metabolic bone diseases

METABOLIC BONE DISEASES

• Calcium and Phosphate ion regulation• Vitamin D metabolism and absorption• Effects of active vitamin D• PTH (primary, secondary, tertiary)• Paget’s disease (classification, clinical

manifestations, treatment)• Rickets (classification, clinical

manifestations, treatment)

Bone remodeling (bone metabolism)

• A lifelong process where mature bone tissue is removed from the skeleton (a process called bone resorption) and new bone tissue is formed (a process called ossification or new bone formation).

Bone remodeling occurs in four steps:

1. Activation,

2. Osteoclast resorption,

3. Surface preparation,

4. Building new bone tissue.

Metabolic Bone Disorders

• Metabolic bone diseases are disorders of bone strength, usually caused by abnormalities of minerals (such as calcium or phosphorus), vitamin D, bone mass or bone structure. 

• At times occur because bone formation and remodelling is not prioritized if the materials are required more urgently somewhere else (e.g. muscle contraction and coagulation).

Calcium and Phosphate regulation

• Following two are responsible for the regulation and supply of calcium and phosphate for the bone formation:

1. Active Vitamin D (1,25, Dihydrocholecalciferol)

2. Parathyroid Hormone

Vitamin D metabolism

1,25-dihydroxycholecalciferol

• Increases absorption of calcium from intestines.• Increase absorption of phosphate from the intestines. • Decreases calcium excretion in the kidney.• PTH production supression.• Regulates Osteoblast function.• Facilitate PTH induced Osteoclast function.

OVER ALL: • Increases calcium in blood.• Increases PO4 in blood.• Aids bone formation.

Vitamin D sources

Parathyroid Hormone

• Increases renal reabsorption of calcium.• Releases calcium from skeletal stores.• Increases the bone resorption of calcium.• Decreases renal reabsorption of phosphate.• Increases the bone resorption of phosphate.

OVER ALL:• Increases serum calcium levels.• Bone resroption (chronic continuous excess).

Hyperparathyroidism• Hyperparathyroidism is overactivity of the parathyroid glands resulting

in excess production of parathyroid hormone (PTH). The parathyroid hormone regulates calcium and phosphate levels and helps to maintain these levels.

Primary hyperparathyroidism

• Primary hyperparathyroidism causes hypercalcemia (elevated blood calcium levels) through the excessive secretion of parathyroid hormone (PTH), usually by an adenoma (benign tumors) of the parathyroid glands. It is the commonest cause of elevated calcium levels.

• “Stones" refers to kidney stones, nephrocalcinosis, and diabetes insipidus (polyuria and polydipsia). These can ultimately lead to renal failure.

• "Bones" The classic bone disease in hyperparathyroidism is osteitis fibrosa cystica, which results in pain and sometimes pathological fractures. Other bone diseases associated with hyperparathyroidism are osteoporosis, osteomalacia, and arthritis.

• "Abdominal groans” of constipation, indigestion, nausea and vomiting. Hypercalcemia can lead to peptic ulcers and acute pancreatitis. The peptic ulcers can be an effect of increased gastric acid secretion by hypercalcemia.

• "Psychiatric moans" lethargy, fatigue, depression, memory loss, psychosis, ataxia, delirium, and coma.

• "Thrones" refers to polyuria and constipation

• Left ventricular hypertrophy.

• Other signs include proximal muscle weakness, itching, and band keratopathy of the eyes.

• Labs: Serum calcium levels are elevated, and the parathyroid hormone level is abnormally high compared with an expected low level in response to the high calcium. A relatively elevated parathyroid hormone has been estimated to have a sensitivity of 60%-80% and a specificity of approximately 90% for primary hyperparathyroidism. Serum phosphorus will decrease.

• Imaging: radio labeled technitium 99m remains in adenomas.

• Treatment: usually surgical removal of the gland(s) containing adenomas, but medication may also be required.

The brown tumor is a bone lesion that arises in settings of excess osteoclast activity, such as hyperparathyroidism. 

Secondary hyperparathyroidism

• Secondary hyperparathyroidism refers to the excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia (low blood calcium levels) and associated hypertrophy of the glands. This disorder is especially seen in patients with chronic renal failure.

