Intercontinental Bone Health Expert Forum - Dubai, UAE, 16-17 October 2015: Day 2

Management of Bone Pain
Carla Ida Ripamonti

Pain is the very common, found in 75% of patients with common tumors. Its therapy requires a multidisciplinary approach. Pain relieving strategies also include its prevention.

An ideal pain-relieving strategy should have some caracteristics,..
Pain at rest is an early symptom of bone-metastasis.
Assessment of pain can be done through several instruments such as VAS or NRS.

Pain management - main guidelines
Mild pain (NRS: 1-3)
NSAIDs/Paracetamol

Mild-Moderate (NRS: 4-6)
Add weak opioids

Moderate-Severe (NRS: 7-10)
Strong opioids +/- NSAIDs/Paracetamol.

In bone BMA (Pam / Zol or Deno) should be added once bone-metastases established.

Breakthrough pain control may require IV, buccal/sublingua or intranasal fentanyl.

Denosumab vs Zol in pain control (Cleeland CS, Clin Cancer Res, 2006): Time to pain improvement is similar. Time to reach NRS4+ Pain was superior with denosumab.

All patients with bone pain should be evaluated by radiation therapy. But only 60.-70% obtain some pain relief, only 30% obtain complete pain control. Single radiation equally effective compared to conventional radiation therapy (Chow Clin Oncol 2012)

Radioisotopes, cementoplasty, precutaneous radiofrequency ablation are suitable to some patients, with limited data in clinical trials.

Adverse Reactions of Bisphophonates
Fred Saad

Oral and IV agents, can remain in the body for decades.
A single 5 mg Zol suppresses bone markers for 2 years. Zol 5 mg can be given every year for the treatment of osteoporosis.

Adverse effects: increased bone pain, digestive symptoms, flu-like, hypoCa, skin rahs, osteonecrosis, atypical fractures, kidney dysfunction.

Short-term adverse events
1. Erosive esophagitis with oral bisphosphonates. Up to 30% discontinuation rates due to these symptoms. Follow usual intake recommendations (on an empty stomach, non-recumbent, with water).
2. Fever, myalgias, arthralgias within 24-72 h after infusion (idyosyncratic gamma/delta T-Cell activation). Occurs in 1/3 in the first infusion, 1/15 in the second and 1/35 in further infusions.
3. Severe musculoskeletal pain
4. Esophageal cancer with oral bisphopnates: avoid oral biphosphonates to patients with esophageal disease.
5. Ocular inflamation (uveitis, conjunctivitis, episcleritis and scleritis). Very rare, and can be caused by oral or IV bisphophonates. Can occur at any time.
6. Renal dysfunction (focal segmental glomerular sclerosis with nephrotic syndrome and renal insufficiency. Other: transient ATN, etc).
6.1. Dosing according to renal function as follows:
ClCr 60+: 4 mg, 50.60: 3.5 mg, 40-49: 3.3 mg, 30-39: 3 mg, Avoid Zol if CrCl less than 30 ml/min.
The duration of bisphosphonate infusion should be no less than 15 min. Avoid dhydration, other nephrotoxic agents.

Zol appears to be as effective as Denosumab (the 18% superiority in efficacy with Denosumab in clinical trials is probably due to a 18% underdosing of Zol).

Long-term effects
1. Atrial fibrillation (FDA did not recommend withdrawal of bisphophonates in AFib due to lack of convincing data).
2. Atypical fractures, including sutrochanteric femoral fractures (after prolonged bisphophonates).
3. ONJ: future presentation during this meeting.

Dr. Saad treats patients continuously until progression or limiting toxicity.
Dr. Moos (see next lecture) does not use cisplatin and Zol on the same day.

Adverse event profile of Denosumab
Roger von Moos

Combined analysis of 3 trials. Adverse effects mainly related to OTHER anti-neoplastic therapies.
(Lipton A, Eur J Cancer, 2012).

1. Skin infections with Denosumab similar to Zol (less than 1%).
2. ONJ: the risk increases with denosumab exposure: 1-yr: 1%, 2-yr: 3%, 3-yr: 4.2%, 5.9%, Long-term denosuma: 8.2%
3. Hypocalcemia: 30% if untreated with Ca/Vit D. Decreases to 5% with Ca/Vit D supplementation, The risk of denosumab-induced hypocalcemia greater during the first 6 months on therapy.
4. Renal impairment prevalent in cancer patients (CrCl less than 90 ml/min: 50-65%): Denosumab does not increase the risk of renal impairment compared to Zol. Denosumab is cleared in the reticuloendothelial system. No kidney excretion of Denosumab. No need for dose adjustment for renal failure with Denosumab (in the clinical trials, dose was decreased in 18% patients in the Zol arm).
5. Acute phase reactions with Denosumab in 10% (About 35% with Zol).

Strategies to manage and prevent osteonecrosis of the jaw (ONJ)
Carla Ripamonti.

Exposure of the jaw bone for 6 weeks without other cause.
Risk factors: the usual suspects (poor hygiene, poor dental health, medical comorbidities, use of BMA).

ONJ occurs in 1-9% with bisphonates (Pooled analysis: 2.4% with bisphophonates).
ONJ can occur with other agents.
Mechanism: inflamation/infection associated with osteocyte death may be the underlying pathophysiology.
In RCTs the risk of ONJ is similar in both Zol and Deno in dental screened patients prior to initiation of de BMA.

Avoid elective jaw procedures
Preventid dentistry prior to treatment.
Good examination of the dental PRIOR to the initiation of BMA (Ripamonti C, Ann Oncol, 2009): Decreases 77% the risk of ONJ.
Promotion of adequate hygiene.
Antibiotic prophylaxis prior to dental procedures is required in patients treated with BMJ (1 week before, and 1 week after the procedure. BMA may be re-started once healed).
Treatment: Conservative use of antibiotics, and careful removal of the sequestrum.
Ozone Oil Supsension may be effective (Ripamoni C, Oral Oncol, 2011). O3Gas was effective in about 75% ITT analysis (Ripamonti, J Bone Oncology, 2012).
BP discontinuation: no evidence that cessation of BP will impact on the natural history of ONJ. Re-initiation of the BMA may be acceptable in some cases (clinical/risk analysis). No change of the BMA is needed. Previous Head/Neck RT is not a contraindication for BMA therapy. Hyperbaric oxygen does not appear to be effective.