Osteoporosis
MRS RISHITA D PATEL

Osteopenia and Osteoporosis
• The term osteopenia refers to decreased bone mass, and osteoporosis
is defined as osteopenia that is severe enough to significantly increase
the risk of fracture.
• Radiographically, osteoporosis is considered bone mass at least 2.5
standard deviations below mean peak bone mass in young adults and
osteopenia as 1 to 2.5 standard deviations below the mean atraumatic
or vertebral compression fracture signifies osteoporosis.

• The disorder may be localized to a certain bone or region,
as in disuse osteoporosis of a limb, or may involve the entire skeleton,
as a manifestation of a metabolic bone disease.
• Generalized osteoporosis, in turn, may be primary or secondary to a
large variety of conditions.

Pathogenesis
• Peak bone mass is achieved during young adulthood. Its magnitude is
determined largely by hereditary factors, especially polymorphisms in the
genes that influence bone metabolism
• Physical activity,
muscle strength, diet, and
hormonal state also make important contributions.

• Once maximal skeletal mass is attained, a small deficit in bone
formation accrues with every resorption and formation cycle of each
bone metabolic unit.
• Accordingly, age-related bone loss, which may average 0.7% per year, is
a normal and predictable biologic phenomenon.
• Both sexes are affected equally and whites more so than blacks.

1. Age-related changes
• Bone cells and matrix have a strong impact on bone metabolism.
• Osteoblasts from older individuals have reduced proliferative and
biosynthetic potential when compared with osteoblasts from younger
individuals.
• Also, the cellular response to growth factors bound to the extracellular
matrix becomes attenuated in older individuals.
• The net result is a diminished capacity to make bone.
• This form of osteoporosis, known as senile osteoporosis, is categorized
as a low-turnover variant.

2. Reduced physical activity
• Increases the rate of bone loss in experimental animals and humans,
because mechanical forces stimulate normal bone remodeling.
• The decreased physical activity that is associated with normal aging
contributes to senile osteoporosis.

3. Genetic factors
• Account for only a small fraction of cases.
• Polymorphisms in other genes may account for the variation in peak bone
density within a population.
• In genome-wide association studies, the top associated genes include
RANKL, OPG, and RANK, all of which encode key regulators of osteoclasts.
• Also associated are the HLA locus (perhaps reflecting the effects of
inflammation on calcium metabolism) and the estrogen receptor gene.

4. Calcium nutritional state
• Contributes to peak bone mass.
• Adolescent girls (more than boys) tend to have insufficient calcium
intake in the diet.
• This calcium deficiency occurs during a period of rapid bone growth,
restricting the peak bone mass ultimately achieved.
• Thus, these individuals are at greater risk of developing osteoporosis.
• Calcium deficiency, increased PTH concentrations, and reduced levels
of vitamin D may also have a role in the development of senile
osteoporosis.

5. Hormonal influences
• Postmenopausal osteoporosis is characterized by an acceleration of
bone loss.
• In the decade after menopause, yearly reductions in bone mass may
reach up to 2% of cortical bone and 9% of cancellous bone.
• Women may lose as much as 35% of their cortical bone and 50% of
their cancellous bone by 30 to 40 years after menopause.
• It is thus no surprise that post-menopausal women suffer
osteoporotic fractures more commonly than men of the same age.
• Estrogen deficiency plays the major role in this phenomenon and
close to 40% of postmenopausal women are affected by
osteoporosis.

• Decreased estrogen levels after menopause actually increase both bone
resorption and formation but the latter does not keep up with the former,
leading to high-turnover osteoporosis.
• The decreased estrogen appears to increase secretion of inflammatory
cytokines by blood monocytes and bone marrow cells.
• These cytokines stimulate osteoclast recruitment and activity by increasing
the levels of RANKL, diminishing the expression of OPG gene, decreasing
osteoclast proliferation and preventing osteoclast apoptosis.
• Cytokines such as IL-6, TNF-α, and IL-1 have also been implicated in
postmenopausal osteoporosis, either independently or as downstream
mediators of estrogen signaling.

MORPHOLOGIC FEATURES
• Except disuse or immobilisation osteoporosis which is localised to the
affected limb, other forms of osteoporosis have systemic skeletal
distribution.
• Most commonly encountered osteoporotic fractures are: vertebral
crush fracture, femoral neck fracture and wrist fracture.
• There is enlargement of the medullary cavity and thinning of the
cortex.
• Histologically, osteoporosis may be active or inactive type

Active osteoporosis
is characterized by increased bone resorption and formation i.e.
accelerated turnover.
There is an increase in the number of osteoclasts with increased
resorptive surface as well as increased quantity of osteoid with
increased osteoblastic surfaces.
The width of osteoid seams is normal.

Inactive osteoporosis
has the features of minimal bone formation and reduced resorptive
activity i.e. reduced turnover.
Histological changes of inactive osteoporosis include decreased
number of osteoclasts with decreased resorptive surfaces, and
normal or reduced amount of osteoid with decreased osteoblastic
surface.
The width of osteoid seams is usually reduced or may be normal

• The prevention and treatment of senile and postmenopausal
osteoporosis includes exercise, appropriate calcium and vitamin D
intake, and pharmacologic agents, most commonly bisphosphonates,
which reduce osteoclast activity and induce apoptosis.
• Although menopausal hormone therapy has been used to prevent
fracture, complications, particularly deep venous thrombosis and
stroke, have prompted search for more selective estrogen receptor
modulators.
• Denosumab, an anti-RANKL antibody, has shown promise in treating
some forms of postmenopausal osteoporosis.
• Other novel investigational therapeutic approaches include anti-
sclerostin antibodies and cathepsin K inhibitors.

