalities of parathyroid hormone, calcium, phosphorus, fibroblast growth factor 23, and vitamin D metabolism'.)

-Multiple myeloma or amyloidosis suggests osteomalacia may be due to generalized proximal tubule dysfunction (acquired Fanconi syndrome).

-Chronic liver disease can lead to osteomalacia through multiple mechanisms, including loss of 25-hydroxylation of vitamin D or decreased bile acid secretion with consequent malabsorption. (See "Evaluation and treatment of low bone mass in primary biliary cholangitis (primary biliary cirrhosis)", section on 'Pathogenesis'.)

•Medications

-Certain medications (eg, carbonic anhydrase inhibitors, certain antiretroviral therapies, enzyme-inducing antiseizure medications) may cause osteomalacia due to proximal (type 2) renal tubular acidosis. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA'.)

-Some antiseizure medications can cause vitamin D deficiency due to accelerated vitamin D catabolism. (See "Antiseizure medications and bone disease", section on 'Effect of ASM type'.)

-Some intravenous iron formulations (eg, ferric carboxymaltose) have been associated with osteomalacia due to fibroblast growth factor 23 (FGF23)-mediated hypophosphatemia [20].

-The bisphosphonate etidronate can cause osteomalacia through direct inhibition of mineralization. Other bisphosphonates do not cause osteomalacia. (See "Epidemiology and etiology of osteomalacia", section on 'Mineralization inhibitors'.)

-Excessive ingestion of aluminum salts in antacids can lead to osteomalacia due to inhibition of gastrointestinal phosphate absorption and consequent hypophosphatemia [21].

•Metal and mineral exposures

-Exposures to fluoride or aluminum suggest osteomalacia due to a mineralization inhibitor. Excessive fluoride exposure may result, for example, from ingestion of fluoride-containing dental products or inhalation of electronic or computer cleaning products ("huffing"). (See "Epidemiology and etiology of osteomalacia", section on 'Mineralization inhibitors'.)

-Exposure to heavy metals (eg, lead, copper, cadmium) may cause osteomalacia due to proximal (type 2) renal tubular acidosis or through direct effects on mineralization. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA'.)

●Physical examination – In adults with osteomalacia, skeletal deformities are rare. Findings such as mild short stature, long bone bowing, and/or tooth loss suggest a possible inherited bone disorder such as X-linked hypophosphatemia or hypophosphatasia; these disorders can have subtle presentations and remain undetected until adulthood. On examination, focal or diffuse tenderness of bones strongly suggests osteomalacia. Kyphosis and height loss may develop consequent to multiple vertebral compression fractures. Abnormal gait due to proximal muscle weakness may be present in severe disease. With etiologies of osteomalacia that cause hypocalcemia, signs of tetany (eg, Trousseau's sign, Chvostek's sign) may be present. In tumor-induced osteomalacia, subcutaneous tumors may be palpable, particularly in the extremities [22].

Skeletal imaging for suspected osteomalacia

Imaging tests — In adults with suspected osteomalacia, we obtain plain radiographs of the spine and other skeletal regions based on localized signs and symptoms (eg, areas of pain, tenderness, or deformity). Although no imaging findings are exclusive to osteomalacia, certain findings can support the diagnosis.

BMD measurement is not required for the diagnosis of osteomalacia, and reduced BMD does not distinguish osteoporosis from osteomalacia. However, once a diagnosis of osteomalacia is established, BMD measurement is performed to determine the severity of bone loss and provide a baseline for subsequent monitoring. (See 'Monitoring' below.)

Diagnostic findings — Radiographic findings of hallmark vertebral body changes or Looser zones help confirm the diagnosis. Additional findings may be present in severe disease or osteomalacia due to longstanding secondary hyperparathyroidism. However, the absence of these radiographic findings does not exclude osteomalacia; abnormal laboratory findings evolve earlier in disease course, and laboratory testing is therefore more sensitive than skeletal imaging. (See 'Laboratory tests' below.)

Vertebral body changes — Inadequate mineralization of osteoid and loss of secondary trabeculae lead to a loss of radiologic distinctness of vertebral body trabeculae, making the radiograph appear of poor quality (image 1 and image 2). With more advanced disease, softening leads to a concavity of the vertebral bodies, sometimes called "codfish vertebrae." The vertebral disks appear large and biconvex. Spinal compression fractures may occur, but these are more common in osteoporosis.

