Osteomalacia: what is it, symptoms, treatment, prognosis

What is osteomalacia?

Vitamin D deficiency is the most common nutritional deficiency in children and adults. Osteomalacia - a disease characterized by softening of bones in adults, which usually occurs due to prolonged vitamin D deficiency. It leads to abnormal mineralization of osteoids. Against, rickets describes insufficient mineralization of the cartilage of growth plates in children.

There are several types of cells that make up bone and are involved in the coordinated process of bone remodeling. Osteoclasts (bone resorbing cells) are responsible for breaking down bones by secreting collagenase. Osteoblasts are responsible for the deposition of the osteoid matrix, a collagen scaffold in which inorganic salts are deposited that form bone mineralization. This complex process is directly and indirectly influenced by hormonal signals, namely parathyroid hormone (PTH) and calcitonin, both of which act in response to serum calcium levels.

In processes that reduce the amount of vitamin D or its bio-products, normal serum calcium levels will be maintained by mobilizing calcium from the bones. In particular, PTH will be secreted by the parathyroid glands in response to this hypocalcemia due to vitamin D deficiency and will try to bring the body back to normal serum calcium levels blood. Bones are the main target for calcium intake, and osteomalacia occurs due to the extraction of calcium from the bones. Consequently, in adults, processes that disrupt vitamin D metabolism and its production put them at risk over time to develop osteomalacia and its clinical manifestations.

Signs and symptoms

Symptoms of osteomalacia are nonspecific but may include:

• proximal muscle weakness and wasting;
• myalgia and arthralgia;
• muscle spasms;
• an altered or "waddling" gait;
• deformities of the spine, limbs or pelvis (prolonged osteomalacia);
• aching bone pain (lower spine, pelvis, or lower extremities)
  • worsening due to activity and weight;
• increased falls;
• hypocalcemic seizures or tetany.

Causes and risk factors

Osteomalacia is a metabolic bone disease characterized by impaired bone matrix mineralization. Bone is created by the deposition of hydroxyapatite crystals on the osteoid matrix. Common and overlooked causes of this condition are detailed below.

Decreased Vitamin D Production:

• Cold climates reduce skin exposure to sunlight and skin synthesis.
• Dark skin and relatively elevated levels of melanin compete with 7-dehydrocholesterol, which absorbs ultraviolet B (UVB) light.
• Obesity can lead to increased sequestration of adipose tissue, which leads to a decrease in the amount of calcidiol substrate available for activation.
• In the elderly, vitamin D production declines and vitamin stores decrease with age.

Decreased absorption of vitamin D:

• Malnutrition can cause vitamin D deficiency even with sufficient exposure to sunlight.
• Malabsorption syndromes such as Crohn's disease, cystic fibrosis, celiac disease, cholestasis, and gastrointestinal surgery (eg, gastric bypass) are associated with inadequate absorption of fat-soluble vitamins (A, D, E, and K).

Altered Vitamin D Metabolism:

• Chronic kidney disease leads to structural damage and loss of 1-alpha-hydroxylase, as well as suppression of enzymatic activity due to hyperphosphatemia.
• Nephrotic syndrome leads to abnormal excretion of vitamin D binding protein, which binds to serum calcidiol.
• Liver disease (For example, cirrhosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis) lead to insufficient production of calcidiol.
• Pregnancy is associated with decreased calcidiol levels, and the American College of Obstetricians and Gynecologists is currently time recommends 1,000 to 2,000 international units (IU) per day if severe vitamin D deficiency is identified in pregnant women.

Hypophosphatemia or hypocalcemia:

• Renal tubular acidosis, for example, Fanconi syndrome, alters the absorption and excretion of ions.
• Tumor osteomalacia, also known as oncogenic osteomalacia, is a rare acquired paraneoplastic disease characterized by hypophosphatemia and renal failure.
  • It is usually caused by benign tumors of the skin, muscles, or bones of the extremities or sinuses.

Medicines:

• Antiepileptic drugs, including phenobarbital, phenytoin, and carbamazepine, increase calcidiol catabolism by inducing P-450 activity.
  • Likewise, isoniazid, rifampicin, and theophylline also cause vitamin D deficiency.
• Antifungal agents such as ketoconazole increase the need for vitamin D by inhibiting 1-alpha hydroxylase (CYP27B1).
• Long-term steroid use also contributes to the deficiency, possibly by increasing the activity of 24-hydroxylase.

Epidemiology

There is evidence that the histological prevalence of osteomalacia at autopsy reaches 25% in European adults. However, the true incidence of osteomalacia worldwide remains largely underestimated. The risk group includes people with dark skin, obesity, limited exposure to the sun, people with low socioeconomic status and poor nutrition. These risks vary around the world and depend on geographic location, cultural preferences and ethnicity. Health care providers should take these factors into account, as well as other relevant clinical evidence when choosing to conduct further research or recommending supplementation vitamin D.

Pathophysiology

To understand the pathological processes that lead to vitamin D deficiency and its subsequent manifestations, it is first necessary to detail the metabolism of this vitamin.

The synthesis of active vitamin D (calcitriol) begins organically in the skin, where cholecalciferol (vitamin D3) is formed by UV-B radiation, converting 7-dehydrocholesterol (provitamin D3) in epidermal keratinocytes and dermal fibroblasts into pre-vitamin D, which spontaneously isomerized to form cholecalciferol.

