Spinal Fusion and Bisphosphonates
Recently I received an email from a 56-year-old woman asking for information or help regarding a failed spinal fusion (arthrodesis) after a laminectomy in February 2006 to remove a cyst, with the fusion needed to stabilize the spine post-surgery. She noted she was a low-risk patient for fusion failure since she didn't smoke or have other risk factors.
The immediate result was successful and she was able to walk again. She noted the following: 1) One month after the surgery her rheumatologist put her back on Fosamax. 2) Her doctors agreed to keep her on estrogen since it has bone-forming properties, 3) Two months after surgery, her Ear, Nose and Throat specialist switched her from Nasonex, a barely-absorbed nasal steroid, to dexamethasone, a potent corticosteroid, which caused her to develop pituitary adrenal suppression, 4) In December 2006 a CT scan and X-rays showed there was no fusion and that three of six stabilizing screws that had been placed during surgery were loose. 5) At least three surgeons have told her she will not heal at this point and will need a different surgery to affect healing. 6) She was currently trying what she described as a "bone growth stimulator," which I assume would be something like Forteo (teriparatide), as a means of stimulating fusion. So far there had been no success from that method. Based upon her email I've done some research to see what, if anything, she was taking as medication might have contributed to her failure to get spinal fusion. The following pertinent abstracts should shed some light on this issue.
Spine. 2005 Nov 15;30(22):2516-22, Alendronate inhibits spine fusion in a rat model, Huang RC and others. PMID: 16284589. This study used Sprague-Dawley rats to test the effect of alendronate (Fosamax) on L4-L5 spinal fusions. Controls got saline, one test group got the equivalent dose of alendronate that humans get and the other test group got 10 times the normal human dose of alendronate via subcutaneous osmotic pumps starting the day of surgery. After eight weeks the results showed palpation fusion rates were lower in the alendronate groups. Alendronate was found to inhibit spine fusion in rats, although fusion masses were radiographically larger and denser in alendronate-treated rats than in controls. The authors conclude: "We recommend that patients undergoing spine arthrodesis should not take alendronate until fusion is achieved."
Spine. 2005 Sep-Oct;5(5):542-7, The effects of the antiresorptive agents calcitonin and pamidronate on spine fusion in a rabbit model, Babat LB and others. PMID: 16153583. This study used New Zealand white rabbits as their spinal fusion model. The PAM, pamidronate, (Aredia) group got 1.2 mg pamidronate subcutaneously 3 times/weekly for 4 weeks before surgery and 0.6 mg/day for 4 weeks after surgery. The CAL (calcitonin) group got 14 IU/day for 4 weeks postoperatively only, and the CON (control) group had no drug intervention. There was no statistically significant difference in spinal fusion rates among the groups. The authors concluded, "Though one must be careful in extrapolating animal data to humans, this study suggest that calcitonin is not detrimental to spine fusion. Pamidronate, however, does lead to a mechanically less robust fusion. Based on this study, there is no evidence to support a recommendation to stop antiresorptive therapy for osteoporosis in the spine fusion patient."
Spine. 2005 May 15;30(10):1116-21, The influence of alendronate treatment and bone graft volume on posterior lateral spine fusion in a porcine model, Xue Q and others. PMID: 15897823. This study used 22 pigs, 11 as controls with no alendronate, and 11 test pigs that got alendronate 10 mg/day for 3 months after surgical fusion of the lumbar spine. Results showed no statistical difference in the either the fusion rate or the fusion mass volume between groups. The authors concluded: "Alendronate treatment in this study decreased fusion mass remodeling without inhibiting fusion rate."
Clin Orthop Relat Res. 2004 Aug;(425):135-42, High-dose alendronate uncouples osteoclast and osteoblast function: a study in a rat spine pseudarthrosis model. Sama AA and others. PMID: 15292798. This study looked at osteoclast and osteoblast function after alendronate in Sprague-Dawley rats with spinal fusion success only mentioned as a side note. One group of rats acted as controls, a second group got a therapeutic dose of alendronate and the last group got one-log overdose of alendronate. Compared to controls, the alendronate groups had limited histologic remodeling and poor osteoclastic and osteoblastic function with fewer osteoclasts present also. The authors conclude: "The results suggest that the effect of alendronate was dose dependent and animal model dependent and that the supranormal doses of alendronate had a deleterious effect on osteoclastic and osteoblastic function in this model."