Looser zones — Looser zones, commonly referred to as pseudofractures, are insufficiency fractures and are typically associated with pain. On radiograph, they appear as narrow, radiolucent lines, 2 to 5 mm in width with sclerotic borders. They lie perpendicular to the cortical margins of bones and are a characteristic radiologic finding in osteomalacia, typically late in the disease course (image 3) [9]. Looser zones are not exclusively found in osteomalacia. However, in individuals with clinical symptoms consistent with osteomalacia, Looser zones are usually sufficient to confirm the diagnosis if they are bilateral, symmetric, and/or found at sites characteristic for osteomalacia. The most common sites include the femoral neck, the medial part of the femoral shaft, immediately under or a few centimeters beneath the lesser trochanter, and the pubic and ischial rami. They may also occur at the ulna, scapula, clavicle, rib, and metatarsal bones.

The term "Milkman syndrome" refers to the combination of multiple bilateral and symmetric pseudofractures in a patient with osteomalacia [11]. Pseudofractures can also be seen with bone scans (skeletal scintography) where they appear as hot spots (ie, focal areas of increased radiotracer activity) [10]. Increased radiotracer uptake in the costochondral junctions of the ribs may be evident ("rachitic rosary sign"); however, skeletal scintigraphy is not usually needed in the diagnostic evaluation of osteomalacia.

Looser zones (pseudofractures) reflect impaired repair of bone after injury due to mechanical stress. Whereas some locations are typical for stress fracture, in other locations, Looser zones may result from erosion of bone by arterial pulsations [12,13]. This latter mechanism is consistent with the bilateral, symmetric pattern of Looser zones and their frequent location in apposition to arteries [23].

Other radiographic findings

●Severe osteomalacia – More severe osteomalacia can lead to shortening and bowing of the tibia, pathologic fractures, coxa profunda hip deformity (image 4A-B), and cephalopelvic disproportion (image 5).

●Secondary hyperparathyroidism – Skeletal changes induced by longstanding secondary hyperparathyroidism (eg, from severe vitamin D deficiency) are less common. These include subperiosteal resorption of the phalanges, bone cysts, and resorption of the distal ends of long bones such as the clavicle and humerus. (See "Primary hyperparathyroidism: Clinical manifestations", section on 'Skeletal'.)

Laboratory tests — Laboratory findings are used to both confirm the diagnosis of osteomalacia and determine the underlying etiology (table 1 and algorithm 1). Laboratory tests are usually performed simultaneously with imaging studies once the diagnosis of osteomalacia is suspected. The initial laboratory evaluation should include measurement of serum concentrations of:

●Calcium

●Phosphate

●Alkaline phosphatase (total and bone specific [if available and clinical suspicion for osteomalacia is high])

●25-hydroxyvitramin D (25[OH]D)

●Parathyroid hormone (PTH)

●Electrolytes, blood urea nitrogen (BUN), and creatinine

The goal of the laboratory evaluation is to distinguish nutritional osteomalacia due to vitamin D and/or calcium deficiency from phosphate wasting syndromes and other less common causes of osteomalacia (table 1 and algorithm 1). The serum 25(OH)D level distinguishes vitamin D deficiency, the most common etiology of osteomalacia, from other potential etiologies.

Severe vitamin D deficiency — In osteomalacia due to vitamin D deficiency, 25(OH)D (calcidiol) is typically very low (eg, <12 to 15 ng/mL [30 to 37.5 nmol/L]). Lesser degrees of vitamin D deficiency are common but only rarely associated with osteomalacia [24], warranting consideration of other etiologies. (See 'Alternative etiology suspected' below.)

In addition to secondary hyperparathyroidism, biochemical findings of osteomalacia due to vitamin D deficiency include low to low-normal calcium and phosphate levels and an elevated alkaline phosphatase (both total and bone specific) [1]. Due to 1-alpha-hydroxylase stimulation by PTH, the serum concentration of 1,25-dihydroxyvitamin D may be normal, low, or high, depending upon the severity and duration of vitamin D deficiency, and is therefore not helpful in making the diagnosis [25].

Vitamin D deficiency may be due to various etiologies. The cause can usually be determined based on clinical history. Nutritional osteomalacia is most common and results from limited sun exposure with inadequate vitamin D intake or gastrointestinal malabsorption. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Groups at high risk'.)

Vitamin D deficiency also may result from advanced liver disease, nephrotic syndrome, or medications that accelerate vitamin D catabolism (eg, selected antiseizure medications). (See "Causes of vitamin D deficiency and resistance", section on 'Calcidiol (25-hydroxyvitamin D)'.)

Alternative etiology suspected — If severe vitamin D deficiency is excluded (eg, 25[OH]D level ≥12 to 15 ng/mL [30 to 37.5 nmol/L]) or an alternative cause is suspected based on clinical findings, the alkaline phosphatase level can differentiate between hypophosphatasia and other possible etiologies of osteomalacia.

