What is bone metabolism?

Bone metabolism is a continual cycle of bone growth and resorption that is carefully orchestrated by the dynamic relationship between osteoclasts, osteoblasts, and an array of hormonal and regulatory influences.

The three important cells involved in bone metabolism: 

• Osteoclasts are large multinucleated cells that RESORB bone. 
• Osteoblasts, which FORMS bone. 
• Osteocytes help to MAINTAIN bone. 

For a detailed overview of bone formation please refer to the “Clinical anatomy – Bone” lesson. We will cover the major key points below:

Bone formation

Osteoblasts are differentiated from mesenchymal cells - the two factors RUNX2 and OSX are expressed in these cells. There are other factors involved this progress such as bone morphogenic protein (BMP) and fibroblast growth factor (FGF).  The osteoblast produces osteoid that is made from type 1 collagen which encourages minerals such as calcium and phosphate to bind to it and form hydroxyapatite. Over a period, the osteoblast will become embedded into the tissue and it matures to become osteocyte.¹

Bone removal

The osteoblast expresses a protein called RANK L, this binds to a receptor called RANK - which is found on osteoclasts precursor cells. This process helps the monocyte differentiate into osteoclast. The osteoclast helps to resorb bone and release minerals such as calcium and phosphate that are vital in maintaining homeostasis. Once enough minerals are released, the osteoblast can produce a protein called OPG, this competitively binds to RANK preventing resorption.¹

What are Bisphosphonates?

Bisphosphonates are a class of drugs that are used to suppress bone resorption and help to encourage bone deposition. 

Bisphosphonates can be administered orally or via IV.

Pharmacology of Bisphosphonates

This picture illustrates the core chemical structure of bisphosphonates, with R1 and R2 being side chains which increase the affinity for bone and calcium.²

Bisphosphonates can be divided into two groups, non-nitrogenous or nitrogenous. 

The table below gives examples of the different groups. 

How do they work?

Bisphosphonates have an extremely high affinity for bone, this enables them to be deposited within the bone.  

Non-nitrogen containing

Inorganic pyrophosphate (PPi) is a compound that is found naturally within the human body and is release as by-product of many cell processes.  PPi prevents calcification of bone by binding onto hydroxyapatite crystals. The bisphosphonates are structurally similar to PPi. When administered, bisphosphonates are taken up by the osteoclast and are integrated with ATP making it non-hydrolysable. This process leads to osteoclast apoptosis, as the product of this reaction is cytotoxic.³

Nitrogen containing

The nitrogen containing bisphosphonates inhibit the farnesyl pyrophosphate synthase enzyme by binding directly to it. This enzyme is vital as it is involved in the production of cholesterol and isoprenoid lipids, as well as the activation of proteins involved in osteoclast regulation. Without the activation of these proteins apoptotic signals are induced in the osteoclast, leading to cell death.^3,4

What are Bisphosphonates used for?

These drugs are used in different bone diseases: 

Osteoporosis

Common skeletal condition where there is a decrease in bone mass leading to an increased risk of fracture. There are two types of osteoporosis.

• Postmenopausal (type 1): This is where decrease in oestrogen causes the increase of osteoclast activity. Occurs in females in between 4^th and 5^th decade. 

• Age- related (type 2) ³

Some drugs may also predispose patients to osteoporosis, such as long-term treatment with corticosteroids or proton pump inhibitors.

Paget's Disease

In pathology the osteoblast is mutated causing a disorder of bone remodelling. This leads to poorly formed woven and lamella bone being deposited. In short, the old bone is replaced by new bone that is prone to fractures and is deformed that can cause pain. ³

Bisphosphonates in Malignancy

Some cancers such as prostate and breast cancer are capable of metastasising to the bone or the bone marrow, this consequently leading to hypercalcemia, severe bone pain, skeletal destruction, and fractures. ³

Administration of Bisphosphonates

• When used for osteoporosis bisphosphonates are often once taken weekly, monthly and sometimes even less than this for infusions.
• For oral bisphosphonates the patient must take the tablet on an empty stomach (and at least 30 mins before food) whilst sitting or standing and remain upright for 30 minutes. This is to prevent reflux of the medication which can cause irritation of the oesophagus.⁵

Clinical Relevance

One of the major risks of bisphosphonates is medication related osteonecrosis of the jaw (MRONJ). This is where bone is exposed and becomes necrotic. This is a potential oral side effect of bisphosphonates as they slow bone turnover and therefore delay healing. This pathology is also associated with anti-angiogenic drugs as well. 

