4. RANKL Knockout Mice
• severe osteopetrosis / defects in tooth eruption (25)
• complete absence of osteoclasts
• defects of T and B cells / lack lymph nodes
– defects in thymic differentiation
– normal splenic structure and Peyer’s patches (25)
• Unexpected defects in mammary gland development (26)
5. Osteoclastogenesis
Basic Multicellular Units.
Bone constantly resorbed and formed at specific sites
1. Osteoclast Migration to sites (activation)
2. resorption of a packet of bone
3. a reversal phase characterized by:
– apoptosis of the osteoclasts
– followed by a phase of bone formation by newly formed osteoblasts
11. Drug and Bone
• Antiresorptive (also called anti-catabolic)
– Estrogens
– bisphosphonates (eg, alendronate, risedronate, ibandronate, zoledronate),
– Calcitonin
– raloxifene
• Anabolic (Riggs and Parfitt 2005)
Teriparatide, recombinant human (PTH) 1–34,
anabolic / bone forming - strengthens bone and reduces fracture risk
increasing bone formation / size
• Antiresorbtive and Anabolic
Strontium ranelate,
Dual action antiresorptive and anabolic properties.
• Stabilisationor increase BMD:
– filling in the remodeling space and prolonging secondary mineralization
– maintaining bone microarchitecture
– reducing trabecular perforation,
– ecreasing cortical porosity.
12. Bisphosphonates - Basic Chemistry
• Pyrophosphate
• Substitution of Carbon for Oxygen
– Resistance to hydrolysis
– Bone matrix accumulation
– Extremely long half-life
• Nitrogen-containing side chain
– Increases potency, toxicity
– Direct link to ONJ cases
13. Action of Bisphosphonates
• Osteoclastic toxicity
– Apoptosis
– Inhibited release of bone induction proteins
BMP, ILG1, ILG2
– Reduced bone turnover, resorption
– Reduced serum calcium
– Hypermineralisation
“sclerotic” changes lamina dura - alveolar bone
14. Medical Indications for IV BPs
• Bone metastasis
• Hypercalcemia
• RANKL-mediated osteoclastic resorption
• Multiple myeloma,
• Breast CA, Prostate CA
• Paracrine-like effect
• PTH-like peptide osteoclastic resorption
• Small cell carcinoma
• oropharyngeal cancers
• Endocrine-like effect
15. Indications for Oral Bisphosphonates
• Paget’s Disease of bone
– Accelerated bone turnover
– Reduced compressive strength
– increased vascularity
– Bone pain
– Elevated AP levels
• Osteoporosis
Effects of estrogen loss:
– Decreased bone turnover / renewal
– Adipocyte differentiation
– osteoblastic differentiation
– increased fibrofatty marrow
– Progressively porotic bone
– DEXA scan for BMD values
Paget’s Disease
16. Pharmacokinetics
• Oral Bisphosphonates
– Absorbed in small intestine
– Less if taken with meal
– 1-10% available to bone
• Circulating half-life: 0.5-2 hrs
– Rapid uptake into bone matrix
– 30-70% of IV/oral dose accumulates in bone
– Remainder excreted in urine
• Repeated doses accumulate in bone
– Removed only by osteoclast-mediated resorption
– “Biologic Catch 22”
17. Denosumab
• More potent inhibitor of osteoclasts
• Binds to RANKL cf osteoprotegerin (OPG) – Longer Duration
• prevents interaction of RANKL and RANK
• reduces osteoclast
– Differentiation
– Activity
– survival
• inhibits bone resorption
19. Denosumab
• Osteonecrosis of the Jaws (ONJ) Reported
• ONJ - Function of Osteoclast Depletion
• Common Problem with all drugs inhibiting Osteoclasis
• Denosumab ONJ reversible ?
• Note CTX levels may be very low <10pg/ml
• Rate of recovery faster than Bisphosphonates?
