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Osteoporosis
Ninian PeckittFRCS FFD RCS FDS RCS FACCS
Oral and Maxillofacial Surgeon / Facial Plastic Surgeon
Now test his reflexes and be careful…
and remember what Daddy said about people with brittle bones
Osteoporosis
WHO definiton Osteoporosis (2003)
• Disease characterised by:– low bone mass– microarchitectural deterioration– enhanced bone fragility – increase in fracture risk
• Osteoporosis occurs when:– bone turnover increases– bone resorption > bone formation– loss of bone mass
Osteoporosis• Significant cause of morbidity and mortality
• Fractures – Significant Health System Costs
• Bisphosphonates reduce risk of fracture by 50%
• Issues
– Low Diagnosistic Rates
– Non-adherence
Osteoporosis Prevention
Osteoporosis - Diagnosis• The presence or history of an osteoporotic fracture
• Occurrence of low trauma fractures
• Low bone mass in the absence of fracture
• Osteoporosis - BMD deficit of 2.5 standard deviations or more below the young adult reference mean in postmenopausal Caucasian populations
• Osteopenia - BMD deficit 1 - 2.5 standard deviations below the young adult reference mean.
Bone Mineral DensityEach standard deviation decrease in BMD :
• x2 increase in the risk of fracture (Marshall et al, 1996)
• Osteoporotic Fractures - 1:2 Female 1:3 Male >60yrs
• Vertebral Fractures - Cascade Effect– (#1) risk subsequent vertebral fractures x4– (#3) risk subsequent vertebral fractures x11
Klotzbuecher et al, 2000
Other Risk FactorsRisk - Osteoporotic fractures (Nguyen et al, 2004) include
• Family history of fracture
• Sedentary lifestyle or physical inactivity
• Smoking / excessive alcohol intake
• Short reproduction lifetime / late menarche / early menopause
• Low Body Weight / anorexia nervosa
• Hyperthyroidism / low testosterone levels - men / corticosteroids / Ca++ and vitamin D deficiency / GRH therapy
Osteoporosis - Prevalence
• 585,800 Australians who self Δ osteoporosis
• 496,400 women and 89,400 men
• 2 million Australians– osteoporosis or – osteopenia
Medical Possession RatioThe Medication Possession Ratio (MPR) %
the amount of therapy in possession by the patients at specific points in time.
• adherence (MPR >80%) for reduction fracture risk
• MPR <80% Fracture Risk increases
• Therapy adherence estimated
– 30.6% to 55.3% for weekly medications
– 19.4% to 40.4% for daily medications.
Fractures – Non Adherence
• Bisphosphonates reduce risk of fracture by 50%
• 114,434 non- adherence fractures - Australia 2005
Cost of Non Adherence• Greater Healthcare Utilisation
• Loss of Productivity
• Greater need for personal care
• Greater Need for Aids to enhance Mobility
• Reduced Quality of Life – The Burden of Disease
Cost of Non Adherence Australia 2005
• Estimated Costs $83.3m ($51.2m to $115.5m)
• Healthy Life Lost $102.8m ($41.1 to $164.5m)
• Total Economic Burden $186.1m ($92.3 to $280.0m)
• Non Adherence Fractures 10,950 (2005-2010 projections)
• Net Present Value $1.7 billion ($0.8 billion to $2.6 billion)
Bisphosphonates• Alendronate* (Fosamax, Alendro)
• disodium etidronate (Didrocal)
• risedronate (Actonel)
Optimum Bioavailability
• Stringent posture and pre- and post-dose fasting requirements
• Biphosphonates containing a Nitrogen Molecule are more powerful
PBS Funding Conditions – Pre-existing Fracture
* Revenue $3.2 billion in 2005
Bisphosphonates: Anti-Resorptive potency Drug Trade Name Potency Adminitration
etidronate Osteum Difosen 1 Orally
clodronate Bonefos 10 Orally / iv
tiludronate Skelid 10 Orally
pamidronate Aredia, Linoten, Pamifos, Xinsidona 100 iv
alendronate Fosamax Fosavance 1,000 Orally
risedronate Actonel Acrel 5,000 Orally
ibandronate Bondronat 10,000 Orally / iv
zoledronate Zometa Aclasta 85,000 iv
Bisphosphonates - Potency
Bisphosphonates - Changes in Bone Markers
BisphosphonatesIntravenous bisphosphonates
• to reduce bone pain, malignant hypercalcemia• skeletal complications suffered by patients with Paget’s Disease• myeloma and for the treatment of bone metastasis
– e.g. Carcinoma Breast Lung Prostate Thyroid
Oral bisphosphonates
• Osteoporosis• Paget’s disease• Osteogenesis Imperfecta
Osteonecrosis of the Jaws
Osteonecrosis of the Jaws
Definition ONJ (Sawatari and Marx 2007)
Exposed bone in the mandible or maxilla that fails to heal within 8 weeks in a patient receiving, or who has received, a systemic bisphosphonate, and who has not received local radiation therapy to the jaws.
