Bisphosphonate therapy for non cancer pain
1 / 61

Bisphosphonate Therapy for Non-Cancer Pain - PowerPoint PPT Presentation

  • Uploaded on

Bisphosphonate Therapy for Non-Cancer Pain. Marco Pappagallo, MD Director, Pain Medicine Research & Development Professor, Department of Anesthesiology Mount Sinai School of Medicine, NY. Bone Pain.

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
Download Presentation

PowerPoint Slideshow about 'Bisphosphonate Therapy for Non-Cancer Pain' - cassius

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Bisphosphonate therapy for non cancer pain
Bisphosphonate Therapy for Non-Cancer Pain

Marco Pappagallo, MDDirector, Pain Medicine Research & DevelopmentProfessor, Department of AnesthesiologyMount Sinai School of Medicine, NY

Bone pain
Bone Pain

bisphosphonates widely used in the battle against cancer-related bone pain

What is bone pain
What is Bone Pain?

Powerpoint presentation

What we were taught


Adapted from: Patrick Mantyh, PhD,

The mechanisms and pharmacology of bone pain

AAPM 2005 Annual Meeting Lecture

Powerpoint presentation


Adapted from: Patrick Mantyh, PhD,

The mechanisms and pharmacology of bone pain

AAPM 2005 Annual Meeting Lecture

Powerpoint presentation


Adapted from: Patrick Mantyh, PhD,

The mechanisms and pharmacology of bone pain

AAPM 2005 Annual Meeting Lecture

Calcitonin gene related peptide cgrp nerve fibers
calcitonin gene-related peptide (CGRP) nerve fibers

In bone, small nerve fibersexpress

  • Transient Receptor Potential Vanilloid Subtype 1 (TRPV1) – i.e., the capsaicin receptor

  • High affinity Tyrosine Kinase Receptors (Trka) for NGF (nerve growth factor)

Bone pain mechanisms role of ngf

  • expression enhanced in bone inflammation, bone cancer, trauma, fractures

  • produced by many cellular elements

  • induces hyperalgesia via upregulation of transcription for genes encoding pain receptors (e.g. capsaicin receptor TRPV1)

Powerpoint presentation


role of NGF

Adapted from: Patrick Mantyh, PhD,

The mechanisms and pharmacology of bone pain

AAPM 2005 Annual Meeting Lecture

Bone pain mechanisms role of protons h
Bone Pain Mechanisms fibersrole of protons (H+)

  • Acidic microenvironment (pH 4.0) due to release of protons from activated OSTEOCLASTS

  • Low pH activates TRPV1 and ASICs (Acid-Sensing Ion Channels)

From osteoclasts to bisphosphonates
From Osteoclasts to fibers Bisphosphonates

History of bisphosphonates

  • Designed as synthetic analogues of pyrophosphate

  • Initially used in industry as water softening agents in irrigation systems


  • blocks precipitation of calcium phosphate in plasma, urine, and soft tissues

  • commonly used as an anti-tartar agent in toothpaste

  • In the body, rapidly hydrolyzed by alkaline phosphatase

Powerpoint presentation

Pyrophosphate fibers

Generic Bisphosphonate

History of bisphosphonates1

  • Etidronate, first bisphosphonate for medical use

  • In 1969, bisphosphonates discovered as bone loss inhibitors

Powerpoint presentation

Etidronate fibers








Fda approved indications
FDA approved indications fibers

  • Hypercalcemia of Malignancy

  • Osteolytic Bone Metastases

  • Osteoporosis

  • Paget’s disease of bone


  • chemical adsorption onto hydroxyapatite

  • cellular uptake by osteoclasts, macrophages, tumor cells, etc

Bioavailability fibers

  • Less than 1% of the oral dose absorbed

  • GI absorption suppressed by food intake

  • For a more rapid and effective action, bisphosph can be given by IV infusion.