• Clinical features: Bone and joint pain are common, as are limb deformities. The elevated PTH has also pleiotropic effects on blood, immune system and neurological system.

• Labs: The PTH is elevated due to decreased levels of calcium or 1,25-dihydroxy-vitamin D3. It is usually seen in cases of chronic renal disease or defective calcium receptors on the surface of parathyroid glands. Serum phosphorus will increase.

• Treatment: If the underlying cause of the hypocalcemia can be addressed, the hyperparathyroidism will resolve.

• In patients with chronic renal failure, treatment consists of dietary restriction of phosphorus, supplements with an active form of vitamin D such as calcitriol, Hectorol, Zemplar(paricalcitol), etc. and phosphate binders which can be divided into calcium-based and non-calcium based.

Subperiosteal resorption

Thirty year-old patient with chronic renal failure and elevated parathyroid hormone.

Subperiosteal resorption is most evident on the radial sides of proximal and middle phalanges.

Note the shaggy outer cortical surface in the mid-to-distal shaft of the middle finger proximal phalanx.

Tertiary hyperparathyroidisim

• Tertiary hyperparathyroidism is a state of excessive secretion of parathyroid hormone (PTH) after a long period of secondary hyperparathyroidism and resulting in hypercalcemia. It reflects development of autonomous (unregulated) parathyroid function following a period of persistent parathyroid stimulation.

• Serum calcium increases. PTH levels are increased. Serum phosphorus remains increased.

• The basis of treatment is still prevention in chronic renal failure, starting medication and dietary restrictions long before dialysis treatment is initiated. Cinacalcet has greatly reduced the number of patients who ultimately require surgery for secondary hyperparathyroidism; however, 5% of patients do not respond to medical therapy.

• When secondary hyperparathyroidism is corrected and the parathyroid glands remain hyperfunctioning, it becomes tertiary hyperparathyroidism. The treatment of choice is surgical removal of three and one half parathyroid glands.

Paget’s disease of the bone

• Paget Disease of Bone, or osteitis deformans, is a condition of older individuals characterized by progressive skeletal deformation due to problems in bone resorption and remodeling. Likely due to a viral infection, it stimulates an increase in osteoclast activity. This leads to increased bone resorption coupled with abnormal and excessive bone remodeling.

• It is relatively common and can affect up to 4% of individuals over 40 and up to 11% over the age of 80 1. There may a slight male predilection.

Clinical features• Paget Disease is often asymptomatic and may take

months to years to diagnose. Skeletal bone deformity and enlargement may be the first presentation. 

• localised pain and tenderness• increased focal temperature due to hyperaemia (due

to hypervascularity)• increased bone size: historically changing hat size

was a give-away• bowing deformities• kyphosis of the spine• decreased range of motion

Stages

There are three stages classically described (but is part of continuous spectrum)

• lytic (incipient active): predominated by osteoclastic activity• mixed (active): osteoblastic as well as osteoclastic activity• sclerotic/blastic (late inactive)

Markers• serum alkaline phopatase (ALP) elevated• urine hydroxyproline increase

Imaging • Xray (skull, pelvis, humerus, femur)• CT scan (Vertebrae, Skull)• MRI • Bone Scan

Complications• osseous weakening resulting in deformity and fractures• arthritis• neural compression

– deafness is the most common complication– cranial nerve paresis may occur– basilar invagination may occur in advanced cases with 

hydrocephalus orbrainstem compression• secondary development of tumours (e.g. osteosarcoma: ≈1%

of cases), which is often highly resistant to treatment• high output congestive cardiac failure• hyperparathyroidism (~10%)

Treatment • Calcitonin – Inhibits osteoclast formation.• Bisphosphonates – Induces apoptosis of osteoclasts.

Sites of involvement• Usually polyostotic and asymmetric

– Pelvis (75%) most common, followed by:• Lumbar spine• Thoracic spine• Proximal femur• Calvarium• Scapula• Distal femur• Proximal tibia• Proximal humerus

This 92 year-old male patient presented for assessment of acute hemiparesis.

An incidental finding was marked thickening of the calvarium.

The diploic space is widened and there are ill-defined sclerotic and lucent areas throughout.

