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Letters to the Editor
associated or not, have been evoked to explain SNHL: the
presence of autoantibodies, vasculitis and/or a granulomatous process. Various antigenic targets, such as
type II collagen and anti-68 kDa had been incriminated
[4]. Circulating immune complexes have been found in
patients with SNHL, leading to the hypothesis that their
deposition in the inner ear and labyrinthic vessels could
result in vasculitis and ischaemic injury [5]. Also, in analogy with cases of deafness in granulomatosis with polyangiitis, it has been suggested that granulomatous
inflammation could lead to hearing loss [6]. The dramatic
improvement with high-dose CSs and anti-TNF suggests,
in our patient, a relationship between this symptom and its
underlying inflammatory disorder.
The efficacy of anti-TNF in autoimmune SNHL has been
reported with controversial results: mostly negative for
etanercept [7] and possibly positive for infliximab [8] or
adalimumab [9]. Also, a possible induction of SNHL with
adalimumab has been suggested [10] in two cases.
However, these cases of unilateral deafness could
suggest a possible infectious origin. No cases of
CD-associated SNHL treated with anti-TNF have been
reported, and the possible role of granulomatous inflammation might explain the dramatic improvement observed
in our patient. In conclusion, even though it is rare, severe
deafness could occur and be inaugural in IBD associated
with SpA.
Rheumatology key messages
.
Severe deafness might complicate SpA associated
with IBD and could improve with anti-TNF.
Disclosure statement: R.S. has received speaking and
consulting fees (<$10 000) from Pfizer. All other authors
have declared no conflicts of interest.
Marie Jachiet1,*, Claire Lependu1,*,
Dorothée Fragny2,*, Xavier Mariette1,
Christine Lepajolec2 and Raphaèle Seror1
1
Rheumatology Department, INSERM U1012 and
2
Otorhinolaryngology Department, Hôpital Bicêtre, Assistance
Publique des Hôpitaux de Paris (AP-HP), Université Paris-Sud
11, Paris, France.
Accepted 17 October 2012
Correspondence to: Raphaèle Seror, Rheumatology
Department, Hôpital Bicêtre, 78 rue du Général Leclerc,
94275 Le Kremlin, Bicêtre, France.
E-mail: [email protected]
*Marie Jachiet, Claire Lependu and Dorothée Fragny
contributed equally to this study.
References
1 Levitan HL. The etiologic significance of deafness in ulcerative colitis. Int J Psychiatry Med 1973;4:379–87.
2 Akbayir N, Calis AB, Alkim C et al. Sensorineural hearing
loss in patients with inflammatory bowel disease: a
www.rheumatology.oxfordjournals.org
subclinical extraintestinal manifestation. Dig Dis Sci 2005;
50:1938–45.
3 McCabe BF. Autoimmune sensorineural hearing loss. Ann
Otol Rhinol Laryngol 1979;88(5 Pt 1):585–9.
4 Gottschlich S, Billings PB, Keithley EM, Weisman MH,
Harris JP. Assessment of serum antibodies in patients
with rapidly progressive sensorineural hearing loss and
Meniere’s disease. Laryngoscope 1995;105(12 Pt 1):
1347–52.
5 Kanzaki J, O-Uchi T. Circulating immune complexes in
steroid-responsive sensorineural hearing loss and the
long-term observation. Acta Otolaryngol Suppl 1983;393:
77–84.
6 Dettmer M, Hegemann I, Hegemann SC. Extraintestinal
Crohn’s disease mimicking autoimmune inner ear disease:
a histopathological approach. Audiol Neurootol 2011;
16(1):36–40.
7 Cohen S, Shoup A, Weisman MH, Harris J. Etanercept
treatment for autoimmune inner ear disease: results of a pilot
placebo-controlled study. Otol Neurotol 2005;26(5):903–7.
8 Van Wijk F, Staecker H, Keithley E, Lefebvre PP. Local
perfusion of the tumor necrosis factor alpha blocker
infliximab to the inner ear improves autoimmune neurosensory hearing loss. Audiol Neurootol 2006;11:357–65.
9 Morovic Vergles J, Radic M, Kovacic J, Salamon L.
Successful use of adalimumab for treating rheumatoid
arthritis with autoimmune sensorineural hearing loss: two
birds with one stone. J Rheumatol 2010;37:1080–1.
10 Conway R, Khan S, Foley-Nolan D. Use of adalimumab
in treatment of autoimmune sensorineural hearing loss:
a word of caution. J Rheumatol 2011;38:176; author
reply 176.