ONJ
• following oral surgery (dental extraction)
• spontaneous cases are recorded
• Alveolar Bone x15 turnover (Marx)
Osteonecrosis of the JawsONJ (Sawatari and Marx 2007)
• 6 doses of monthly iv biphosphonate or
• 3 yrs of weekly alendronate or risedronate
are required…….
…….. before a patient is at risk for ONJ
96% ONJ - iv bisphosphonates
4% ONJ - oral bisphosphonates
Osteonecrosis of the JawsONJ http://jada.ada.org/cgi/content/full/137/8/1144
• ONJ Low Risk 0.7 per 100,000 person-years’ exposure to alendronate
• Other nitrogen-containing oral bisphosphonates expected to have a similar risk profile
• ONJ can occur spontaneously
• ONJ associated with dental extractions
• ONJ increase >65 years
Osteonecrosis of the JawsONJ http://jada.ada.org/cgi/content/full/137/8/1144
• ONJ Oral gluco-corticoid use for chronic conditions
• ONJ – associated with Periodontitis
• ONJ associated with prolonged use of bisphosphonates
• ONJ bilateral and multifocal reports in cancer patients
• ONJ Tori and other bony exostoses may increase the risk of developing BON.
ToriToriTorus Maxillaris and Mandibularis
• Midline Palate
• Lingual side of premolars (90 % Bilateral )
• Familial Incidence 5-40%
• Occur early in Life / Associated with Bruxism
• Size of Torus correlates with increased bone Density
- Post Menopausal women
http://jcem.endojournals.org/cgi/content/full/88/5/2081
Bisphosphonates and Dental Implants
Bis-Phossyjaw?• Phossy jaw - white phosphorus 19th Cent
• Phosphonecrosis of the Jaw
– Unusual necrosis of the Jaw in (Young) Match Workers
– Pain and Disfigurement
– Eerie glow in the dark (phosphorescence)
• Tip of the Iceberg – Potential Epidemic?
Estimation of Bone TurnoverThe C-terminal telopeptide (CTX) blood test (β Cross Laps)
• Fasting Saerum CTX Test - an index of bone turnover
• Cross linked octapeptide fragment from type 1 bone collagen is released (98% of bone protein)
– released when osteoclasts resorb bone– Serum CTX level α osteoclastic resorbiton at time blood is drawn
– CTX 50 pg/mL - 450pg/mL 1
– Normal values > 300pg/mL and commonly 400-550pg/mL 1
• Risk assessment,2 suggests a value of
– <100 pg/mL is high risk
– >150 pg/mL is low risk
– Australian trial 3 favours >200 pg/mL as a safe level for a bone invasive procedure.
1. Marx RE : J Oral Maxillofac Surg 65:2397-2410, 2007
2. Therapeutic Guidelines. Therapeutic guidelines: oral and dental. Melbourne: TG, 2007 3. Goss AN. CTX (the cross laps test). Australian Dental Association Bulletin 2008; 368:11
CTX and ONJ Prevention Kunchur, Need, Hughes Goss (Adelaide)
• 348 Patients Fasted Morning Test
• 222 Patients at Risk
• 15 Patients had ONJ
• 113 Controls
Kunchur R, Need A, Hughes T Goss A
Clinical Investigation of C-Terminal Cross Linking Telopeptide Test in Prevention and Management of Bisphosphonate-ssociated Osteonecrosis of the Jaws
JOMS 2009: 7, 1167-1173
Kunchur, Need, Hughes Goss (Adelaide)
Long term Bisphosphonates n=215
• Older Med Compromised Patients (71 ± 11.6 yrs)
• Average CTX 238 ± 144 pg/ml
• 98pts <200pg/ml
1pt CTX = 126pg/ml ONJ
Kunchur, Need, Hughes Goss (Adelaide)
IV Bisphosphonates
7 pts NO ONJ CTX= 329 ± 354 (with 4 < 200pg/ml)
15pt ONJ
12pts post extraction 3pts spontaneously 7 pts no drug holiday CTX = 116 pg/ml
Kunchur, Need, Hughes Goss (Adelaide)
CTX < 150pg/ml
Did not correlate with clinical risk factors of....
