Osteomalacia

Etiology

Osteomalacia is a metabolic bone disease characterized by impaired mineralization of bone matrix.[4] Bone creation occurs by the deposition of hydroxyapatite crystals on the osteoid matrix. Details of the most common and sometimes overlooked causes are as follows:

Decreased Vitamin D Production

• Cold weather climates reduce skin sunlight exposure and cutaneous synthesis.
• Dark skin and relatively increased melanin compete with 7-dehydrocholesterol ultraviolet-B light absorption.
• Obesity can lead to increased adipose sequestration, which results in less calcidiol substrate available for activation.
• Vitamin D production decreases in older individuals, and the storage of vitamin D declines with age.

Decreased Vitamin D Absorption

• Nutritional deficiency can cause vitamin D deficiency even with adequate sunlight exposure.
• Malabsorptive syndromes such as Crohn disease, cystic fibrosis, celiac disease, cholestasis, and surgical alteration of the gastrointestinal tract, such as gastric bypass, are associated with deficient absorption of fat-soluble vitamins A, D, E, and K.

Altered Vitamin D Metabolism

• Chronic kidney disease leads to structural damage, loss of 1-alpha-hydroxylase, and suppressed enzymatic activity secondary to hyperphosphatemia.
• Nephrotic syndrome leads to pathologic excretion of vitamin D-binding protein, which binds to serum calcidiol.
• Liver disease, including cirrhosis and metabolic dysfunction-associated steatotic liver disease, leads to deficient production of calcidiol.
• Pregnancy is associated with decreased calcidiol levels, and the American College of Obstetricians and Gynecologists recommends treating with at least 1000 to 2000 international units daily when vitamin D deficiency is identified.

Hypophosphatemia or Hypocalcemia

• Renal tubular acidosis, such as in Fanconi syndrome, alters ion absorption and excretion.
• Multiple intravenous iron infusions have been found to cause hypophosphatemia and osteomalacia.[5]
• Tumor-induced osteomalacia, also known as oncogenic osteomalacia, is a rare acquired paraneoplastic disease characterized by hypophosphatemia, elevated or inappropriately normal levels of fibroblast growth factor 23, and renal phosphate wasting.[6][7][8][9]
  •  Tumor-induced osteomalacia is commonly caused by benign tumors involving the skin, muscles, bones of the extremities, or the paranasal sinuses.[10]

Medications

• Antiepileptic drugs, including phenobarbital, phenytoin, and carbamazepine, enhance the catabolism of calcidiol via induction of cytochrome P450 activity.[11]
• Isoniazid, rifampicin, and theophylline may also precipitate vitamin D deficiency in the same manner as antiepileptic medications. 
• Antifungal agents such as ketoconazole increase vitamin D requirements by inhibiting 1-alpha-hydroxylase.
• Long-term corticosteroid use also has implications for vitamin D deficiency, possibly by increasing 24-hydroxylase activity.[12][13][14][15]

Epidemiology

The prevalence of postmortem histological osteomalacia histologically is as high as 25% in adult Europeans have been reported. However, the true global incidence of osteomalacia remains vastly underestimated.[11] At-risk individuals include those with dark skin, limited sun exposure, low socioeconomic status, poor diet, and frequent wearers of full-body clothing. These risks vary worldwide and are contingent on geographic location, cultural preferences, and ethnicity. Healthcare professionals should take these factors, as well as other relevant clinical findings, into account when choosing to obtain further studies or recommending vitamin D supplementation.[16][17]

Pathophysiology

Reviewing vitamin D metabolism to understand the pathologic processes that result in vitamin D deficiency and its subsequent manifestations is essential (see Image. Vitamin D Metabolism). The synthesis of active vitamin D (calcitriol) organically begins in the skin, where cholecalciferol (vitamin D3) is formed by the action of ultraviolet B radiation in epidermal keratinocytes and dermal fibroblasts converting 7-dehydrocholesterol (provitamin D3) to pre-vitamin D, which spontaneously isomerizes to form cholecalciferol.

Subsequently, cholecalciferol is transported to the liver, where it is converted to calcidiol, 25-hydroxyvitamin D (25[OH]D), by 25-hydroxylase. Therefore, patients with chronic liver disease would have a higher risk of developing vitamin D deficiency. This particular form of vitamin D is partially water-soluble and has a short half-life. The vitamin 25(OH)D is also the best indicator of overall vitamin D status because this measurement accurately reflects total vitamin D levels from dietary intake, natural sunlight exposure, and converted adipose stores in the liver. The estimate is that approximately 40% to 50% of circulating 25(OH)D derives from skin conversion.[18]

Enzymatic conversion to calcitriol, 1,25(OH)D, occurs in the kidneys by 1-alpha-hydroxylase. Similarly, chronic renal disease, among other renal pathologies, can cause vitamin D deficiency, which is why secondary and, eventually, tertiary hyperparathyroidism can develop with long-term renal failure. The activity of 1-alpha-hydroxylase is strictly regulated. 