Low alkaline phosphatase (hypophosphatasia) — In the setting of a clinical presentation consistent with osteomalacia, a low alkaline phosphatase level suggests hypophosphatasia as the underlying etiology. Alkaline phosphatase is a marker of bone turnover and can be low in any setting where bone turnover is low such as in young, healthy women. Low alkaline phosphatase is not necessarily a pathologic finding unless accompanied by a clinical scenario suggesting osteomalacia. Conversely, the lower limit of the normal range varies across alkaline phosphatase assays, and a low value that falls within the reference range does not invariably exclude hypophosphatasia. In hypophosphatasia, total and bone-specific alkaline phosphatase levels are typically low while the serum calcium and phosphate concentrations are normal. Reduced activity of the alkaline phosphatase enzyme results in accumulation of substrates, including phosphoethanolamine, inorganic pyrophosphate, and pyridoxal 5'-phosphate (PLP), in blood and urine. In patients not taking a vitamin B6 (pyridoxine) supplement, elevated levels of plasma PLP and urine phosphoethanolamine are markers of hypophosphatasia [26,27]. The diagnosis is confirmed by genetic testing of the ALPL gene. However, disease severity is highly variable and does not clearly correlate with specific pathogenic variants or measured alkaline phosphatase levels [28-31]. (See "Epidemiology and etiology of osteomalacia", section on 'Hypophosphatasia'.)

Normal or elevated alkaline phosphatase — If the alkaline phosphatase is normal or elevated, the serum phosphate level helps to differentiate among potential etiologies.

●Low serum phosphate – Osteomalacia with hypophosphatemia may result from primary renal phosphate wasting and/or secondary hyperparathyroidism.

•Normal PTH level – The absence of secondary hyperparathyroidism suggests primary renal phosphate wasting, although secondary hyperparathyroidism may be evident in X-linked hypophosphatemia. In adults, primary renal phosphate wasting is usually caused by acquired conditions, such as tumor-induced osteomalacia or Fanconi syndrome. Nonetheless, some hereditary hypophosphatemic disorders may present initially during adulthood.

In primary renal phosphate wasting, serum calcium and 25(OH)D levels are normal, PTH is usually normal but may be mildly elevated, and serum alkaline phosphatase is often high. Serum phosphate is low with elevated phosphate clearance, and hypophosphatemia is often more severe than in hypophosphatemia due to hyperparathyroidism. (See "Hypophosphatemia: Evaluation and treatment".)

-Hereditary hypophosphatemia – Forms of hereditary hypophosphatemia that may present initially in adulthood are autosomal dominant hypophosphatemia, X-linked hypophosphatemia, and hypophosphatemic rickets with hypercalciuria. The clinical features and diagnosis of these disorders are reviewed separately. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia".)

-Tumor-induced osteomalacia – In adults with tumor-induced osteomalacia, hypophosphatemia results from tumoral production of a phosphaturic hormone, usually FGF23. A low or low-normal 1,25-dihydroxyvitamin D level and an elevated serum FGF23 level suggest the diagnosis [32-34], which warrants efforts to localize the underlying tumor. Depending on the specific assay used, the FGF23 level may fall within the reference range. In the absence of overt FGF23 elevation, a 1,25-dihydroxyvitamin D level that is low or inappropriately normal in the setting of hypophosphatemia suggests an FGF23-mediated process. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Tumor-induced osteomalacia' and "Hypophosphatemia: Causes of hypophosphatemia", section on 'Increased urinary excretion'.)

-Fanconi syndrome – Fanconi syndrome describes generalized proximal tubular dysfunction. Hypophosphatemia is accompanied by hypouricemia, aminoaciduria, and glucosuria, as well as proximal (type 2) renal tubular acidosis due to bicarbonate wasting. In contrast to FGF23-mediated hypophosphatemia, the serum 1,25-dihydroxyvitamin D level in Fanconi syndrome is typically elevated or in the high-normal range. In adults, Fanconi syndrome is usually acquired due to multiple myeloma, medications, or exposure to heavy metals (table 4). The diagnosis is established through demonstration of multiple proximal tubular defects and identification of an underlying cause. Heavy metals in the urine may be increased if they are the underlying cause. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA'.)

•Elevated PTH level – Osteomalacia with hypophosphatemia due to secondary hyperparathyroidism may be caused by isolated proximal renal tubular acidosis or nutritional osteomalacia due to low calcium intake.

-Isolated proximal renal tubular acidosis – Proximal (type 2) renal tubular acidosis is characterized by hyperchloremic metabolic acidosis and hypophosphatemia. In this setting, acidosis-induced hypercalciuria leads to secondary hyperparathyroidism and increased phosphaturia. Unlike Fanconi syndrome, isolated proximal renal tubular acidosis does not present with other tubular defects, primary renal phosphate wasting is absent, and, consequently, hypophosphatemia is generally milder. Isolated proximal renal tubular acidosis is rare. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA'.)