Rheumatology 2013;52:1147–1149
doi:10.1093/rheumatology/kes319
Advance Access publication 13 December 2012
Treatment of fracture non-union in a young adult
with combination anabolic and anti-resorptive
bone therapy
SIR, We report successful bone healing following combination treatment with teriparatide and zoledronic acid
after a diagnosis of prolonged non-union. A 21-year-old
female with extended oligoarticular JIA diagnosed at the
age of 8 years sustained a low-impact short oblique
closed fracture of her right lower tibia. She had previously
received prolonged courses of CSs and was undergoing
treatment with MTX, LEF, alendronic acid weekly, calcium
and vitamin D supplementation. The fracture failed to
unite over 2 years during which conservative management
was followed by cortico-cancellous bone autograft, BMP
7 impregnated implant, US stimulation of the fracture site,
external fixation and treatment of a staphylococcal infection. She had resection of her non-union with application
of an Ilizarov fixator for bone transport reconstruction of a
large bone defect. Unfortunately, the regenerated bone
was of very poor quality with no visible calcification on
X-ray.
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Letters to the Editor
FIG. 1 Serial plain radiographs of proximal tibial bone defect.
Site of fracture non-union after bone transport (a) after 12 weeks of teraparatide 20 mg/day; (b) 4 weeks after infusion of
5 mg zoledronic acid; (c) 36 months after initial fracture, with intramedullary nail in situ.
She was referred to the Bone Clinic, Oxford, UK, and
treated for both vitamin D deficiency and low BMI
(17.0 kg/m2) with oral vitamin D and dietary advice.
Since her arthritis was well controlled, treatment with
MTX 20 mg/week and LEF 10 mg/day was temporarily
stopped to minimize any adverse effects on bone healing.
She was not currently using CSs. Given the long history of
non-union, alendronic acid was discontinued and she was
commenced on teriparatide 20 mg/day.
Over a 12-week period, she developed a firm tissue
bridge between the bone ends that was palpable clinically. There was no evidence of calcification radiographically (Fig. 1a). There was concern about continued use of
the Ilizarov fixator as she suffered recurrent local pin-site
infections and could not bear weight. After extensive discussion regarding potential risks and benefits, she then
received a single zoledronic acid infusion (5 mg). Within
4 weeks early radiographic calcification of the tissue
bridge was demonstrated (Fig. 1b) and 2 months later
her external fixation was exchanged for an intramedullary
nail and weight bearing was encouraged. She restarted
MTX and LEF and 36 months after the initial fracture she
had good arthritis control and bone healing (Fig. 1c).
In this patient, the aetiology of fracture non-union and
poor regenerate bone formation was likely to be
multi-factorial. Adults with JIA have reduced BMD compared with healthy controls [1]. Pathological changes of
bone in JIA might occur for several reasons including malnutrition, medication (long-term CS use), lack of muscle
force/inactivity, hormonal dysregulation, cytokine activity
and growth retardation [2]. Other contributory factors
include her low BMI, indicating suboptimal nutrition [3],
low vitamin D [4] and localized infection. Disease-modifying drugs including MTX have not been shown to be detrimental to bone density in JIA [5].
Bone healing following prolonged non-union was
induced by combined treatment with teriparatide and a
single zoledronic acid infusion; while calcification of the
callus could have occurred in the absence of zoledronic
acid, the callus should have started to calcify within
12 weeks of teriparatide therapy. Experimentally, PTH
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enhances fracture healing in both healthy and elderly or
malnourished animals, as measured by the size and
strength of callus formation [6]. In a study of 112
post-menopausal women with fractures of the distal
radius, low-dose teriparatide (20 mg daily for 8 weeks) significantly reduced time to fracture bridging compared with
placebo (7.4 weeks vs 9.1, P = 0.006) [7]. The same result
was not seen for women receiving 40 mg teriparatide and
so the results of this study need to be interpreted with
caution. In an open-label study, pelvic fractures in osteoporotic women healed significantly more quickly if they
were given 100 mg recombinant PTH 1-84 once daily for
24 months in addition to 100 mg calcium and 800 IU vitamin D3 compared with those given dietary supplementation alone. The mean time for complete cortical bridging of
the fracture site, as determined by CT scanning, in the
21 women given PTH was 7.8 weeks compared with
12.6 weeks in the 44 women who were not (P < 0.001) [8].
Clinical use of zoledronic acid and other bisphosphonates to aid fracture healing is not well described, although these drugs are routinely prescribed to increase
bone density in osteoporotic patients for fracture prevention. In a rat closed fracture model, bolus treatment with
zoledronic acid improved both the strength and size of
callus formation compared with both placebo controls
and weekly zoledronic acid treatment [9] suggesting that
the clinical use of bisphosphonates in fracture healing
warrants further investigation.
