This article outlines comprehensive strategies for managing bone metastases-associated pain in cancer patients, emphasising multimodal approaches. The goal is not only pain relief but also prevention of pain progression and skeletal-related events, ultimately improving patients' quality of life.

Bone metastases (BM)

Bone metastases (BM) represent a common complication of cancer, reaching an incidence of up to :

• Prostate cancer (PC) - 65–90% 
• Breast cancer (BC) - About 65–75%
• Colorectal cancer - Skeletal involvement is less frequent in other malignancies, ranging from approximately less than 10%
• Lung cancer- 17–64%

Since cancer-induced bone pain (CIBP) is complex and includes multiple processes, different approaches should be used depending on the stage of the disease and the type of pain to maximise pain relief and quality of life (QoL).

Anticancer treatment

Anticancer treatment includes systemic treatment techniques (chemotherapy, hormone therapy, immunotherapy, and molecular treatment) as well as local surgery and/or radiotherapy (RT).

1. Causal treatment reduces the tumour mass and local tissue infiltration and thus decreases the pain intensity; hence, anticancer treatment may be regarded as symptomatic treatment, as well.
2. Systemic treatment alone may lead to relief of most symptoms in some cancers eg. Hormone receptor-positive, HER-2 negative metastatic breast cancer.
3. Analgesic treatment includes pain management with analgesics (non-opioid and opioid analgesics according to the World Health Organization (WHO) analgesic ladder), bone-targeted therapies (osteoclast inhibitors, such as bisphosphonates and denosumab), and adjuvants (corticosteroids, anticonvulsants). We will discuss some of the relevant strategies.

Radiotherapy

1. There is high-quality evidence that single-dose, low-fractionated RT should be used in adults with pain related to bone metastases if indicated and available.
2. External beam radiation therapy (EBRT) should be explored for all patients with bone metastases.
3. A single fraction of 8 Gy, which is low-fractionated, has the same efficacy as lengthier regimens, such as 5 fractions of 4 Gy (20 Gy) or 10 fractions of 3 Gy (30 Gy) (high-fractionated), in terms of both the onset and duration of pain reduction.
4. Clinical data show that under both schedules, about 25% of patients experienced complete pain relief and about 70% experienced either partial or complete pain relief.
5. Patients usually see a reduction in discomfort within one to two weeks. In certain cases, re-irradiation with a dose of 8 Gy may be considered in patients with recurrent bone pain.

Radiopharmaceuticals

EBRT may not be efficacious for patients with widespread pain that is difficult to localise. Systemic administration of radiopharmaceuticals (e.g., strontium-89, samarium-153, rhenium, radium-223) may be offered to patients with diffuse bone pain due to osteoblastic or mixed osteoblastic–osteolytic metastases.

Surgery

1. It should be considered for patients with metastatic spinal cord compression (mSCC), particularly those with spinal instability, unknown primary histology, recurrence after previous RT, or a solitary site of compression.
2. Although the best surgical technique for treating spinal metastases is still up for debate, posterolateral fusion combined with autologous bone grafting is the recommended approach.
3. Although the best surgical technique for treating spinal metastases is still up for debate, posterolateral fusion combined with autologous bone grafting is the recommended approach.
4. Patients with spinal metastases but no neurological damage who experience chronic pain may benefit from minimally invasive procedures such as balloon kyphoplasty or percutaneous vertebroplasty.
5. The application of minimally invasive thermoablation—a combination of cryoablation and RF ablation techniques, is one of the latest advancements.  For example, magnetic resonance-guided high-intensity focused ultrasound or microwave ablation can be utilised to treat painful bone metastases.

Bone directed therapies

Bisphosphonates

1. They are defined as “nitrogen-containing” (N-BPs: zoledronate, ibandronate, etc.) or “non-nitrogen-containing” (non-N-BPs: clodronate, etidronate, etc.). The former inhibits farnesyl pyrophosphate synthase, which is essential for osteoclast survival and activity; the latter is metabolised to cytotoxic adenosine triphosphate analogues that induce osteoclast apoptosis.
2. Clinical studies have shown significant pain relief and reduced risk of SREs with the use of bisphosphonates, but no significant changes in QoL scores have been found.
3. Data from clinical studies the pain reduction and duration of pain relief were similar for each of the bisphosphonates studied (clodronate, ibandronate, pamidronate, zoledronate).
4. However, zoledronic acid remains the most widely used with the best available data. The variable renal effects when prescribing bisphosphonates should be considered. Osteonecrosis of the jaw is another serious adverse effect.

Denosumab

1. It is a human, monoclonal, synthetic antibody that binds to RANKL(receptor activator of nuclear factor kappa beta ligand) to prevent its interaction with RANK. The binding of RANKL to RANK is required for physiological and tumour-induced proliferation and maturation of osteoclasts.
2. Patients with bone metastases had better quality of life and functioning when treated with denosumab, which decreases osteoclast function and delays SREs and the return of bone discomfort.
3. Prior to the injection of denosumab, dental treatments to avoid osteonecrosis of the jaw are necessary. Research contrasting bisphosphonates and denosumab has revealed that while denosumab raises the risk of osteonecrosis of the jaw and does not affect bone pain or time to pain relief, it does reduce the risk of SREs and enhance functional results more than bisphosphonates.

Analgesics

Pain from bone metastases should be treated according to the World Health Organization’s analgesic ladder. This ladder is a three-step algorithm for cancer pain, which encourages prompt oral administration of pain medications, starting with non-opioids (paracetamol (acetaminophen) and non-steroidal anti-inflammatory drugs) and graduating to mild then strong opioids as the need arises. Adjuvant medications may be added at any step of the ladder.

Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Bipinesh Sansar, DM Medical Oncology, Associate Professor Medical Oncology at MPMMCC and HBCH, Varanasi.