-Nutritional osteomalacia (isolated calcium deficiency) – Although nutritional osteomalacia is usually due to vitamin D deficiency, it rarely may be caused by isolated calcium deficiency. In contrast to proximal renal tubular acidosis, urine calcium is very low, and metabolic acidosis is absent. The diagnosis is supported by a history of malabsorption and/or negligible intake of calcium-containing foods (table 3).

●Normal or elevated serum phosphate – If hypophosphatemia is absent, clinical history and estimated glomerular filtration rate (eGFR) help determine the underlying etiology.

•Mineralization inhibitors – Mineralization inhibitors include aluminum, fluoride, and heavy metals, and exposure usually can be determined through clinical history. In skeletal fluorosis, serum calcium and phosphate are typically normal and alkaline phosphate is elevated. Serum, urine, and bone fluoride content are increased [16]. (See "Epidemiology and etiology of osteomalacia", section on 'Mineralization inhibitors'.)

•Disorders of bone matrix – In the bone matrix disorders fibrogenesis imperfecta and axial osteomalacia, alkaline phosphatase, calcium, phosphate, and vitamin D are usually normal. As laboratory findings are typically normal in these rare disorders, differentiation from osteoporosis may be difficult. Bone biopsy is often required to establish the diagnosis. (See 'Bone biopsy if the diagnosis or etiology remains uncertain (rarely performed)' below and "Epidemiology and etiology of osteomalacia", section on 'Defective bone matrix'.)

•Chronic kidney disease – In individuals with chronic kidney disease (eGFR <60 mL/min/1.73 m²), diminished renal 1-alpha-hydroxylase activity leads to reduced formation of 1,25-dihyrdoxyvitamin D. A low 1,25-dihydroxyvitamin D level and elevated PTH support chronic kidney disease as an underlying etiology of osteomalacia. Phosphate retention occurs early in chronic kidney disease, so hypophosphatemia is absent despite secondary hyperparathyroidism. Chronic kidney disease-related bone disease often has a mixed skeletal pathology that can include osteomalacia and always warrants additional evaluation. (See "Evaluation of renal osteodystrophy".)

Bone biopsy if the diagnosis or etiology remains uncertain (rarely performed) — Bone biopsy using double tetracycline labeling is infrequently performed in clinical practice and is indicated only when the diagnosis of osteomalacia is uncertain or noninvasive testing fails to identify the cause. Bone biopsy may be performed if chronic kidney disease-mineral and bone disorder (CKD-MBD) is suspected [35], and evaluation for renal osteodystrophy is the most common indication for biopsy [36]. Biopsy also may be needed to assess for one of the rare disorders of defective bone matrix, such as axial osteomalacia or fibrogenesis imperfecta. (See "Epidemiology and etiology of osteomalacia", section on 'Defective bone matrix'.)

The histomorphometric characteristics of osteomalacia include (picture 1) [37,38]:

●Prolonged mineralization lag time (an index of the time interval between matrix apposition and its subsequent mineralization)

●Excess osteoid (unmineralized bone matrix) accumulation

•Widened osteoid seams

•Increased osteoid volume

All of these features are necessary for the histomorphometric diagnosis because other disorders may show one of these findings. Wide osteoid seams reflecting high bone turnover, for example, can be seen with hyperthyroidism, Paget disease of bone, and hyperparathyroidism. However, the mineral apposition rate is elevated in these disorders in contrast to the low values seen in osteomalacia. (See "Epidemiology and etiology of osteomalacia", section on 'Pathogenesis'.)

DIFFERENTIAL DIAGNOSIS — Other causes of bone fractures, bone pain, and reduced bone mineral density (BMD) include osteoporosis, malignancy, Paget disease of bone, and hyperparathyroidism. Most of these diagnoses can be distinguished from osteomalacia by the clinical history, physical examination, and a combination of laboratory and radiologic studies. Bone biopsy using double tetracycline labeling may be performed in rare cases that are difficult to diagnose using noninvasive methods [39].

●Osteoporosis – Osteoporosis most commonly affects postmenopausal women, older adults (age >65 years), and patients treated with chronic glucocorticoid therapy but also can affect adults without these risk factors. In the absence of fractures, osteoporosis is not associated with bone pain. (See "Osteoporotic fracture risk assessment" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women".)