As with any synthetic biologic process, feedback loops exist to regulate calcitriol production and include the following:

• Positive feedback by PTH
• Positive feedback by decreased serum phosphate levels
• Negative feedback by fibroblast growth factor 23, secreted by osteocytes in the bone matrix, ultimately inhibits renal phosphate absorption.[8][6]
• Negative feedback by calcitriol inhibition of 1-alpha-hydroxylase, which in turn decreases calcitriol synthesis and also stimulates 24-hydroxylase activity; 24-hydroxylase effectively removes circulating calcitriol by converting it to biologically inactive 24,25-dihydroxy vitamin D 24,25(OH)D.[19]

History and Physical

When evaluating for osteomalacia, the comprehensive medical history should include a review of the patient's family and surgical history. Other pertinent questions should focus on activity level, hobbies, dietary restrictions, and an assessment of socioeconomic status. Patients with osteomalacia typically experience symptoms such as diffuse bone pain, particularly in the lower back, pelvis, hips, and legs, aggravated by activity and weight-bearing. They may also have muscle weakness, leading to difficulty walking or climbing stairs and increased falls. Myalgias, arthralgias, fatigue, and general malaise are common, and in severe cases, patients may experience fractures or bone deformities with minimal trauma. These symptoms often progress gradually, making early diagnosis challenging.

Physical signs in patients with osteomalacia are nonspecific and may include the following:

• Proximal muscle weakness and wasting
• Diffuse bone tenderness, particularly in weight-bearing areas such as the lower back, pelvis, hips, and legs
• Muscle spasms
• Altered or "waddling" gait
• Bowed legs (genu varum)
• Spinal, lower extremities, or pelvic deformities (in long-term osteomalacia)
• Fractures or pseudofractures (Looser zones) with minimal trauma
• Positive Chvostek or Trousseau sign indicating associated hypocalcemia
• Hypocalcemic seizures or tetany [20]

Evaluation

No single laboratory finding is specific to osteomalacia. However, patients with osteomalacia typically have hypophosphatemia, hypocalcemia, or both. Additionally, increased alkaline phosphatase activity is typically characteristic of any disease with impaired osteoid mineralization. Some sources believe that hypophosphatemia or hypocalcemia and increased bone alkaline phosphatase levels are necessary to suspect osteomalacia. Low bone mineral density (BMD) and focal uptake at Looser zones can appear on plain x-rays and bone scintigraphy as the disease progresses. Fukumoto et al proposed the following findings of definite or possible osteomalacia, which require validation with further studies:

• Hypophosphatemia or hypocalcemia
• High bone alkaline phosphatase
• Muscle weakness or bone pain
• Less than 80% BMD of the young adult–mean
• Multiple uptake zones by bone scintigraphy or radiographic evidence of Looser zones (pseudofractures)[18][21]

Definite osteomalacia is defined as having all of the 5 above findings. Possible osteomalacia is defined as having the first 2 findings and 2 of the 3 remaining findings described above.

In another review by Uday and Hogler, new criteria were proposed for the diagnosis of osteomalacia, and include the following: 

• Elevated PTH levels
• Elevated alkaline phosphatase levels
• Low urine calcium levels
• Low calcium intake (usually <300 mg/day) or low calcidiol levels (<30 nmol/L) [22]

The use of the above criteria can help with the diagnosis of osteomalacia only in cases where kidney or liver problems are lacking.

The serum level of 25(OH)D is currently regarded as the best marker of vitamin D status and is usually severely low (<10 ng/mL) in patients with nutritional osteomalacia. Other sensitive biomarkers of early calcium deprivation include increased serum PTH and decreased urinary calcium. Radiographic findings may include Looser zones or pseudofractures, a classic finding in osteomalacia. These may represent poorly repaired insufficiency fractures and are visible as transverse lucencies perpendicular to the osseous cortex; they typically occur bilaterally and symmetrically at the femoral necks, shafts, pubic and ischial rami.

