Do bisphosphonates affect bone healing

Do bisphosphonates affect bone healing?

A meta-analysis of randomized controlled trials

By: Deting Xue, Fangcai Li, Gang Chen, ShiguiYan and Zhijun Pan

Xue et al. Journal of Orthopaedic Surgery and Research 2014, 9:45http://www.josr-online.com/content/9/1/45

introduction

• two kinds of drugs

• Ansbolic and catabolic

• treating patients with bisphosphonates during bone healing is controversia

• Several studies have addressed the effects of bisphosphonates on indirect bone healing. The results are inconsistent.

• E.g– Lenehan et al.

• found that ethane-1-hydroxy-1,1-diphosphonate inhibited indirect fracture healing in a dose-dependent manner in mature beagle dogs

– Kim et al.• A Prospective study• found that bisphosphonates did not affect

intertrochanteric• indirect fracture healing [

Lenehan TM, Balligand M, Nunamaker DM, Wood FE Jr: Effect of EHDP on fracture healing in dogs. J Orthop Res 1985, 3:499–507

Kim TY, Ha YC, Kang BJ, Lee YK, Koo KH: Does early administration of bisphosphonate affect fracture healing in patients with intertrochanteric fractures? J Bone Joint Surg Br 2012, 94:956–960

From miller 6th edition

So shall we use bisphosphonates for the patients with osteoporotic fractures or spinal fusion?

Methods and materials

• Medline (1966–May 2013

• Embase (1980–May 2013)

• Science Citation Index (1981–May 2013)

• Cochrane Central Register of Controlled Trials (CENTRAL

• Cochrane Database of Systematic Reviews (Cochrane library, Issue 1, 2013)

• also searched unpublished trials and those in progress using clinical trials repositories

• Terms …….

• Two reviewers independently screened the titles and abstracts of identified papers

Study selection and outcomes

• RCTs

• bisphosphonates affecting fracture healing, regardless of the doses and duration of drugs used

• Exclusions

– Studies included patients with diseases that affecting bone mineral density (BMD) or bone metabolism, such as renal or adrenal insufficiency, diabetes, and any history of taking any medication known to affect BMD, such as corticosteroids.

– studies that were not peer-reviewed randomized controlled trials

• Bone healing criteria

– all of the study used radiographic

– examination to evaluate bone healing, but one study* did not provide bone healing criteria

* Adolphson P, Abbaszadegan H, Boden H, Salemyr M, Henriques T: Clodronate increases mineralization of callus after Colles’ fracture

• Delayed fracture union criteria

– one or more clinical symptoms at least 6 weeks after surgical repair

• pain,

• inability to ambulate

• gait disorder

– Plus radiographic findings

• Fracture nonunion criteria

– incomplete bony bridging through cages in lumbar spine in 12 months postoperation

– or no cortices bridging at the fracture site in more than 8 months postoperation.

The primary outcome was the indirect bone healing time and fracture nonunion.

8 studies2508 patientsCalcium supplement was used in three trials (1,6,8) 3 trials : distal radius fractures (1,2,7)2 trials: lumbar fusion (4,8)2: hip # (5,6)1: tibial osteotomy(3)

• Evaluation of bone healing in short term

(within 3 months)

• Based on 2 studies.

Nagahama K, Kanayama M, Togawa D, Hashimoto T, Minami A: Does alendronate disturb the healing process of posterior lumbar interbody fusion? A prospective randomized trial. J eurosurg Spine

Harding AK AWD, Geijer M, Toksvig-Larsen S, Tagil M: A single bisphosphonateinfusion does not accelerate fracture healing in high tibial osteotomies.

• Evaluation of bone healing in long term

(more than6 months)

• based on four studies

Adolphson P, Abbaszadegan H, Boden H, Salemyr M, Henriques T: Clodronate increases mineralization of callus after Colles’ fracture: a randomized, double-blind, placebo-controlled, prospective trial in 323 pateints

Nagahama K, Kanayama M, Togawa D, Hashimoto T, Minami A: Does alendronate disturb the healing process of posterior lumbar interbody fusion? A prospective randomized trial. J Neurosurg Spine 2011, 14:500–507.

