Calcium, Vitamin D and bone density

Physiology: Calcium, Vitamin D and bone density

Calcium

-          99% in bone, 1% in blood

-          Obtained through diet (mainly dairy products), absorption controlled by vitamin D.

Calcium Regulation

-          Controlled by Parathyroid hormone, secreted from the parathyroid gland.

-          An increase in PTH, will cause an increase in calcium levels in the blood. This occurs my two main mechanisms:

o   Decreasing calcium secretion by the kidneys

§ This results in a increased secretion of phosphate ions

o   Increasing calcium absorption from bone, by action on osteocytes

Cell	Info	Function
Osteoblast	Found on the surface of bone. Constantly active, and depositing new bone tissue.	Produce osteoid – which is a collagen based material, which makes up the raw material of bone. These cells also help mineralise the bone to give it its strength.normal bone is about 30% osteoid, and 70% mineral salts (mainly calcium and phosphate).  There is a reduction in number of osteoblasts with age
Osteoclast	Found within the bone matrix. Constantly active and reabsorbing bone tissue	Remove bone tissue, and allow bone remodelling. Usually, at any one time, 1% of bone is being reabsorbed by osteoclasts. When when the bone is reabsorbed, the products of the reabsorption do not go straight into the ECF, instead they are trapped behind the osteocyctic membrane system.
Osteocyte	Essentially an osteoblast that has become trapped in the bone matrix. Found throughout bone, but most importantly, help form the osteocytic membrane system. This is a thin membrane that covers the bone, and separates bone from extracellular fluid.	Through the osteocytic membrane system, helps to regulate the concentration of solutes in the fluid around bone. PTH acts on these cells to increase the amount of calcium pumped out of the bone fluid system.

Normal bone formation

1)      Osteoid is made by osteoblasts. Consists of 95% collagen, and hyaluronic acid, and peptidoglycans. Collagen fibres tend to run lengthways in bone. Osteoid is very similar to cartilage, however, its structure allows salts to rapidly precipitate within it.

2)      Mineralisation – the main salt that forms contain both calcium and phosphate, and is called hydroxyapatite. Initially the crystals that form are not hydrozyapatitie, but over weeks and months, they will gradually be converted to this form. The precursor forms are knwon as amourphous crystals. These crystals can be rapidly reabsorbed if calcium is needed in the circulation.

a.       Calcium and phosphate will naturally form crystals once their concentrations are over a certain level. In normal ECF and other fluids, there are inhibitors of crystal formation that prevent calcium and phosphate forming crystals, despite their high concentration. In the fluid around bone behind the oesteocytic membrane system, these inhibitors are not present.

Normal Bone reabsoprtion

This is constantly occurring, and happens on about 1% of bone at any one time. Osteocytes have a ruffled border which is in direct contact with the bone matrix. They secrete:

-          Enzymes – which break down the osteoid

-          Acid – including lactic acid, which breaks down the mineral crystals

Osteoclasts also phagocytose fragments of bone crystal to help break them down, before releasing the products.

Ongoing process

Normally (except when we are growing) bone deposition and bone absorption occur at the same rate. Osetoclasts will absorb bone in little cylindrical ‘tunnels’ a few mm in length. This process takes about 3 weeks. Osteoblasts will the deposit bone matrix in concentric layers around the central lamina, until they encroach on a blood vessel, that is often at the centre of one of these holes. The areas around the blood vessel is known as the Haversian canal. The new area of bone that has been deposited is known as an osteon, and this process takes several months.

Why does bone remodelling occur?

-          It allows the alteration of bone strength in relation to the weight bearing the bone has to perform

-          It allows reshaping of the bone in relation to stress patterns

-          Old organic material in bone degenerates, making old bone weaker than new bone

o   In children, rates of remodelling are fast – and they have strong bones

o   In the elderly, rates are much slower, and bones are more brittle

Fractures

At the site of a fracture, osteoprogenitor cells will rapidly differentiate to form large numbers of osteoblasts, to aid the rapid reformation of bone. An organic matrix between the two bone ends will quickly be formed. This is known as a callus. This will then gradually be mineralised over the following weeks and months.

Stress on a bone site increases the rate of new bone formation. Surgeons can manipulate this effect, and in some fractures, the bones are held together strongly to create the impression of stress, so the fracture will heal more quickly.

Vitamin D regulation

Vitamin D has two important effects:

-          Increasing calcium absorption from the GI tract

-          Alteration of bone deposition and absorption

However, it does not exhibit either of these effects directly, and has to be converted to another substance first.

