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Case 10: Bone Metabolism and Treatment Considerations

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John Tankersley

on 31 October 2013

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Transcript of Case 10: Bone Metabolism and Treatment Considerations

What is Antiresorptive Therapy?
Case 10: Bone Metabolism and Treatment Considerations
Group 12
Jonathan Tankersley
Michael Chilton
Rubi Perez
Bone Loss
The previous dentist was concerned regarding the unexplainable bone loss and irregular trabecular patterns in the mandible. These could be symptoms of multiple oral health issues, however, the medical and dental history allow us to narrow down the possibilities. (4)
Courtney Kiel
Megan Bender
Jose Gonzales
Case Overview:
The dentist most likely suspected that the patient is experiencing bone loss due to a systemic disease.(4) This would explain the loss of bone without chronic periodontal disease and the irregular trabecular bone in the radiograph. (5)
Common causes of bone loss :
Osteoporosis/ osteopenia
Dentures/ Bridgework
Profile Details:
Mandolina, is a 44 year old Caucasian that is a new patient in your dental office. She had visited another dentist on a regular basis until he retired eight months ago. Her oral hygiene is good with the exception of keeping her third molars clean. Her previous dentist recommended that she see her physician due to radiographic evidence of bone loss in the lower jaw that could not be explained. She visits your office today to establish herself as a new patient, for a comprehensive dental examination and to address some dental pain and swelling.

General health is good
No allergies
Has signs of having undergone early menopause
Her bone mineral density (BMD) appeared to be reduced with some deterioration of bone microarchitecture
Her physician stated he would like to start her on antiresorptive medication her next visit
Medical History
Dental History
Regular visits (every 6 months) up until 8 months ago when she had her last cleaning
Difficulty cleaning her third molars
Dentist recommended they be removed
During last visit, her previous dentist found bone loss (unexplainable)
No signs of gingivitis or periodontitis
Small carious lesion on the posterior surface of the last molar on the lower right side

Intro Oral Exam:
Lower right third molar (#32) showed a large carious lesion on its distal surface with mobility and a buccal fistula with exudate present.

The radiographs show a large radiolucent area on its distal surface entering into the pulp and at the apex of the root also irregular trabecular in the alveolar bone of the lower arch.

The tooth is deemed nonrestorable.

Is bone formation affected by age and gender, and if so how do bone formation mechanisms differ?
Patient Diagnosis
The dentist would recommend a physician's consult because the patient is displaying symptoms of a serious disease. As a dentist, he would typically not diagnose the disease, but would alert the patient to the signs and recommend a visit to the physician for confirmation and treatment. Once the condition is under control, the dentist can proceed with his treatment plan for her oral health.
Physician's Consult
Bone Remodeling
Mandolina’s previous dentist recommended removal of all third molars.
Do you agree with this assessment?
With your current knowledge of her condition, would you remove them? Would you have any concerns?
Would you remove the teeth before or after antiresorptive therapy began? Why?
What is bone remodeling?
What is the mechanism of action for antiresorptive drugs on bone formation in this condition?
Bone remodeling is a complex process by which old bone is constantly being replaced by new tissue.
This process is dependent upon interactions between different cells and is regulated by many different biochemicals.
Our skeleton is a metabolically active organ that is constantly replaced throughout our life.
Bone remodeling is necessary to replace/repair damaged bone. This maintains the integrity of our skeleton. [25]
"Bone remodeling serves to adjust bone architecture to meet changing mechanical needs and it helps to repair microdamages in bone matrix preventing the accumulation of old bone" [25]
Bone Density Loss
The patient test (DEXA scans) revealing bone mineral density reduction is concerning because it is a major sign of a larger problem. (6)The treatment for bone porosity could lead to complications with the removal of her third molars. (7)
Types of Antiresorptive Therapy
Decrease bone remodeling by decreasing osteoclast activity and inducing osteoclast apoptosis
Inhibits osteoclast activity without decreasing osteoblast collagen synthesis
Estrogen and raloxifene (SERM)
Suppress bone remodeling to the premenopausal range, maintaining the function of osteoblasts and osteocytes (11)
Mandolina reported pain and swelling in her lower right posterior jaw upon chewing. The patient is more than likely experiencing pain from pulpitis resulting from an endodontic infection. The carious lesion on #32 could be a route of infection for bacteria to enter the pulp canal. The patient also reports tooth mobility which may be a result of osteomyelitis or osteoporosis.

