Rickets (Osteomalacia): Causes

Pathogenesis (development of disease)

There are many causes of rickets or osteomalacia. Rickets

In all forms of rickets, there are changes in the calcium–phosphate product. There is decreased storage of calcium and phosphate in the bones. One can distinguish calcipenic from phosphopenic forms of rickets:

Calcipenic rickets (E83.31) include:

  • Hypocalcemia
  • Vitamin D deficiency
  • Vitamin D-dependent rickets type I (VDDR-1: mutation of 1α-hydroxylase) – autosomal recessive inheritance.
    • VDDR1A – elevated elevated vitamin D3 levels are typical.
    • VDDR1B – results in elevated cholecalciferol levels.
  • Vitamin D-dependent rickets type II (VDDR-II: mutation of the vitamin D receptor) – autosomal recessive inheritance.
    • VDDR2A – mutation in the gene of the intracellular vitamin D receptor.
    • VDDR2B – underlying gene defect is unknown.

Phosphopenic rickets include:

  • Osteopathy of prematurity
  • Familial hypophosphatemic rickets (ICD-10 E83.30).
  • Tumor-induced hypophosphatemic rickets (ICD-10 E83.38)
  • Fanconi syndrome – see under genetic disorders.

Osteomalacia

Either a deficiency of active vitamin D or a disorder in phosphate metabolism is responsible for osteomalacia. The lack of calcium or a phosphate results in decreased mineralization of the osteoid (bone ground substance). Furthermore, lack of vitamin D at the vitamin D receptors of muscle cells leads to muscle weakness. Vitamin D-dependent/calcipenic osteomalacia:

  • Hereditary vitamin D-dependent forms:
    • Vitamin D-dependent rickets type I (VDDR-1: mutation of 1α-hydroxylase) – autosomal recessive inheritance.
      • VDDR1A – elevated elevated vitamin D3 levels are typical.
      • VDDR1B – results in elevated cholecalciferol levels.
    • Vitamin D-dependent rickets type II (VDDR-II: mutation of the vitamin D receptor) – autosomal recessive inheritance.
      • VDDR2A – mutation in the gene of the intracellular vitamin D receptor.
      • VDDR2B – underlying gene defect is unknown.
  • Inadequate intake of vitamin D in the diet (eg, vegan diet).
  • Malabsorption (see below)
  • Drugs that affect vitamin D metabolism via the pregnane X receptor (→ increase expression of 24-hydroxylase, leading to increased degradation of vitamin D3 and calcitriol):
  • Lack of UV light exposure

Hypophosphatemic/phosphopenic form of osteomalacia:

  • Malabsorption (see below).
  • Genetic disorders: e.g., renal tubular partial disorder (Fanconi syndrome) (see genetic disorders below).
  • Tumor-induced hypophosphatemic osteomalacia (so-called oncogenic osteomalacia): by phosphatonins (mostly fibroblast growth factor 23, FGF23 for short), it comes to an influence on the vitamin D, calcium and phosphate balance.
  • Drugs (see below)

Etiology (causes)

Biographical causes

  • Genetic burden from parents, grandparents
    • Genetic diseases
      • 1α-Hydroxylase deficiency (vitamin D-dependent rickets type II; autosomal recessive inheritance).
      • 25-hydroxylase deficiency (autosomal recessive inheritance) → deficiency of 25-(OH)-vitamin D3.
      • Genetic disorder of the vitamin D receptor (vitamin D-dependent rickets type II; autosomal recessive inheritance).
      • Hypophosphatasia (HPP; synonyms: Rathbun syndrome, phosphatase deficiency rickets; phosphatase deficiency rickets) – rare, genetic disorder with usually autosomal recessive inheritance; currently not curable bone metabolism disorder, which manifests itself mainly in the skeletal structure.
      • Cystic Fibrosis (ZF) – genetic disease with autosomal recessive inheritance, characterized by the production of secretions in various organs to be tamed.
      • Phosphate diabetes (synonym: x-linked hypophosphatemic rickets (“X-linked hypophosphatemic rickets” [XLH]) – X-linked dominant inherited form of rickets caused by hypophosphatemia; associated with increased renal (“kidney-related”) excretion of phosphate and resulting in decreased bone mineralization.
      • Renal tubular acidosis (RTA) – genetic disease with autosomal recessive inheritance that leads to a defect defect H+ ion secretion in the tubular system of the kidney and, as a result, demineralization of bone (hypercalciuria, hyperphosphaturia/increased excretion of calcium and phosphate in the urine and hypophosphatemia).
      • Cystinosis (hereditary form of Fanconi syndrome): autosomal recessive lysosomal storage disease caused by mutations in the CTNS gene; triad of glucosuria (increased urinary excretion of glucose), hypophosphatemia, and aminoaciduria (urinary excretion of amino acids) is referred to as Fanconi syndrome
  • Age – older age wg : skin aging; renal or hepatic insufficiency with decreased conversion of provitamin 7-dehydrocholesterol to calcitriol [higher risk of osteomalacia].

