Chronic Bone Pathologies

chronic pathologies of bone and cartilage

**Overview

• Bone Loss (Osteoporosis)
• Bone Destruction (Paget disease)
• Nutritional deficiencies as a cause of bone pathology (Osteomalacia)
• Endocrinopathies as a cause of bone disease (Hyperparathyroidism)

Osteopenia & Osteoporosis

• Osteopenia refers bone loss.
• Osteoporosis refers to bone loss where the severity is great enough to induce bone fracture.
  Radiographic Definitions
• Osteopenia refers to bone loss that is 1 to 2.5 standard deviations below the mean.
• Osteoporosis refers to bone loss that is greater than/equal to 2.5 standard deviations below the mean.
  • Now, we see images of healthy bone and osteoporotic bone, which, it's easy to appreciate, is quite porous.
  • Indicate that there is a loss of trabeculae: especially the horizontal trabeculae, with thickening of the vertical trabeculae.
    Key Causes
• So let's address the key causes of transformation from healthy bone to osteoporotic bone, which we diagram, now, as a dense, healthy bone long bone, transforming to a thinned out, porous bone to help us remember what each of these is doing to bone.
• Indicate that increased age leads to senile bone biology, meaning the biological potential of osteoblasts and the cellular response to growth factors is impaired even in the setting of normal calcium and phosphate levels.
• Indicate that reduced physical exercise, especially reduction in resistance training (weight lifting) (think about the tremendous osteoporosis that occurs in astronauts who exist in zero gravity for extended periods of time and can't even rely on their own body mass to produce).
• When it comes to osteoporosis, indicate that deficiencies in calcium and vitamin D and excess parathyroid hormone are problematic – there are numerous causes for these deficiencies and for hyperparathyroidism.
• Along these lines, indicate that postmenopausal women have a reduction in estrogen that leads to accelerated bone loss via increase in bone resorption at a faster pace than bone formation.
• Now, indicate that genetic factors play a key role, as well, especially important is RANKL, which we'll see has been a target of reduction in bone loss therapy.
• Finally, indicate two key modifiable risk factors for osteoporosis: tobacco abuse and glucocorticoid (ie, steroid) administration.
• Indicate that osteoporosis leads to fractures (vertebral fractures (thoracic, lumbar) and long bone fractures) that can cause skeletal deformities (lumbar lordosis and kyphoscoloiosis) or such manifestations as pulmonary embolism (which can lead to death).

Asymptomatic screening

Some considerations for asymptomatic screening are:

• Perimenopausal women ready to start drug therapy.
• Radiographic evidence of bone loss.
• Patients who have been on chronic steroids.
• Asymptomatic hyperparathyroidism.

Two key modalities are:

• DEXA scan (dual-energy x-ray absorptiometry).
• Quantitative CT (computed tomography).

Osteoporosis Therapeutics

So, let's use the therapeutics of osteoporosis to review its pathogenesis. Indicate that mainstays of treatment and prevention involves:

• Physical exercise (specifically, weight-bearing)
• Calcium with vitamin D supplementation
• Bisphosphonates, which are bone resporption inhibitiors.
• Calcitonin to increase bone mass.
• Estrogen replacement (again estrogen reduction leads to bone resorption at a greater rate than formation) but this is complicated by cardiovascular side effects of estrogen replacement.
• Raloxifene, which is a selective estrogen receptor modulator.
• Teriparatide, which is a human PTH analog (a synthetic form of PTH) but there is worry about its risk of causing osteosarcoma.
• Denosumab, which is a RANKL inhibitor.

Paget disease

• Now, let's address Paget disease (ostetitis deformans), which creates INCREASED but disordered bone mass, which begins ~ age 70 (hence "osteitis deoformans")
• Indicate that the clinical presentation is that of skull thickening, which can manifest with hearing loss (which we represent anatomically as a memory device) – we'll learn additional clinical manifestations momentarily.
• Show that on histopathological slide, the lamellar bone forms a classic mosaic pattern.
• The key to this pathological finding is the breakdown and rebuilding that occurs in the disease process.

Indicate that there are three phases:

• Osteolytic, in which osteoclasts are the prominent finding – they break down the bone.
• Mixed, in which there is both osteoclast and osteoblasts, and which ends with a predominance of osteoblasts building-up bone.
  • Although this sounds promising, as shown, the bone is osteosclerotic, which means it has a disordered, jigsaw-like pattern from the prominent cement lines, which makes it thick but unstable.
    Clinical complications of Paget disease
• Osteosarcoma, which is rare but life-threatening.
• Chalk-stick fractures (especially in the long bones of the lower limbs – so-named for it's chalk-stick or carrot stick snapped appearance).
• Heart failure because the hypervascular bone drives forms a shunt, in essence, thus there is a high-output heart failure that can arise.
• Skull thickening: we draw a lion's head to remember that a syndrome of lion-face (leontiasis ossea) can occur where the skull thickens so greatly it's hard to hold upright.
  • And we show with a sagittal MRI of the brain how this can lead to central nervous system compression. Specficially, there is platybasia (flattening of the skull base) and ultimately basilar invagination (where the odontoid tip projects up into the foramen magnum).
  • Thus, tremendous posterior fossa compression results from the heavy head and one can easily imagine how this can manifest with compression (crushing) of exiting cranial nerve roots and additional neurological manifestations (for instance, hearing loss from bony destruction).

Renal osteodystrophy

This the term for the bone pathology that accompanies chronic renal disease.

• To best understand the relationship between the kidneys and bones, let's remind ourselves of some basic renal anatomy
• Indicate the renal corpuscle, then the proximal tubule, nephron loop, distal tubule, and collecting duct (these terms are important to any literature involving the kidney).
  • We include the renal arterial and venous vasculature, as well, for reference.
• Indicate that in renal tubular disease, there is acidosis, this drop in pH results in demineralization of bone (specifically it dissolves hydroxyappatite), causing osteomalacia (a softening and instability of bone).
• Then, show that in chronic renal failure, there is a loss of activated vitamin D (1,25-OH2-vitamin-D3) and thus a reduction in calcium.
• Indicate that this, in combination with hyperphosphatemia, leads to hyperparathyroidism, which we saw, causes further bone destruction and bone loss.

Rickets vs. osteomalacia

Now, let's consider the difference between rickets, which we learned along with the congenital skeletal dysplasias, and osteomalacia, which is its acquired bone pathology counterpart.

• Indicate that both are due to vitamin D deficiency.
• But show that in rickets there is growth plate abnormality and the bones are bowed and short.
• Whereas in osteomalacia, which occurs in adults, the bones are soft from undermineralization during remodeling, which leads to fractures.

hyperparathyroidism

Now, indicate that hyperparathyroidism is an important cause of bone pathology. Show a histological section.

• Encircle an osteoclast, which we can see is chewing up bony matrix.
• So let's recall some basic physiology of bone remodeling.
• Draw an osteoblast.
• Show that both Vitamin D and Parathyroid hormone (PTH) stimulate osteoblasts to secrete factors that promote osteoclastogenesis.
• Specifically show that they promote the release of RANKL (an osteoprotegerin ligand, which is in the tumor necrosis factor family (TNF family)).
• It stimulates differentiation from pre-osteoclast to osteoclast, which we draw as dome-shaped: we show its site of active bone resorption, including the bony matrix.
  • As we can imagine, if left unchecked, hyperparathyroidism leads to unabated osteoclast-mediated destruction of bone.