Age
Gender
Co-morbidities
Bone Disease
Bisphosphonate Duration
Kunchur, Need, Hughes Goss (Adelaide)
CTX Statistical Significant Difference Aledronate compared with risedronate (p< .0001)
Bisphosphonates: Anti-Resorptive potency Drug Trade Name Potency Adminitration
etidronate Osteum Difosen 1 Orally
clodronate Bonefos 10 Orally / iv
tiludronate Skelid 10 Orally
pamidronate Aredia, Linoten, Pamifos, Xinsidona 100 iv
alendronate Fosamax Fosavance 1,000 Orally risedronate Actonel Acrel 5,000 Orally ibandronate Bondronat 10,000 Orally / iv
zoledronate Zometa Aclasta 85,000 iv
Kunchur, Need, Hughes Goss (Adelaide)
Drug Holiday
CTX Value circa 25pg/ml/month
Kunchur, Need, Hughes, Goss (Adelaide)
Conclusions
• CTX not predictive of ONJ (individual patient)
• Risk Zone 150-200pg/ml
• If medically appropriate cease bisphosphonate
• Until patient out of “Risk Zone”
Medicolegal Implications
Suggested Protocol
Medicolegal Implications of ONJ
• Delay Surgery if CTX <200pg/ml
• Drug Holiday for Oral Surgery
• CTX elevation 25pg/ml/month (if Reversible)
Predicting risk for bisphosphonate-related osteonecrosis of thejaws: CTX versus radiographic markers
Fleischer et alOral Surgery Oral Medicine Oral Pathology Oral Radiology and EndodontologyVol. 110 No. 4 October 2010
Predicting risk for bisphosphonate-related osteonecrosis of thejaws: CTX versus radiographic markers
Fleischer et al 2010
Classification of Osteonecrosis of the Jaws
Grade Severity1 Asymptomatic2 Mild3 Moderate4 Severe
Grade Size (diameter*)
1A Single lesion, <0.5 cm
1B Multiple lesions, largest <0.5 cm
2A Single lesion <1.0 cm
2B Multiple lesions, largest <1.0 cm
3A Single lesion, ≤2.0 cm
3B Multiple lesions, largest ≤2.0 cm
4A Single lesion >2.0 cm
4B Multiple lesions, largest >2.0 cm
*Lesion size measured as the largest diameter
Incidence of ONJ @36 months
International Myeloma Foundation's web-based survey included 1203 respondents
Myeloma 904Breast Cancer 299
Bisphosphonate n %
zoledronate 210 10%
palmidronate 413 4%
Strontium
Strontium• Strontium is the only element that has been found to work as a
“dual-acting bone agent”
• Reduces the rate of bone turnover • helps to build new bone of high quality • Bone Density improved 8-14%
• Research conducted for pharmaceutical companies>5,000 women over three years
• bone density improvement of 8-14%. (strontium ranelate)
• No evidence that prescription strontium outperforms strontium citrate $120/yr
StrontiumStrontium Ranelate, increases bone mass through:
• its stimulatory effect of osteoblasts • inhibitory effect of osteoclasts
• At the recommended daily dosage of 2g in granules form,Protelos (strontium ranelate), has shown a significant reduction of
• vertrebral fractures• hip fractures in• decreased back pain• decreased body height loss compared to the placebo group
At this time, it is primarily recommended for post-menopausal women, but not pregnant, or breast-feeding females
Strontium• The action of strontium is closely related to that of calcium
• retention of strontium varies inversely with calcium intake.
• Supplementing larger amounts of strontium increases calcium, but not magnesium retention
• iStrontiuhas the potential to lower
– stomach acid levels, insulin, WBC, – germanium, fluoride, bismuth, and silicon.
These effects should be kept in mind when considering strontium in the treatment of osteoporosis
Strontium• In order to help increase Bone Mineral Density (BMD)• over 1,000 mg of strontium has to be ingested daily
(versus a few mg / day obtained through normal food intake), well tolerated by some patients
• Complications – dental caries,
nausea, abdominal spasms, diarrhoea headaches, – skin irritation, swollen glands, Fainting / seizures memory problems– difficulty breathing / rickets, blood clots, seizures.
Additional caution is required by those with :• kidney problems• history of venous blood clots, • or have an intolerance to aspartame, which is found in Protelos.
Strontium• Since calcium inhibits strontium absorption, calcium supplements, antacid
remedies, and food in general should not be taken within 2 hours before, and 2 hours after taking Protelos.
• Similarly to iodine pills being somewhat protective in case of a nuclear accident, taking small amounts of the (non-radioactive) trace mineral strontium may offer the same protection when being exposed to the radio-active form of strontium.
• Some toothpastes that are marketed for "Sensitive Teeth" contain strontium chloride part of their formulation
Strontium• Strontium is only effective when taken with
• 1,500 mg Ca++ and 800 IUs of vitamin D
…and this is where things become tricky.
• Calcium is absorbed best when taken in increments of 500 mg- preferably with meals and at least four hours apart.
• Strontium is best taken on an empty stomach before going to bed and definitely shouldn’t be taken with calcium.
• Calcium can reduce the bioavailability of strontium by 60-70%.
Strontium• Sound complicated?
• Despite the very attractive improvements in bone density offered by treatment with strontium….