Production of vitamin D₃ (aka cholecalciferol)

There are various vitamin D coumpounds, and they all perform roughly the same function. The most important is D₃.

Vitamin D is produced when 7-dehydrocholesterol in the skin, comes into contact with UV light. It can also be absorbed in the diet.

-          Conversion in the liver – D3 is converted to 25- hydrocycalciferol in the liver. This product is slightly active. This has several benefits:

o   Regulates the level of active vitamin in the blood – even with very high vitamin D intake/production, there is a limit as to how much the liver can convert, thus it stops levels getting too high.

o   Is not stored for very long – again limiting the amount of the active substance in the blood. Vitamin D on the other hands, can be stored for months.

-          Conversion in the kidney – from 25-h, to 1,25-dihydroxycalciferol. This is the most active product, 1000 time more active than 25-h.

o   This production is dependent on PTH – in the absence of PTH, it does not occur.

Regulation of vitamin D levels

-          1,25-dhc in the kidneys production is directly related to calcium concentration in the plasma. The higher the calcium concentration, the less 1,25-dhc is produced. This leads to reduced absorption of calcium from the GI tract, and increased secretion by the kidney, as secondary effects of reduced vitamin D3 activity.

Effect on bone

-          Moderate levels of 1,25-dhc cause increased bone mineralisation

-          Very high levels of 1,25-dhc cause bone absoprtion

For more info on calcium regulation, and bone remodelling, see osteoporosis

Notes by Tom Leach

Osteoporosis

Osteoporosis Notes

Osteoporosis is the most common bone disorder. It is a reduction in bone mass and alteration of bone structure, not just a reduction in bone density. The easiest way to measure the extent of the disease is with bone density scans.

The condition in itself is clinically silent, however, it massively increases the risk of fractures, which increases the risk of mortality.

Epidemiology

-          Most common bone disorder

-          Genetic factors are very important – in twins, concordance is 60-90%. Many genes have been implicated, and it is likely that numerous genes are involved.

o   Osterogenesis imperfecta is a type of monogenic osteoporosis that has been well described, but is rare compared to multigenic and multifactorial causes. OI actually comprises of 4 subtypes, which are classified by the presence of a blue sclera. In some cases, this is apparent in childhood, but may resolve with age. In some cases, affected children are born with multiple fractures. There is also often joint hypermobility, aortic root dilation (causing aortic regurg) and hearing loss. These secondary features are related to defects in collagen.

-          More common in women (4:1)

-          More common in Caucasian population than in other races

-          Affects 35% of the over 50’s in the UK

Causes

-          Post menopausal bone loss is the most common cause – this is related to oestrogen deficiency

-          Hyperparathyroidism

-          Malabsroption (e.g. coeliac’s disease)

-          Osteomalacia

o   Most commonly the result of vitamin D deficiency

-          Multiple myeloma

-          Hypopituitarism

Aetiology

-          Family history

-          Alcohol excess

-          Smoking

-          Amenorrhoea

-          Late menarche

-          Early menopause – including surgical menopause

-          Lack of weight bearing exercise

-          Drugs:

o   Corticosteroids

§ Including Cushing’s disease

o   Anticonvulsants

o   Heparin

o   Thyroxine

o   Extreme alcohol excess

-          Low calcium and/or vitamin D intake

Clinical features

-          Fracture

-          Reduced height (vertebral fracture)

-          Stooping posture – kyphosis, aka dowager’s hump – as a result of wedge shaped fractures of the vertebral bodies.

-           

Pathology

Essentially, there is loss of bone mass, despite normal mineralisation.

-          As opposed to osteomalacia – which occurs when bone is not being properly mineralised, despite the normal production of bone matrix.

Caused by a loss of coupling between bone deposition and bone absorption mechanisms. This can result in excess osetoclast activity, decreased osteoblast activity, or both. The process of mineralisation of new bone matrix remains normal.

Osteoporosis affects both trabecular (long thick bones, e.g. femur) and cortical bone (high surface area, think bones, e.g. spine). When it affects trabecular bones, reabsoprtion of bone is the main mechanism.

Post menopausal osteoporosis

This is the most common type of osteoporosis. Bone mass naturally declines with age. Peak bone mass occurs several years after puberty, and then steadily declines. In women, this decline is increased during and after menopause. This, coupled with the fact that women have a lower peak bone mass than men, means post-menopausal women are at particularly high risk.