• CTX Monitoring required
20. 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)
21. Classification of Osteonecrosis of the Jaws
Grade Severity
1 Asymptomatic
2 Mild
3 Moderate
4 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
22. AAOMS Staging of ONJ
• Patients at risk (Subclinical)
• No apparent exposed/necrotic bone in pts treated w/ IV or oral BPs
• Patients with ONJ
• Stage 1: Exposed/necrotic bone, asymptomatic, no infection
• Stage 2: Exposed/necrotic bone, pain, infection
• Stage 3: Exposed/necrotic bone, pain, infection + :
Pathologic fracture
or … extra-oral fistula
Or … osteolysis extending to inferior border
26. AAOMS Stage 0 Lesions
• Spontaneous Numbness and Pain
• No exposed bone
• No prior dental antecedent
• Positive image findings:
– Sclerosis
– Positive bone scan
27. Osteonecrosis of the Jaws
ONJ (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
Note 25-35% non compliance for Oral Medication
28. Osteonecrosis of the Jaws
ONJ http://jada.ada.org/cgi/content/full/137/8/1144
• Initially denied by Industry – (Dr R.E. Marx attacked when ONJ reported)
• ONJ Low Risk 0.7 per 100,000 person-years’exposure to alendronate (Fosamax)
• but reported 25-35% non compliance in oral medication
• 50% compliance required for therapeutic effect www.ncbi.nlm.nih.gov/pmc/articles/PMC3017316/
• Risk is therefore underestimated by circa 35%
• 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
29. Risk of ONJ www.ncbi.nlm.nih.gov/pmc/articles/PMC3017316/
Risk is under-reported (Peckitt)
• 25-35% of patients non compliant on Oral Therapy
• 50% compliancy required for therapeutic effect (Oral Drugs)
• There is a move towards i.v. drugs to improve compliance
• Move to i.v. drugs will increase the risk of ONJ significantly
• Advanced ONJ is probably untreatable and causes significant morbidity
Osteonecrosis of the Jaws
30. Risk of ONJ www.ncbi.nlm.nih.gov/pmc/articles/PMC3017316/
The consequences of a severe complication and its treatability
• require computation into Risk/Benefit Analysis
• before safety guidelines are formulated
• A “rare” serious complication is not necessarily acceptable
– if the effect of bisphosphonates is irreversible
– if there is no effective treatment for advanced stages of ONJ
– Patient Safety takes Priority over Financial Profit
In a multibillion $ Industry - Marketing ≠ Science
Osteonecrosis of the Jaws
31. Osteonecrosis of the Jaws
ONJ 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 ONJ.
32. Tori
Torus 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
34. 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?
35. Estimation of Bone Turnover
The 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
36. 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
37. 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
38. 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
39. Kunchur, Need, Hughes Goss (Adelaide)
CTX < 150pg/ml
Did not correlate with clinical risk factors of....
Age
Gender
Co-morbidities
Bone Disease
Bisphosphonate Duration
40. Kunchur, Need, Hughes Goss (Adelaide)
Statistical Differnece - 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
41. Kunchur, Need, Hughes Goss (Adelaide)
Drug Holiday
CTX Value circa 25pg/ml/month
42. Kunchur, Need, Hughes, Goss (Adelaide)
Conclusions
• CTX not presictive of ONJ (individual patient)
• Risk Zone 150-200pg/ml
• If medically appropriate cease bisphosphonate
• Until patient out of “Risk Zone”
44. Predicting risk Bisphosphonate-related ONJ :
CTX versus radiographic markers
Fleischer et al
Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology
Vol. 110 No. 4 October 2010
48. Dental Logistics
• All Patients commencing Osteoporosis Treatment – should be “Dentally Fit”
• A “Certificate of Dental Fitness” prior to Osteoporotic Treatment is suggested
• Patients should not commence treatment until “Dentally Fit”
• Dental Treatment Planning should
– Reduce risk of oral surgical intervention for duration of treatment
– Dental Sepsis should be eradicated
– Periodontal Disease must be controlled
– Early extraction of teeth of poor prognosis
– Dental Implants not necessarily contraindicated
• IV Bisphosphonates
– Risk of ONJ
– More Aggressive Dental Assement / Treatment Planning
– Consider Dental Clearance
49. Certificate of Dental Fitness
Should be Mandatory
For any Patient being treated by any drugs that alter bone turnover
50. Certificate of Dental Fitness
Awareness
• General Medical Practitioners
• General Dental Practitioners
• Hospital Specialists
• Chief Medical Officers MOH
• Government - Department of Health
• Drug Companies
– Should advise that Certificate of Dental Fitness is mandatory prior to commencing treatment
– Inadequate Dental Care provision and action to prevent ONJ could be considered negligent
51. Certificate of Dental Fitness
Patient
Osteoporosis
Dental
Assessment
Dentally Fit?
