The Bisphosphonates: analogs of Pyrophosphate

Transcription

1 Bisphosphonates

2 The Bisphosphonates: analogs of Pyrophosphate Alendronate (Fosamax ) Clodronate (Bonefos ) Etidronate (Didrocal ) Ibandronate (Boniva ) Pamidronate (Aredia ) Risedronate (Actonel ) Tiludronate (Skelid ) Zoledronic acid (Zometa )*

3 * What is pyrophosphate? Pyrophosphate: Normal in plasma and urine A physiologic regulator of calcium Thought to have potential for treatment of diseases in which there was ectopic mineralization. Problem: only worked when given parenterally and was rapidly metabolized

4 * Bisphosphonates: Also have a high affinity for calcium Can work given parenterally, orally or topical Long half life *Fleisch, H. Bisphosphonates: Mechanisms of Action. Endocrine Reviews, 19(1), , 1998

5 History 1865: First synthesized in Germany Industrial uses only Corrosion inhibitors 1968: The ability to bind to calcium has led to the study of potential uses in diseases that either result in the abnormal accumulation of calcium or the loss of normal bone. Diseases of bone, soft tissues, teeth, calcium metabolism, infection...

6 In Vivo and In Vitro Effects of Bisphosphonates Decreases abnormal deposition of calcium in soft tissues: ectopic calcification. Decreases abnormal formation of bone in soft tissues: ectopic ossification. Has bactericidal properties. Inhibits/reduces bone resorption. Inhibits angiogenesis.

7 Diseases of Ectopic Calcification and Ossification that could be treated with Bisphosphonates Atherosclerosis Dental calculus (a very effective anti-tarter agent) Premature calcification of bio-prosthetic valves Urinary stones Scleroderma Dermatomyositis Calcinosis syndromes Fibrodysplasia ossificans progressiva Post spinal cord injury Cranial trauma Post total hip replacement

8 Diseases of Increased Bone Resorption that could be treated Osteoporosis Pagets disease with Bisphosphonates Tumoral osteolysis Hyperparathyroidism Bacterial arthritis Post traumatic osteonecrosis of femoral heads in adolescents

9 Role of bisphosphonates in treatment of osteoporosis

10 Other diseases possibly treated with bisphosphonates Bacterial infections (multi-drug resistent e-coli) Other types of infections, i.e. MRSA... Scott Luhan, UNC, Chapel Hill

11 Human Adverse Events/Observed: Issues with Bisphosphonate Treatment Studies suggest that osteonecrosis of the jaw is a dose-related effect of bisphosphonate therapy (IV>PO). In high doses, bisphosphonates can produce brittle bone disease which is subject to fractures. Recent JADA, ADA recognizes ONJ as a problem in patients who are taking Bsp s and require dental surgery.

12 Human Adverse Events/Observed: Issues with Bisphosphonate Studies Most of the successful studies have been done in animals. In human studies there is little data, much of it contradictory (dental calculus is an exception). Much information on use of bisphosphonates are with anecdotal reports.

13 Human Adverse Events/Observed: Legal Issues Multiple class action lawsuits against the producers of bisphosphonates. Fear by dentists that residual bisphosphonates in donor tissue may lead to ostenecrosis of the jaw and law suits.

14 What are the consequences of using bone from donors being treated with bisphosphonates? Are residual bisphosphonates present in demineralized bone? Is demineralized bone from a bisphosphonate donor as osteoinductive as bone from an untreated donor? Are we at risk for law suits if the active molecule actually does prevent bone incorporation and leads to poor or no healing?

15 What should tissue banks do? Ignore the issue because decalcified bone would probably not have enough residual bisphosphonate to be clinically significant. Defer donors who are taking bisphosphonates (approximately 80 million people are taking them now). Accept and process donors but with restrictions as to use. Hold till further data supports the safety of the tissues.

16 STAC Scientific and technical affairs committee was asked to investigate this issue by: Physicians Hospitals Tissue banks Scientists Deliberated and decided that a two phased approach was necessary to answer this question In-vivo animal study Analytical study

17 In-vivo study Collaboration with Dr. Barbara Boyan of Georgia Institute of Technology Purpose: To determine the effects of bisphosphonates on DBM osteoinductivity Method: ASTM draft guidance standard for osteoinductivity of DBM using nude mouse model Results: Histology and histomorphometry Start protocol: 3Q 2007 Expected completion date: 1Q 2008

18 In-vivo Obstacles Quite possible that slight differences in concentrations won t be detectable invivo need more sensitive method Difficulty with knowing starting concentration of bisphosphonate in donor tissue Difficulty in controlling length of treatment and dosages in-vivo

19 Analytical Collaboration with Bob Orheim, Analytical Chemistry Inc, Tukwila, Washington Three phased approach: 1.Use of mass spec to determine minimal doses detectable limit of sensitivity 2.Allograft bone: compare a donor with no hx of use vs one with a hx of use. Make untx bone powder and DBM and measure. 3. Expanded study: multiple tissues from multiple banks from multiple donors using different medications.

20 Analytical Study Expected Start: 3Q 2007 Expected completion: Phase 1 early 4Q 2007 Start of Phase 2 and 3 dependent upon results of Phase 1 and possibly preliminary data from in-vivo study.

21 What does this mean for us? Should have data to present at mid-year meeting Data will be published in a peer reviewed journal Data will be published on AATB website

22 So what s in your toothpaste?