INTRODUCTION — Osteomalacia is a disorder of bone, characterized by decreased mineralization of newly formed osteoid at sites of bone turnover. Several different disorders cause osteomalacia via mechanisms that result in hypocalcemia, hypophosphatemia, or direct inhibition of the mineralization process. (See "Epidemiology and etiology of osteomalacia".)
This topic review will present an overview of the clinical manifestations, diagnosis, and treatment of adults with osteomalacia. The treatment of nutritional, hereditary vitamin D-resistant, and pseudovitamin D-deficient rickets in children is discussed separately. (See "Etiology and treatment of calcipenic rickets in children" and "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia".)
CLINICAL FEATURES
Clinical manifestations — Osteomalacia may be asymptomatic and present radiologically as osteopenia. It can also produce characteristic symptoms, independently of the underlying cause, including diffuse bone and joint pain, muscle weakness, and difficulty walking [1-3]. In a report of 17 patients with osteomalacia on bone biopsy, the following findings were observed [4]:
●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)
These symptoms may be insidious in onset. Bone pain is usually most pronounced in the lower spine, pelvis, and lower extremities, as well as where fractures have taken place, and may be associated with tenderness to palpation. The pain is characterized as dull and aching and is aggravated by activity and weight bearing. Fractures may occur with little or no trauma, typically involving the ribs, vertebrae, and long bones. Abnormal spinal curvature or deformity of the thorax or pelvis appears only in severe osteomalacia of long duration [1].
The muscle weakness characteristically is proximal and may be associated with muscle wasting, hypotonia, and discomfort with movement [1]. There may also be a waddling gait. It is likely that high levels of parathyroid hormone (PTH) and low levels of phosphate and calcitriol all contribute to the myopathy since similar findings occur in severe primary hyperparathyroidism.
Osteomalacia secondary to hypophosphatasia, caused by mutations in the ALPL gene, is associated with poorly healing metatarsal or other fractures, chondrocalcinosis, and premature loss of teeth during childhood and adulthood [5].
Laboratory findings — Laboratory abnormalities in osteomalacia are largely dependent upon the cause of the osteomalacia (table 1). (See "Epidemiology and etiology of osteomalacia", section on 'Etiologic diagnosis'.)
In retrospective reviews of patients with biopsy-proven nutritional osteomalacia, the following laboratory abnormalities were observed [4,6]:
●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 in 100 percent
●PTH elevated in 100 percent
The majority of patients (40 of 43) in these reviews had nutritional osteomalacia from either a gastrointestinal disorder or suboptimal nutrition and inadequate sun exposure. In these cases, 25(OH)D levels were very low (<10 ng/mL [25 nmol/L]), which differentiates vitamin D deficiency from the other causes of osteomalacia, such as the renal phosphate wasting syndromes.
Radiographic findings — The radiological abnormalities in adults who develop osteomalacia are less striking than those seen in children with rickets (see "Overview of rickets in children"). Reduced bone mineral density (BMD) with thinning of the cortex is the most common finding, but it is very nonspecific. More specific are changes in vertebral bodies and Looser zones. Infrequently, radiologic evidence of secondary hyperparathyroidism can be seen.
Changes in vertebral bodies — 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. There may be spinal compression fractures, but these are more common in osteoporosis.
Looser zones — Looser pseudofractures, fissures, or narrow radiolucent lines, 2 to 5 mm in width with sclerotic borders, are a characteristic radiologic finding in osteomalacia (image 3) [7]. They often are bilateral, symmetric, and lie perpendicular to the cortical margins of bones. They are most commonly found at the femoral neck, on the medial part of the femoral shaft, immediately under the lesser trochanter or a few centimeters beneath, and in the pubic and ischial rami. They may also occur at the ulna, scapula, clavicle, rib, and metatarsal bones. Pseudofractures can also be seen with bone scans (skeletal scintography) where they appear as hot spots (ie, focal areas of increased radiotracer activity) [8]. The term "Milkman syndrome" refers to the combination of multiple bilateral and symmetric pseudofractures in a patient with osteomalacia [9].
