Parathyroid hormone, calcium and bone

Question 1

Functions of the skeleton

Answer 1

• mechanical; provides support and muscle attachments
• protective; for organs and bone marrow
• metabolic; ion homeostasis, especially calcium and phosphate

Question 2

Structure of bone

Answer 2

Bone is made of specialised connective tissue. The extracellular matrix is able to calcify via mineralisation, which occurs with formation of hydroxyapatite crystals. The fibres are collagen (90%) and non-collagenous proteins (osteocalcin, osteonectin, osteopontin). Several types of cells are present.

Question 3

Types of bone

Answer 3

• compact (cortical) bone; a hard outer layer that is dense, strong and durable
• cancellous (trabecular/spongy) bone; lighter, less dense and more flexible, consisting of a network of trabeculae

Question 4

Cell types in bone

Answer 4

• osteocytes; embedded in the calcified bone matrix, have long processes
• osteoblasts; bone forming cells
• osteoclasts; bone resorbing cells

Question 5

Osteoblasts

Answer 5

Bone forming cells, which produce matrix components and aid calcification. These originate from mesenchymal stem cells. Markers are alkaline phosphatase and osteocalcin.

Question 6

Osteoclasts

Answer 6

Bone resorbing cells, which produce acid to resorb mineral and enzymes to resorb the matrix. They eat away at bone from the surface inwards, at resorption pits/lacunae. These cells originate from the bone marrow lineage, so are multinucleate. They bind to bone via integrins. Markers are carbonic anhydrase, tartrate-resistant acid phosphatase (TRAP), RANK and the calcitonin receptor.

Question 7

Osteoclast activation

Answer 7

Osteoblasts can activate osteoclast precursor cells via the RANK ligand/receptor interaction. The expression of the RANK ligand by osteoblasts is regulated by factors such as vitamin D, parathyroid hormone and prostaglandins.

Question 8

Osteoclast inhibition

Answer 8

A decoy receptor called osteoprotegrin (OPG) dampens the activation of osteoclasts by binding to the RANK ligand. It’s expression is regulated by factors such as oestrogens, IL-4 and TGFb.

Denosumab is an anti-osteoporotic drug which acts as a monoclonal antibody for the RANK ligand.

Question 9

Bone remodeling

Answer 9

Bone is a dynamic living tissue, constantly being resorbed and formed via the activity of osteoblasts and osteoclasts. In adults, the entire skeleton is replaced every ~10 years, and peak bone mass is reached around 20-30y. Remodeling allows the body to fix damaged sections, reshape the skeleton during growth, and regulate calcium levels. It is under the control of several hormones, including parathyroid hormone, calcitonin, vitamin D, estrogen in women, and testosterone in men.

Question 10

Vitamin D

Answer 10

A fat soluble steroid with hormonal activity. It is important for bone development and metabolism and works together with parathyroid hormone (PTH) to maintain bone health.

Question 11

Functions of vitamin D

Answer 11

• calcium absorption in bowel
• maintaining serum calcium and phosphate levels
• osteoid mineralisation and bone remodelling
• neuromuscular function
• immune function
• reduction of inflammation

Question 12

Sources of vitamin D

Answer 12

Vitamin D3 (calciol, cholecalciferol) is synthesised from cholesterol in the skin upon exposure to UV, and is also found in some animal products/fortified foods eg. oily fish, eggs, milk, cereals.

Vitamin D2 (ergocalciferol) is found in some plant foods, eg. mushrooms.

Question 13

Physiology of vitamin D

Answer 13

In the liver, vitamin D is converted by 25-hydroxylase into 25-hydroxy-vitamin D (calcidiol), which is released into the blood and binds to vitamin D binding proteins. This is the major storage form of vitamin D, mainly produced during the summer.

In the kidneys, 1-alpha hydroxylase produces 1,25-dihydroxy-vitamin D (calcitriol) in response to low blood calcium or phosphate levels. This is the biologically active form of vitamin D.