Bone Remodeling
Cells Involved in Modeling and Remodeling
Osteoclast- involved in bone resorption
activated when preosteoclasts are stimulated to differentiate by growth factors and cytokines
In the resorption process ostoclasts are digesting mineral matrix and old bone [23]
Osteoblast- involved in bone formation
responsible for bone matrix synthesis
synthesize collagen as well non-collagenous proteins like osetocalcin and osteonectin
osteonectin is a glycoprotein in the bone that binds calcium. Initiates mineralization [24]
osteocalcin- most abundant non-collagenous bone in the body but the exact function still is not known. [24]
How does that mechanism differ when compared to the use of antiresorptive drugs in the treatment of bone cancer?
The bone density loss is a major sign of osteopenia or osteoporosis. (6) The fact that she is losing bone density without infection or any of the other typical causes, along with her diagnosis of early menopause, reinforces this conclusion.(6) This is a very serious condition that requires treatment, but those treatment options could affect the timing and treatment planning of the dentist as well.
-Bone formation increases with age and peaks around the 3rd decade of life (1)

-Bank analogy

-Lifestyle choices become more important
There are several treatment options depending on the severity of the disease. The intake of calcium and vitamin D, which are essential to bone health, need to be increased. (7) Also, physical and weight bearing exercises are encouraged to strengthen the bone mass. (7) Many times the patient will be prescribed bisphosphonates, which are bone antiresorptive medications. (7)These medications will play a major role in the treatment plan
of the dentist.
Estrogen Deficiency Effects
Detrimental effects:
Supression of osteocyte survival
Impairs osteoblast response to mechanical stimuli
Extends bone resorption phase by reducing osteoclast apoptosis (11)
1: http://www.niams.nih.gov/Health_Info/Bone/Osteoporosis/bone_mass.asp
2. Siqueira JF. Endodontic infections: Concepts, paradigms, and perspectives. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;94:281-293.
3. Odontogenic cutaneous fistulas: clinical and epidemiologic characteristics of 75 cases Elizabeth Guevara-Gutierrez
4. Reasons for Jaw Bone Deterioration and Loss. (2010, April 23). Infuse Bone Graft. Retrieved October 28, 2013, from https://www.infusebonegraft.com/omf_reasons_for_jaw_bone_loss.html
5. Hildebolt, C. F. (1997). Osteoporosis and oral bone loss. Dentomaxillofacial Radiology, 26, 3-15.
6. Bone Mineral Density. (2011, February 23). WebMD. Retrieved October 28, 2013, from http://www.webmd.com/osteoporosis/bone-mineral-density-test
7. Osteoporosis Medication Types, Home Remedies, and More. (n.d.). WebMD. Retrieved October 28, 2013, from http://www.webmd.com/osteoporosis/guide/osteoporosis-treatments
8.Sedghizadeh PP, Kumar SK, Gorur A, Schaudinn C, Shuler CF, Costerton JW. Microbial biofilms in osteomyelitis of the jaw and osteonecrosis of the jaw
secondary to bisphosphonate therapy. J Am Dent Assoc 2009; 140: 1259-1265.
9. Akira Goda, Analysis of the factors affecting the formation of the microbiome
associated with chronic osteomyelitis of the jaw. http: onlinelibrary.wiley.com.libdb.db.uth.tmc.edu:2048store/10.1111/1469-0691.12400/asset/clm12400. pv=1&t=hnerixui& s=61cf1ca2843dc2f2f5d
10. Vijayan A, Orbital abscess arising from an odontogenic infection. J Contemp Dent Pract. 2012 Sep 1;13(5):740-3. http://www.ncbi.nlm.nih.gov/pubmed/23250186
11. ENDOCRINE REGULATIONS, VOL. 37, 227–240, 2003
12. Nature Reviews Rheumatology 9, 263-264 (May 2013) | doi:10.1038/nrrheum.2013.57
13. J Bone Miner Res. 1998 Apr;13(4):581-9.
14. Philippe Clézardin, Frank H. Ebetino and Pierrick G.J. Fournier Cancer Res 2005;65:4971-4974
15. Clinical Oral Investigations Springer-Verlag Berlin Heidelberg 2013
16: http://www.niams.nih.gov/Health_Info/Bone/Bone_Health/Pregnancy/default.asp
17.WBDS (2012). Impacted wisdom teeth: Reasons to extract third molars. (pericoronitis / infection / decay / gum disease / cysts / tumors). Retrieved October 30, 2013, from http://www.animated-teeth.com/wisdom_teeth/t2_wisdom_tooth_extraction.htm
18.Reirez, Zorzi, & Lovat (2008). Bisphosphonates and osteonecrosis of the jaw: a case report. SciELO, 62(2). Retrieved from http://www.scielo.br/scielo.php?pid=S1807-59322008000200020&script=sci_arttext
19: Riggs, B Lawrence, Mary L Bouxsein, Cynthia H McCollough, Peggy A Rouleau, James M Peterson, Elizabeth J Atkinson, Jon J Camp, Richard A Robb, L Joseph Melton III, and Sundeep Khosla. "Population-Based Study Of Age And Sex Differences In Bone Volumetric Density, Size, Geometry, And Structure At Different Skeletal Sites." <i>Journal of Bone and Mineral Research</i> 19.12 (2004): 1945-1954. <i>Wiley Online Library</i>. Web. 31 Oct. 2013.
19.American Academy of Family Physicians (2013). Retrieved 30, 2013, from www.aafp.org/afp/2012/0615/p1134.html
20.JADA (2011). Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis. JADA, 142(11). Retrieved from http://jada.ada.org/content/142/11/1243.long#ref-4
22. Krassas, G. E., and Ph Papadopoulou. "Oestrogen action on bone cells." Journal of Musculoskeletal and Neuronal Interactions 2.2 (2001): 143-152.
23. "Bone Remodeling." <i>Applications Sante</i>. N.p., n.d. Web. 30 Oct. 2013. &lt;http://www.medes.fr/home_fr/applications_sante/osteoporose/eristo/osteoporosis/Bone_Remodeling.htmlFind a website by URL or keyword...&gt;.
24. Raggatt, Liza J., and Nicola C. Partridge. "Cellular and molecular mechanisms of bone remodeling." Journal of Biological Chemistry 285.33 (2010): 25103-25108.
25. Hadjidakis, Dimitrios J., and Ioannis I. Androulakis. "Bone remodeling." Annals of the New York Academy of Sciences 1092.1 (2006): 385-396.
26. "Bone Development and Structure." <i>Earth Physiology</i>. N.p., n.d. Web. 30 Oct. 2013. &lt;http://www.nsbri.org/humanphysspace/focus6/ep_development.html&gt;.
27. Crockett, Julie C., et al. "Bone remodelling at a glance." Journal of cell science 124.7 (2011): 991-998.
Endodontic infections
Antiresorptive Drugs and Osteoporosis
How do cancer drugs differ from osteoporosis drugs?
In addition to reducing osteoclast activity....
Bone growth factor secretion is blocked
Oncogene activity is blocked
Angiogenesis is blocked
Reduced osteoclast activity can also cause osteonecrosis of the jaw
Philippe Clézardin, Frank H. Ebetino and Pierrick G.J. Fournier Cancer Res 2005;65:4971-4974