Looser zones (pseudofractures) have been postulated to represent either [10,11]:
●Stress fractures that have been repaired by the laying down of inadequately mineralized osteoid, or
●Erosion of bone by arterial pulsations, since they often lie in apposition to arteries
Secondary hyperparathyroidism — Skeletal changes induced by longstanding secondary hyperparathyroidism (eg, related to severe vitamin D deficiency) are less frequent than the above abnormalities. When they do occur, they 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'.)
Other radiograph findings — 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).
Bone mineral density — Several studies have demonstrated markedly reduced spine, hip, and forearm BMD (as measured by dual-energy x-ray absorptiometry [DXA]) in patients with osteomalacia related to vitamin D deficiency [4,6]. However, BMD measurement is not required for the diagnosis of osteomalacia, and BMD (DXA) findings are unable to differentiate osteomalacia and osteoporosis.
In contrast, BMD tends to be normal or increased (especially at the lumbar spine) in adults with X-linked hypophosphatemic rickets (XLH), axial osteomalacia, fibrogenesis imperfecta, and skeletal fluorosis [12-14]. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'X-linked hypophosphatemia' and "Epidemiology and etiology of osteomalacia", section on 'Defective bone matrix'.)
Histomorphometric findings — Bone biopsy using double tetracycline labeling is infrequently performed in clinical practice, but it may be indicated to assess for one of the rare disorders of defective bone matrix. (See 'Diagnosis' below and 'Evaluation' below.)
The histomorphometric characteristics of osteomalacia include (picture 1) [15,16]:
●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 turnover, for example, can be seen with hyperthyroidism, Paget disease, and hyperparathyroidism. However, the mineral apposition rate is elevated in these disorders in contrast to the low values in osteomalacia. (See "Epidemiology and etiology of osteomalacia", section on 'Pathogenesis'.)
DIAGNOSIS — Osteomalacia may be difficult to diagnosis. It should be suspected in cases of bone pain associated with gastrointestinal (GI) malabsorption, chronic hepatic disease, or chronic kidney disease. Transiliac crest bone biopsy with double tetracycline labeling and histomorphometric assessment is the most accurate way to diagnose osteomalacia, and it is often considered the gold standard for research purposes. However, it is infrequently performed clinically because it is invasive and because the diagnosis can usually be made from a combination of clinical (eg, bone pain and tenderness, fractures, and/or muscle weakness); laboratory findings, which depend on the cause (table 1); and radiologic findings. (See 'Evaluation' below.)
A delay in diagnosis of osteomalacia is commonly reported [4,17,18]. 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, malignancy, pseudohypoparathyroidism, osteoarthritis, malabsorption, irritable bowel syndrome with depression, fibromyalgia, and somatization disorders.
EVALUATION — Laboratory findings are used to diagnose and determine the etiology of osteomalacia (table 1). The initial laboratory evaluation should include measurement of serum concentrations of:
●Calcium
●Phosphate
●Alkaline phosphatase
●25-hydroxyvitramin D (25[OH]D)
●Parathyroid hormone (PTH)
●Electrolytes, blood urea nitrogen (BUN), and creatinine
The majority of patients have nutritional osteomalacia and will have a very low serum 25(OH)D (<10 ng/mL [25 nmol/L]), low to low-normal serum calcium and phosphate, and high PTH and alkaline phosphatase (both total and bone-specific) levels.
Clinical evaluation, including history of gastrointestinal diseases or surgical procedures, sun exposure, dietary habits, and onset (insidious or acute) and duration of symptoms, may help determine the etiology of osteomalacia. Indices of renal tubular phosphate handling and assessment of serum fibroblast growth factor (FGF) 23 levels may assist in the evaluation of etiologies of hypophosphatemia. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia".)
Radiographs may be helpful in certain settings (eg, severe bone pain) to distinguish osteomalacia from conditions such as multiple myeloma or Paget disease of bone. Bone biopsy and histomorphometry should be performed only when the diagnosis of osteomalacia is in doubt or the cause of osteomalacia is not determined by noninvasive testing (eg, 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'.)
Interpretation of laboratory abnormalities — The goal of the laboratory evaluation is to distinguish vitamin D deficiency or resistance from the phosphate wasting syndromes and other less common causes of osteomalacia (table 1):
●In nutritional osteomalacia, 25(OH)D (calcidiol) is typically very low (<10 ng/mL [25 nmol/L]), calcium and phosphate are low to low-normal, and PTH and alkaline phosphatase levels are high [1]. 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 [19].