• …..many people are discouraged by the demanding regimen and the length of time it takes to improve their bone health.
Strontium• Mayo Clinic• 84% improvement Bone Pain• Probable increase in bone mass 78%• McCaslin, F.E., Jr., and Janes, J.M. effect of strontium lactate in the
treatment of osteoporosis. Proc Staff Meetings Mayo Clin, 1959, 34:329-334
StrontiumOSTEOPOROSIS STUDY-MCGILL (1985)• In 1985, Dr. Stanley C. Skoryna followed his bone cancer study with a small-
scale study of three men and three women with osteoporosis using 600 to 700 mg/day of strontium carbonate. Bone biopsies of the hip bones taken before and after six months of treatment showed a 172% increase in the rate of bone formation after strontium therapy, with no change in bone resorption.
(Marie, P.J., Skoryna, S.C., Pivon, R.J., Chabot, G., Glorieux, F.H., Stara, J.F. Histomorphometry of bone changes in stable strontium therapy. In: Trace substances in environmental health XIX, edited by D.D. Hemphill, University of Missouri, Columbia, Missouri, 1985, 193-208.)
StrontiumSTRATOS TRIAL (2002)• The STRATOS trial (strontium ranelate (SR) for treatment of osteoporosis) studied
osteoporotic women using both a placebo and strontium in doses of 170, 340 or 680 mg/day for two years. The scientists evaluated lumbar and hip bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA). The study found a significant reduction in new vertebral fractures and also a significant positive change in bone metabolism in the group that received 680 mg/day of strontium for two years. The authors concluded that the 680 mg/day dose offered the best combination of efficacy and safety, and stated without equivocation that strontium ranelate therapy increased vertebral BMD and reduced the incidence of vertebral fractures.
(Meunier, P.J., Slosman, D.O., Delmas, P.D., Sebert, J.L., Brandi, M.L., Albanese, C., Lorenc, R., Pors-Nielsen, S., De Vernejoul, M.C., Roces, A., Reginster J.Y. Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis&emdash;a 2-year randomized placebo controlled trial. J Clin Endocrinol Metab, May 2002; 87(5):2060-6.)
StrontiumSTRATOS TRIAL (2004)• The STRATOS research team followed its first trial with a much larger study
of 1,649 osteoporotic postmenopausal women over a three year period. Participants received 2 gm/day of strontium ranelate (providing 680 mg strontium) or placebo, as well as calcium and vitamin D supplements before and during the study. In addition to suffering fewer fractures, patients in the strontium group increased lumbar bone mineral density by an average of 14.4 percent and femoral neck BMD an average of 8.3 percent. The authors concluded that “treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures.”(Meunier PJ, Roux C, Seeman E et al. (2004). "The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis.". New England Journal of Medicine 350: 459–468. doi:10.1056/NEJMoa022436. PMID 14749454.)
TROPOS STUDY (2005)• While the STRATOS studies concentrated on the lumbar spine and femoral neck, the
Treatment of Peripheral Osteoporosis (TROPOS) study focused on nonvertebral fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle, humerus) and bone density. The study allocated either 2 grams/day of strontium ranelate or a placebo to 5,091 postmenopausal women with osteoporosis. This was a double-blind placebo-controlled 5-yr study with a main statistical analysis over 3 yr of treatment.
• After three years, the research found an 8.2% improvement in the femoral neck and a 9.8% improvement in the total hip bone density and concluded that strontium ranelate offers a safe and effective means of reducing the risk of fracture associated with osteoporosis.
• (Reginster JY, Seeman E, De Vernejoul MC et al. (2005). "Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: treatment of peripheral osteoporosis (TROPOS) study". J Clin Metab. 90: 2816–2822. doi:10.1210/jc.2004-1774. PMID 15728210.)
STRONG STUDY-PHASE II (2007)• Osteologix, Inc (San Francisco, California) announced the results of its phase II
clinical trial in 2007. The trial enrolled 289 postmenopausal women with low bone mineral density (BMD) and evaluated three doses of strontium malonate (NB S101) against one dose level of strontium ranelate (Protelos® ). It reported that at 3 months, strontium malonate had significantly increased lumbar spine BMD at all doses tested, with the most significant increase of 2.66% (P <.01) for the 2 g dose. This compared favourably against Protelos (2 g) which increased lumbar spine BMD by 1.96% (P <.05). Strontium therapy was well-tolerated and side effects were generally mild in all dose groups. There were no significant differences in the side effect profiles among the four treatment groups.
• NB S101 is administered in a once-daily 1 g tablet whereas Protelos is administered as a sachet to be dissolved in water. The amount of free strontium in the Protelos product is 680 mg whereas the amount of free strontium in NB S101 is 465 mg. Osteologix states that the bioavailability of free strontium has been increased in its product NB S101 compared with Protelos.
