bisphosphonate lecture lahore malcolm harris
TRANSCRIPT
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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
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3
Osteoblast
OsteoclastOsteocyte
bone resorption is from the Latin sorptum - to suck in
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Formation v Resorption
The osteoblast v the osteoclast.
Children & adolescents ; formation > resorption
Adults formation = resorption
Postmenopause resorption > formation
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A resorbing Osteoclast by Dr Tim Arnett
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Reducing resorption
to increase bone mass
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This is the phosphonate radical
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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
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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
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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
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• 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
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normal bone and osteoporotic bone (by Professor Alan Boyde)
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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was also helpful but • has been withdrawn due to ovarian and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
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Bisphosphonate complications
• Impaired bone turnover
• Reduced angiogenesis
• Both lead to Osteonecrosis
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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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16
Osteonecrosis of maxilla
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Ischaemic necrosis – no vessels no cells!!
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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
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• 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
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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.
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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%
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Why treat hypercalcaemia of malignancy?
Hypercalcaemia of terminal malignancy is intolerable
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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
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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
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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
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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
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Resorbing osteoclast essential for bone remodelling EM by Professor Alan Boyde
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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
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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
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Is osteonecrosis of the jaws a new disease• devised by the biochemist• induced by the physician and • provoked by the dentist??
• remember Phossy Jaw?
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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
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Mother and children making matches for Bryant and May
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Match makers with phossy jaws
Osteonecrotic mandible Hunterian Museum RCS Osteonecrotic mandible Hunterian Museum RCS
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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;
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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 ?
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osteoclasts
osteocytes
Bone Remodellingosteoblast
bone resorption is from Latin sorptum - to suck in