●In primary renal phosphate wasting, serum phosphate is low and phosphate clearance is elevated. Serum 1,25-dihydroxyvitamin D levels are frequently inappropriately normal for the degree of hypophosphatemia (1,25-dihydroxyvitamin D should increase in response to severe hypophosphatemia). Serum calcium and 25(OH)D levels are normal, PTH level is normal or mildly elevated, and serum alkaline phosphatase is often high. Patients may also have other tubular defects (hypouricemia, aminoaciduria, and glucosuria) if the phosphate wasting is part of a generalized Fanconi syndrome. Heavy metals in the urine may be increased if they are the cause of the Fanconi syndrome. Tumor-induced osteomalacia and hereditary hypophosphatemic rickets are associated with elevations in serum FGF23 levels [20-22]. (See "Hypophosphatemia: Causes of hypophosphatemia" and "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia".)
●Type 2 (proximal) renal tubular acidosis is characterized by hyperchloremic metabolic acidosis and hypophosphatemia. The latter reflects both proximal renal tubule phosphate wasting and secondary hyperparathyroidism due to acidosis-induced hypercalciuria. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA'.)
●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 plasma PLP is a marker of hypophosphatasia. The condition can be confirmed by genetic testing of the ALPL gene, but mutations do not clearly correlate with disease severity in this condition that is characterized by marked variability in clinical expression [23,24]. (See "Epidemiology and etiology of osteomalacia", section on 'Hypophosphatasia'.)
●In fibrogenesis imperfecta and axial osteomalacia, alkaline phosphatase, calcium, phosphate, and vitamin D are usually normal. (See "Epidemiology and etiology of osteomalacia", section on 'Defective bone matrix'.)
●In skeletal fluorosis, serum calcium and phosphate are usually normal and alkaline phosphate is elevated. Serum, urine, and bone fluoride content is increased [14].
DIFFERENTIAL DIAGNOSIS — Other causes of bone fractures, bone pain, and reduced bone mineral density (BMD) include osteoporosis, malignancy, Paget disease, 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 [25].
●Osteoporosis occurs in different settings from osteomalacia, particularly postmenopausal women, older adult subjects, and patients treated with chronic corticosteroid therapy. (See "Osteoporotic fracture risk assessment" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women".)
Osteoporosis is characterized by normal serum levels of calcium, phosphate, and alkaline phosphatase; alkaline phosphatase levels can be low in patients treated with potent antiresorptive osteoporosis therapies. This is in contrast to the frequent findings of one or more of the following in the different causes of osteomalacia: hypophosphatemia, hypocalcemia, low levels of 25-hydroxyvitamin D (25[OH]D) (<10 ng/mL [25 nmol/L]), and increased parathyroid hormone (PTH) and alkaline phosphatase levels (table 1) [26]. Although 25(OH)D levels may be low in patients with osteoporosis and a subset of these patients may also have secondary elevations of PTH, 25(OH)D levels rarely are below 10 ng/mL (25 nmol/L). (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. In such patients, treatment with bisphosphonates, teriparatide, or other osteoporosis medications is not appropriate; treatment with antiresorptive medications may exacerbate hypocalcemia. Osteomalacia related to vitamin D deficiency should be treated with vitamin D and calcium, which often results in marked improvement in BMD. (See 'Vitamin D deficiency' below.)
●In patients with Paget disease of bone, alkaline phosphatase is elevated, but bone scan and radiographic findings are unique. Plain radiographs of involved areas reveal cortical thickening, expansion, coarsening of trabecular markings and mixed areas of lucency and sclerosis. (See "Clinical manifestations and diagnosis of Paget disease of bone".)