Any dental procedure that affects the bone is regarded as a risk factor for MRONJ , these include dental trauma such as poor fitting dentures, extractions, minor oral surgery and more. Dental infection and untreated periodontal disease may increase the risk for MRONJ as some evidence suggests.⁶

Anti-angiogenic Drugs

Bevacizumab and Aflibercept

Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF).⁷ VEGF is released to promote endothelial cell growth by forming new blood vessels. Aflibercept works in a same way but it is ‘recombinant fusion protein’ and it binds to VEGF.⁸

Sunitinib

This works by inhibiting receptor tyrosine kinase (RTK). This enzyme is responsible for cell proliferation, metabolism, and helps cells to differentiate and migrate. It is vital for phosphorylation of nucleotides, for example ATP.⁹

SDCEP Guidelines⁶ 

Risk Categories

Patients who have taken bisphosphonates in the past are categorised into risk groups. 

The table below describes the two categories:⁶ 

Low Risk Patient Management

• Can carry all routine dental treatment
• If an extraction is indicated or procedure that involves the bone:
  • Explain to the patient the risks and benefits of the treatment.
  • Avoid prescribing antibiotics or antiseptic prophylaxis however, if it is clinically indicated then prescribe it. 
  • Encourage the patient to contact the practice if there is pain, swelling, altered sensation in the extracted area.
  • Review the extraction socket, if it has failed to heal within 8 weeks it is vital you REFER to oral surgery/ special care dentistry as they are suspected to have MRONJ.⁵

High Risk Patient Management

• You can conduct most dental treatment but need to tailor the preventive advice to the patient. 
• Consider liaising with oral surgery/ special care dentistry specialist for higher risk patients who are treated for cancer to aid with clinical assessment and treatment planning. 
• If an extraction is indicated seek other alternatives and if there is absence of infection, consider retaining the roots. 
  • Explain to the patient the risks and benefits of the treatment.
  • Avoid prescribing antibiotics or antiseptic prophylaxis however, if it is clinically indicated then prescribe it. 
  • Encourage the patient to contact the practice if there is pain, swelling, altered sensation in the extracted area.
  • Review the extraction socket, if it has failed to heal within 8 weeks it is vital you REFER to oral surgery/ special care dentistry as they are suspected to have MRONJ.⁵

Clinical Tip - Bisphosphonate Treatment Initiation¹¹

Currently the guidance in the BNF is that all patients who are about to/have just started bisphosphonate treatment and who:

• Have been diagnosed with cancer
• Have poor dental health status

Should receive a dental check-up and appropriate treatment as soon as possible. Dentures must also be examined - poorly fitting dentures should be corrected. In short, we want to correct any dental issues before the patient starts taking the bisphosphonates.

In addition, dental clinicians must ensure they advise patients to:

• Maintain good oral hygiene
• Attend routine dental check-ups
• Arrange an appointment if they experience any tooth mobility, dental pain, oral swelling, or non-healing sores.

How to assess the different stages of MRONJ orally

As per SDCEP guidance if you suspect a patient has MRONJ you should follow your local protocol and refer appropriately to oral surgery/special care or the named specialist.

However, for completeness, the following information may assist in understanding the progress of MRONJ¹⁰:

Stage 0

Exposed bone is not present however, patients may present with the following symptoms: 

• Dull ache pain in the mandible that spreads to TMJ. 
• Sinusitis leading to thickened sinus walls. 
• Paraesthesia or anaesthesia of the trigeminal nerve. 
• Chronic pain in the tooth that is not of odontogenic origin. 

Clinical findings:

• Periapical or periodontal fistula which is NOT caused by caries. 
• Increased mobility of the teeth with no evidence of chronic periodontal disease or trauma. 

Radiographic findings: 

• Thickening of the lamina dura and smaller PDL space. 
• Change in the trabecular structure. 
• Resorption of the alveolar bone with no evidence of chronic periodontal disease. 

Stage 1

This is where the bone is exposed but is  asymptomatic, and there is no significant soft tissue infection. 

Management: Treated with antibiotics, antibacterial mouth rinses and review the patient quarterly. 

Stage 2

The bone is exposed, patient presents with pain, soft tissue and/or bone infection.

Management: Treated with oral antibiotic therapy, antibacterial mouth rinses and carry out debridement to ease the pain and reduce the infection.  

Stage 3

The bone is exposed, and patient presents with soft tissue infection or pain and pathological fracture. This may expand further than the alveolar bone to maxillary sinus, zygoma, mandible etc. 

Management: Treated with oral antibiotic therapy, antibacterial mouth rinse, carry out surgical debridement or removal of infected tissue.