One of the most common infections of the oral cavity
One of the main routes of infection through a carious lesion

Mainly due to an invasion of bacteria of the dentinal tubles through a carious lesion caused by an undisturbed biofilm
lack of good oral hygiene in the area
Acid producing lactobacilli and certain streptococci advance caries
Porphyromonas, Prevotella, Fusobacterium, Treponema, Peptostreptococcus, Eubacterium, and Campylobacter(2).
endogenous and poymicrobial

Intra-oral exam revealed a "Buccal fistula present and radiograph shows a large radiolucent area on its distal surface entering into the pulp and at the apex of the root.
Possibility of necrotic pulp and the spreading of the infection beyond the tooth leading to apical periodontitis. This condition can lead to inflammation and pain causing bone loss and the formation of the bucal fistula(3).

Tooth pain upon chewing may be a result of necrosis of the pulp due to pulpitis. (3)
Causes for Extractions:

Periodontal disease
Pathology (cysts, tumors) associated with a wisdom tooth
Problems associated with poor tooth alignment/ impacted molar
Risk of damage to adjacent teeth/ root resorption
Chronic pain or discomfort
Complications associated with tooth decay (17)
What is bothering her?
Tooth #32

Pain and swelling in lower right posterior jaw over the last few days when chewing
Loose tooth
Large carious lesion on its distal surface
Buccal fistula with exudate
Difficult to clean
Radiographs shows a large radiolucent area on its distal surface entering into the pulp and the apex of the root also irregular trabecular patterns in the alveolar bone of the lower arch
Tooth is deemed

Third molars are usually extracted due to:

In the case of Mandolina, should the third molars be extracted?

Based on the information presented, the removal of all third molars at once would not be recommended. The tooth that has the large carious lesion should be extracted first and the dentist should wait to see how well the surrounding tissue heals.
If possible
, extraction should be done prior to antiresorptive therapy and should be followed by antibacterial therapy. Extractions of the remaining third molars should be done since they are difficult to clean and may cause further problems. (18)

What can happen if the teeth are extracted after the patient is undergoing antiresorptive treatment?