Cholecalciferol is subsequently transported to the liver, where it is converted to calcidiol, 25-hydroxyvitamin D [25 (OH) D], via 25-hydroxylase (CYP2R1). Therefore, it makes sense that patients with chronic liver disease would be at risk of developing vitamin D deficiency. This particular form of vitamin D is partially water soluble and has a short half-life. It is worth noting that 25 (OH) D is also the best indicator of overall vitamin D status because it is the most accurate measurement. reflects the total amount of vitamin D received from food, natural exposure to sunlight and converted fat stores into liver. It is estimated that approximately 40-50% of circulating 25 (OH) D comes from skin transformation.

Enzymatic conversion to calcitriol, 1,25-dihydroxyvitamin D [1,25 (OH) D], occurs in the kidneys by 1-alpha hydroxylase. Likewise, chronic kidney disease, among other renal pathologies, can cause vitamin D deficiency, therefore, secondary and, ultimately, tertiary hyperparathyroidism can develop with chronic renal failure. It is important to understand that the activity of 1-alpha hydroxylase is highly regulated.

As with any synthetic biological process, there are feedback loops that regulate the production of calcitriol, namely:

• Positive feedback on parathyroid hormone (PTH)
• Positive feedback on lowering serum phosphate levels
• Negative feedback on fibroblast growth factor 23 (FGF-23) secreted by osteocytes in the bone matrix, which also inhibits renal phosphate absorption
• Negative feedback due to inhibition of 1-alpha-hydroxylase by calcitriol, which, in turn, reduces the synthesis of calcitriol, and also stimulates the activity of 24-hydroxylase (CYP24R1).
  • 24-hydroxylase effectively removes circulating calcitriol, converting it to biologically inactive 24,25-dihydroxyvitamin D [24,25 (OH) D].

Diagnostics

There are various tests that can be performed to determine if someone has osteomalacia.

• The most important indicator is low vitamin D levels, but low calcium levels or a significant drop in phosphate levels can also indicate osteomalacia.
• X-rays may be taken to check for signs of osteomalacia.
• A bone mineral density scan can be helpful in assessing the amount of calcium and other minerals present in a patient's bone segment. These scans are not required to diagnose osteomalacia. However, they can provide important information about a patient's bone health.

In rare cases, a clinician may perform a bone biopsy, in which a sample of bone is taken and examined.

Treatment

After the diagnosis of osteomalacia is established, it is very important for the doctor to know the etiology.

Treatment should focus on reversing the underlying disorder and then correcting vitamin D and electrolyte deficiencies.

When a doctor determines that vitamin D deficiency is the underlying cause, treatment can result in a significant increase in bone strength and soreness over several weeks. Serum and urine calcium levels should be monitored first at 1 and 3 months and then every 6–12 months until 24-hour urinary calcium excretion is normal. Serum 25 (OH) D can be measured 3-4 months after starting therapy. If present hypercalcemia or hypercalciuria, the dose may be adjusted to prevent excess vitamin A. For severely deficient patients, the following is a possible dosage approach:

• 50,000 IU ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) orally once a week for 6-8 weeks, then
• 800 IU of vitamin D3 per day.

Ergocalciferol is present in plant sources and in fortified food alternatives. Cholecalciferol is commonly found in fish, meat, and eggs. With vitamin D supplementation, accumulating evidence supports the use of cholecalciferol versus ergocalciferol because its lateral the chain has a higher affinity for vitamin D-binding protein, thereby giving it a longer half-life and a higher ability to raise levels vitamin D.

Since inadequate calcium intake can contribute to the development of osteomalacia, patients should also take at least 1000 mg per day during treatment. This dose may be increased in patients with malabsorption syndromes, who may also require an increased dosage of vitamin D compared to those indicated above. Patients with liver and kidney disease will not be able to use vitamin D2 or D3 effectively, so calcidiol or calcitriol is considered.

Serum calcium and phosphate levels may return to normal after a few weeks of treatment, but normalization of bone alkaline phosphatase lags behind and may remain elevated for several months.

Forecast

Osteomalacia is a preventable disorder of bone metabolism. Since most cases are associated with vitamin D deficiency, it can usually be treated appropriately. If other clinical factors have contributed to the development of osteomalacia, treatment will need to be adapted and adjusted if necessary.

Once an appropriate treatment plan has been identified and developed, laboratory values ​​may begin to return to normal within a few weeks of starting therapy. The improvement in symptoms is also noticeable during the same period. Patients require interval laboratory monitoring after initiation of therapy. In general, osteomalacia treatment can take from several months to a year, depending on the cause.

Complications

Due to the poor mineralization of osteoids, several complications can occur if osteomalacia is left untreated. Stress (fatigue) fractures can manifest as bone pain. As a rule, they are bilateral, perpendicular to the cortex, and usually affect the femoral neck, pubic and sciatic branches. There are also reports of more fractures in the ribs, shoulder blades and collarbones. Compression fractures of the spine are less common and are usually associated with osteoporosis. Researchers also reported kyphoscoliosis with prolonged osteomalacia.