●In patients with multiple myeloma, weakness, fatigue, and bone pain are common. Conventional radiographs often reveal lytic lesions, as well as diffuse osteopenia and vertebral fractures. Many patients have anemia and abnormal renal function at diagnosis, whereas patients with osteomalacia generally have normal renal function. Alkaline phosphatase is not usually elevated in multiple myeloma, and hypercalcemia may be present in some patients. Multiple myeloma is a common cause of type 2 renal tubular acidosis in adults [27]. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)
●In patients with hyperparathyroidism, both PTH and calcium are elevated, whereas calcium levels are either low or normal in most forms of osteomalacia. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)
TREATMENT — The treatment of osteomalacia should be directed at reversal of the underlying disorder, if possible, and correction of hypophosphatemia, hypocalcemia, and vitamin D deficiency.
Vitamin D deficiency — Vitamin D supplementation in patients who are deficient in this hormone leads to a dramatic improvement in muscle strength and bone tenderness within weeks. Effects are typically most dramatic when adequate calcium intake occurs simultaneously. Bone mineral density (BMD) may improve within three to six months [6]. Multiple preparations of vitamin D and its metabolites are available. Vitamin D, rather than its metabolites, is used when possible since the cost is modest. Vitamin D metabolites are required when there is abnormal vitamin D metabolism (significant liver or renal disease). The recommended preparation and dose vary with the clinical condition, as described below.
With each regimen, the serum calcium concentration and urinary calcium excretion are monitored (eg, initially after one month and three months, and then less frequently [every 6 to 12 months]), until 24-hour urinary calcium excretion is normal. The serum calcium concentration is monitored to permit early detection of hypercalcemia from excessive dosing. Serum 25-hydroxyvitamin D (25[OH]D) should be measured approximately three to four months after initiating therapy. The dose should be adjusted to prevent hypercalciuria or hypercalcemia. In most cases, serum calcium and phosphate are normal after a few weeks of treatment, but alkaline phosphatase remains elevated for several months. Healing of osteomalacia is considered to have occurred when there are increases in urinary calcium excretion and BMD. Healing of nutritional osteomalacia may take many months to a year or more and varies with the degree and duration of the deficiency [28].
In addition to vitamin D supplementation, all patients should maintain a calcium intake of at least 1000 mg per day since inadequate intake of calcium may contribute to the development of osteomalacia [29,30]. The combination of calcium and vitamin D is more likely to produce radiographic evidence of nearly complete healing of rickets (58 versus 19 percent in Nigerian children with nutritional rickets) [29]. A higher calcium dose (up to 4 g/day) may be necessary in patients with significant gastrointestinal (GI) malabsorption.
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'.)
●For patients with severe vitamin D deficiency (25[OH]D <12 ng/mL [30 nmol/L]), one common approach is to treat with 50,000 international units of vitamin D2 or D3 orally once per week for six to eight weeks, and then 800 to 1000 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 to treat deficiency.
●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 GI malabsorption (eg, postsurgical or related to conditions such as cystic fibrosis). Patients who remain deficient or insufficient on such doses will need to be treated with hydroxylated vitamin D metabolites (calcidiol or calcitriol), which are more readily absorbed.
●In liver disease, the vitamin D metabolite calcidiol (25[OH]D) should be used 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. Although a typical initial dose is 20 to 40 micrograms per day, the dose in severe liver disease may be as high as 50 to 200 micrograms/day [4,31]. Calcidiol is not readily available in the United States, so calcitriol may be used in patients with severe liver disease who remain deficient after treatment with vitamin D2 or vitamin D3.
●Calcitriol (1,25-dihydroxyvitamin D) is a vitamin D metabolite available in capsules of 0.25 and 0.5 micrograms. It has a rapid onset of action and the half-life is only six hours. It is associated with a risk of hypercalcemia, and patients should be followed carefully. It is most useful in those with decreased synthesis of calcitriol, as occurs in chronic renal failure or in type 1 vitamin D-dependent rickets (due to an inactivating mutation in the 1-hydroxylase gene). (See "Etiology and treatment of calcipenic rickets in children", section on '1-alpha-hydroxylase deficiency'.)
Other causes — The treatment of hereditary and acquired renal phosphate wasting syndromes, renal osteodystrophy, and renal tubular acidosis are discussed in greater detail elsewhere:
●Hereditary hypophosphatemic rickets can be treated with burosumab (a human anti-FGF23 monoclonal antibody) or phosphate supplementation and calcitriol. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Treatment with burosumab' and "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Treatment'.)