Certificate of
Dental Fitness
Dental
Disease
Treatment
Dental Fit
Certificate of
Dental Fitness
Oral / IV Drug
Therapy
Malignancy
Dental
Assessemnt
Dentally Fit?
Certificate of
Dental Fitness
Dental
Disease
Treatment
Dentally Fit
Certificate of
Dental Fitness
IV Drug
Therapy
Avoid Future Extractions
Poor Prognosis of Dentition
Consider Dental Clearance
52. ONJ Prevention
Patient
Oral Drugs
Dental Assessment
Radiographs
Treatment Plan
CTX > 200pg/ML
Oral Surgery
CTX<200pg/ML
Repeat 3monthly
IV Drugs
Dental Assessment
Radiographs
Treatment Plan
CTX>200pg/mL
Oral Surgery
CTX < 200pg/ML
Repeat 3 Monthly
Drug Holiday
Drug Holiday: CTX 25 pg/mL / month
Consider Root Canal Therapy rather than Extractions in Irreversible / High Risk Cases
54. Antiresorbtive Medications
Intravenous (IV) bisphosphonates (BPs)
– hypercalcemia of malignancy
– skeletal-related events (SRE) breast, prostate and lung cancers
– multiple myeloma
– improvement of survival is controversial
– significant positive effect on the quality of life for patients
– IV BPs, ie once yearly infusion of zolendronate (Reclast®) and a parenteral formulation of ibandronate
(Boniva®) administered every three months, have FDA approval for management of osteoporosis
55. ONJ Incidence
• oncology patient population (1-15%)
• osteoporosis patient population, 0.001% - 0.01%
marginally higher than the incidence in the general population (<0.001%).
56. New Insights of ONJ Pathophysiology
• anti-resorptive effects of Bisphosphonates and Demosumab
• effects of BPs on gamma delta T-cells
• monocyte and macrophage function,
• as well as the role of local bacterial infection, inflammation and necrosis
57. Other ONJ Risk Factors
• glucocorticoid use
• maxillary or mandibular bone surgery
• poor oral hygiene
• chronic inflammation
• diabetes mellitus
• ill-fitting dentures
• other drugs, including anti-angiogenic agents.
58. Prevention Strategies for ONJ
• Elimination or stabilization of oral disease prior to initiation of anti-resorptive agents,
• As well as maintenance of good oral hygiene.
• In those patients at high risk for the development of ONJ
including cancer patients receiving high-dose BP or Dmab therapy
consideration should be given to withholding anti-resorptive therapy following extensive oral surgery
until the surgical site heals with mature mucosal coverage
59. Management of ONJ
• stage of the disease
• size of the lesions
• as well as the presence of contributing drug therapy and comorbidity
60. Management of ONJ
Conservative therapy
• antibiotic oral rinses
• systemic antibiotic therapy
Localized surgical debridement
• indicated in advanced non-responsive disease and has been successful.
• enhanced osseous wound healing with teriparatide risk of osteosarcoma?
• Experimental therapy includes
– bone marrow stem cell intralesional transplantation
– low-level laser therapy
– local platelet-derived growth factor application
– hyperbaric oxygen
– tissue grafting
61. Definition ONJ
Original Definition
“area of exposed bone in the maxillofacial region that does not heal
within eight weeks after identification by a health care provider,
in a patient who was receiving or had been exposed to a bisphosphonate
(BP) and has not received radiation therapy to the craniofacial region”
62. Definition ONJ Update AAOMS
Definition Update
1. current or previous treatment with anti-resorptive or anti-angiogenic agents
2. exposed bone or bone that can be probed through an intraoral or extraoral
fistula(e) in the maxillofacial region that has persisted for more than eight weeks
3. no history of radiation therapy to the jaws or obvious metastatic disease to the
jaws
63. Task Force Definition of ONJ
AAOMS Taskforce Definition
1. Exposed bone in the maxillofacial region that does not heal within
eight weeks after identification by a health care provider
2. Exposure to an anti-resorptive agent
3. No history of radiation therapy to the craniofacial region.
64. Oral Ulceration and Bone
Sequestration OUBS
OUBS
• oral ulceration and bone sequestration (OUBS) / absence of anti-resorptive therapy
• Uncommon but typically associated with significant morbidity
• OUBS described as “lingual mandibular sequestration and ulceration”
(predilection for involvement of posterior lingual mandibular bone)
• The sequestrum can slough spontaneously resulting in rapid resolution
• Some cases, conservative surgical removal of the dead bone is indicated to permit efficient
healing.
