Osteoporosis: Causes

Pathogenesis (disease development)

The maximum bone mass (peak bone mass) is reached in the 30th to 35th year of life and is 60-80% genetically predetermined. In normal bone metabolism, there is a steady balance between bone resorption and bone formation. This balance is maintained until about the age of 40. After that, the body loses about 0.5% of bone mass per year. Among other things, a genetic component contributes to the development of osteoporosis, although it has not yet been conclusively clarified which genes are involved.Furthermore, physiological remodeling plays an important role in the development of osteoporosis. This is influenced by a wide variety of hormones (parathyroid hormone, vitamin D, estrogens, testosterone, and others), but also by diet and adequate exercise. Two types of cells play the main role in bone metabolism: osteoblasts are cells that build bone. The building of bone is controlled by the hormone calcitonin. This is produced in the thyroid gland. It promotes the activity of the bone-building osteoblasts. As more and more calcium is built up in the bones, calcitonin has a lowering effect on the serum calcium level. These are the osteoclasts. These cells are responsible for bone breakdown and are controlled by the hormone parathyroid hormone, which is produced in the parathyroid gland.When bone is broken down, calcium is released from the bones and enters the blood, increasing the serum calcium level. The main causes of bone substance loss in the second half of life are estrogen and later testosterone deficiency, as well as physiological aging processes (chronic inflammatory diseases and the chronic pro-inflammatory state that drives aging). Furthermore, an undersupply of calcium and vitamin D in old age, as well as secondary hyperparathyroidism (→ increased secretion of parathyroid hormone (PTH) by the parathyroid glands) triggered by this. Estrogens serve as a kind of brake on osteoclasts. In men, testosterone has a comparable task.Women suffer from osteoporosis more frequently than men. The data on the incidence for women range from 30-50% after menopause (menopause in women). After menopause, estrogens are no longer produced and their regulating, protective effect on our bone metabolism ceases. Nevertheless, not all women are affected, as the risk of osteoporosis is determined individually by the interaction of various risk factors.Men are more likely to be affected by senile osteoporosis after the age of 70, which is related to the decrease in testosterone production and the decrease in exercise.

Etiology (Causes)

Biographic causes

  • Genetic burden (familial clustering); heritability (inheritability) is 50% to 80%:
    • Genetic risk dependent on gene polymorphisms:
      • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
        • Genes: LRP5, VDR
        • SNP: rs3736228 in gene LRP5
          • Allele constellation: CT (1.3-fold).
          • Allele constellation: TT (1.7-fold)
        • SNP: rs1544410 in gene VDR
          • Allele constellation:AA (increased risk).
          • Allele constellation:GG (lowered risk).
      • A genome-wide association study (GWAS) has now demonstrated 518 gene variants that influence bone density and explain about one-fifth of the genetic variance in osteoporosis.
    • Genetic diseases
      • Defect in vitamin D3 receptor – genetic defect with autosomal recessive inheritance; vitamin D-dependent rickets type 2.
      • Ehlers-Danlos syndrome (EDS) – genetic disorders that are both autosomal dominant and autosomal recessive; heterogeneous group caused by a disorder of collagen synthesis; characterized by increased elasticity of the skin and unusual tearability of the same.
      • Gene defect in collagen type I alpha-1 gene – can cause the following diseases: Ehlers-Danlos syndrome, osteogenesis imperfecta type 1, type 2 and type 3, infantile cortical hyperostosis.
      • Glycogen storage diseases – group of diseases with both autosomal dominant and autosomal recessive inheritance in which glycogen stored in body tissues cannot be broken down or converted to glucose, or can only be broken down incompletely.
      • Hemochromatosis (iron storage disease) – genetic disease with autosomal recessive inheritance with increased deposition of iron as a result of increased iron concentration in the blood with tissue damage.
      • Homocystinuria (homocystinuria) – collective name for a group of autosomal recessive hereditary metabolic diseases, lead to increased concentration of the amino acid homocysteine in blood and urine.
      • Hypophosphatasia (HPP; synonyms: Rathbun syndrome, phosphatase deficiency rickets; phosphatase deficiency rickets) – genetic disorder with autosomal recessive inheritance, manifested mainly in skeletal structure; defective bone and tooth mineralization, premature loss of deciduous and permanent teeth.
      • Kallmann syndrome (synonym: olfactogenital syndrome) – genetic disorder that can occur sporadically, as well as be inherited in an autosomal-dominant, autosomal-recessive, and X-linked recessive manner; symptom complex of hypo- or Anosmia (decreased to absent sense of smell) in conjunction with testicular or ovarian hypoplasia (defective development of the testis or ovaries, respectively); prevalence (disease frequency) in males 1: 10,000 and in females 1: 50,000.
      • Klinefelter syndrome – genetic disease with mostly sporadic inheritance: numerical chromosomal aberration (aneuploidy) of the sex chromosomes (gonosomal abnormality) that occurs only in boys or Men occurs; in the majority of cases characterized by a supernumerary X chromosome (47, XXY); clinical picture: large stature and testicular hypoplasia (small testis), caused by hypogonadotropic hypogonadism (gonadal hypofunction); usually spontaneous onset of puberty, but poor pubertal progress.
      • Marfan syndrome – genetic disease that can be inherited both autosomal dominant or occur sporadically (as a new mutation); systemic connective tissue disease, which is notable mainly by tall stature, spider limbs and hyperextensibility of the joints; 75% of these patients have an aneurysm (pathological (pathological) bulge of the arterial wall).
      • Gaucher’s disease – genetic disease with autosomal recessive inheritance; lipid storage disease due to the defect of the enzyme beta-glucocerebrosidase, which leads to storage of cerebrosides mainly in the spleen and marrow-containing bones.
      • Osteogenesis imperfecta (OI) – genetic diseases with autosomal dominant inheritance, more rarely autosomal recessive inheritance; 7 types of osteogenesis imperfecta are differentiated; the main feature of OI type I is altered collagen, which leads to abnormally high bone fragility (brittle bone disease)
      • Porphyria – genetic metabolic diseases with both autosomal dominant emals and autosomal recessive inheritance; the process of biosynthesis of heme is disturbed.
      • Thalassemia – autosomal recessive hereditary synthesis disorder of the alpha or beta chains of the protein portion (globin) in hemoglobin (hemoglobinopathy/diseases resulting from impaired formation of hemoglobin)
        • Α-Thalassemia (HbH disease, hydrops fetalis/generalized fluid accumulation); incidence: mostly in Southeast Asians.
        • Β-Thalassemia: most common monogenetic disorder worldwide; incidence: People from Mediterranean countries, Middle East, Afghanistan, India and Southeast Asia.
  • Gender – Women are more often affected than men. Men have a higher bone mass than women: The ratio of men to women in terms of frequency of the disease is about 1: 2.
  • Age – with age, bone mass decreases, the bone becomes more porous and brittle.
  • Hormonal factors
    • Estrogen deficiency in girls and young women, e.g., late menarche (delayed puberty, > 15 years of age).
    • Early onset of menopause (< 45 years of age) or early ovariectomy (removal of the ovaries).
    • Menopause (menopause in women)
    • Andropause (menopause of the male)