  • transient distribution to liver and other organs

  • as a sponge, metabolically active bone adsorbs IV dose

  • pharmacokinetics is complex; bisphs remain attached to bone for weeks to months

  • amount of drug released in plasma related to rate of bone metabolism and turnover

Non nitrogen containing bisphosphonates
Non-nitrogen-containing Bisphosphonates fibers

  • First generation bisphos, such as ETIDRONATE, TILUDRONATE, and CLODRONATE

  • accumulation of a cytotoxic ATP analogue compound

Nitrogen containing bisphosphonates
Nitrogen-containing Bisphosphonates fibers


  • Block addition of hydrophobic molecules to proteins ; important for cell membrane function and sub-cellular protein trafficking

Anti osteoclast effect
Anti- fibersOsteoclast Effect

  • Inhibition of osteoclast activity, and reduction of their life span

  • Bisphos may affect other cellular elements present in bone (e.g., endothelial cells, ostocytes, mast-cells, macrophages)

Bisphosphonates as analgesics

Preclinical studies
Preclinical Studies fibers

DOSE DEPENDENT ANALGESIC EFFECT in animal models of inflammatory pain, cancer pain, neuropathic pain

  • Goicoechea et al., J Pharmacol, 1999;

  • Cui et al., Pain, 2000;

  • Oelzner et al. Inflamm Res,2000;

  • Bonabello et al., Pain, 2001;

  • Walker et al., Pain , 2002;

  • Harada et al., Inflamm Res,2004;

  • Kawabata et al., Neuropharmacology, 2006;

  • Bianchi et al., European Journal of Pain, 2007;

Iv pamidronate as analgesic
IV Pamidronate as fibersAnalgesic

  • Metastatic bone pain

  • Ankylosing spondylitis

  • Paget’s disease

  • Rheumatoid arthritis


  • Chronic back pain

    Hortobagyi et al., 1996; Lipton et al., 1994; Maksymowych et al., 1998; Van Offel et al., 2001; Maccagno et al., 1994; Kubalek et al., 2001;

    Fulfaro et al., 1998; Varenna et al., 2000; Pappagallo et al,. 2003

Iv bisphosphonates for m etastatic bone pain
IV BISPHOSPHONATES for fibersmetastatic bone pain

IV bisphos treatment for hypercalcemia due to bone metastases associated with a quick relief of severe cancer bone pain

Fulfaro et al., 1998; Hortobagyi et al., 1996; Purohit et al. 1994; Coleman et al. 1997

Iv bisphosphonates for ankylosing spondylitis
IV Bisphosphonates for fibersAnkylosing Spondylitis

Two open-label trials and a RCT indicate that IV pamidronate can reduce morning stiffness and back pain in patients with NSAID-refractory ankylosing spondylitis (AS)

Maksymowych et al J Rheumatol 1998; Maksymowych et al., J Rheumatol 2001; Maksymowych et al., Arthritis Rheum 2002;46:766–73.

Iv bisphosphonates for paget s disease of bone
IV Bisphosphonates for fibersPaget’s Disease of Bone

Bisphos play a relevant therapeutic role in modifying the disease course, and improving pain and mobility

Walsh et al. Bone 2004;34:747–54., Bombassei et al., Am J Med Sci 1994.

Vasireddy et al., Clin Rheumatol 2003;22:376–80.

Iv bisphosphonates for rheumatoid arthritis
IV Bisphosphonates for fibersRheumatoid Arthritis

Some evidence of benefit,

in the management of pain and

prevention of bone erosions

Rovetta et al. Minerva Med 2003; Jarrett et al., Arthritis Rheum 2006; Romas E. Best Pract Res Clin Rheumatol 2005;

Iv pamidronate for chronic mechanical back pain
IV Pamidronate for fibersChronic Mechanical Back Pain

  • Patients (n=25) with NSAIDs-refractory chronic LBP and with no osteoporotic fractures or metastatic disease

  • Average pain decreased from baseline by 3.6 points (on 0–10 NRS)

  • Bisphosph-related pain relief not associated with an increase in opioid analgesics

    . Pappagallo et al., J Pain Symptom Manage 2003;

Powerpoint presentation

A Pilot Trial of IV Pamidronate for Low Back Pain - Identifier:NCT00101790Sponsored by the National Institute of Neurological Disorders and Stroke

  • Four study groups, each group with subjects randomly assigned to pamidronate (n=7) or to placebo (n=4)

  • Dosage: 30 mg of PAM in the 1st group, 60 mg in the 2nd group, and 90 mg in the 3rd group

  • Subjects in the 4th group will receive 2 treatments of best tolerated / more effective PAM dose

Powerpoint presentation

CRPS/RSD fibers

Marco Pappagallo, MD

Crps rsd iasp diagnostic criteria

  • Inciting Noxious Event (e.g.,trauma) or a Cause of Limb Immobilization (e.g., cast, stroke)