Spine J. 2004 Jan-Feb;4(1)36-43, The effect of alendronate sodium on spinal fusion: a rabbit model, Lehman RA Jr and others. PMID: 147491192. This is another study with New Zealand white rabbits undergoing L5-L6 spinal fusion. Controls had no drug therapy and test animals got 200 micrograms of alendronate/day for three weeks. After applying various tests, the authors concluded: "Alendronate sodium appears to inhibit or delay bone fusion in a rabbit model." Additionally they recommended: "These finding suggest that a discontinuance of alendronate sodium postoperatively during the acute fusion period may be warranted."
J Neurosurg. 2001 Jan;94(1 Suppl):76-81, The effects of dexamethasone on bone fusion in an experimental model of posterolateral lumbar spinal arthrodesis, Sawin PD and others, PMID: 11147871. This is yet another study with New Zealand white rabbits as the model for lumbar fusion, this time comparing controls to animals that received intramuscular dexamethasone (0.05 mg/kg) twice daily. The animals were killed after 42 days and spinal fusions were assessed via radiography, manual palpation and biomechanical testing. Seven (58%) of controls achieved fusion while no dexamethasone-treated rabbits achieved fusion. The authors concluded: "The corticosteroid agent dexamethasone inhibited bone graft incorporation in a rabbit model of single-level posterolateral lumbar spinal fusion, inducing a significantly higher rate of nonunion, compared with that in saline-treated control animals.
Osteoporos Int. 2007 Jun 14; [Epub ahead of print], Glucocorticoid-induced osteoporosis: pathophysiology and therapy, Canalis E and others, PMID: 17566815l. See this study for some idea of the effect of corticosteroids (glucocorticoids such as cortisone) on bone mineralization. osteoporosis and fracture risk. Up to 50% of patients on long-term corticosteroid therapy, not also receiving preventive medications, can have fractures.
Editor's comments: The studies on spinal fusion involving one of the bisphosphonates, such as alendronate, are mixed. Some did, however, note worse results if the lab animals were receiving a bisphosphonate at the time of, or after, spinal fusion surgical procedures. Thus, there is some doubt about whether bisphosphonate therapy should be continued during the early healing phase after such surgery. I would also suggest that none of these studies actually tested to see if discontinuing active bisphosphonate therapy after spinal fusion surgery was beneficial. Without such controlled clinical trials, one must wonder how effective that discontinuation might be, especially in light of the fact that Fosamax has a 10-year half-life. There, however, is no doubt that glucocorticoid therapy, such as dexamethasone, is contraindicated during the active healing phase after spinal fusion surgery. I was unable to find a single case report that found one of the bisphosphonates as the suspected cause after a nonhealing spinal fusion. In view of the millions of doses of these medications in the age group of people who would need a spinal fusion, it is almost unimaginable that, were the bisphosphonates responsible for spinal fusion failure, there wouldn't be a single case report yet. Of course, it is also possible for various reasons that my searches simply didn't uncover published reports to that effect. In the woman's case I describe above, we will never know for certain the cause of her failure to achieve spinal fusion. My primary suspect would be the dexamethasone, and with the slight possibility that the Fosamax was a contributing factor. Conclusions: If you are having any kind of osseous (bone) surgical procedure, particularly a surgery requiring spinal fusion, or have had a fracture that is in the healing phase, discuss the fact that you have osteoporosis and are taking a medication such as Fosamax with your physicians and care providers. And, by all means, don't take long-term high doses of a glucocorticoid if you expect bone healing to occur. Additionally, it would be beneficial to see some retrospective studies of humans who underwent spinal fusion while also taking a bisphosphonate to see if healing is equal to those having spinal fusion but not taking a bisphosphonate.