Reduced levels of oestrogen mean that normal osteoclast and osteoblast activity is no longer in conjunction, and osteoclast activity slightly exceeds osteoblast activity, so that over time, bone mass is reduced.

Corticosteroid induced osteoporosis

Steroids affect bone density regulatory mechanisms at several places:

-          Decreased absorption of calcium from the gut

-          Decrease muscle mass – which can affect bone remodelling by altering the normal weight bearing stressors normally exerted on bone

-          Increasing osteoclast activity

Diagnosis

-          Bone mineral density two standard deviation BELOW the mean value for young adults of the same sex. This is assessed using a DEXA scan.

o   More mild reduction in bone density are classed as osteopenia. This is likely to progress to osteoporosis, so preventative measures may be initiated at this stage.

o   The BMD is assessed on a scale relative to 0.

§ >0 – better BMD than the reference

§ 0 to -1 – in the top 84% of the population

§ -1 to -2.5 – osteopenia

§ <-2.g - osteoporosis

-          Thyroid Function Test

-          Vitamin D levels

-          Myeloma screen

o   ESR

o   Serum immunoglobulins / electrophoresis

o   Urinary Bence Jones Protein

-          X-ray – not very sensitive or specific. Often osteoporosis only presents with a fracture, so you will end up doing one anyway!

-          Screening programs are not widely undertaken, as their efficacy is not proven

Complications

Fractures mainly depend on the type of bone affected by the osteoporosis. The lumbar vertebrae, wrist and the hip are the most commonly affected bones.

-          Vertebral fractures.

o   This can present ‘silently’, perhaps as an exaggerated kyphosis – Dowager’s Hump. This is particularly common in elderly women, and can also cause a reduction in height.

§ Only 30% of vertebral fractures are symptomatic

o   It may also present as acutely, especially when the nerves and nerve roots are involved.

§ Thoracic spine – pain radiates around the front of the torso

§ Lumbar spine – sciatic and femoral nerves may be involved.

§ Sudden onset back pain

§ 25% may feel nauseous and/or vomit

§ Localised tenderness

o   Management

§ Bed rest (1-2 weeks) may be helpful

§ TENS can relieve pain

§ Diazepam (muscle relaxant) may also be helpful

§ Initiate preventative treatments (calcitonin, bisphosphonates)

§ Physiotherapy

-          Non-spinal fractures

o   Managed in the standard way

Treatment

The aim of treatment is to reduce the risk of fracture.

Lifestyle changes

May be sufficient for some patients. Measures include:

-          Sufficient daily calcium intake – the equivalent to 1 pink of milk per day (1200-1500mg)

-          Smoking cessation

-          Reduction in alcohol intake

-          Increase weight bearing exercise

o   Not only increases bone density, but also helps to prevent falls.

o   At least 30 minutes weight bearing exercise 3x per week is needed to increase bone density

Drug treatments

-          NICE guidlines:

o   1^st line – use a bisphosphonate

o   2^nd line – if no improvement, try a different bisphosphonate

o   3^rd line – if no improvement, try strontium

Drug treatments can reduce the risk of fracture by up to 50%

Supplements

Many patients also receive dietary supplements as adjuncts to their pharmacological therapy:

-          Calcium

-          Vitamin D

Used alone, they reduce the risk of fracture only by 4%! In very elderly patients, for whom vit D deficiency is the main mechanism of bone density loss, they may be sufficient

  

Bisphosphonates – e.g. risedronate, clodronate, pamidronate, etidronate

The different drugs have similar mechanisms, but different efficacy. The most effective is usually pamidronate given IV. Etidronate is the least effective, and has to be given in higher doses, which increase the side effects.

The drugs are essentially analogues of pyrophosphate.

Mechanism

-          Bind to hydroxyapatite crystals in the bone, and are then taken up by osteoclasts – resulting in a high concentration of the drugs in these particular cells. Once within the cell they:

o   Cause apoptosis – by acting as analogues to ATP

o   Inhibit cholesterol synthesis mechanisms – which eventually results in apoptosis

o   Inhibit binding of the osteoclasts ruffled border to the bone surface – and thus the osteoclast cannot resorb the bone.

Pharmacokinetics

-          Poorly absorbed from the gut

-          Should be taken on an empty stomach – as they can bind to calcium in food, after which, the drug cannot be absorbed.

o   Only about 10% of the oral dose is absorbed under normal circumstances

o   Usually taken weekly, and with plenty of water.