  • Pain, Allodynia / Hyperesthesia disproportionate in severity to any inciting noxious event

  • At some point in time, evidence of regional abnormal skin color / To changes, edema, sudomotor activity

  • CRPS 1:Diagnosis of Exclusion

Technetium 99 bisphosphonate in bone scintigraphy
Technetium-99 Bisphosphonate in fibersBone Scintigraphy

  • May show regional skeletal changes in several cases of CRPS

  • Utilizes a technetium-99 radio-labeled bisphosphonate (medronate, oxidronate) as an intravenous marker

Powerpoint presentation

3 phase BONE SCAN fibers



in theblood pool phase(2 min after infusion)

2.INCREASED PERIARTICULAR TRACER UPTAKE during the mineralization phase (3 hrs after infusion)

Reportedly 50% sensitivity

90% specificity

The BONE SCANtracer is a bisphosphonate mixed with radioactivetechnetium and injected for detecting abnormal bone metabolism and disease.

Higher Sensitivity inCRPS of < 6 mo.

Powerpoint presentation


  • Maillefert et al., 1995; open label

  • Cortet et al., 1997; open label

  • Kubalek et al., 2001; open label

  • Robinson et al., 2004; RCT


    5. Varenna et al., 2000; RCT


    6. Adamiet al., 1997; open label

    7. Manicourt et al., 2004; RCT

Iv pamidronate for crps

  • Maillefert et al. 1995: improvement in 7 of 11 patients

  • Cortet et al., 1997: improvement in pain and physical function in 10 women and 13 men

  • Kubalek et al., 2001: excellent pain relief in 25 of 29 patients from IV pam at 60 mg/day for 3 consecutive days

  • Robinson et al, 2004: RCT (n=27) of IV pam 60 mg as a single dose vs. placebo; significant improvement in pain and function at 1 and 3 months postinfusion (active treatment group n=14)

Iv clodronate
IV Clodronate fibers

  • Varenna et al, (2000): RCT (N=32) of IV clodronate, efficacy at 6 mo, after 300 mg daily for 10 days (active tx group, n=15);urine NTx as predictive factor for efficacy

IV / Oral Alendronate

  • Adami et al.,(1997): IV alendronate relieved CRPS by at least 50% in 13 patients out of 20

  • Manicourt et al.,(2004): in a RCT (N=40) of oral alendronate, efficacy (improvement in pain and joint mobility) for post-traumatic CRPS of the lower extremity at 3 mo after 40 mg daily for 8 wks (alendronate-treated group, n = 19)

Powerpoint presentation

Open label pilot trial of IV ibandronate for CRPSBreuer B, Pappagallo M, Goldfarb R, et al., The Journal of Pain, 2007

  • Objectives:

  • assess safety of IV ibandronate 6mg daily for 3 days in patients with CRPS

  • evaluate analgesia

  • explore correlation between tx response and bone scan findings

Iv ibandronate for crps rsd results n 10 at 3 mo post intervention
IV Ibandronate for CRPS/RSD: IV ibandronate for CRPSResults (N=10) at 3 mo Post-intervention

  • Patient Global Impression of Change:

    • 4 subjects with much improvement

    • 6 subjects with minimal improvement

  • Brief Pain Inventory: significantly lower than baseline for average pain p = 0.007; worst pain p = 0.004

  • Neuropathic Pain Scale:descriptors significantly improved for

    • unpleasantness, sensitivity, depth, intensity, surface, heat, cold, sharpness, and dullness.

Iv ibandronate for crps rsd
IV Ibandronate for CRPS/RSD IV ibandronate for CRPS

  • Aside from transitory flu-like symptoms, ibandronate was well tolerated

  • No hypocalcemia or delayed adverse events reported

Iv ibandronate for crps rsd bone scan findings in the affected limb
IV Ibandronate for CRPS/RSD: IV ibandronate for CRPSBone Scan Findings in the Affected Limb

  • Uptake (compared with contralateral limb)

    • 5 subjects with an increased uptake

    • 2 subjects with a decrease uptake

    • 3 subjects with no difference

  • Subjects (N=5) with positive bone scans improved more than those having decreased uptake (N=2) in neuropathic pain qualities (p≤0.03)

Iv ibandronate for crps rsd conclusion
IV Ibandronate for CRPS/RSD - Conclusion IV ibandronate for CRPS