Behavioral causes

  • Nutrition
    • Inadequate dietary intake of vitamin D (e.g. vegan diet).
    • Micronutrient deficiency (vital substances) – see prevention with micronutrients.
  • Lack of UV irradiation

Disease-related causes

Congenital malformations, deformities, and chromosomal abnormalities (Q00-Q99).

  • Biliary atresia – Failure of the bile ducts to attach.
  • For further details, see “Biographical causes” below.

Endocrine, nutritional and metabolic diseases (E00-E90).

Liver, gallbladder and bile ducts – Pancreas (pancreas) (K70-K77; K80-K87).

  • Cirrhosis of the liver
    • Alcohol toxic cirrhosis – alcohol-related liver disease leading to connective tissue remodeling of the liver with functional impairment.
    • By chronic active hepatitis (liver inflammation).
    • Primary biliary cholangitis (PBC, synonyms: non-purulent destructive cholangitis; formerly primary biliary cirrhosis) – relatively rare autoimmune disease of the liver (affects women in about 90% of cases); starts primarily biliary, i.e. at the intra- and extrahepatic (“inside and outside the liver”) bile ducts, which are destroyed by inflammation (= chronic non-purulent destructive cholangitis). In the longer course, the inflammation spreads to the entire liver tissue and eventually leads to scarring and even cirrhosis; detection of antimitochondrial antibodies (AMA); PBC is often associated with autoimmune diseases (autoimmune thyroiditis, polymyositis, systemic lupus erythematosus (SLE), progressive systemic sclerosis, rheumatoid arthritis); Associated with ulcerative colitis (inflammatory bowel disease) in 80% of cases; long-term risk of cholangiocellular carcinoma (CCC; bile duct carcinoma, bile duct cancer) is 7-15%.

Mouth, esophagus (esophagus), stomach, and intestine (K00-K67; K90-K93).

  • Crohn’s disease – chronic inflammatory bowel disease; it usually progresses in episodes and can affect the entire digestive tract; characteristic is the segmental affection of the intestinal mucosa (intestinal mucosa), that is, several intestinal sections may be affected, which are separated by healthy sections from each other
  • Celiac disease (gluten-induced enteropathy) – chronic disease of the mucosa of the small intestine (small intestinal mucosa), which is based on hypersensitivity to the cereal protein gluten.

Genitourinary system (kidneys, urinary tract – sex organs) (N00-N99).

  • Chronic renal failure (renal impairment) → decreased 1α-hydroxylation.

Medications

  • Vitamin D deficiency caused by increased metabolism due to medication:
  • Deficiency of 25-(OH)-vitamin D3, due to deficient 25-hydroxylase.
  • Deficiency of 1,25-(OH)2-vitamin D3 due to decreased 1α-hydroxylation.
  • Target organ resistance to vitamin D
    • Phenytoin (antiepileptic drug)
  • Hypophosphatemia (phosphate deficiency in the blood): phosphate-binding antacids, diuretics, and steroids.
  • Drugs that affect vitamin D metabolism via the pregnane X receptor (→ increase expression of 24-hydroxylase, leading to increased degradation of vitamin D3 and calcitriol):

Operations

  • Bariatric surgery/obesity surgery (→ malabsorption/insufficient breakdown of food components).
  • Small bowel resection

Other causes

  • Lack of UV irradiation