-          Pamidronate is only available IV, all other agents only available as oral preparations

-          They are rapidly removed from the blood by the kidney, but as they bind to salts, they stay deposited in bone for long periods

Unwanted effects

-          GI upset – which can be severe!

-          Bone pain

-          Oesophagitis – to reduce the risk, the patient should take the drug:

o   With a full glass of water

o   At least 30 minutes before food

o   And stay stood or sat upright for at least 30 minutes after the tablet is taken

-          Headache

Uses

As well as osteoporosis, bisphosphonates are used in Paget’s disease, and sometimes used against bone metastases.

HRT

No longer used as mainstream treatment, but if other treatments are not tolerated or effective, then it may be useful in women in post-menopausal osteoporosis.

-          Most effective when started early in menopause, and continued for >5 years

-          Bone loss continues, and is possibly increased upon stopping HRT

-          Also increases the risks of cardiovascular disease and stroke

Strontium

Sometimes used as an alternative to bisphosphonates

Calcitonin

Sometimes used in those for whom bisphosphonates are not very effective

Notes by Tom Leach

Paget's Disease of the Bone

Paget's Disease of the Bone

Along with osteoporosis, this is a common degenerative bone disease

Epidemiology and Aetiology

This is the second most common bone disorder (after osteoporosis), and affects >5% of the over 55’s in the UK. The prevalence varies between countries and races. The UK has the highest incidence. It is rare in Scandinavia, China and Japan.

-          Increased incidence in Pet Owners

-          Genetic susceptibility

-          Essentially unknown aetiology; environmental factors in a predisposed individual (possibly viral infection is the environmental factor)

-          Incidence increases with age

o   Rare under 50

-          Slight male predominance

Clinical features

-          Chronic progressive disease

-          Often asymptomatic, and discovered incidentally with a raised ALP in the blood, or discovered incidentally on x-ray

-          Only 15-30% of cases have symptoms

-          Bone pain! – the most common symptom

-          May affect bones anywhere in the skeleton, but common sites include; pelvis, lumbar spine, femur, thoracic spine, sacrum, skull, tibia, humerus

-          Usually only affects one site! – it is not ‘systemic’ like osteoporosis, and does not spread to other sites.

-          Osteoarthritis

-          Fractures – bones are prone to fracture because they become more brittle

-          Deafness / Headaches – occurs in some patients due to compression of the vestibulocochlear nerve, when the skull is affected

-          Osteosarcoma – used to be more common, now only affects 1% of patients.

Pathology

-          Increased number of osteoclasts. Osteoclasts also often larger. The osteoblasts are normal, but are often over active, due to increased factors released by osteoclasts.

-          Essentially, an accelerated rate of bone turnover – with subsequent rapid new bone formation – and this new bone does not have a normal bone matrix – the matrix is disorganised

-          The bones increase in size, but become more brittle, and thus more prone to fracture.

Investigations

-          Blood tests

o   Raised ALP – ALP can be an indicator of osteoblastic activity

§ Also check γ-GT – to rule out a liver cause!

o   Serum calcium and phosphates will be normal

-          X-ray

o   Widening of the cortical region – i.e. the hollow cortex at the centre of the bone (where marrow is produced) is wider

o   Mixed areas of sclerosis and lysis – on the x-ray will look like lots of opaque dark splodges in the bone

o   Bone deformities

§ Bone bends anteriorly in the tibia

§ Bone bends laterally in the femur

o   May also show what appears to be localised osteoporosis in areas of very high osteoclast activity – called osteoporosis circumscripta – this is particularly apparent in the skull

-          Bone scan – increased isotope uptake in affected bones

-          Urine – may contain collagen due to very high bone resorption

Treatment

Knowing who and when to treat is the biggest problem. It is essentially based on symptoms severity. Reasons to treat include:

-          Severe pain

-          Nerve compression from expanding bone

-          Fractures

Other management options include:

-          Orthoses – braces, usually plastic that support and protect a bone

-          Analgesia

-          Education

-          Treat the complications – e.g. joint replacement

-          Bisphosphonates

o   These are the ‘mainstay’ of treatment. They inhibit osteoclast activity, and cause osteoclast apoptosis. they damage the cytoskeleton of the osteoclast, so the cell is then unable to bind to bone, and to perform its bone resorption duties.

o   Are often able to induce disease remission. Typical regimen will last 2 months.