Question 14

Risk factors for vitamin D deficiency

Answer 14

• living in northern latitude
• excessive suncream use/covering clothing
• air pollution (reduced UVB)
• obesity
• pregnancy, breastfeeding and infancy
• being older/housebound
• bowel disease (absorption issues)
• dark skin pigmentation

Question 15

Presentation of vitamin D deficiency

Answer 15

Mostly asymptomatic, presents if deficiency is prolonged:

• tingling numbness + very late tetany
• muscle pain + proximal weakness
• seizures
• hypocalcaemic dilated cardiomyopathy (infants)
• osteomalacia: fractures, back and pelvis pain
• rickets (children): soft, pliable bones

Question 16

Investigations for vitamin D deficiency

Answer 16

The first line investigation for vitamin D deficiency is serum 25-hydroxy-vitamin D, or 1,25-dihydroxy-vitamin D levels in patients with renal disease.

• <25-30nmol/L = deficiency
• > 50nmol/L = sufficiency

Question 17

Treatment for vitamin D deficiency

Answer 17

Vitamin D replacement is considered if serum 25(OH)D levels are <25nmol/L, or 25-50nmol/L if other criteria are met. Treatment with vitamin D3 is preferred, but vitamin D2 is also suitable. A high loading dose is used to quickly correct the deficiency, then a lower maintenance dose is given.

Question 18

Osteoporosis

Answer 18

A metabolic bone disease secondary to an imbalance between bone breakdown and remodelling (osteoclast and osteoblast activity). Reduced bone mass and structural deterioration leads to increased bone fragility and susceptibility to fracture.

Question 19

Risk factors for primary osteoporosis

Answer 19

• old age
• prolonged immobility
• menopause

Question 20

Risk factors for secondary osteoporosis

Answer 20

• low BMI
• steroid use
• tobacco and alcohol
• endocrine conditions (eg. diabetes, Cushing’s disease, hypogonadism, hyperthyroidism, hyperparathyroidism)
• liver or renal failure
• dietary deficiencies (eg. calcium, protein)

Question 21

Investigation of osteoporosis

Answer 21

Osteoporosis is asymptomatic, and generally not found until injury occurs. Assessment of osteoporosis includes calculating 10y fracture risk. If intermediate or high (=/>10%), a dual-energy X-ray absorptiometry (DXA) scan can be used to measure bone mineral density (BMD).

Question 22

Prevention of osteoporosis

Answer 22

If fracture risk is low/intermediate, prevention may be with lifestyle changes, such as a nutrient-rich diet, exercise, reduction of alcohol and tobacco, and maintaining a healthy BMI.

Question 23

Parathyroid hormone (PTH)

Answer 23

PTH is released by the parathyroid glands in response to low calcium levels. It has 3 main actions:

• increasing osteoclast activity (bone resorption) and increasing Ca and PO4 release from bones
• increasing Ca and decreasing PO4 absorption in the kidneys
• increasing active vitamin D (1,25(OH)2D) by activating 1-alpha-hydroxylase in the kidneys

Question 24

Types of hyperparathyroidism

Answer 24

Primary: the parathyroid gland produces excess PTH, independently of calcium levels, due to adenoma or hyperplasia.

Secondary: hypocalcaemia causes excess PTH to be released. Commonly caused by chronic kidney disease or vitamin D deficiency.

Tertiary: prolonged secondary hyperparathyroidism results in the glands acting autonomously, leading to hypercalcaemia.

Question 25

Presentation of hyperparathyroidism

Answer 25

Most cases are asymptomatic and are found incidentally. Symptoms are usually a manifestation of hypercalcaemia:

• STONES: renal calculi, raised GFR, polyuria, nocturia, thirst
• BONES: pain from demineralisation, low BMD
• GROANS: nausea and vomiting, constipation, indigestion
• MOANS: lethargy, fatigue, confusion, depression

Question 26

Investigation of hyperparathyroidism

Answer 26

Biochemical analysis is used to diagnose hyperparathyroidism:

• elevated PTH is found in all types.
• primary/tertiary; high Ca, low/normal PO4, low vitamin D
• secondary; low Ca, low/normal PO4, low vitamin D

Question 27

Treatment of hyperparathyroidism

Answer 27

Primary: parathyroidectomy (98-99% cure rate, complications include hypoparathyroidism and recurrent laryngeal nerve damage).

Secondary: vitamin D supplementation in deficiency, 1,25-dihydroxy-vitamin D and phosphate binders in renal failure

Tertiary: surgery/calcimimetics