Osteomalacia and Rickets

These are essentially the same disorder. In children, the disease is rickets but after fusion of the epiphyseal plates it is known as osteomalacia.

The most common cause is vitamin D deficiency.

The condition is characterised by normal bone formation with abnormal bone mineralisation, thus there isexcess osteoid and cartilage, and insufficient bone.

Causes

-          Vitamin D deficiency – due to lack of sunlight ± insufficient dietary intake. Both often occur simultaneously. Common in the elderly (e.g. often indoors for long periods) and also in dark skinned populations residing in non-native climes (e.g. in the UK) – particularly if they cover up their skin (e.g. common in Inidan Pakistani women and girls in the UK. As a result, chapatti flour is fortified with vitamin D).

-          Renal osteomalacia – resulting in vitamin D deficiency. Often occurs in patients with long-term renal pathologies.

-          Drug Induced – particularly with anticonvulsants

-          Vitamin D resistant rickets / osteomalacia – a collection of inherited diseases, including familial hypophosphataemia, and a disorder where the vitamin D receptor is defective.

o   Type I hereditary vitamin D-dependent rickets – caused by ineffective conversion of vitamin D precursors in the kidneys (25()H)D to 1,25(OH)D. Autosomal recessive

o   Type II hereditary vitamin D-dependent rickets – due to mutations in the 1,25(OH)D receptor, causes end-organ resistance to vitamin D

o   Both are treated with high levels of calcitriol  ( 1,25()H)2vitamin D )

-          Hypoparathyroidism

-          Low dietary calcium / phosphate (rare)

Clinical Features

-          Muscle aches

-          Muscle weakness

-          Bone Pain / pain on walking

-          Predisposition to fractures – especially in the elderly

-          Tetany – parasthesia of the lips, tongue and face, sometimes facial and carpopedal spasm, rarely seizures. May be hard to distinguish from other causes of seizure.

-          In children

o   Generally unwell

o   Delayed walking / crawling / sitting

o   In pregnancy, amy affect the foetus, especially the skull of the newborn (pingpong ball like skull - craniotabes)

§ Craniotabes is also seen in syphilis, and neonates with this are often tested for the disease.

o   Rachitic Rosary – bead like nodules on the ribs

o   Kyphoscoliosis

o   Bowed legs and ‘knock knees’ only occur in severe cases in older children.

Investigations

-          Vit D – often ↓

-          Alkaline phosphate: may be ↑ or ↔

-          Parathyroid hormone ↑

-          ↓Calcium

o   Low vitamin D results in low absorption of calcium in the diet, which inturn stimulates increased PTH production. High levels of PTH also increase phosphate excretion, but may normalise serum calcium levels.

-          ↓Phosphate

-          Renal failure (in renal osteomalacia)

-          X-ray – usually of radius / ulnar

o   Diagnosis cannot be made with X-ray alone – also need PHT and 25(OH)D level to rule out other causes of demineralisation.

o    Rickets

§ Changes most easily seen at the ends of the radius and ulnar

§ Ragged bone edges

§ Apparent increased distance from arm bones to carpal bones (Due to demineralisation of this area).

§ Fuzzy, cup-shaped diaphyses (ends of the bone)

§ General increase in radiolucency of the bone

o   Osteomalacia

§ Reduced amount of cortical bone

§ Partial fractures

Treatment

-          Vitamin D supplements + calcium  are first line – 400U tablets, 1-2 times/day

o   After 3 weeks, x-ray improvements can be seen. Typically starting at the very tip of the bone, and continuing down through the affected segment

o   Malapborption might require calciferol (1,25(OH)2D) - 1mg/day (equivalent to 40,000 units of Vit D!)

o   Vit-D resistant rickets should be treated with calciferol 10,000 unites/day

o   Renal osteomalacia is best treated with alfacalcidol

o   Hypercalcaemia is common with all vit D treatments, especially alfacalcidol.

Osteoporosis

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 withbone 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 toosteoporosis, 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 thehip 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 pamidronategiven 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

Marfan Syndrome

Marfan Syndrome  is an autosomal dominant connective tissue disorder.

Epidemiology and Aeitiology

-          25% of cases occur without family history

-          Reduced life expectancy – average is around 60

Pathology

-          The result of a mutation in the fibrillin-1 gene (FBN-1) which results in decreased production of extracellular microfibril. Microfibril is involved in the maintenance of elastic fibres, and as a result, there is an alteration in the properties of elastic fibres

Signs and Symptoms

These can be divided into major and minor signs:

-          Major signs – diagnostic is >2 present

o   Long limbs, tall, long, spindly fingers (arachnodactyly)

§ The thumb sign – the distal phalanx of the thumb extends beyond the edge of the clenched fist

o   Arm length height

o   Upwards lens dislocation in the eye (aka ectopia lentis) – the margin of the dislocation lens may been seen through an undilated pupil

o   Pectus deformity (e.g. excavatum or carinatum [outwards])

o   Aortic dissection / dilatiation – particularly at the aortic root. The arotic media is less resistant to stretching, particularly in areas of high pressure – hence the involvement of the aortic root. In severe cases, dissection can occur before the age of 10! Aortic regurg and endocarditis are also common

o   Dural ectasia – widening of the neural canal

-          Minor signs – may support diagnosis

o   Mitral valve prolapse – and accompanying late systolic murmur at the apex

o   High arched palate – can cause altered / unusual voice in some patients

o   Joint Hypermobility

o   Genu recuvatum – hyperextension of the knee, thus is appears to curve backwards

o   Scoliosis

o   Reduced subcutaneous fat

Diagnosis

-          Usually clinical. CT scan may be useful to detect dural ectasia

Treatment

-          The disease is incurable.

