Chronic Bone Pathologies (Osteoporosis, Paget, Osteopenia, Etc.)

chronic pathologies of bone and cartilage

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.

Osteoporotic bone is quite porous.
Loss of trabeculae: especially the horizontal trabeculae, with thickening of the vertical trabeculae.

Key Causes

Transformation from healthy bone to osteoporotic bone = dense, healthy bone long bone transforms to a thinned out, porous bone.
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.
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).
Deficiencies in calcium and vitamin D and excess parathyroid hormone are problematic – there are numerous causes for these deficiencies and for hyperparathyroidism.
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.
Genetic factors play a key role, as well, especially important is RANKL; RANKL been a target of reduction in bone loss therapy.
Two key modifiable risk factors for osteoporosis: tobacco abuse and glucocorticoid (ie, steroid) administration.
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:

Two key modalities are:

Osteoporosis Therapeutics

Let's use the therapeutics of osteoporosis to review its pathogenesis.

Mainstays of treatment and prevention involve:

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

Aka, ostetitis deformans, creates INCREASED but disordered bone mass, which begins ~ age 70 (hence "osteitis deoformans")
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.
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.

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 show 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
Renal corpuscle, then the proximal tubule, nephron loop, distal tubule, and collecting duct.
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).
In chronic renal failure, there is a loss of activated vitamin D (1,25-OH2-vitamin-D3) and thus a reduction in calcium.
This, in combination with hyperphosphatemia, leads to hyperparathyroidism, which causes further bone destruction and bone loss.

Rickets vs. osteomalacia

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

hyperparathyroidism

Hyperparathyroidism is an important cause of bone pathology.

In the histology slide, we can see an osteoclast, which is chewing up bony matrix.
Basic physiology of bone remodeling:
Both Vitamin D and Parathyroid hormone (PTH) stimulate osteoblasts to secrete factors that promote osteoclastogenesis.
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 are dome-shaped, in sites of active bone resorption, including the bony matrix.

As we can imagine, if left unchecked, hyperparathyroidism leads to unabated osteoclast-mediated destruction of bone.