Additionally, radiographs can show decreased distinctness of vertebral body trabeculae due to the inadequate mineralization of osteoid. Although not required for diagnosis, study results have demonstrated reduced BMD in the spine, hip, and forearm (see Image. Osteomalacia in Hip Joint, Radiograph). Iliac crest bone biopsy is considered the gold standard for establishing the diagnosis of osteomalacia. Due to this test's invasive and more aggressive nature, it should be reserved for when the diagnosis is in doubt, or the cause of osteomalacia is equivocal by any of the noninvasive methods.[21][23]

Treatment / Management

After establishing the diagnosis of osteomalacia, it is crucial to evaluate the etiology. Treatment should focus on reversing the underlying disorder, if possible, and correcting the vitamin D and other nutritional or electrolyte deficiencies. When the clinician has determined that vitamin D deficiency is the underlying cause of certain symptomatology, treatment may significantly improve strength and relieve bone tenderness within weeks. Serum calcium and urine calcium levels should be monitored, initially after 1 and 3 months, and after that, every 6 to 12 months until 24-hour urine calcium excretion is normal. Serum 25(OH)D level can be measured 3 to 4 months after starting therapy. If hypercalcemia or hypercalciuria is present, the dose can be adjusted to prevent excessive vitamin D dosing.

For patients with severe vitamin D deficiency, a possible dosing approach is as follows:

• 50,000 IU (international units) ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) orally 1 day per week for 8 to 12 weeks, followed by
• 800 IU to 2000 IU vitamin D3 daily for maintenance therapy

Ergocalciferol is present in plant sources and fortified nutritional alternatives. Cholecalciferol is usually in fish, meat, and eggs. When using vitamin D supplements, accumulating evidence favors the use of cholecalciferol over ergocalciferol because cholecalciferol's side chain has a higher affinity for vitamin D binding protein, thus conferring a longer half-life and a more potent ability to increase vitamin D levels. Since inadequate calcium intake may contribute to the development of osteomalacia, patients should also take at least 1000 mg of calcium per day while being treated for vitamin D deficiency. This dose may need to be increased in patients with malabsorption syndromes, who may also have increased vitamin D dosing requirements. Patients with liver and renal disease may be unable to utilize vitamin D2 or D3 effectively, so calcidiol or calcitriol should be considered.[24] Healing from osteomalacia is achieved when there are increases in urine calcium excretion as well as in BMD. Serum calcium and phosphate may normalize after a few weeks of treatment, but normalization of bone alkaline phosphatase usually lags, and those levels may stay elevated for months.[25]

Differential Diagnosis

Depending on the presenting symptoms, the initial differential diagnosis of osteomalacia can be extensive. Clinical history, physical examination, laboratory values, and imaging may be necessary to help narrow down the possibilities. However, specific diagnoses may present with similar symptoms and lab values and will require exclusion.

These conditions include metastatic disease, primary hyperparathyroidism, and renal osteodystrophy. Osteoblastic bone metastases have similar lab findings and may also show multiple zones of uptake by bone scintigraphy. Further evaluation may be warranted to exclude malignancy. Multiple myeloma can present with similar clinical symptoms (ie, bone pain and weakness) but will often reveal lytic lesions on radiographs. Patients with multiple myeloma may also have anemia and decreased renal function.

Primary hyperparathyroidism should present with hypophosphatemia, increased bone alkaline phosphatase, and increased zones of uptake. However, it usually presents with hypercalcemia, which is atypical in osteomalacia. In renal osteodystrophy, hyperphosphatemia, rather than hypophosphatemia, is most frequently observed.

Prognosis

Osteomalacia is a preventable metabolic bone disorder. Most cases are related to vitamin D deficiency, so they can usually be treated appropriately and even considered cured. If other clinical factors have contributed to the development of osteomalacia, then treatment will need to be tailored and adjusted as necessary depending on the other findings.

Once identified and an appropriate treatment plan is in place, laboratory values may begin to normalize within weeks of initiation. Symptom improvement is also appreciable in a similar period. Patients will require interval lab monitoring after starting therapy. Overall, complete healing of osteomalacia may vary and can take many months to over a year, depending on the initial cause.

Complications

Due to poor osteoid mineralization, several complications may occur if osteomalacia is left untreated. Insufficiency fractures, also known as Looser zones, can present as bone pain and occur with little or no trauma. They are typically bilateral, perpendicular to the cortex, and usually involve the femoral neck, pubic and ischial rami. Reports also exist of Looser zones in the ribs, scapulae, and clavicles.

Spinal compression fractures are less common and are usually associated with osteoporosis. Researchers have also reported kyphoscoliosis in patients with long-standing osteomalacia.[26]