Dataset Information

Risk of cancer after lumbar fusion surgery with recombinant human bone morphogenic protein-2 (rh-BMP-2).

ABSTRACT:

Study design

Retrospective cohort study among Medicare beneficiaries with lumbar spinal fusion surgery.

Objective

To determine the risk of subsequent cancer among patients who received recombinant human bone morphogenic protein (rhBMP) at surgery compared with those who did not.

Summary of background data

rhBMP is commonly used to promote bone union after spinal surgery. BMP receptors are present on multiple cancer types, but the risk of cancer after receiving rhBMP has not been well studied.

Methods

We identified 146,278 subjects aged 67 years and older who underwent surgery in 2003 to 2008 and were followed through 2010 for a new diagnosis of 1 of 26 cancers. Proportional hazards models were used to determine cancer risk associated with rhBMP use.

Results

rhBMP was administered in 15.1% of the cohort. After an overall average follow-up of 4.7 years, 15.4% of rhBMP-treated and 17.0% of untreated patients had a new cancer diagnosis, with most commonly recorded types as prostate, breast, lung, and colorectal. In a multivariate proportional hazards model, there was no association of rhBMP with cancer risk (hazard ratio: 0.99, 95% confidence interval: 0.95-1.02). There was also no association of rhBMP with the risk of any individual cancer types. The results were consistent in analyses using 2 secondary definitions of incident cancer.

Conclusion

In this large population-based analysis of Medicare beneficiaries, we found no evidence that administration of rhBMP at the time of lumbar fusion surgery was associated with cancer risk.

Level of evidence

SUBMITTER: Cooper GS

PROVIDER: S-EPMC4006942 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Bone morphogenic proteins (BMPs) play a key role in bone formation. Consequently, it was expected that topical application of recombinant human (rh)BMP-2 and rhBMP-7 would improve the healing of complex fractures. However, up to 36% of fracture patients do not respond to this therapy. There are hints that a systemic increase in transforming growth factor ?1 (TGF?1) interferes with beneficial BMP effects. Therefore, in the present work we investigated the influence of rhTGF?1 on rhBMP signaling in primary human osteoblasts, with the aim of more specifically delineating the underlying regulatory mechanisms. METHODS: BMP signaling was detected by adenoviral Smad-binding-element-reporter assays. Gene expression was determined by reverse transcription polymerase chain reaction (RT-PCR) and confirmed at the protein level by western blot. Histone deacetylase (HDAC) activity was determined using a test kit. Data sets were compared by one-way analysis of variance. RESULTS: Our findings showed that Smad1/5/8-mediated rhBMP-2 and rhBMP-7 signaling is completely blocked by rhTGF?1. We then investigated expression levels of genes involved in BMP signaling and regulation (for example, Smad1/5/8, TGF? receptors type I and II, noggin, sclerostin, BMP and activin receptor membrane bound inhibitor (BAMBI), v-ski sarcoma viral oncogene homolog (Ski), Ski-related novel protein N (SnoN) and Smad ubiquitination regulatory factors (Smurfs)) and confirmed the expression of regulated genes at the protein level. Smad7 and SnoN were significantly induced by rhTGF?1 treatment while expression of Smad1, Smad6, TGF?RII and activin receptor-like kinase 1 (Alk1) was reduced. Elevated SnoN expression was accompanied by increased HDAC activity. Addition of an HDAC inhibitor, namely valproic acid, fully abolished the inhibitory effect of rhTGF?1 on rhBMP-2 and rhBMP-7 signaling. CONCLUSIONS: rhTGF?1 effectively blocks rhBMP signaling in osteoblasts. As possible mechanism, we postulate an induction of SnoN that increases HDAC activity and thereby reduces the expression of factors required for efficient BMP signaling. Thus, inhibition of HDAC activity may support bone healing during rhBMP therapy in patients with elevated TGF? serum levels.