The most commonly used medications for osteoporosis are the antiresorptive bisphosphonates, which inhibit osteoclast activity thereby reducing bone resorption. Antiresorptive therapy is continued for at least 5 years (some patients may need treatment for longer periods.

Osteonecrosis of the jaw
is a possibility if the teeth are extracted while being treated with bisphosphonates.

This condition is specifically known as the
Antiresorptive agent-induced osteonecrosis of the jaw- ARONJ
. (19)

ARONJ may be occur due to a decrease of the bone’s ability to repair itself, a decrease in blood vessel formation, or the possible effects of infection.

ANOJ may develop in patients taking bisphosphonates for as little as 12 months. The risk increases the longer the patient takes the bisphosphonates. Most of the ARONJ cases occur after prolonged therapy, usually more than 5 years.

The risk for oral necrosis of the jaw for a patient with osteoporosis who are treated with bisphosphonates is
. Study results range from less than 1 in 100,000 getting ONJ from bisphosphonate therapy to 1 in 263,158.
Bisphosphonate-related osteonecrosis of the jaw at extraction site of tooth #18. Necrotic, nonhealing exposed bone extends up the ramus and to the buccal aspect of tooth #19.
Antiresorptive Drugs
Goal: Restore bone density by decreasing bone remodeling
Nitrogen Containing Bisphosphonates
Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation (i.e. modification) of GTP-binding proteins, including Ras, with farnesyl diphosphate synthase (13)
Osteomyelitis of the Jaw
Chronic inflammation of the jaw bone due to deep bacterial invasion of the cortical bone from an odontogenic infection.
Formation of polymicrobial biofilm on the bone surface observed in
investigations of osteomyelitis(7).

May exhibit abscess or fistulas with pus formation(8).

Bacteria present consists of mostly gram - red complex common in periodontal infections. (8)

Patient has a buccal fistula present; a strong indicator of a infection that has extended beyond the tooth itself.
Nitrogen Containing Bisphosphonates
cortical osteotomy combined with
antimicrobial therapy or antimicrobial monotherapy (8)
A bacterial investigation should be done to determine if bacteria is causing the bone resorption(8).
The fistula should be drained and the patient possibly treated with antibiotic prophylaxis for the endodontic infection and possible osteomyelitis (10).
Extraction of #32 should follow antibacterial therapy.
The osteoblast will secrete ground substance rich in collagen. The collagen will be essential for mineralization of hydroxyapatite and other crystals.

The collagen will join into strands to form osteoids. These osteoids are the spiral fibers of the bone matrix. [23]
Osteoblasts will induce calcium salts and phosphorous precipitation from our blood. [23]
These minerals that have precipitated will form bonds with the newly synthesized osteoids causing them to mineralize into bone tissue. [23]
Fun fact
: osteoblast have estrogen receptors. Estrogen can induce the formation and increase the activity of osteoblasts. Furthermore, estrogen has been shown to inhibit the release of osteoclast stimulatory factors and enhance the release of osteoclast inhibitory factors. [22]
An osteocyte forms whenever the osteoblast becomes entrapped by the bone matrix that has formed around it. This osteocyte remains within a small pit known as the lucana. It can communicate with the surrounding through channels called canaliculi.
"By secreting substances through their dendrites, osteocytes can recruit or inhibit osteoclasts and osteoblasts and thus influence the remodeling of surrounding bone" [23]

Systemic skeletal disease characterized by low bone mass with micro-architectural deterioration
Post menopause, production of oestrogens decreases, leading to osteoporosis in skeletal bones, marks the beginning of bone loss and deformities may occur.
may include jawbones, particularly the mandible
increasing attention in relation to the susceptibility to periodontal disease in post-menopausal women
Chronic apical periodontitis develops as a chronic inflammatory process
presence of periapical radiolucency, from inflammatory processes promoting bone resorption
Acceleration of bone loss due to chronic apical periodontitis in post-menopausal women