●Definitive treatment for tumor-induced osteomalacia is complete tumor resection, which leads to prompt reversal of the biochemical abnormalities and healing of the bone disease over a period of weeks to months. Two small open label studies of burosumab in adults with tumor-induced osteomalacia have documented clinical improvements and a favorable safety profile [32,33], suggesting that this therapy may be useful for patients with unresectable tumors.
●In renal insufficiency, both oral and intravenous calcitriol, as well as other vitamin D analogs, can be used. (See "Management of secondary hyperparathyroidism in adult dialysis patients" and "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)
●Osteomalacia of renal tubular acidosis is treated with vitamin D as well as therapies to correct acidosis. (See "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis".)
●For hypophosphatasia, there have been few treatment options [34,35]. Enzyme replacement therapy (asfotase alfa) for perinatal, infantile, and juvenile-onset hypophosphatasia became available in October 2015 [36]. In a preliminary report, infusion of recombinant human tissue-nonspecific isoenzyme of alkaline phosphatase was associated with improvement in skeletal radiographs and in pulmonary and physical function in infants and young children [37]. 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 [36]. 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 sustained up to six years [38,39].
The efficacy and safety of asfotase alfa has also been evaluated in a small randomized trial (followed by a 4.5-year open-label treatment extension phase) in adolescents and adults with pediatric onset hypophosphatasia [39]. Treatment with asfotase alpha was associated with a significant reduction in pyridoxal 5'-phosphate (PLP) levels and improved functional abilities [39]. (See "Epidemiology and etiology of osteomalacia", section on 'Hypophosphatasia' and "Periodontal disease in children: Associated systemic conditions", section on 'Hypophosphatasia'.)
●For patients with the rare skeletal disorder of defective bone matrix (axial osteomalacia and fibrogenesis imperfecta), there are no established therapies, although a report of two brothers with fibrogenesis imperfecta reported clinical, radiographic, and histologic improvement following treatment with recombinant human growth hormone [40]. Patients with axial osteomalacia do not appear to deteriorate over time. In contrast, patients with fibrogenesis imperfecta develop severe skeletal pain, debilitating fractures, and progressive immobility [13]. (See "Epidemiology and etiology of osteomalacia", section on 'Defective bone matrix'.)
PREGNANCY — Severe vitamin D deficiency can result in osteomalacia during pregnancy [41-43]. 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. Pregnant women with osteomalacia have similar symptoms as nonpregnant adults (see 'Clinical manifestations' above). They may present with persistent and nonspecific musculoskeletal pain and inability to bear weight. Evaluation reveals similar biochemical findings as in nonpregnant adults, but results should be interpreted in the context of expected changes in calcium metabolism during normal pregnancy, including lower total serum calcium, elevated 1,25(OH)2 vitamin D, and suppressed parathyroid hormone (PTH) levels [44]. In some case reports, women presenting with fractures in pregnancy were found to have severe osteomalacia [43,45]. Severe osteomalacia has been associated with cephalopelvic disproportion, necessitating cesarean delivery [45].
In case reports, pregnant women 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) [43,45]. The administration during pregnancy of such a high dose of vitamin D has not been adequately studied. In case series from the 1960s, pregnant women with osteomalacia were safely treated with calcium and 3000 to 6000 international units of vitamin D daily [46]. There are modern day trials evaluating vitamin D dosing in pregnant women with vitamin D deficiency, some of whom had secondary elevations in serum PTH, but none of whom had vitamin D deficiency of sufficient severity and duration to cause osteomalacia [47,48]. In these trials, vitamin D supplementation at 12 to 27 weeks gestation with 400, 800, 2000, or 4000 international units D3 daily or 200,000 international units as a single oral dose was safe and successfully increased serum vitamin D concentrations. These trials are reviewed in detail separately. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Pregnancy'.)