A distinction between osteoporosis and osteomalacia is critical because individuals with osteomalacia should not receive treatment with bisphosphonates, teriparatide, or other osteoporosis medications; in such patients, treatment with antiresorptive medications may exacerbate hypocalcemia and bone disease [40]. (See 'Vitamin D deficiency' below.)

In osteoporosis, serum levels of calcium, phosphate, parathyroid hormone (PTH), and alkaline phosphatase are normal, although alkaline phosphatase levels can be low in patients treated with potent antiresorptive osteoporosis therapies or elevated in the setting of fracture healing. In contrast, most etiologies of osteomalacia lead to abnormal findings in one or more of these laboratory values (table 1 and algorithm 1) [41]. Although 25-hydroxyvitamin D (25[OH]D) levels may be low in patients with osteoporosis and some patients may have secondary PTH elevation, very low 25(OH)D levels (eg, <12 to 15 ng/mL [30 to 37.5 nmol/L]) should raise clinical suspicion for osteomalacia as an alternative or coexisting diagnosis. (See 'Laboratory findings' above.)

Reduced BMD does not distinguish osteoporosis from osteomalacia. Patients with osteomalacia due to vitamin D deficiency may have markedly reduced spine, hip, and forearm BMD. (See 'Vitamin D deficiency' below.)

●Paget disease – In patients with Paget disease of bone, alkaline phosphatase is elevated, but bone scintigraphy and radiographic findings are unique. Plain radiographs of involved areas show cortical thickening, expansion, coarsening of trabecular markings and mixed areas of lucency and sclerosis. If plain radiographs do not demonstrate such characteristic findings, bone scintigraphy may be needed to establish the diagnosis, particularly during earlier stages of disease. (See "Clinical manifestations and diagnosis of Paget disease of bone".)

●Multiple myeloma – In patients with multiple myeloma, weakness, fatigue, and bone pain are common. Conventional radiography often reveals lytic lesions, as well as diffuse osteopenia and vertebral fractures. Many patients have anemia and abnormal kidney function at diagnosis, whereas most patients with osteomalacia have normal kidney function. In multiple myeloma, alkaline phosphatase is usually normal, and hypercalcemia may be present. Multiple myeloma can cause Fanconi syndrome/proximal renal tubular acidosis in adults [42] and therefore also may be in the differential etiology for osteomalacia. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

●Primary hyperparathyroidism – In patients with primary hyperparathyroidism, both PTH and calcium are elevated, whereas calcium levels are either low or normal in most causes of osteomalacia. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

TREATMENT — The treatment of osteomalacia depends on the underlying etiology.

Vitamin D deficiency — Patients with osteomalacia due to vitamin D deficiency should receive vitamin D supplementation and achieve adequate calcium intake (table 5). Vitamin D supplementation leads to a dramatic improvement in muscle strength and bone tenderness within weeks, and adequate calcium intake augments these therapeutic effects. Bone mineral density (BMD) typically improves within three to six months of treatment initiation [8].

Such patients should not receive treatment with bisphosphonates, teriparatide, or other osteoporosis medications; treatment with antiresorptive medications may exacerbate hypocalcemia and bone disease.

Vitamin D regimen — For most patients with osteomalacia due to nutritional vitamin D deficiency, we initially treat with vitamin D, rather than its metabolites. Vitamin D is usually sufficient to normalize 25-hydroxyvitamin D (25[OH]D) levels and is less expensive. In patients with abnormal vitamin D metabolism (eg, due to chronic liver or kidney disease), vitamin D metabolites are often required. The treatment of vitamin D deficiency is reviewed in detail separately and briefly summarized here. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Vitamin D replacement'.)

●Low intake or limited sun exposure – For patients with significant vitamin D deficiency (25[OH]D <12 ng/mL [30 nmol/L]), one common approach is to treat with 25,000 to 50,000 international units (625 to 1250 micrograms) of vitamin D2 or D3 orally once per week for six to eight weeks, followed by a maintenance dose (eg, 600 to 800 international units of vitamin D3 daily) thereafter. However, the efficacy of this practice compared with daily, weekly, or monthly dosing has not been rigorously established. Some patients may require 50,000 international units of vitamin D2 or D3 orally two to three times per week for six to eight weeks. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Dosing'.)

●Gastrointestinal malabsorption – In malabsorptive states, oral dosing and duration of treatment depend upon the vitamin D absorptive capacity of the individual patient. Doses of vitamin D of 10,000 to 50,000 international units daily may be necessary to replete patients with significant gastrointestinal malabsorption (eg, due to bariatric surgery, celiac disease, cystic fibrosis). If such doses fail to normalize the vitamin D level, treatment with hydroxylated vitamin D metabolites (calcidiol or calcitriol) may be needed, as these metabolites are more readily absorbed.