Behavioral causes

  • Nutrition
    • High intake of sodium and table salt – High intake of table salt followed by an increase in natriuresis (excretion of sodium in the urine) promotes hypercalciuria (increased excretion of calcium in the urine) and thus a negative calcium balance. A 2.3 g increase in sodium intake leads to a 24-40 mg increase in calcium excretion. The increased calcium excretion favors the development of osteoporosis.The study results to date conclude that a table salt intake of up to 9 g/day in a healthy individual does not increase the risk of osteoporosis. However, the current daily intake of table salt in the general population is 8-12 g.
    • Micronutrient deficiency (vital substances) – inadequate supply of calcium and vitamin D and too high a proportion of phosphates, oxalic acid (chard, cocoa powder, spinach, rhubarb) and phytic acid/phytates (cereals and legumes) – see Prevention with micronutrients.
  • Pleasure food consumption
  • Physical activity
    • Physical inactivity
    • Prolonged immobilization
  • Psycho-social situation
    • Stress
    • Insufficient sleep duration: postmenopausal (female menopause) women who slept 5 hours or less at night had a 63% higher risk of osteoporosis compared with women who slept 7 hours per night.
  • Underweight – A low body weight (body mass index < 20) or weight loss of more than 10% in recent years is associated with an increased risk – however, this does not mean that overweight should be aimed for, but rather a normal weight or an age-appropriate ideal weight
  • Lack of exposure to sunlight