Colón-Emeric C, Nordsletten L, Olson S, Major N, Boonen S, Haentjens P, Mesenbrink P, Magaziner J, Adachi J, Lyles KW, Hyldstrup L, Bucci-Rechtweg C, Recknor C: Association between timing of zoledronic acid infusion and hip fracture healing. Osteoporos Int 2011, 22:2329–2336

Li C, Wang HR, Li XL, Zhou XG, Dong J: The relation between zoledronic acid infusion and interbodyfusion in patients undergoing transforaminal lumbar interbody fusion surgery. Acta Neurochir(Wien) 2012, 154:731–738

Discussion

• Meta-analysis results showed that not statistically significant differences were found in short- and long-term postoperation between two groups

• timing of bisphosphonates infusion did not affect indirect bone healing

• In subgroup analysis, bisphosphonate-treated groups had statisticallysignificant higher lumbar infusion rate at 6 months postoperation.

• It is still unclear whether bisphosphonates therapy affects indirect bone healing

• animal studies have demonstrated that bisphosphonates treatment after surgery would increase callus formation, delay callus remodeling, but without influencing the strength of healed bone or bone healing 1,2

Li C, Wang HR, Li XL, Zhou XG, Dong J: The relation between zoledronic acid infusion and interbody fusion in patients undergoing transforaminal lumbar interbody fusion surgery. Acta Neurochir (Wien) 2012, 154:731–738

Cao Y, Mori S, Mashiba T, Westmore MS, Ma L, Sato M, Akiyama T, Shi L, Komatsubara S, Miyamoto K, Norimatsu H: Raloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats. J Bone Miner Res 2002, 17:2237–2246

• Van der Poest

– Evaluated whether alendronate prevented bone loss in Colles' fractures

– BMD of distal radius increased significantly at 3 and 6 months compared with that of the control group

– no significant differences of anatomic and functional outcomes between the alendronate group and control group after 1 year follow-up

. van der Poest CE, Patka P, Vandormael K, Haarman H, Lips P: The effect of alendronate on bone mass after distal forearm fracture. J Bone Miner Res 2000, 15:586–593

• Harding et al

– In HTO, infusion of zoledronic acid increased the pin fixation of external fixation but did not affect the bone healing.

• Bisphosphonates reduced osteoclast activity, but more and more clinical results showed that they did not have advert effects on bone healing.

• timing of infusion bisphosphonates was a controversy

• In an animal study, Amanat et al. found that delayed infusion of zoledronic acid increased more callus volume compared to both saline and infusion of zoledronic acid immediately at the time of the fracture

Amanat N, McDonald M, Godfrey C, Bilston L, Little D: Optimal timing of a single dose of zoledronic acid to increase strength in rat fracture repair. J Bone Miner Res 2007, 22:867–876

• However, our analysis results found that the timing of infusion bisphosphonate did not affect fracture healing. This was consistent with Colon-Emeric's report

• reason may be that the dose of bisphosphonates for treating osteoporosis is sufficient for affecting bone healing in animal but insufficient for human.

Colón-Emeric C, Nordsletten L, Olson S, Major N, Boonen S, Haentjens P, Mesenbrink P, Magaziner J, Adachi J, Lyles KW, Hyldstrup L, Bucci-Rechtweg C, Recknor C: Association between timing of zoledronic acid infusion and hip fracture healing. Osteoporos Int 2011, 22:2329–2336

Limitations

• limitations inherent to any metaanalysis based on pooling of data from different trials with different doses of drugs, duration, fracture sites, and patient groups

• reporting may be influenced by expectations of the investigators and patients

• Surgical technique of doctors may also influence the healing results

• number of the included studies and participants were relatively small

Thank You