●Chronic liver disease – In severe liver disease, the vitamin D metabolite calcidiol (25[OH]D) may be necessary because it does not require hepatic 25-hydroxylation. The onset of action is more rapid and the half-life of two to three weeks is shorter than that of vitamin D3 and similar to that of vitamin D2. A typical initial dose is 20 to 40 micrograms daily, but the dose in severe liver disease may be as high as 50 to 200 micrograms daily [7,43]. Calcidiol is not readily available in the United States, so calcitriol may be used in patients with severe liver disease if vitamin D2 or D3 fails to normalize the 25(OH)D level.

●Chronic kidney disease – In chronic kidney disease, treatment entails replacement of activated 1,25-dihydroxyvitamin D (calcitriol). Both oral and intravenous calcitriol, as well as other vitamin D analogs, can be used. Calcitriol has a rapid onset of action and a short half-life that may require more than once-daily dosing in some patients. Calcitriol increases risk of hypercalcemia, and patients should be followed carefully. It is most useful in adults with decreased calcitriol synthesis, as occurs in chronic kidney disease. Calcitriol treatment in chronic kidney disease is reviewed separately. (See "Management of secondary hyperparathyroidism in adult patients on dialysis" and "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)

Calcium intake — In addition to vitamin D supplementation, all patients with vitamin D deficiency should maintain a calcium intake of 1000 to 1200 mg per day and achieve the recommended intake for their age group (table 5). Inadequate calcium intake may contribute to the development of osteomalacia [44,45], and the combination of calcium and vitamin D is more likely to produce radiographic evidence of recovery than vitamin D alone [44]. In patients with significant gastrointestinal malabsorption, a higher calcium dose (up to 4 g/day) may be necessary. In patients with hypercalciuria and nephrolithiasis, lower doses of calcium supplementation may be appropriate.

Monitoring — Treatment monitoring entails serial measurement of BMD, serum alkaline phosphatase, and serum and urinary calcium levels. Increases in urinary calcium excretion and BMD and a decrease in alkaline phosphatase are evidence of recovery from osteomalacia. Healing of osteomalacia may take many months to a year or longer and varies with the severity and duration of vitamin D deficiency [46].

●BMD – Baseline BMD should be measured by dual-energy x-ray absorptiometry (DXA). BMD values indicate the severity of disease and are monitored during treatment to verify osteoid mineralization. We remeasure BMD one year after treatment initiation. The frequency of subsequent measurements depends on the severity of bone loss and response to vitamin D treatment.

●Serum and urinary calcium – During treatment, 24-hour urinary calcium excretion and serum levels of alkaline phosphatase, parathyroid hormone (PTH), phosphate, and calcium are monitored regularly (eg, one month and three months after treatment initiation and then every 6 to 12 months). Monitoring the serum calcium concentration allows early detection of hypercalcemia from excessive vitamin D dosing. In most cases, serum calcium and phosphate normalize after a few weeks of treatment, but alkaline phosphatase may remain elevated for several months.

●Serum 25(OH)D measurement – Serum 25(OH)D should be measured approximately two to four months after initiating therapy. The dose should be adjusted as needed to normalize serum 25(OH)D while avoiding hypercalciuria or hypercalcemia due to excessive dosing.

Other causes — The management of osteomalacia due to hereditary and acquired renal phosphate wasting syndromes, hypophosphatasia, and Fanconi syndrome/renal tubular acidosis requires treatment of the underlying cause. These are discussed in greater detail elsewhere.

●Renal phosphate wasting

•Hereditary disorders – The treatment of autosomal dominant hypophosphatemia, X-linked hypophosphatemia, and hypophosphatemic rickets with hypercalciuria is reviewed separately. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia".)

•Acquired disorders

-Fanconi syndrome/proximal renal tubular acidosis – Osteomalacia due to Fanconi syndrome/proximal renal tubular acidosis is treated with vitamin D as well as therapies to correct acidosis. If possible, the precipitating exposure (eg, medication, heavy metal) should be removed. (See "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis".)

-Tumor-induced osteomalacia – Definitive treatment for tumor-induced osteomalacia is complete tumor resection, which leads to reversal of the biochemical abnormalities and healing of the bone disease over a period of weeks to months. If complete tumor resection is not possible, medical management with the human anti-fibroblast growth factor 23 (FGF23) monoclonal antibody burosumab is an option. The treatment of tumor-induced osteomalacia is reviewed in detail separately. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Treatment'.)

