1. Do bisphosphonates affect bone
healing?
A meta-analysis of randomized
controlled trials
By: Deting Xue, Fangcai Li, Gang Chen, Shigui
Yan and Zhijun Pan
Xue et al. Journal of Orthopaedic Surgery and
Research 2014, 9:45
http://www.josr-online.com/content/9/1/45

3. introduction
• two kinds of drugs
• Ansbolic and catabolic
• treating patients with bisphosphonates during
bone healing is controversia

4. • 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–

5. From miller 6th edition

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

7. 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• also searched unpublished trials and those in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

8. • Terms …….
• Two reviewers independently screened the
titles and abstracts of identified papers

9. Study selection and outcomes
• RCTs
• bisphosphonates affecting fracture healing,
regardless of the doses and duration of drugs
used

10. • 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– studies that were not peer-reviewed randomized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

11. • 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

12. • 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

13. • 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.

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

15. 8 studies
2508 patients
Calcium 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)

17. • 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 bisphosphonate
infusion does not accelerate fracture healing in high tibial osteotomies.

18. • 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 interbody
fusion in patients undergoing transforaminal lumbar interbody fusion surgery. Acta Neurochir
(Wien) 2012, 154:731–738

19. 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.

20. • 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

21. • 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

22. • 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.

23. • 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

24. • 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

25. 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

28. Thank You