Women who are diagnosed with osteomalacia during pregnancy should receive adequate calcium (approximately 1000 to 1500 mg daily) and vitamin D. We typically start with 2000 to 4000 international units daily and measure the serum 25-hydroxyvitamin D (25[OH]D) and calcium and urinary calcium excretion after one month and three months, then less frequently (every 6 to 12 months), until 24-hour urinary calcium excretion is normal. If the initial dose does not improve serum 25(OH)D after three to four months, the dose of vitamin D can be increased by 1000 to 2000 international units/day, with continued monitoring of serum vitamin D and calcium and urinary calcium. The serum calcium concentration is monitored to permit early detection of hypercalcemia from excessive dosing. The dose of vitamin D should be decreased, as needed, to prevent hypercalciuria or hypercalcemia.
SUMMARY AND RECOMMENDATIONS
●Clinical features – The clinical manifestations of osteomalacia may include bone pain and tenderness, muscle weakness, difficulty walking, and a waddling gait. Laboratory findings depend upon the underlying cause of osteomalacia (table 1). Typical laboratory features of nutritional osteomalacia include elevations in alkaline phosphatase and parathyroid hormone (PTH) and decreases in calcium, phosphate, and 25-hydroxyvitamin D (25[OH]D) concentrations. (See 'Clinical manifestations' above and 'Laboratory findings' above.)
●Radiographic findings – The characteristic radiologic findings are Looser pseudofractures, fissures, or narrow radiolucent lines. In addition, inadequate mineralization of osteoid and loss of secondary trabeculae lead to a loss of radiologic distinctness of the vertebral body trabeculae and concavity of the vertebral bodies (codfish vertebrae). Bone mineral density (BMD) is not required for the diagnosis of osteomalacia, and reduced BMD does not distinguish osteoporosis from osteomalacia. However, several studies have demonstrated markedly reduced spine, hip, and forearm BMD (as measured by dual-energy x-ray absorptiometry [DXA]) in patients with osteomalacia related to vitamin D deficiency. (See 'Radiographic findings' above.)
●Diagnosis – Osteomalacia should be suspected in cases of bone pain associated with malabsorption, chronic hepatic disease, or chronic kidney disease. The diagnosis is based upon a combination of clinical features (bone pain, tenderness, and fractures; muscle weakness), laboratory results (table 1), radiologic findings, and, rarely, histomorphometric analysis of transiliac crest bone biopsy sample obtained after double tetracycline labeling. (See 'Diagnosis' above.)
●Evaluation – Laboratory abnormalities (table 1) are used to diagnose and determine the etiology of osteomalacia. Initial laboratory evaluation should include measurement of serum concentrations of calcium, phosphate, alkaline phosphatase, 25(OH)D, PTH, electrolytes, blood urea nitrogen (BUN), and creatinine. Radiographs may be helpful in certain settings (severe bone pain), to distinguish osteomalacia from multiple myeloma or Paget disease of bone. Bone biopsy and histomorphometry should be performed only when the diagnosis of osteomalacia is in doubt or the cause of osteomalacia is not determined with noninvasive testing, eg, to assess for one of the rare disorders of defective bone matrix. (See 'Evaluation' above.)
●Treatment – Treatment of osteomalacia depends upon the underlying etiology.
•Vitamin D deficiency – For patients with osteomalacia secondary to severe vitamin D deficiency, vitamin D repletion leads to a dramatic improvement in muscle strength and bone tenderness within weeks. Many clinicians treat nutritional deficiency (25[OH]D <12 ng/mL [30 nmol/L]) with 50,000 international units of vitamin D2 or D3 orally once per week for six to eight weeks, followed by a maintenance dose (eg, 800 international units of vitamin D3 daily) thereafter. (See 'Vitamin D deficiency' above and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Dosing'.)
•Other causes – Specific treatments aimed at more rare causes of osteomalacia are described briefly above and in more detail elsewhere. (See 'Other causes' above and "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Treatment with burosumab'.)
●Monitoring – After initiation of vitamin D treatment, serum alkaline phosphate, PTH, and calcium levels and urinary calcium excretion should be monitored (eg, initially after one month and three months, and then less frequently [every 6 to 12 months]). The serum calcium concentration is monitored to permit early detection of hypercalcemia from excessive dosing. Serum 25(OH)D should be measured approximately three to four months after initiating therapy. The dose should be adjusted to prevent adverse effects of hypercalciuria or hypercalcemia. Biological and radiological abnormalities may take up to one year or more to disappear. (See 'Vitamin D deficiency' above.)
