bisphosphonate lecture lahore malcolm harris

Bisphosphonates and Dental Practice

Malcolm Harris malcolm.harris@uclan.ac.uk

osteoid

osteoblasts

bone derived growth factors

Systemic hormones, PTH & Vit. D and local factors - function and repair

stimulate bone formation

Bone Remodelling is formation v resorption

osteoclast activation

osteoblasts

osteoid

RANKL

3

Osteoblast

OsteoclastOsteocyte

bone resorption is from the Latin sorptum - to suck in

Formation v Resorption

The osteoblast v the osteoclast.

Children & adolescents ; formation > resorption

Adults formation = resorption

Postmenopause resorption > formation

A resorbing Osteoclast by Dr Tim Arnett

Reducing resorption

to increase bone mass

This is the phosphonate radical

This is the Bisphosphonate molecule

• R1 attaches to bone calcium and is ingested by the active osteoclast. • R2 paralyses the osteoclast which dies - apoptosis.

• bisphosphonates also reduce blood vessel formation

Bisphosphonates and the osteoclast

Prenylation – releases energy to produce the ruffle borderand bone resorption

• no prenylation – no energy release

• apoptosis of cell (cell death)• no ruffled border-• osteoclast detaches from

bone - reduced resorption

Bisphosphonates reduce osteoclast resorption

and increases bone mineral density

Is valuable in; osteoporosis

Pagets disease

• high doses are palliative in malignant bone

destruction - controls hypercalcaemia

• resorption > deposition• reduction in bone mineral density• prone to fractures especially hip and

vertebrae• mostly post menopausal women exacerbated• by smoking and long term NSAIDs• chronic steroid therapy

Osteoporosis

normal bone and osteoporotic bone (by Professor Alan Boyde)

Osteoporosis Treatment

• Bisphosphonates, calcium, and vitamin Dreduce resorption and increase bone density • oestrogen hormone replacement therapy

was also helpful but • has been withdrawn due to ovarian and

breast Ca risk

Bisphosphonate complications

• Impaired bone turnover

• Reduced angiogenesis

• Both lead to Osteonecrosis

Bisphosphonates and osteonecrosis of the jaws (ONJ)

Cause apoptosis of the osteoclastcell (cell death) also inhibit of blood vessel formation.

The sterile dead alveolar bone can become exposed through surgery or periodontal disease and gets superficially infected But no separation without osteoclasts

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Osteonecrosis of maxilla

Ischaemic necrosis – no vessels no cells!!

Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic.

J Oral Maxillofac Surg 2003;61(9):1115-7

• ONJ is very rare in a post menopausal osteoporosis patients on oral alendronate • 0.7 cases in a 1,000 patients a year NB• Osteoporosis patients - may have delayed

bone healing without bisphosphonates

Intravenous bisphosphonates • Are greatest risk for jaw osteonecrosis

• 94% of published cases.

• 6 – 12% of IV Bisphophonate patients

• The mandible > the maxilla (2:1 ratio)

• 60% are preceded by a dental procedure.

The precipitating event of osteonecrosis

• Spontaneous 25.2%

• dental extraction 37.8%

• periodontal surgery 11.2%

• root canal therapy 10.9%,

• dental implants 3.4%

• root canal therapy 0.8%

Why treat hypercalcaemia of malignancy?

Hypercalcaemia of terminal malignancy is intolerable

groans (constipation), moans (psychosis) bones (bone pain), stones (kidney stones) and psychiatric overtones (depression and confusion).

Other symptoms fatigue, anorexia, nausea, vomiting, pancreatitis and urinary frequency

Hypercalcaemia of Malignancy

ONJ – Presentation and Treatment• pain and exposed bone. - mandible > maxilla

• stop the bisphosphonate

• antibiotics and antifungals only if infected

• chlorhexidedine mouthwashes x2 daily.

• trim sharp edges only

• surgical treatment is to be avoided-exposes more dead bone to infection

Dental Prophylaxis and Bisphosphonate Therapy

• clinical and radiographic examination • complete oral hygiene and dental treatment

before initiating any surgery e.g implant insertion

• maintain optimum oral hygiene

Osteoporosis and implant integration• careful choice of site – avoid areas of

alveolar loss and sparse trabeculae

• ensure no dento alveolar contraindications

• maintain oral osteoporotic therapy but

• suspend intravenous bisphosphonate

3-6months

• informed consent

Resorbing osteoclast essential for bone remodelling EM by Professor Alan Boyde

Denosumab

human monoclonal antibody for treatment

of osteoporosis, bone metastases,

rheumatoid arthritis, multiple myeloma, and giant

cell tumour of bone

It inhibits RANKL , the primary signal for

ostoclast bone removal

http://en.wikipedia.org/wiki/Denosumab

Denosumab

can also cause chemonecrosis of the jaws

Chemonecrosis of the jaw is RANKL inhibition by

any cause.

Not simply Bisphosphonate related necrosis

Treatment ; suspend RANKL inhibitor and

activate RANKL

Is osteonecrosis of the jaws a new disease• devised by the biochemist• induced by the physician and • provoked by the dentist??

• remember Phossy Jaw?

Phossy jaw• chronic painful necrosis of the jaws in match

makers

• who dipped match sticks into volatile yellow

phosphorus paste.

• women and children under nine years worked

16 hours a day for 20 pence

• The matches sold at 1p for 12 boxes

Mother and children making matches for Bryant and May

Match makers with phossy jaws

Osteonecrotic mandible Hunterian Museum RCS Osteonecrotic mandible Hunterian Museum RCS

Phossy jaw

• In 1891 the Salvation Army opened a clean, well-lit factory using harmless red phosphorus to make matches

• 1898 elsewhere matchmakers went on strike against abominable pay, conditions and illness

• This was the first UK unskilled workers strike• 1908 yellow phosphorus was banned

• Reintroduced 1942 until now in Napalm;

Plus ca change plus que c’est la meme chose

The more things change the more they are the same

Alphonse Karr 1849

• Any questions ?

osteoclasts

osteocytes

Bone Remodellingosteoblast

bone resorption is from Latin sorptum - to suck in