Gout
• GOUT AND GOUTY ARTHRITIS
• Gout is a disorder of purine metabolism manifested by the following
features, occurring singly or in combination:
1. Increased serum uric acid concentration (hyperuricemia).
2. Recurrent attacks of characteristic type of acute arthritis in which
crystals of monosodium urate monohydrate may be demonstrable in
the leucocytes present in the synovial fluid.
3. Aggregated deposits of monosodium urate monohydrate (tophi) in and
around the joints of the extremities.
4. Renal disease involving interstitial tissue and blood vessels.
5. Uric acid nephrolithiasis.

• The disease usually begins in 3rd decade of life and affects men more
often than women.
• A family history of gout is present in a fairly large proportion of cases
indicating role of inheritance in hyperuricaemia.
• Clinically, the natural history of gout comprises 4 stages:
• asymptomatic hyperuricaemia,
• acute gouty arthritis,
• asymptomatic intervals of intercritical periods, and
• chronic tophaceous stage. I

TYPES AND PATHOGENESIS
• The fundamental biochemical hallmark of gout is hyperuricaemia.
• A serum uric acid level in excess of 7 mg/dl, which represents the upper limit
of solubility of monosodium urate in serum at 37°C at blood pH, is associated
with increased risk of development of gout.
• Thus, pathogenesis of gout is pathogenesis of hyperuricaemia.
• Hyperuricemia and gout may be classified into 2 types:
metabolic and renal, each of which may be primary or secondary. Primary
refers to cases in which the underlying biochemical defect causing
hyperuricaemia is not known,
while secondary denotes cases with known causes of hyperuricaemia.

1. Hyperuricaemia of metabolic origin:
• This group comprises about 10% cases of gout which are
characterised by there is either an accelerated rate of purine
biosynthesis, or an increased turnover of nucleic acids.
• The causes of primary metabolic gout include a number of specific
enzyme defects in purine metabolism which may be either of
unknown cause or are inborn errors of metabolism.
• The secondary metabolic gout is due to either increased purine
biosynthesis or a deficiency of glucose-6-phosphatase.

• 2. Hyperuricaemia of renal origin:
• About 90% cases of gout are the result of reduced renal excretion of
uric acid.
• Altered renal excretion could be due to reduced glomerular filtration
of uric acid, enhanced tubular reabsorption or decreased secretion.
• The causes of gout of renal origin include diuretic therapy, drug-
induced (e.g. aspirin, pyrazinamide, nicotinic acid, ethambutol and
ethanol), adrenal insufficiency, starvation, diabetic ketosis, and
disorders of parathyroid and thyroid.
• Renal disease rarely causes secondary hyperuricaemia such as in
polycystic kidney disease and leads to urate nephropathy.

MORPHOLOGIC FEATURES
• The pathologic manifestations of gout include:
• acute gouty arthritis, chronic tophaceous arthritis, tophi in soft
tissues, and renal lesions as under:
1. Acute gouty arthritis This stage is characterised by acute synovitis
triggered by precipitation of sufficient amount of needle-shaped
crystals of monosodium urate from serum or synovial fluid.
There is joint effusion containing numerous polymorphs, macrophages
and microcrystals of urates.

• The mechanism of acute inflammation appears to include
phagocytosis of crystals by leucocytes, activation of the kallikrein
system, activation of the complement system and urate-mediated
disruption of lysosomes within the leucocytes leading to release of
lysosomal products in the joint effusion.
• Initially, there is monoarticular involvement accompanied with
intense pain, but later it becomes polyarticular along with
constitutional symptoms like fever.
• Acute gouty arthritis is predominantly a disease of lower extremities,
affecting most commonly great toe. Other joints affected, in order of
decreasing frequency, are: the in step, ankles, heels, knees, wrists,
fingers and elbows.

2. Chronic tophaceous arthritis
• Recurrent attacks of acute gouty arthritis lead to progressive
evolution into chronic arthritis.
• The deposits of urate encrust the articular cartilage.
• There is synovial proliferation, pannus formation and progressive
destruction of articular cartilage and subchondral bone.
• Deposits of urates in the form of tophi may be found in the
periarticular tissues.

3. Tophi in soft tissue
• A tophus (meaning ‘a porous stone’) is a mass of urates measuring a few
millimeters to a few centimeters in diameter.
• Tophi may be located in the periarticular tissues as well as
subcutaneously such as on the hands and feet.
• Tophi are surrounded by inflammatory reaction consisting of
macrophages, lymphocytes, fibroblasts and foreign body giant cells.

4. Renal lesions Chronic gouty arthritis frequently involves the kidneys.
• Three types of renal lesions are described in the kidneys: acute urate
nephropathy, chronic urate nephropathy and uric acid nephrolithiasis.
i) Acute urate nephropathy is attributed to the intratubular deposition of
monosodium urate crystals resulting in acute obstructive uropathy.
ii) Chronic urate nephropathy refers to the deposition of urate crystals in
the renal interstitial tissue.
iii) Uric acid nephrolithiasis is related to hyperuricaemia resulting in
hyperuric acid uria.