65. OUBS
• The incidence of OUBS in the general population is not well defined
• OUBS cases captured? in data pertaining to drug-related ONJ?
• Prevalence OUBS not known
66. OUBS - Differential Diagnosis
• alveolar osteitis
• Sinusitis
• gingivitis/periondontitis
• periapical pathosis
• cement-osseous dysplasia showing secondary sequestration.
Bone inflammation and infection are usually present in patients with
advanced ONJ, and appear to be secondary events.
Extremes of skeletal phenotypes [osteoporosis vs. osteopetrosis] (mice with altered expression of these molecules)
Research identified :
- the signaling mechanisms involved in the RANKL/RANK pathway
- metabolic bone disorders
common postmenopausal osteoporosis
rare (i.e. familial expansile osteolysis)
Control of osteoclastogenesis that has emerged in the post OPG/RANKL/RANK era.
RANKL on the surface of preosteoblastic/stromal cells binds to RANK on the osteoclastic precursor cells
M-CSF, binds to its receptor, c-Fms, on preosteoclastic cells, appears to be necessary for osteoclast development because it is the primary determinant of the pool of these precursor cells (32)
RANKL, however, is critical for the differentiation, fusion into multinucleated cells, activation, and survival of osteoclastic cells
OPG puts a brake on the entire system by blocking the effects of RANKL
A number of proresorptive cytokines, such as TNF- and IL-1, modulate this system primarily by stimulating M-CSF production (thereby increasing the pool of preosteoclastic cells) and by directly increasing RANKL expression (33)
In addition, a number of other cytokines and hormones, such as TGF-ß (increased OPG production) (34), PTH (increased RANKL/decreased OPG production) (35), 1,25-dihydroxyvitamin D3 (increased RANKL production) (36), glucocorticoids (increased RANKL/decreased OPG production) (37), and estrogen (increased OPG production) (38, 39) exert their effects on osteoclastogenesis by regulating osteoblastic/stromal cell production of OPG and RANKL
However, not all regulation of the osteoclast is exclusively via the osteoblast because calcitonin acts directly on osteoclastic cells (40), and estrogen has been shown to induce apoptosis of osteoclasts (41) as well as inhibit osteoclast differentiation by interfering with RANK signaling, principally RANKL-induced JNK activation and c-Jun activity and expression (42, 43)
Moreover, TGF-ß can also stimulate RANK expression on preosteoclastic cells, and thus enhance osteoclastic sensitivity to RANKL (44)
Recent studies have also found that the ability of preosteoblastic/stromal cells to support osteoclast development is lost rapidly during differentiation down the osteoblast pathway, due principally to down-regulation of RANKL and increased OPG production (45). Again, this makes eminent sense in terms of the basic multicellular unit, because whereas early osteoblastic cells in the marrow orchestrate the process of osteoclast development, it would clearly be counterproductive for the mature osteoblastic cells laying down osteoid on the bone surface to at the same time be stimulating osteoclast development, which would destroy the work they have just completed.
Control of osteoclastogenesis that has emerged in the post OPG/RANKL/RANK era.