Causes related to disease

  • Achlorhydria – lack of production of hydrochloric acid in the gastric mucosa.
  • Anorexia nervosa (anorexia nervosa)
  • Amyloidosis – extracellular (“outside the cell”) deposits of amyloids (degradation-resistant proteins) that can lead to cardiomyopathy (heart muscle disease), neuropathy (peripheral nervous system disease), and hepatomegaly (liver enlargement), among other conditions.
  • Depression (due tolack of appetite with poor diet, lower physical activity, higher stress hormone levels, medication).
  • Endocrinological disorders:
    • Andropause (male menopause; androgen deficiency).
    • Acromegaly (“giant growth”; increase in size of the body end limbs or acra).
    • Diabetes mellitus
    • Hypercortisolism (excessive cortisol secretion) including subclinical hypercortisolism.
    • Hyperparathyroidism (parathyroid hyperfunction), primary (pHP) – characteristics of primary.
    • Hyperparathyroidism are an elevated parathyroid hormone level and serum calcium levels.
    • Hyperprolactinemia
    • Hyperthyroidism (hyperthyroidism) and latent hyperthyroidism – if not treated.
    • Hypogonadism (hypogonadism) or dysfunction of the ovaries or testes.
    • Anterior pituitary insufficiency
    • Hypothalamic amenorrhea
    • Menopause (female menopause; estrogen deficiency).
    • Cushing’s disease – group of diseases leading to hypercortisolism (hypercortisolism; excess of cortisol).
    • Adrenal insufficiency (adrenal weakness).
    • Prolactinoma – prolactin-forming tumor (hyperprolactinemia).
  • Eating disorders – anorexia nervosa – anorexia -, bulimia – binge eating disorder.
  • Hematological diseases (blood diseases)/neoplasms (neoplasms).
    • Aplastic anemia – anemia (anemia) characterized by pancytopenia (reduction of all cell series in the blood; stem cell disease) and concomitant hypoplasia (functional impairment) of the bone marrow.
    • Diffuse bone metastases
    • Hemolytic anemia – anemia (anemia) characterized by increased degradation or decay (hemolysis) of erythrocytes (red blood cells), which can no longer be compensated by excess production in the red bone marrow.
    • Lymphomas and leukemias (blood cancer).
    • Malignancies with PTHrP production.
    • Mastocytosis – two main forms: cutaneous mastocytosis (skin mastocytosis) and systemic mastocytosis (whole body mastocytosis); clinical picture of cutaneous mastocytosis: Yellowish-brown spots of varying size (urticaria pigmentosa); in systemic mastocytosis, there are also episodic gastrointestinal complaints (gastrointestinal complaints), (nausea (nausea), burning abdominal pain and diarrhea (diarrhea)), ulcer disease, and gastrointestinal bleeding (gastrointestinal bleeding) and malabsorption (disorder of food absorption); In systemic mastocytosis, there is an accumulation of mast cells (cell type that is involved in, among other things, allergic reactions). Among other things, involved in allergic reactions) in the bone marrow, where they are formed, as well as accumulation in the skin, bones, liver, spleen and gastrointestinal tract (GIT; gastrointestinal tract); mastocytosis is not curable; course usually benign (benign) and life expectancy normal; extremely rare degeneration mast cells (= mast cell leukemia (blood cancer)).
    • Pernicious anemia – anemia (anemia) caused by a deficiency of vitamin B12 or, less commonly, folic acid deficiency.
    • Plasmocytoma (multiple myeloma) – malignant systemic disease.
    • Thalassemia (Mediterranean anemia) (see below “Genetic diseases“).
  • Hepatitis (liver inflammation)
  • Heart failure (cardiac insufficiency)
  • Hyponatremia (sodium deficiency)
  • Immobility due to diseases
  • (Latent) metabolic acidosis (metabolic acidosis).
  • Liver cirrhosis
  • Malabsorption – impaired absorption of nutrients and vital substances (macro- and micronutrients), e.g.:
    • Ulcerative colitis – chronic inflammatory disease of the mucosa of the colon or rectum.
    • Lactose intolerance (intolerance to lactose).
    • Crohn’s disease – chronic inflammatory bowel disease; it usually progresses in relapses and can affect the entire digestive tract; characteristic is the segmental affection of the intestinal mucosa (intestinal mucosa), that is, several intestinal segments may be affected, which are separated by healthy sections from each other
    • Pancreatic insufficiency – inability of the pancreas to produce enough digestive enzymes (= exocrine pancreatic insufficiency, EPI) and in the later stages also hormones such as insulin (= endocrine pancreatic insufficiency).
    • Primary biliary cirrhosis – form of liver cirrhosis (liver shrinkage), which occurs mainly in women and is caused by a non-purulent bile duct inflammation destroying the bile ducts.
    • Celiac disease (gluten-induced enteropathy) – chronic disease of the mucosa of the small intestine (small intestinal mucosa), which is due to hypersensitivity to the cereal protein gluten.
  • Maldigestion – impaired utilization of nutrients and vital substances (macro- and micronutrients).
  • Multiple sclerosis (MS) – neurological disease that can lead to paralysis or spasticity of the extremities.
  • Myasthenia gravis (MG; synonyms: myasthenia gravis pseudoparalytica; MG); rare neurologic autoimmune disease in which specific antibodies against the acetylcholine receptors are present, with characteristic symptoms such as abnormal load-dependent and painless muscle weakness, asymmetry, in addition to local, also temporal variability (fluctuation) over the course of hours, days or Weeks, an improvement after recovery or rest periods; clinically can be differentiated a purely ocular (“concerning the eye”), a faciopharyngeal (face (Facies) and pharynx (pharynx) concerning) emphasized and a generalized myasthenia; about 10% of cases already show a manifestation in childhood.
  • Renal disease – e.g. renal insufficiency (kidney weakness).
  • Organ transplants / immunosuppressants
  • Paresis (paralysis)
  • Pulmonological diseases (lung diseases)
  • Rheumatological diseases, e.g.:
    • Rheumatoid arthritis
    • Bekhterev’s disease (ankylosing spondylitis; Latinized Greek: spondylitis “inflammation of the vertebrae” and ankylosans “stiffening” – chronic inflammatory rheumatic disease with pain and stiffening of joints).
    • Lupus erythematosus
  • Sarcoidosis – chronic disease with formation of granulomas (nodules) that occur mainly in the lungs and skin.
  • Scoliosis – permanent lateral curvature of the spine.
  • Subclinical inflammation (English “silent inflammation”) – permanent systemic inflammation (inflammation that affects the whole organism), which runs without clinical symptoms.