-          Treatment aims to minimise the risk of aortic dissection by preventing excessive dilation of the aortic root. This is usually managed with:

o   Β- blockers – e.g. atenolol, propanolol – these reduce the contractility of the heart, and thus reduce the pressure in the aortic root, reducing the risk of dilation and dissection

o   Annual Echocardiogram – dilation of >5cm is repaired surgically

o   Risk in pregnancy – pregnant women are at particularly high risk of cardiac complications.

Compartment Syndrome

This is a syndrome that results from swelling of a muscle. The muscle is retained in its fixed volume fascia, however, and thus the swelling of the muscle causes occlusion of the blood supply. this can result ininfarction, and can cause an ischaemic contraction known as Volkmann’s Ischaemic Contracture.

It typically occurs in the forearm and calf, but can also occur in the thigh and foot.

Causes

-          Trauma – compartment syndrome is often a complication of fracture.

-          Continued pressure on a limb – e.g. lying for hours in the same position on the same limb – often seen in drug and alcohol abuse. 

Pathophysiology

-          Swelling of the muscle – usually as a result of post-traumatic bleeding and oedema.

o   Initially only venous flow is disturbed, and arterial flow (due to its greater pressure) still occurs.

o   Eventually, the pressure within the compartment exceeds the arterial pressure, and the muscle begins to undergo ischaemia.

§ The main arteries in the compartment have a higher pressure than the arterioles, and thus these may not be occluded until late on, if at all

§ Other structures close by are also affected by the ischaemia – e.g. nerves, but the nerves are not affected until the pressure is very high!

§ This means that distal pulses and neurological exam are usually normal until VERY LATE ON!

·         If there are reduced or absent pulses, then it is likely the diagnosis is too late to stop severe ischaemic damage.

Clinical features and diagnosis

-          Often co-exists with fractures

-          You should be suspicious if there is:

o   Pain increasing over time – despite appropriate analgesia and joint immobilisation

-          People particularly at risk are children/young adults with:

o   Tibial shaft fractures

o   Forearm injuries

o   Crush injuries

-          There is often increased pain on passive flexion and extension of the fingers and toes of the affected limb

-          Measure compartment Pressure:

o   <30mmHg is normal

o   >40mmHg is high

o   Compare diastolic arterial and compartmental pressures – the difference needs to be>30mmHg for adequate perfusion.

o   In children – compartment pressures are not routinely monitored

Treatment

-          Fasciotomy – of the muscle compartments involved. Do it as soon as possible! To minimise the risk of irreversible ischaemia.

o   If there is any doubt over the diagnosis, perform fasciotomy anyway!

Carpal Tunnel Syndrome (CTS)

Epidemiology and Aetiology

-          More common in women

-          Typical presentation at age 30-50

-          Associated with gout, pregnancy, the pill, premenstrual state, rheumatoid arthritis, diabetes, acromegaly, obesity, amyloidosis

-          Some believe that jobs that involve repetitive flexing of the wrist may be involved.

o   RSI – repetitive strain injury – is a fallacy and doesn’t actually exist! There is usually another underlying diagnosis.

Pathology

-          Compression of the median nerve as it passes through the carpal tunnel (under the flexor retinaculum)

Signs and symptoms – are those of median nerve compression:

-          Wasting of the thenar eminence (the chunky muscle on the palmar aspect of the base of the thumb) – is often a late sign

-          Parasthesia of the lateral 3½ fingers (thumb, forefinger and middle finger)

-          Pain / tingling in the lateral 3 fingers

o   Pain is often worse at night and may wake the patient. It is often a burning or aching sensation.

-          The median nerve also supplies the lateral part of the palm but typically, this is spared as this branch of the median nerve does not pass through the carpal tunnel.

Examination

-          Look for wasting of the thenar eminence

-          Check sensation on the lateral 3½ fingers

-          Phalens Test – ask the patient to hold their wrists in a flexed position for 1-2 minutes. May elicit / exaggerate typical symptoms

-          Tinel’s Test – tap over the medial aspect of the inside of the wrist. Can induce tingling sensations. Less likely to elicit signs than Phalens

o   “Tinels – Tapping, Phalens – Flexing”

Investigations

-          Diagnosis is usually clinical, but occasionally in difficult cases, nerve conduction may be performed.

Management

-          Conservative – occasionally simple life-style changes (e.g. placement of computer keyboard) may be beneifical.

-          Splint – can be worn at night to reduce nocturnal symptoms, and many patients may also wear it during the day

-          Pain relief – is typically in the form of NSAIDs

-          Carpal Injection – hydrocortisone acetate – can be used if other methods have failed to control symptoms. Inject just dorsal to the wrist crease. Provide pain relief for approximately 1 month. Longer acting pain relief is no more effective than placebo.

o   May cause a sensation of shooting and tingling if you touch the nerve. If this is the case, you are in the wrong place! You are not aiming for the nerve itself, but for the flexor tendons.

o   Wearing a splint for a few days after injection can reduce the symptoms induced at time of treatment

-          Surgical decompression can be used for patients who still fail to respond. This can be open or endoscopic surgery.

o   Wearing a splint for a few days after injection can reduce the symptoms induced at time of treatment