Bisphosphonates - By Dr. Ian Muldowney

Bone tumors are relatively common tumors in dogs, specifically primary bone tumors such as osteosarcoma.  However, secondary bone involvement  with , multiple myeloma, histiocytic sarcoma, apocrine gland anal sac adenocarcinomas and transitional cell carcinomas, are also commonly observed in veterinary practice.¹  Because of the intense and often chronic pain caused by focal bone destruction and the  decrease in quality of life, amputation remains the treatment of choice for local control of appendicular bone tumors.²  However, amputation is not an option for every patient.  Profound preexisting orthopedic or neurologic disease may prohibit a dog from functioning acceptably with only  three  limbs.  In addition, some pet owners do not have the financial recourses to pursue aggressive surgery while others find the idea of amputation anathema.   For all of these reasons, a palliative approach is often pursued.   

Palliative treatment aims to alleviate the  bone pain associated with the tumor. Bone pain from skeletal tumors develops by two mechanisms:  first, as the malignant osteoblasts rapidly proliferate, normal stromal cells stimulate nociceptors, which are found at highest concentrations in the periosteum, leading to the sensation of pain.  Second, continuous pain stimulation is maintained by the chronic dysregulation of bone resorption by osteoclasts.^{3, 6}

Because of the multimodal genesis of bone cancer pain, many patients remain refractory to traditional oral and transdermal analgesics.  The use of bisphosphonate therapy is becoming increasingly more common in veterinary oncology.  Bisphosphonates are synthetic analogues of pyrophosphates that have an affinity for bone mineral and decrease pain by inhibiting reabsorption of bone by osteoclasts.  These molecules interfere with normal intracellular signaling mediated by GTP-binding proteins and cause disruption of cellular interactions with the extracellular matrix, thus leading to apoptosis of osteoclasts. ⁴ 

While many bisphosphonates are commercially available, two of the more commonly used bisphosphonates in veterinary medicine are pamidronate and zoledronate.  Both are administered as an intravenous infusion up to every twenty-eight days and have been demonstrated to maintain analgesic effects for up to four months.^5,6,7  While these infusions are largely well tolerated, mild gastrointestinal toxicity and, rarely, renal insufficiency have been reported. ^2,6 

Overall, bisphosphonates remain a relatively safe and effective treatment for alleviating pain and improving quality of life in dogs with bone tumors. Oral bisphosphonate therapy is not routinely indicated in dogs as esophageal irritation is a common sequelae. People are advised to remain vertical for 60 minutes after taking any oral bisphosphonate. The horizontal orientation of the esophagus in dogs and cats versus the vertical orientation of the esophagus in a standing person preclude this recommendation for veterinary patients.

Dr. Ian Muldowney

References

1.  Fan, et al.  Evaluation of Intravenous Pamidronate Administration in 33 Cancer-Bearing Dogs with Primary or Secondary Bone Involvement.  J Vet Intern Med 2005;19:74–80.

2.  Kozicki AR, et al.  Adjuvant therapy with carboplatin and pamidronate for canine appendicular osteosarcoma.  Veterinary Comparative Oncology 2013.

3.  Goblirsch MJ, et al.  Biology of bone cancer pain.  Clinical Cancer Research, 12: 6231-6235, 2006.

4.  Gourion-Arsiquaud S, et al.  Bisphosphonate treatment modifies canine bone mineral and matrix properties and their heterogeneity.  Bone,  2010; 46: 666-672.

5.  Poirier VJ, et al.  The bisphosphonates alendronate and zoledronate are inhibitors of canine and human osteosarcoma cell growth in vitro.  Veterinary Comparative Oncology 2003; 1: 207–215.

6.  Fan, et al.  Single-Agent Pamidronate for Palliative Therapy of Canine Appendicular Osteosarcoma Bone Pain.  J Vet Intern Med, 2007;21:431-439.

7.  Fan, et al.  Double-Blind Placebo-Controlled Trial of Adjuvant Pamidronate with Palliative Radiotherapy and Intravenous Doxorubicin for Canine Appendicular Osteosarcoma Bone Pain.  J Vet Intern Med 2009;23:152–160.