Evidence regarding the use of teriparatide and zoledronic acid combination therapy in osteoporosis treatment
has been investigated; 137 post-menopausal women,
given an infusion of 5 mg zoledronic acid as well as daily
20 mg teriparatide experienced significantly faster increases in spinal BMD after 13 and 26 weeks (P < 0.001)
compared with receiving either therapy in isolation, suggesting a synergistic mechanism between teriparatide
and zoledronic acid [10]. The regulation of bone mineralization is a dynamic and complex process involving endocrine, paracrine and autocrine effects. While the precise
mechanism for the synergism between teriparatide and
zoledronic acid is not known, in a recent animal model,
www.rheumatology.oxfordjournals.org
Letters to the Editor
synchronous use of zoledronic acid and teriparatide led to
an increase in calcified callus size as well as trabecular
thickness in part through suppression of receptor activator of nuclear factor-kB (RANKL) and maintenance of
osteoprotogerin [11]. Our case report supports the hypothesis that teriparatide and zoledronic acid work synergistically to promote fracture healing and that such dual
therapy warrants further investigation in patients with fracture non-union and poorly formed regenerate bone.
Rheumatology key message
.
Teriparatide with zoledronic acid is an option for
patients with treatment-resistant fracture non-union.
Acknowledgements
We would like to thank the patient for her consent in
publishing this report.
Funding: Oxford NIHR Musculoskeletal BRU.
Disclosure statement: M.K.J. has in the past 5 years
received consultancies, honoraria and speaker fees from
Novartis and Lilly. All other authors have declared no
conflicts of interest.
Ruth A. Corrigan1, Anne Miller2, Martin A. McNally2
and M. Kassim Javaid2
1
cross-sectional long-term followup study. Arthritis Rheum
1999;42:790–8.
2 Roth J, Bechtold S, Borte G, Dressler F, Girschick HJ,
Borte M. Osteoporosis in juvenile idiopathic arthritis—a
practical approach to diagnosis and therapy. Eur J Pediatr
2007;166:775–84.
3 Hedström M, Ljungqvist O, Cederholm T. Metabolism
and catabolism in hip fracture patients: nutritional and
anabolic intervention—a review. Acta Orthop 2006;77:
741–7.
4 Brinker MR, O’Connor DP, Monla YT, Earthman TP.
Metabolic and endocrine abnormalities in patients with
nonunions. J Orthop Trauma 2007;21:557–70.
5 Bianchi ML, Cimaz R, Galbiati E, Corona F, Cherubini R,
Bardare M. Bone mass change during methotrexate
treatment in patients with juvenile rheumatoid arthritis.
Osteoporos Int 1999;10:20–5.
6 Ellegaard M, Jørgensen NR, Schwarz P. Parathyroid
hormone and bone healing. Calcif Tissue Int 2010;87:
1–13.
7 Aspenberg P, Genant HK, Johansson T et al. Teriparatide
for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J Bone Miner
Res 2010;25:404–14.
8 Peichl P, Holzer LA, Maier R, Holzer G. Parathyroid
hormone 1-84 accelerates fracture-healing in pubic bones
of elderly osteoporotic women. J Bone Joint Surg Am
2011;93:1583–7.
Oxford University Medical School and 2Nuffield Department
of Orthopaedics, Rheumatology and Musculoskeletal
Sciences, University of Oxford, Nuffield Orthopaedic Centre,
Oxford, UK.
Accepted 3 October 2012
Correspondence to: M. Kassim Javaid, Oxford NHR
Musculoskeletal BRU, NDORMS, University of Oxford, Botnar
Research Centre, Nuffield Orthopaedic Centre, Windmill
Road, Oxford OX3 7HE, UK.
E-mail: [email protected]
9 McDonald MM, Dulai S, Godfrey C, Amanat N, Sztynda T,
Little DG. Bolus or weekly zoledronic acid administration
does not delay endochondral fracture repair but weekly
dosing enhances delays in hard callus remodeling. Bone
2008;43:653–62.
References
11 Li YF, Zhou CC, Li JH et al. The effects of
combined human parathyroid hormone (1-34) and
zoledronic acid treatment on fracture healing in
osteoporotic rats. Osteoporos Int 2012;23:
1463–74.
1 Zak M, Hassager C, Lovell DJ, Nielsen S, Henderson CJ,
Pedersen FK. Assessment of bone mineral density in
adults with a history of juvenile chronic arthritis: a
www.rheumatology.oxfordjournals.org
10 Cosman F, Eriksen EF, Recknor C et al. Effects of
intravenous zoledronic acid plus subcutaneous
teriparatide [rhPTH(1-34)] in postmenopausal
osteoporosis. J Bone Miner Res 2011;26:
503–11.
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