Nutrition and Hormones
Vitamin A- needed for ostoblast acitivity
Deficiency stunts bone growth [27]
Vitamin C- needed for synthesis of collagen
Deficiency slows down bone growth
Vitamin D- contribute to bone growth by increasing calcium absorption from GI tract to blood [26]
Vitamin K and B12- needed for synthesis of bone protein. Deficiency leads to decreased bone density [27]
75 women > 50 yrs post menopause
27 women with periapical radiolucencies
marginally significant association between the presence of periapical radiolucencies and low BMD.
As a result, the inflammation-induced osteolysis present in post-menopausal osteoporosis could be a systemic aggravating factor in chronic apical periodontitis.
hGH- promotes growth of all body tissue including bone. [26]
Insulinlike growth factors- secretion is stimulated by hGH. Stimulates osteoblasts and protein synthesis [27]
Insulin- promotes bone growth by increased synthesis of bone protein [27]
Parathyroid hormone- promotes bone resorption by osteclasts. Also promotes synthesis of the active form of Vitamin D. [26]
Calcitonin- inhibits bone resorption by osteoclasts [27]
Estrogen [22]
a. During bone resorption, bisphosphonates are taken up by the osteoclasts (i.e. bind to hydroxyapatite)
b. After engulfing bisphosphonates, osteoclasts undergo changes (including loss of ruffled border and become inactive) preventing further resorption
c. Eventually, osteoclasts detach from bone surface and can persist in bone marrow as large, multinucleated inactive cells, while the resorption lacuna is filled with new bone
d. After treatment discontinuation, new bone remodeling cycles can release embedded bisphosphonates. Uptake of these compounds by osteoclasts results in decreased resorption
e. Bisphosphonates might also be released from bone by desorption, at a rate dependent on their binding affinity (12)

Mandolina is more than likely experiencing pain from pulpitis resulting from an endodontic infection.
The carious lesion on #32 was the route of infection for bacteria to enter the pulp canal. The patient also reports tooth mobility which may be a result of osteomyelitis or osteoporosis.
The previous dentist most likely recommended a physician's consult because he or she suspects that the patient is experiencing bone loss due to osteoporosis.
The bone density loss is a major sign of osteopenia or osteoporosis. In order to treat this we may increase the calcium and vitamin treatment or prescribe bisphosphonates. The patient may also increase their load bearing exercise regimen.
The bone remodeling process is dependent upon osteoblasts and osteoclasts. This process is continuous throughout ones life and may be influenced by various vitamins and hormones.
Bone formation increases with age and peaks around the 3rd decade of life. Females tend to have lower bone mass when compared to men. Due to menopause women also exhibit a sharper decline in bone mass after going through menopause.
The aim of antiresorptive drugs is to decrease the amount of remodeling.
Antiresorptive drugs include bisphosphonates, calcitonin, and Raloxifene.
We recommend that the patient initially extracts tooth #32 only prior to antiresorptive treatment.
However, benefits provided by antiresorptive therapy in patients with osteoporosis may outweigh the low risk of developing osteonecrosis of the jaw and can be placed on it prior to extraction(s).
Direct effects
Decrease tumor cell invasion and adhesion
Decrease proliferation
Increase apoptosis

Indirect effects
Decrease tumor angiogenesis (14)
In order to avoid complications such as ARONJ, if possible it is recommended that the patient delay the bisphospnonate therapy in order to perform the dental treatment required, in this case the extraction(s). Once proper dental health is regained, the patient can proceed with the antiresorptive therapy. (18)

, benefit provided by antiresorptive therapy in patients with osteoporosis may outweigh the low risk of developing osteonecrosis of the jaw
. (20) The dentists should fully disclose all the risks associated with the procedure.

Dental treatment should be continued even if the patient is placed on antiresorptive therapy. The dentist should extract #32 first and wait for an adequate healing response. If it is adequate, the dentist can consider a more accelerated surgical treatment plan involving the multiple third molar extractions in a single appointment. (20)


Bone remodeling
Plasma calcium homeostasis
Modify bone architecture in order to meet changing mechanical needs
Maintain osteocyte viability
Repair microdamage in bone matrix (11)
Angiogenesis and Osteonecrosis of the Jaw
More common in patients receiving nitrogen containing bisphosphonates than non-nitrogen containing
More common in mandible than maxilla (11,15)
By blocking angiogenesis
Prevents endothelial cells from circulating which stops blood vessel development
Therefore, tumor has no blood supply so the bone begins to die (15)
-Generally, women have smaller bones than men

-Men had 35-42% greater bone areas than women
-Larger bones are stronger (19)

-Pregnancy, Breastfeeding, Menopause (16)

-Not common experiences for men...
How do Bone Formation Mechanisms Change?
-As age increases
-Early: bone formation > bone loss
-Mid: bone formation = bone loss
-Late: bone formation < bone loss
-Women: menopause and estrogen deficiency
-Men: relation between steroid hormones and bone loss not as prominent (21)
Etidronate, tiludronate and clodronate
which lack nitrogen in the side chain, are metabolized within the osteoclasts and macrophages to form toxic methylene-containing analogs of ATP
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