Notes by Tom Leach

Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematosus (SLE) Notes

SLE is an autoimmune connective tissue disease, similar to systemic sclerosis, RA, and mixed connective tissue disease. Often, symptoms of these diseases overlap. In cases where you unable to distinguish exactly which condition is present,we would normally say that mixed connective tissue disease is present.  

Like those other disorders, ANA’s (anti-nuclear antibodies) can be found in blood of many affected patients.

The four key features of Connective Tissue disease:

-          Inflammation

-          Fibrosis / scarring

-          Vasospasm (including Reynaud’s Syndrome)

-          Vascular Thrombosis

The main clinical features, and organ complications associated with connective tissue disease can often be put down to one of the above pathological mechanisms.

There are also specific types of antibody that are more readily associated with the different types of connective tissue disease.

Epidemiology

-          Prevalence is roughly 1 in 4000

-          About 10x more common in women!

-          2-3x more common in Indian Asians than Caucasians

-          5x more common in black Africans than in Caucasians

-          Can present at any age

o   Peak incidence is between 25-35

o   Second peak of incidence is between 50-60

Etiology

-          Strong genetic disposition

o   Family members 50x more likely to have the disease than members of the general population

-          UV light exposure thought to increase the risk

-          Drugs

o   Chlorpromazine, hydralazine, isoniazid

Clinical features

-          Photosensitive rash – can occur anywhere on the body, but typically seen on the face – as this area is most likely to be exposed to the sun!

-          Nonspecific symptoms

o   General malaise

o   Fatigue

o   Low-grade fever

o   Weight loss

o   Alopecia

o   Mucosal ulceration – particularly in the mouth

-          Vascular Changes

o   Nail edge infarcts

o   Splinter haemorrhages

-          Arthritis

o   Usually:

§ Symmetrical

§ Small joints

§ Polyarthritis

o   The arthritis is non-erosive, and thus the joint is permanently damadged, but there may be ligament damage, which can cause deformities similar to rheumatoid arthritis. However, unlike in RA, the deformities are reducible, and they should not affect joint function – e.g. the patient should be able to make a fist.

-          Systemic involvement

o   Nephrosis – anti DNA antibodies are toxic to the kidney

§ You should always do a urine dipstick on any patient you suspect with SLE! If there is nephro damage it will show up as excess protein on dipstick! – there will also possibly excess blood.

o   Nervous system involvement

Diagnosis

According to the American College of Rheumatology (ACR), for a patient to be diagnosed with SLE, they must fulfil 4 of the following 11 criteria:

-          Malar Rash

-          Oral ulceration

-          Discoid Rash – a round or oval rash seen on areas of skin exposed to sunlight

-          Arthritis

-          Photosensitivity

-          Serositis

-          Neurological disorders

o   Seizures

o   Psychosis

-          Renal disorder

o   Proteinuria (>0.5g/day)

o   Red cell casts in urine

-          Haematological disorder

o   Leucopenia

o   Lymphopenia

o   Haemolyitc anaemia

o   Thrombocytopaenia

-          Immunological disorder

o   Antibodies to double stranded DNA

o   Anti-Sm antibodies

-          ANA positive

Investigations

-          Urine dipstick – increased protein, red cell casts

-          Blood – anaemia, thrombocytopenia, leukopenia, lymphpaenia, raised ESR and CRP.

-          ANA testing – positive in 90% of patients. Concentration of antibodies does not reflect the severity of the disease.

-          Antibodies to doublestranded DNA (dsDNA)– highly specific for SLE – but only present in 60% of cases. In some patients, the concentration of the antibodies may reflect the severity of the underlying disease

Complications

-          Increased incidence of atherosclerotic disease

-          Increased risk of thrombosis

-          Increased risk of infection

o   Usually due to immunosuppressive treatment of the disorder

Management

Mild disease

No specific therapies may be needed. The patient may be able to use topical NSAID therapy on the affected areas, and make lifestyle changes (E.g. avoiding the sun), and may otherwise need no further therapy

Mild to moderate disease

Treatment is essentially similar to RA. Patients may use disease modifying drugs (e.g. methotrexate, leflunomide, azathiaprin, hydroxychlorequine), and use steroid injections for specific flare ups.

Organ involvement

Treat the organ complications as separate entities with specific treatments

Neurological disorders

Also treated with specific therapies, e.g. anticonvulsants

Notes by Tom Leach