70. Mechanisms and disturbances of bone remodeling. Osteoporosis, osteomalacia

Page created on May 20, 2019. Last updated on May 20, 2020 at 17:55

Bone remodelling

Bone is a dynamically changing tissue that constantly undergoes degradation and formation. In physiological cases these two processes are of similar magnitude and the bone mass therefore doesn’t change much. This process is called bone remodelling.

Bone consists of 70% inorganic material like water and minerals and 30% organic material. The most important inorganic material of bone is hydroxyapatite, a salt of calcium, inorganic phosphate and a hydroxyl group. The most important organic material is type I collagen. After an organic bone matrix, called osteoid, has been put down, it is be mineralized into bone.

Osteoblasts synthesize and secrete organic matrix and regulate the mineralization of it. Osteoclasts resorb bone. Osteocytes are retired osteoblasts that regulate the function of osteoblasts and osteoclasts. These cells probably work as mechanoreceptors that can detect changes in weight load on the bone and adjust the bone mass accordingly. The majority of cells in bone are osteocytes.

Osteoclasts express a receptor called RANK while osteoblasts and osteocytes express its ligand, RANKL (RANK ligand). This allow the cells to communicate with each other.

Vitamin D has a direct activating effect on osteoclasts and osteoblasts, stimulating both bone resorption and mineralization. Therefore vitamin D doesn’t appear to have a direct net bone mass-changing effect. Instead, vitamin D influences bone mass indirectly by increasing the serum calcium and phosphate levels by increasing absorption from the intestine and reabsorption in the tubules.

Oestrogens and androgens increase the bone-producing activity of osteoblasts, thereby promoting bone formation. They also inhibit osteoclasts.

Acidosis inhibits production of bone matrix and enhances its breakdown. The enzyme alkaline phosphatase is essential for bone matrix production as it provides necessary phosphate by breaking down pyrophosphate.

Bone mass

The total bone mass in the body changes during the life. It increases slowly until the 25 – 30s. After this the bone mass is reduced by around 1% every year. The peak bone mass (the largest bone mass you will have during your life) peaks at around 30 years.

After year 30, when the bone mass starts decreasing, there is no way to increase the bone mass. Eventually the bone mass will decrease to the point where it will become osteoporosis and cause symptoms. There are only two ways to prevent the bone mass from reaching this point:

• By increasing the peak bone mass
• By slowing the loss of bone mass after year 30

The peak bone mass can be increased by doing sports and physical activity regularly before the age of 30, and by having a diet with sufficient protein and calcium. When the peak bone mass is large enough the bone mass will never reach pathological levels (osteoporosis) even in old age. With a high enough peak bone mass osteoporosis can be postponed until the age of 120.

The loss of bone mass can be slowed by the same measures. A sufficient intake of calcium and vitamin D together with regular physical activity slows the process. Sex steroids inhibit bone resorption, so postmenopausal experience rapid loss of bone mass due to oestrogen deficiency.

The bone mass density of a person can be measured with a special X-ray machine called a DEXA scan. The scan gives a score called a T-score, which describes the bone mass.

The T-score is measured in standard deviations compared to an average 30-year old white female. A T-score of -1.0 means that your bone mass is lower than the bone mass of 84% average 30-year old females. A score of -2.5 means that that number is 99%.

Another score called the Z-score is similar but compares your bone mass to a person of the same age and gender instead of to a 30-year old female. This is more relevant for children and younger individuals.

Osteoporosis

Osteoporosis is defined as a T-score < -2.5. It’s characterised by the loss of bone mass, which leads to decreased bone strength and increased susceptibility to fractures. It mostly affects postmenopausal women and elderly. Osteopaenia is a less severe form of osteoporosis and is defined as T-score of -1.0 to -2.5.

We distinguish primary and secondary forms.

Primary osteoporosis is the type that occurs in postmenopausal women and in elderly. It can be considered the “natural” type of osteoporosis. We distinguish two types: type I (postmenopausal osteoporosis) and type II (senile osteoporosis).

Secondary osteoporosis occurs in people with pharmacological or metabolic factors that cause osteoporosis to occur earlier than expected for the age and gender.

Etiology:

Primary osteoporosis:

• Type I (postmenopausal osteoporosis)
  • Postmenopausal women
• Type II (senile osteoporosis)
  • Elderly > 70 years of both genders
• Juvenile osteoporosis
  • Idiopathic

Secondary osteoporosis:

• Endocrine disorders
  • Endogenous Cushing syndrome
  • Hypogonadism
  • Hyperthyroidism
  • Diabetes mellitus
  • Hyperparathyroidism
• Chronic kidney failure
• Chronic liver failure
• Disorders of connective tissue
  • Osteogenesis imperfecta
  • Ehler-Danlos syndrome
• Drugs
  • Long-term corticosteroid therapy
  • Chemotherapeutical drugs
  • Heparin
• Chronic inflammatory diseases
  • IBD
• Metabolic
  • Calcium deficiency
  • Vitamin C deficiency
  • Vitamin D deficiency
  • Protein deficiency
  • Chronic acidosis
• Alcohol abuse
• Cigarette smoking
• Immobilization
• Hypocalcemia
• Autoimmune diseases
  • SLE
  • RA

Pathomechanism:

Glucocorticoids inhibits bone formation and increase bone resorption. Sex steroids inhibit bone resorption. Thyroid hormone increases bone resorption. In insulin deficiency protein synthesis in inhibited, limiting bone formation. Glucocorticoids are frequently used to treat diseases like RA

Vitamin C is essential for collagen synthesis. Immobilization (even just a few weeks) decreases the load on the bone, stimulating bone resorption.

Clinical features:

Osteoporosis is often asymptomatic before a pathological fracture occurs. A pathological fracture is a fracture that occurs after a small force that wouldn’t fracture a healthy bone. Pathological fractures can occur during lifting, bending over even coughing or sneezing.

In postmenopausal osteoporosis mostly the spongy bones like the vertebrae and neck of the femur are affected. Vertebrae can lose so much bone mass that they fracture just from the pressure of the overlying vertebrae. This is called a vertebral compression fracture and can cause loss of height, thoracic hyperkyphosis and back pain. Thoracic hyperkyphosis gives the characteristic “widow’s hump” of older women.

In senile osteoporosis not only the spongy bones but also the compact bones like the tibia, femur and humerus are weakened. Fractures of the femoral neck and hip can be life-threatening.

Treatment:

As already explained no treatment can increase the bone mass to compensate for the lost mass. Treatment can only delay further bone mass loss.

• Ensure sufficient calcium, protein and vitamin D
• Regular physical activity
• Drugs
  • Bisphosphonates – inhibit osteoclasts
  • Oestrogen replacement therapy

Oestrogen replacement therapy is effective in preventing osteoporosis but increases risk for endometrial and breast cancer and thromboembolism.

Osteomalacia

Osteomalacia refers to softening of the bone (malacia means softening in Greek) due to impaired mineralization. The organic part of bone is maintained or even hypertrophic; only the inorganic part is reduced. It’s the adult form of rickets, both of which are almost always related to vitamin D deficiency.

Etiology:

• Vitamin D deficiency
• Phosphate deficiency
  • Fanconi syndrome
  • Insufficient intake

Vitamin D deficiency is by far the most common cause.

Pathomechanism:

Both calcium and phosphate are required for mineralization of bone matrix. In Fanconi syndrome there is a defect in phosphate reabsorption, so phosphate is lost in the urine.

Clinical features:

The lack of mineralization of the bone causes the bones to become soft.

• Pathological fractures
• Muscle weakness
• Bone pain
• Bone deformity