Laboratory diagnoses – laboratory parameters that are considered independent risk factors/causes.

  • Folate deficiency – increases the risk of hip fractures in women.
  • Hyperhomocysteinemia – in men and women: predictor of hip fractures.
  • Hyponatremia (sodium deficiency)
  • Insulin-like Groth factor (ILG-1) – high serum levels in youth are associated with better bone mass acquisition and low levels are associated with decreased bone mass in old age
  • Estrogen deficiency – the higher the serum estrogen level in older men, the denser and stronger the bones are
  • Somatotropic hormone (STH) – growth hormone deficiency.
  • TSH value < 0.3 mU/l

Medication

  • Aluminum-containing drugs
  • Antacids
    • Phosphate-containing antacids
  • Antibiotics
    • Aminoglycosides (neomycin)
    • Chloramphenicol
    • Sulfonamides
  • Antidepressants
    • Selective serotonin reuptake inhibitors (SSRIs).
  • Antidiabetic agents
  • Anticonvulsants/antiepileptics (carbamazepine, diazepam, gabapentin, lamotrigine, lamictal, levetiracetam, phenobarbital, phenytoin, valproic acid).
  • Anticoagulants
    • Heparin – for longer-term therapy
    • Coumarin derivatives (vitamin K antagonists, VKA) [long-term therapy (> 12 months) with a coumarin derivative is an independent risk factor for osteoporotic fractures]
    • Low-molecular-weight heparins (NMHs) – certoparin, dalteparin, enoxaparin, nadroparin, reviparin, tinzaparin).
    • Thyroid hormones
    • Synthetic heparin analogues (fondaparinux)
    • Unfractionated heparin (UFH)
  • Antiviral therapy
    • Protease inhibitors
  • Barbiturates
  • Benzodiazepines
  • Cortisone
  • Dicumarol
  • Diuretics
    • Loop diuretics
  • Bile acid adsorbent (colestyramine)
  • Hormones
  • Immunosuppressants – ciclosporin (cyclosporin A).
  • Laxatives
  • Lithium
  • Proton pump inhibitors (proton pump inhibitors, PPI; acid blockers) – (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole), due to hypochlorhydria, proton pump inhibitors can reduce calcium absorption and thus increase osteoporosis, resulting in an increased risk of femoral neck fractures)
  • Statins: from a dosage of 20 mg for simvastatin, atorvastatin and rosuvastatin.
  • Thiazolidine
  • Cytostatic drugs (chemotherapy)
  • Long-term side effects of tumor therapy: tumor therapy-induced osteoporosis/osteopenia (TTIO); may have a role in the development of TTI osteoporosis:
    • An early therapy-induced menopause (timing of the last menstrual period).
    • Estrogen-suppressing therapy in breast cancer (mammary carcinoma).
    • androgen-suppressive therapy in prostate carcinoma (prostate cancer).
    • prolonged steroid therapy (fracture risk (bone fracture risk) increases with dose and duration).
    • tumor-associated cachexia (emaciation; severe emaciation) with loss of muscle substance.

Environmental pollution – intoxications (poisonings).

  • Air pollutants: particulate matter → higher levels of particulate matter (PM 2.5) were associated with a 4 percent increased risk of fracture; relative risk of 1.041 was significant with a 95 percent confidence interval of 1.030 to 1.051 because of the large number of participants; it was also shown that increased levels of particulate matter and soot in the air may slightly lower parathyroid hormone levels

Other causes

  • Dialysis (blood washing)
  • Gastrectomy (stomach removal)
  • Heart transplantation
  • Pregnancy
  • Lactation