RANKL on the surface of preosteoblastic/stromal cells binds to RANK on the osteoclastic precursor cells
M-CSF, binds to its receptor, c-Fms, on preosteoclastic cells, appears to be necessary for osteoclast development because it is the primary determinant of the pool of these precursor cells (32)
RANKL, however, is critical for the differentiation, fusion into multinucleated cells, activation, and survival of osteoclastic cells
OPG puts a brake on the entire system by blocking the effects of RANKL
A number of proresorptive cytokines, such as TNF- and IL-1, modulate this system primarily by stimulating M-CSF production (thereby increasing the pool of preosteoclastic cells) and by directly increasing RANKL expression (33)
In addition, a number of other cytokines and hormones, such as TGF-ß (increased OPG production) (34), PTH (increased RANKL/decreased OPG production) (35), 1,25-dihydroxyvitamin D3 (increased RANKL production) (36), glucocorticoids (increased RANKL/decreased OPG production) (37), and estrogen (increased OPG production) (38, 39) exert their effects on osteoclastogenesis by regulating osteoblastic/stromal cell production of OPG and RANKL
However, not all regulation of the osteoclast is exclusively via the osteoblast because calcitonin acts directly on osteoclastic cells (40), and estrogen has been shown to induce apoptosis of osteoclasts (41) as well as inhibit osteoclast differentiation by interfering with RANK signaling, principally RANKL-induced JNK activation and c-Jun activity and expression (42, 43)
Moreover, TGF-ß can also stimulate RANK expression on preosteoclastic cells, and thus enhance osteoclastic sensitivity to RANKL (44)
Recent studies have also found that the ability of preosteoblastic/stromal cells to support osteoclast development is lost rapidly during differentiation down the osteoblast pathway, due principally to down-regulation of RANKL and increased OPG production (45). Again, this makes eminent sense in terms of the basic multicellular unit, because whereas early osteoblastic cells in the marrow orchestrate the process of osteoclast development, it would clearly be counterproductive for the mature osteoblastic cells laying down osteoid on the bone surface to at the same time be stimulating osteoclast development, which would destroy the work they have just completed.
Reports of osteonecrosis (also called "osteochemonecrosis" and "bisphosphonate-associated osteonecrosis") of the jaw associated with the use of the bisphosphonates zoledronic acid (Zometa, Novartis, East Hanover, N.J.) and pamidronate (Aredia, Novartis), began to surface in 2003.1,2 Zoledronic acid and pamidronate are intravenous (IV) bisphosphonates used to reduce bone pain, hypercalcemia of malignancy and skeletal complications in patients with multiple myeloma, breast, lung and other cancers and Paget’s disease of bone. The majority of reported cases of bisphosphonate-associated osteonecrosis (BON) of the jaw have been diagnosed after dental procedures such as tooth extraction. Less commonly, BON appears to occur spontaneously in patients taking these drugs.3
As of early 2006, cases of BON also had been reported in individuals taking orally administered nitrogen-containing bisphosphonates, used for the treatment of osteoporosis.3–5 The total number of reported cases of possible BON in people taking alendronate (Fosamax, Merck & Co., Whitehouse Station, N.J.) is approximately 170 worldwide, according to Merck & Co. (C. Arsever, oral communication, March 2006); approximately 12 in people taking risedronate (Actonel), according to Procter & Gamble Pharmaceuticals, Cincinnati (M. Schorr, oral communication, March 2006); and approximately one in a person taking ibandronate (Boniva, Roche Pharmaceuticals, Basel, Switzerland), according to Roche (J. Travis, oral communication, March 2006). For alendronate (the most commonly prescribed oral bisphosphonate), this translates into a spontaneous BON incidence (or rate at which new cases occur) of approximately 0.7 cases per one hundred thousand person-years’ exposure. To date, a true cause-and-effect relationship between osteonecrosis of the jaw and bisphosphonate use has not been established. Table 1 lists all oral and IV bisphosphonates on the market in the United States.
The morning fasting serum CTX test is one of several known serum and urine tests that measures a breakdown product of bone resorption.
The CTX specifically measures a specific crosslink peptide of type I collagen in bone (98% of the total protein in bone).
The serum CTX is considered to best correlate to bone turnover and was chosen due to the fact that a single laboratory (Quest Diagnostics Nichols East Lab in San Juan Capistrano, California) performs this test under standard conditions.
The telopeptide fragment in question is cleaved from the main crosslink chains of collagen by the osteoclast during bone resorption. Its level in the serum is therefore proportional to the amount of osteoclastic resorption occurring at the time the blood is drawn. Even though laboratory normal ranges are said to be between 50 pg/mL and 450
pg/mL, this normal range is not accurate related to the osteoporosis population. Actual normal values are usually well over 300 pg/mL and are most commonly 400 pg/mL to 550 pg/mL in patients not taking bisphosphonates. Lower values represent varying degrees of suppression of normal bone turnover sometimes also called bone remodeling or bone renewal.
Current opinion is that oral surgery can be carried out at a level of 100pg/100mls* but that treatment is safer with
CTX BETA CROSSLAPS >200pg/100mls**
*Therapeutic Guidelines. Therapeutic guidelines: oral and dental. Melbourne: TG, 2007.
**Ref: Goss AN. CTX (the cross laps test). Australian Dental Association Bulletin 2008; 368:11.