Bilateral sequential atypical femur fractures in a patient on zoledronic acid therapy: a case report and review of literature

INTRODUCTION

Bisphosphonates (BPs) are the mainstay of anti-resorptive therapies for osteoporosis. In randomized controlled trials (RCTs), this class of drugs has been shown to prevent osteoporotic fractures by 40 to 70% in women and men with osteoporosis.¹ However the use of these medications is not free from complications. Case reports of unusual fragility fractures in the subtrochanteric and femoral shaft (ST/FS) regions in patients treated with BPs were first reported in 2005 by Odvina et al.²

To our knowledge, we present the first reported case of bilateral sequential atypical femur fractures (AFFs) that was treated with zoledronate for two years. Patient was also a known case of rheumatoid arthritis.

CASE REPORT

A 62 year old female presented to a tertiary care hospital in June 2019 with pain in left thigh since one month. Pain acutely increased after history of trivial trauma at home. Examination revealed swelling of left thigh, movements of left hip and knee were painful and distal pulses present with intact motor and sensory functions. She was known case of rheumatoid arthritis and osteoporosis. Two doses of intravenous zoledronate 5 mg were administered in November 2017 and December 2018. She had undergone bilateral total knee replacement 14 years back.

She underwent X-rays of left thigh which were suggestive of left atypical femur shaft fracture (Figure 1). According to the American Society for Bone and Mineral Research Task Force 2013 revised case definition of AFFs, (Table 1) all five major features and two of the four minor features are present in this patient. On biochemical tests, normal levels of serum calcium 9.0 mg%, serum phosphorous 4.2 mg%, serum Vitamin D3 34 ng/mL, serum parathyroid hormone 18 ph/mL were found. We found plasma beta2 Crosslaps (C-telopeptides) level 171.3 pg/ml (Normal range 50-450), serum P1NP (total procollagen type 1 amino-terminal propeptide) 59.03 ng/ml (normal range 37 - 64), indicating effectiveness of anti-resorptive therapy. Bone mineral density (BMD) measured by dual-energy x-ray absorptiometry DXA (Hologic 4500©) was consistent with osteoporosis. Right femoral neck, 0.503 g/cm² (T‐score=−3.1); right total hip, 0.657 g/cm² (T‐score=−2.3).

*To satisfy the case definition of AFF, the fracture must be located along the femoral diaphysis from just distal to the lesser trochanter to just proximal to the supracondylar flare. In addition, at least four of five major features must be present. None of the minor features is required but have sometimes been associated with these fractures.

Patient was managed with closed reduction and internal fixation with antegrade femur interlock nail, two 6.5 mm cannulated cancellous screws were put missing the nail to splint the neck of femur to prevent fragility fractures of neck (Figure 1). On first postoperative day the patient complained of pain and swelling in the right thigh. There was no history of trauma, on examination painful range of motion of right hip and knee with distal pulses present and intact motor and sensory functions. X-rays were suggestive of right atypical femur fracture. Patient was managed with closed reduction and internal fixation with femur nail (Figure 2). Patient was mobilized full weight bearing as per her pain tolerance. Inj. zoledronate was discontinued and inj. teriparatide 20 µg/80 μl subcutaneous daily, calcium and vitamin D supplements were started. Patient counselled regarding risk of delayed union, non-union and need for secondary procedures.

DISCUSSION

It is unclear, why BPs effectively reduces fracture risk for many types of fracture but become harmful at a single fracture location only in a small percentage of individuals. Micro damage is an energy dissipating mechanism, as stated by Frost in his Mechanostat model of bone turnover.³ Small diffuse cracks form under tension and longer micro cracks form under compression. Cracked region of the bone can’t be recracked to release energy unless it is remodelled. Remodelling is a coupled process with synchrony between osteoclastic bone resorption and osteoblastic bone formation. There are two types of remodelling which are targeted and stochastic (no specific site). Bisphosphonate treatment suppresses not only stochastic remodelling but also the targeted repair of micro damage.⁴ By reducing bone turnover, BP treatment leads to increased matrix mineralization but also increases accumulation of micro damage and non-enzymatic collagen cross-links. This has negative impact on bone matrix properties and contributing to the pathogenesis of atypical femoral fractures (AFFs).⁵ BPs are also known to localize at sites where bone turnover is high, which includes a healing fracture site. By reducing bone remodelling preferentially at micro cracks, BPs negatively affect the repair of micro damage and impending micro crack. Over a period of time, these cracks progress or coalesce with other cracks to create a fracture due to inhibition of repair mechanisms.⁵

In a multi-centric study, 76 cases of AFFs were retrospectively analysed for BMD, prodromal symptoms, and medication history for osteoporosis. Twenty-two patients (28.9%) suffered from prodromal symptoms, 43 (56.5%) had delayed fracture union and bilateral femoral fractures developed in 23 (30.2%).⁶ Thus it is of prime importance to ask for the prodromal symptoms when patient on bisphosphonates comes for follow up. Bilateral fractures is as high as 30%, so incomplete fractures on opposite side can be diagnosed and managed with prophylactic intramedullary nailing.⁷

Patients with an AFF are at a significantly higher risk of delayed healing, non-union and a need for secondary procedures compared with patients with typical femur fractures. In a study of 17 AFFs in 15 patients only 54% of patients healed their fractures following surgical treatment. The other 46% of patients required a secondary revision procedure to achieve fracture healing.⁸ Another study of 33 patients with AFFs undergoing surgical treatment, 30.3% did not heal and required a secondary procedure to achieve fracture healing.⁹ Similarly in a study of 42 patients with 48 fractures, Cho et al reported a primary healing rate of 68.7% with a mean time to union of 10.7 months.¹⁰

CONCLUSION

Improved understanding of AFF risk factors and pathophysiology could help to identify which patients are at highest risk for AFFs prior to starting therapy. Opposite thigh radiographs are necessary to diagnose impending fracture and prophylactic fixation of such fractures is important. Delayed union is a known fact and secondary surgeries are commonly required.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

REFERENCES

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