S.I. KATES AND C.I . ACKERT-BICKNELL. HOW DO BISPHOSPHONATES AFFECT FRACTURE HEALING? INJURY, INT. J. CARE INJURED 47 S1 (2016) S65–S68

PRESENTED BY – DR. SHEETAL KAPSE

GUIDED BY – DR. RAJASEKHAR G.

AUTHORS

1. Stephen L. Kates -

2. Cheryl L. Ackert-Bicknell -

Dept. of Orthopaedic Surgery, Virginia Commonwealth University, Richmond, VA USA

Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, United States

CONTENTS

IntroductionMaterials and methodsResults & DiscussionCross referencesConclusionPros and Cons of studyReferences

Introduction

Bisphosphonates have been in clinical use since 1968 (etidronate), and use of these compounds has increased in prevalence after the Food and Drug Administration approved alendronate for use in September of 1995.

The current best evidence regarding the effects of bisphosphonate use on fracture healing, including evidence from animal models, as well as human studies, with the aim to get the information about the implications of bisphosphonate use on bone healing.

BONE HEALING Via intramembranous ossification, the

osteoblast cells form new bone on the existing bone surface, flanking the fracture site, generating the hard callus.

In the center, a more hypoxic environment and one that is less mechanically sound, chondrocytes form a cartilaginous or soft callus via endochondral ossification.

The osteoclasts remodels the woven bone to lamellar bone, and makes it that makes it mechanically and anatomically to its pre-trauma state.

BISPHOSPHONATES

BPs get incorporated in bone during healing phase

Resorption of BP containing bone

Lasts up to 10.5 years in body

Palmidronate in urine

Acidic lacuna of Osteoclast

Nitrogen containing BPs

calcium

Non-nitrogen containing BPs

Cytoskeletal changes

Incorporating in ATP

Decreases bone

Resorption

Apoptosis of active osteoclasts & stimulation of

osteoblasts

Materials and methods

A literature search of Medline, Google Scholar and PubMed was performed for articles addressing the subject of bisphosphonates on fracture healing and 273 papers were taken for consideration.

Inclusion criteria: 1. Papers were written in

English, 2. Publication of the study

findings in peer-reviewed journals

3. In vitro and in vivo studies that evaluated the implication of Bisphosphonates on fracture healing.

Exclusion criteria: 1. Articles using languages other

than English

2. Letters, reviews, expert opinion publications or other articles that were not primary reports of findings.

Results & Discussion

Less effects on human study

Affects the 26% patients already on BPs

Doesn’t affect when given after fracture

No effects on callus formation

Delays bone remodeling

Remodeling delays maximum by 1 week

Mechanical strength of healed callus is similar

Drug – holiday effect is not clear yet

Cross references

Drake MT, Clarke BL, Khosla S. Bisphosphonates: Mechanism of Action and Role in Clinical Practice. Mayo Clin Proc. 2008 September ; 83(9): 1032–1045.

Osteoporosis

Glucocorticoid-Induced and Transplant-Associated osteoporosis

Immobility-Induced Osteoporosis

Other Causes of Acute Bone Loss

Paget Disease of Bone

Malignancy - Breast Cancer, Prostate Cancer, Multiple Myeloma

Osteonecrosis of the Jaw

Atrial Fibrillation

Over suppression of Bone Turnover

Hypocalcemia

Acute Inflammatory Response

Severe Musculoskeletal Pain

Clinical Uses Adverse effects

Presented 12 cases with pts age 10.7-17.2 Most of them were affected with osteoporosis. Pamidronate or olpandronate was continued for 2-8 years. Normal Linear growth, catch-up growth at puberty, bone

biopsy reports, normal calcium balance, radiographs Concluded the bisphosphonates as beneficial treatment

option specially in whom other therapies are ineffective.

Beneficial in some paediatric diseases, such as osteogenesis imperfecta, polyostotic fibrous dysplasia, patients with severe neuromuscular involvement, and corticosteroid-induced osteoporosis.

New indications - Perthes disease or bone lengthening by distraction osteogenesis.

Little consensus as regards the most suitable type of bisphosphonate, the dose to use, the form of administration and on the duration of treatment.

The long-term secondary effects are still not well known, so caution must be used when using them in growing patients and particularly in girls when reaching fertile age.

R. Fliefel, M. Tro¨ltzsch, J. Ku¨hnisch, M. Ehrenfeld, S. Otto: Int. J. Oral Maxillofac. Surg. 2015; 44: 568–585.

Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review.

74 BRONJ patients between January 2003 - December 2014 in the Department of Oral & Maxillofacial Surgery of the Leiden University Medical Center were diagnosed as per criteria stated by the AAOMS as ……a recent use of bisphosphonates, the presence of exposed or necrotic bone in the oral cavity for more than 8 weeks, and no history of radiation therapy to the jaws.

Treated with combined surgical and antimicrobial treatment and followed up for 6-96 months.

Curation was successful with this surgical approach in 93.2% of the patients (48 pts within in 2 weeks, 21 pts >2 weeks & 5 pts with no healing).

Pros Cons Included animal and

human studies Cessation of BP use (drug

holiday) at the time of fracture may also be prudent after long-term treatment with this class of drugs, however this remains a topic of investigation.

Children

Pros and Cons of study

Conclusion

Human fracture : No significant effect on fracture healing, but patients (26%) with long term use of Bisphosphonates may develop an atypical fracture and delay in fracture healing.

Conversely, there is some evidence to suggest that BP therapy should be stopped in patients that have been already treated long-term with BPs and then suffer an atypical fracture.

“ Double edge sword ”

References

1. Drake MT, Clarke BL, Khosla S. Bisphosphonates: Mechanism of Action and Role in Clinical Practice. Mayo Clin Proc. 2008 September ; 83(9): 1032–1045.

2. R. Fliefel, M. Tro¨ltzsch, J. Ku¨hnisch, M. Ehrenfeld, S. Otto: Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review. Int. J. Oral Maxillofac. Surg. 2015; 44: 568–585.

3. Sarina E.C. Pichardo, Sophie C.C. Kuijpers , J.P. Richard van Merkesteyn. Bisphosphonate-related osteonecrosis of the jaws: Cohort study of surgical treatment results in seventy-four stage II/III patients. Journal of Cranio-Maxillo-Facial Surgery xxx (2016) 1e5.

4. Beumsen, Hamdy and Papapolus. Long-term effects of bisphosphonates on the growing skeleton studies of young patients with severe osteoporosis. MEDICINE. 1997;76:266-83.

5. M. Salom, S. Vidal, L. Miranda. Bisphosphonate applications in children’s orthopaedics. Rev esp cir ortop traumatol. 2011;55(4):302-311