  • A subgroup of patients with CRPS appear to have bisphos-responsive pain

  • Bone pain mechanisms maintaining some of the symptoms of CRPS

Iv bisphosphonates contra indications side effects
IV Bisphosphonates IV ibandronate for CRPS CONTRA-INDICATIONS & SIDE-EFFECTS

Iv bisphosphonates contra indications
IV Bisphosphonates IV ibandronate for CRPS CONTRA-INDICATIONS

  • Pregnancy

  • Renal, Hepatic mod-severe Disease

  • Hypocalcemia

  • Poor Oral Hygiene and Active Endodontic / Periodontal Disease

Side effects
SIDE EFFECTS IV ibandronate for CRPS

  • IV Bisphosphonates well tolerated when appropriately administrated

  • associated with transient and manageable (e.g., acute phase reaction)side effects

  • However, there is an emergent concern about a complication known as osteonecrosis of the jaw (ONJ)

Powerpoint presentation
ONJ in patients with exposed bone

in a subgroup of oncological patients (multiple myeloma, breast, prostate, lung cancer bone metastases) receiving prolonged treatment with potent bisphosphonates (i.e. monthly IV administration)

Onj unclear pathogenesis
ONJ: unclear pathogenesis in patients with exposed bone

Mandible / Maxilla

  • exposed to external environment (chemicals, infections) and to repeated microtrauma

  • in need of mechanisms to deal with chronic infectious, chemical, and mechanical insults

Powerpoint presentation
ONJ in patients with exposed bone

  • Bone histology has revealed necrosis and osteomyelitis

  • Microbiology has showed actinomycetes and mixed bacteria

Onj incidence estimates
ONJ: incidence estimates in patients with exposed bone

  • By 2006, safety databases (USFDA, Novartis, Research on Adverse Drug Events And Reports project) included 3,061 total cases of ONJ

  • Novartis (2005): 0.8 ONJ cases per 1,000 person-years

  • Academic Investigators (2005): 22 ONJ cases per 1,000 person-years

  • Web-based survey * (Dec 2004) from International Myeloma Foundation: incidence of 6.2%

    * Dr Brian Durie (Cedars-Sinai Outpatients Cancer Center, Los Angeles, CA), (IMF) a survey, total of 1203 patients via cancer websites and email lists. American Society of Hematology,December 2004

Powerpoint presentation

INCIDENCE OF ONJ IN PATIENTS WITH BREAST CANCER OR GYNECOLOGICAL MALIGNANCIES Beck et al. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Abstract: Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 1113

  • From April 1999 until May 2006, 10 of 310 (3%) patients with ONJ while receiving bisphos therapy

  • Except one, all ONJ patients had recent dental extractions

  • In ONJ patients, mean tx cycles 27 ±18 (median: 21, range 6-62) and mean duration of bisphos tx 29 ±20 months (median: 22, range 1-67)

Phossy jaw 1830 1910

ONJ caused by exposure to white phosphorus (WP)

Workers in the match industry were exposed to WP fumes during mixing and spreading of the dip material.

Painful toothaches and over time, abscesses of the jaw bone.

White phosphorus

WP is used for signaling, smoke-screening, incendiary (military) purposes; however

WP is also the most abundant form of phosphorus produced industrially.

Most forms of phosphorus chemicals are produced from WP, including chemicals in fertilizers, food additives, pesticides, sodas, tooth-paste, cleaning compounds, and drugs (e.g. illicit production of methamphetamine)

Elemental phosphorus can exist in several allotropes, most commonly white, red, and black.

Onj risk factors

  • Poor oral hygiene

  • Dental procedures (tooth extractions, implants)

  • Chemotherapy

  • Corticosteroid use

  • Coagulopathies

  • Immunosuppression / post-transplantation

  • Local cancerous invasion

  • Local radiation therapy

  • Heavy nicotine use

  • Oral herpes infection

  • Episodes of osteonecrosis / osteomyelitis

  • Others? (white phosphorus?, pyrophosphate in tooth paste?, statins?)

Onj prevention

  • Dental exam and preventive dentistry

  • Avoid invasive dental procedures


  • Bone pain mechanisms (BPMs) are not unique to cancer and might be more prevalent and relevant than previously thought

  • The study of bisphos as analgesics might help us identify and better understand complex pain mechanisms and pursue new research avenues

Powerpoint presentation