●Hypophosphatasia

•Enzyme replacement therapy (asfotase alfa)

-Perinatal, infantile, or juvenile onset – Enzyme replacement therapy with asfotase alfa is available for perinatal, infantile, and juvenile-onset hypophosphatasia [47]. (See "Epidemiology and etiology of osteomalacia", section on 'Hypophosphatasia' and "Periodontal disease in children: Associated systemic conditions", section on 'Hypophosphatasia'.)

In a preliminary report, infusion of recombinant human tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP, encoded by the ALPL gene) was associated with improvement in skeletal radiographs and in pulmonary and physical function in infants and young children [48]. In other open-label prospective studies including a total of 99 patients with perinatal, infantile, or juvenile-onset hypophosphatasia, enzyme replacement therapy was associated with improved overall survival, ventilator-free survival, growth, and bone mineralization compared with a historic cohort [47]. A subsequent study examined the effects of asfotase alfa in 69 infants and young children over several years and found early radiographic and clinical improvement in most patients that was sustained up to six years [49].

-Adolescents and adults with infantile or juvenile-onset hypophosphatasia – An open-label trial in 19 adolescents and adults (aged 13 to 66 years) with hypophosphatasia (18 of 19 with infantile or juvenile-onset hypophosphatasia) compared asfotase alfa (0.3 or 0.5 mg/kg/day) with no treatment (control) for six months followed by a 4.5-year extension phase in which all participants received enzyme replacement therapy [50]. Participants who received asfotase alfa during the primary treatment phase exhibited a decrease in mineralization lag time after one year of treatment. In the overall cohort, median distance walked during the six-minute walk test increased between baseline and five years. In a small subset of adult participants (n = 6) with long-term follow-up, improvement in functional disability was lost after discontinuation of enzyme replacement therapy [51].

-Adult-onset hypophosphatasia – Management of adult-onset hypophosphatasia usually entails symptom-directed interventions to treat pain, dental manifestations, and/or fractures. Asfotase alfa is less well studied in adult-onset hypophosphatasia. Although adults with a history of childhood-onset hypophosphatasia have been included in studies of asfotase alpha, very few adults reporting adult age of symptom onset have been included in these studies.

•Osteoporosis medications (avoid use) – In individuals with hypophosphatasia, antiresorptive therapies should be avoided [52]. Anabolic osteoporosis therapies have been studied in very few patients [53-55]. A primary challenge to this strategy is that antiresorptive therapy is typically required after anabolic agents are discontinued to prevent bone loss; however, in individuals with hypophosphatasia, antiresorptive therapy is contraindicated.

●Bone matrix disorders – For patients with rare skeletal disorders of defective bone matrix (axial osteomalacia and fibrogenesis imperfecta), no established therapies exist, although a report of two brothers with fibrogenesis imperfecta reported clinical, radiographic, and histologic improvement following treatment with recombinant human growth hormone [56]. Axial osteomalacia does not appear to progress over time. In contrast, patients with fibrogenesis imperfecta develop severe skeletal pain, debilitating fractures, and progressive immobility [15]. (See "Epidemiology and etiology of osteomalacia", section on 'Defective bone matrix'.)

PREGNANCY — Severe vitamin D deficiency can result in osteomalacia during pregnancy [57-59]. Risk factors for osteomalacia during pregnancy include limited sun exposure due to protective clothing, malabsorption (eg, celiac disease, cystic fibrosis, gastric bypass surgery), and malnutrition.

●Clinical manifestations – Pregnant women with osteomalacia have similar symptoms as nonpregnant adults. They may present with persistent and nonspecific musculoskeletal pain and inability to bear weight. In some case reports, women presenting with fractures in pregnancy were found to have severe osteomalacia [59,60]. Severe osteomalacia has been associated with cephalopelvic disproportion, necessitating cesarean delivery [60]. (See 'Clinical findings' above.)

●Laboratory evaluation – Biochemical findings are similar to those in nonpregnant adults, but results should be interpreted in the context of expected changes in calcium metabolism during normal pregnancy; these include lower total serum calcium, elevated 1,25-dihydroxyvitamin D (particularly in the third trimester), and lower parathyroid hormone (PTH) levels [61].

●Treatment – Pregnant individuals with osteomalacia should receive adequate calcium (approximately 1000 to 1500 mg daily) and vitamin D. We typically start with 2000 to 4000 international units of vitamin D2 or D3 daily. We measure 24-hour urinary calcium and serum levels of 25-hydroxyvitamin D (25[OH]D) and calcium one month and three months after treatment initiation, then less frequently until 24-hour urinary calcium excretion is normal. If the initial vitamin D dose does not normalize serum 25(OH)D after three to four months, the dose can be increased by 1000 to 2000 international units/day, with continued monitoring of urinary calcium and serum 25(OH)D and calcium. Monitoring the serum calcium concentration allows early detection of hypercalcemia from excessive vitamin D dosing. The dose of vitamin D should be decreased as needed to prevent hypercalciuria or hypercalcemia.