The cortex is thickened and irregular.

The findings probably correspond to the “cotton wool spots” seen on plain films in the later stages of Paget’s disease.

Paget's disease of the skull.

Demonstrate the Tam O'Shanter sign

Bone scan demonstrates intense uptake involving several lower thoracic vertebrae, L3, right hemipelvis, sacrum, left proximal femur and right knee.  

There is expansion and bowing of the involved femur.

There is osseous expansion, coarsened trabeculae, thickened cortex, and increased density of the right 5th rib.

Paget disease of the distal femur in an 80 year old male characterized by cortical thickening and coarsened bony trabeculae.

There is mild loss of medial tibiofemoral compartment joint space without secondary degenerative features.

Lateral radiograph of the tibia in a patient with Paget sarcoma reveals a destructive bone-forming mass in the proximal tibia (osteosarcoma).

Blade of grass sign (candle flame appearance) in lytic phase Paget's disease of bone.

Rickets• Rickets is the softening and weakening of bones in

children, usually because of an extreme and prolonged vitamin D deficiency.

• Vitamin D promotes the absorption of calcium and phosphorus from the gastrointestinal tract. A deficiency of vitamin D makes it difficult to maintain proper calcium and phosphorus levels in bones, which can cause rickets.

• If a vitamin D or calcium deficiency causes rickets, adding vitamin D or calcium to the diet generally corrects any resulting bone problems for your child. Rickets due to a genetic condition may require additional medications or other treatment. Some skeletal deformities caused by rickets may need corrective surgery.

Signs and symptoms of rickets may include:• Bone pain or tenderness

– Arms, Legs, Pelvis, Spine• Dental deformities• Impaired growth• Increased bone fractures• Muscle cramps• Short stature (adults less than 5 feet tall)• Skeletal deformities

– Asymmetrical or odd-shaped skull– Bowlegs– Bumps in the ribcage (rachitic rosary)– Breastbone pushed forward (pigeon chest)– Pelvic deformities– Spine deformities (spine curves abnormally, including 

scoliosis or kyphosis)

Risk factors• Age Children 3 to 36 months old are most at risk of rickets

because their skeletons are growing so rapidly.• Dark skin Dark skin doesn't react as strongly to sunshine as

does lighter colored skin, so it produces less vitamin D.• Northern latitudes Children who live in geographical

locations where there is less sunshine are at higher risk of rickets.

• Premature birth Babies born before their due dates are more likely to develop rickets.

• Anti-seizure medications. Certain types of anti-seizure medications appear to interfere with the body's ability to use vitamin D.

• Exclusive breast-feeding Breast milk doesn't contain enough vitamin D to prevent rickets. Babies who are exclusively breast-fed should receive vitamin D drops.

Angular deformities

Cupping of radius and ulna

Complications• If left untreated, rickets may lead to:• Failure to grow• Abnormally curved spine• Skeletal deformities• Dental defects

• Seizures

Labs• Serum calcium may show low levels of calcium, serum 

phosphorus may be low, and serum alkaline phosphatase may be high from bones or changes in the shape or structure of the bones. This can show enlarged limbs and joints.

• Bone biopsy is rarely performed but will confirm rickets.

Treatment• Replacing calcium, phosphorus, or vitamin D that is

lacking will eliminate most symptoms of rickets. Dietary sources of vitamin D include fish, liver, and processed milk.

• Exposure to moderate amounts of sunlight is encouraged. If rickets is caused by a metabolic problem, a prescription for vitamin D supplements may be needed.

• 400 international units (IU) of vitamin D a day for infants and children.

• Positioning or bracing may be used to reduce or prevent deformities. Some skeletal deformities may require corrective surgery.

Photos of a child with Blount's Disease in a brace.

Blount's disease is a growth disorder of the tibia (shin bone) that causes the lower leg to angle inward, resembling a bowleg.It is also known as "tibia vara".[1]

• In surgical correction of Blount’s disease, the pediatric orthopedist performs an osteotomy, cutting the tibia and fibula as close to the growth plate as possible and realigning the bones. Following the procedure, the surgeon places a fixator on the leg to maintain proper alignment during healing.

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