Elsevier

Bone

Volume 52, Issue 1, January 2013, Pages 360-365
Bone

Original Full Length Article
Teriparatide improves bone quality and healing of atypical femoral fractures associated with bisphosphonate therapy

https://doi.org/10.1016/j.bone.2012.10.006Get rights and content

Abstract

Bone remodelling suppressants like the bisphosphonates reduce bone loss and slow progression of structural decay. As remodelling removes damaged bone, when remodelling suppression is protracted, bone quality may be compromised predisposing to microdamage accumulation and atypical femoral fractures. The aim of this study was to determine whether teriparatide therapy assists in fracture healing and improves bone quality in patients with bisphosphonate associated atypical femoral fractures.

A prospective study was conducted involving 14 consecutive patients presenting during 2 years with atypical femoral fracture. All patients were offered teriparatide therapy unless contraindicated. Age and sex matched control subjects without fragility fractures or anti-resorptive treatment were recruited. High resolution peripheral micro-computed tomography (HRpQCT) scans of the distal radius and distal tibia were analysed for their cortical bone tissue mineralisation density using new software (StrAx1.0, StrAxCorp, Australia) at baseline and 6 months after teriparatide.

Administration of 20 μg of teriparatide subcutaneously daily for 6 months to 5 of the 14 patients was associated with 2–3 fold increase in bone remodelling markers (p = 0.01) and fracture healing. At the distal radius, the proportion of less densely mineralised bone increased by 29.5% (p = 0.01), and the proportion of older, more densely mineralised bone decreased by 16.2% (p = 0.03). Similar observations were made at the distal tibia. Of the nine patients managed conservatively or surgically, seven had poor fracture healing with ongoing pain, one sustained a contralateral atypical fracture and one had fracture union after 1 year. Teriparatide may assist in healing of atypical fractures and restoration of bone quality.

Highlights

► Bisphosphonates suppress bone remodelling, which can lead to microdamage accumulation and atypical femoral fractures. ► Teriparatide given to five patients with atypical fractures was associated with an increase in bone remodelling markers and fracture healing. ► The volume of less densely and more heterogeneously mineralised bone increased and the proportion of older, more densely mineralised bone decreased. ► Teriparatide may assist in healing of atypical fractures and restoration of bone quality.

Introduction

Bone remodelling is the cellular machinery responsible for the removal and replacement of damaged bone with an equal volume of new bone [1]. In adulthood, bone remodelling produces bone loss and structural decay because less bone is deposited than was removed during each remodelling event [2]. After menopause, bone loss and structural decay accelerate as oestrogen deficiency increases the intensity of bone remodelling.

Antiresorptive agents like the bisphosphonates reduce the intensity of bone remodelling slowing the progression of structural decay. Bone mineral density (BMD) does not only stabilise, it increases because refilling of resorptive cavities present at the onset of treatment proceeds with the concurrent appearance of fewer new remodelling cavities [3]. Bone matrix formed months prior to treatment undergoes more complete secondary mineralisation rather than being removed and replaced with younger less fully mineralised bone matrix.

When bone matrix becomes more densely and more completely mineralised, it becomes brittle; it cannot absorb energy by deforming when loaded so the energy imparted to the bone is dissipated by micro-cracking [4]. More homogeneously mineralised bone matrix offers less resistance to micro-crack propagation, so cracks lengthen [5]. Remodelling suppression reduces structural decay but may compromise bone material composition as reduced removal of microdamage, increased occurrence and propagation of microcracks increase net microdamage burden and compromises the material strength of bone [6].

Atypical femoral fractures are transverse or oblique stress fractures without comminution occurring in the cortex of the subtrochanteric region sometimes associated with prolonged remodelling suppression induced by bisphosphonates [7], [8], [9]. Management of complete fractures is surgical fixation using an intramedullary rod. Management of incomplete fractures is uncertain with some investigators proposing prophylactic surgery [7]. Given the benefits of teriparatide in fracture healing [10], [11], [12], several case reports of healing of atypical fractures and osteonecrosis of the jaw [13], [14], [15], we studied 14 patients with atypical femoral fractures associated with bisphosphonate therapy to test the hypothesis that teriparatide treatment will stimulate bone remodelling leading to replacement of more fully mineralised bone matrix with younger more heterogeneously mineralised bone matrix and fracture healing.

Section snippets

Materials and methods

Fourteen patients (13 F, 1 M, age 76 ± 1.9) presented with thigh pain occurring spontaneously or with minimal trauma to Austin Health between June 1, 2009 and September 31, 2011. All reported 4–10 years of exposure to bisphosphonates (alendronate = 11, risedronate = 1, sequential pamidronate/zoledronate = 2). Complete atypical femoral fractures (n = 6) were defined as transverse or short oblique fractures without comminution. Incomplete fractures (n = 8) were defined as an incomplete fracture line on the

Results

Of the 14 patients, 6 had unilateral and 8 had bilateral atypical femoral fractures. Five patients agreed to treatment with teriparatide, one following completion of the stress fracture and four patients because of persisting fracture non-union and ongoing pain during 8–12 months post-incomplete fracture. The remaining nine patients (five with complete, four with incomplete fractures) were not treated due to contraindications [Paget's disease (n = 2), primary hyperparathyroidism (n = 1), multiple

Discussion

We report that treatment of five patients with teriparatide for 6 months was associated with increased bone remodelling and partial or complete healing of atypical fractures and pain relief. Treatment replaced older more fully mineralised bone matrix with younger, less densely mineralised bone matrix restoring the heterogeneity in tissue mineralisation density distribution, a property of bone matrix which limits micro-crack propagation [2].

Atypical femoral fractures are stress fractures

Conclusions

Teriparatide increased remodelling, removed old, more fully mineralised bone matrix and replaced it with new, less fully mineralised bone matrix and improved fracture healing. Surgical fixation did not protect the contralateral femur from fracture. While these findings lack the rigor of a randomized double blind placebo controlled trial, and so should be regarded as hypothesis generating rather than hypothesis testing, they do support the notion that teriparatide may be a reasonable therapeutic

Disclosure

All authors state that they have no conflicts of interest.

Funding

No external funding source.

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