In case reports, pregnant females with severe osteomalacia (diagnosed at the time of delivery) were successfully treated with high-dose vitamin D (600,000 international units intramuscularly as a single dose, after delivery) and calcium supplementation (up to 1.5 g daily) [59,60]. The administration of such high doses of vitamin D during pregnancy has not been adequately studied. In case series from the 1960s, pregnant females with osteomalacia were safely treated with calcium and vitamin D 3000 to 6000 international units daily [62]. Subsequent trials have evaluated vitamin D dosing in pregnant females with vitamin D deficiency, but no participants had vitamin D deficiency of sufficient severity and duration to cause osteomalacia [63,64]. These trials are reviewed in detail separately. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Pregnancy'.)

SUMMARY AND RECOMMENDATIONS

●Clinical features – Clinical manifestations of osteomalacia include bone pain and tenderness, muscle weakness, difficulty walking, and a waddling gait. Laboratory findings depend on the underlying etiology. Radiographic evidence of reduced bone mineral density (BMD) with thinning of the cortex is the most common imaging finding but is very nonspecific. (See 'Clinical features' above.)

●Whom to evaluate – Osteomalacia should be suspected in any adult with bone pain and tenderness, particularly in association with risk factors such as gastrointestinal malabsorption, chronic liver disease, or chronic kidney disease. (See 'Whom to evaluate' above.)

●Diagnostic and etiologic evaluation – The diagnosis is based upon a combination of clinical features, laboratory results, and radiographic findings.

•Clinical history – Clinical history should include characteristic symptoms (bone pain and tenderness, muscle weakness), prior fracture(s), and potential risk factors for specific etiologies. (See 'Clinical history and physical examination' above.)

•Skeletal imaging – We obtain plain radiographs of the spine and other skeletal regions based on localized signs and symptoms (eg, areas of pain, tenderness, or deformity). Radiographic findings of hallmark vertebral body changes or Looser zones are consistent with osteomalacia and help confirm the diagnosis. BMD measurement is not required for the diagnosis of osteomalacia, and reduced BMD does not distinguish osteoporosis from osteomalacia. (See 'Skeletal imaging for suspected osteomalacia' above.)

•Laboratory tests – Laboratory findings are used to both confirm the diagnosis of osteomalacia and to determine the underlying etiology (table 1 and algorithm 1). Initial laboratory evaluation should include measurement of serum concentrations of calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D (25[OH]D), parathyroid hormone (PTH), electrolytes, blood urea nitrogen (BUN), and creatinine. (See 'Laboratory tests' above.)

In osteomalacia due to vitamin D deficiency, 25(OH)D is typically very low (<12 to 15 ng/mL [30 to 37.5 nmol/L]). Other biochemical findings of osteomalacia due to vitamin D deficiency include low to low-normal calcium and phosphate levels, elevated PTH, and elevated alkaline phosphatase (both total and bone specific). (See 'Severe vitamin D deficiency' above.)

●Treatment – Treatment of osteomalacia depends on the underlying etiology.

•Vitamin D deficiency

-Treatment – Many clinicians treat nutritional deficiency (25[OH]D <12 ng/mL [30 nmol/L]) with 25,000 to 50,000 international units (625 to 1250 micrograms) of vitamin D2 or D3 orally once per week for six to eight weeks, followed by a maintenance dose (eg, 600 to 800 international units of vitamin D3 daily) thereafter. Higher doses may be needed in the setting of gastrointestinal malabsorption. In addition to vitamin D supplementation, all patients with vitamin D deficiency should maintain a calcium intake of 1000 to 1200 mg per day and achieve the recommended intake for their age group (table 5). (See 'Vitamin D deficiency' above and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Dosing'.)

In patients with osteomalacia due to severe vitamin D deficiency, vitamin D repletion can lead to a dramatic improvement in muscle strength and bone tenderness within weeks.

-Monitoring – After treatment initiation, serum levels of alkaline phosphatase, PTH, and calcium and urinary calcium excretion should be monitored (eg, initially after one month and three months, and then less frequently [every 6 to 12 months]). Serum 25(OH)D should be measured approximately two to four months after initiating therapy. The vitamin D dose should be adjusted as needed to normalize serum 25(OH)D while avoiding hypercalciuria or hypercalcemia. Laboratory and radiographic abnormalities may take up to one year or longer to resolve. (See 'Vitamin D deficiency' above.)

•Other causes – Specific treatments for rarer causes of osteomalacia are described briefly above and in more detail elsewhere. (See 'Other causes' above.)