Applying low-intensity pulsed ultrasounds (LIPUS) to a zoledronate-associated atypical femoral shaft fracture without cessation of zoledronate therapy for 3 years follow up: a case report

Summary

Reports are increasing regarding atypical femoral fractures (AFFs) caused by minor trauma in patients using bisphosphonates (BPs) for long periods. Patients with malignant skeletal metastases potentially are at greater risk for these AFFs, especially considering the high dose and the duration of treatment with BPs. We evaluated a case of atypical femoral shaft fracture treated with an intramedullary nail in a patient treated for five years with zoledronate who had breast cancer with metastases to bone.

Although bone union was achieved without cessation of zoledronate therapy by applying low-intensity pulsed ultrasounds (LIPUS), the remodeling phase of the fracture healing process was delayed.

For BPs-associated AFFs, LIPUS is an alternative to parathyroid hormone (PTH) analogs such as teriparatide that are contraindicated in patients with malignant skeletal metastases. LIPUS is an effective treatment for fracture healing and may avoid the necessity to discontinue BP therapy.

Introduction

Reports are increasing regarding atypical femoral fractures (AFFs) caused by minor trauma in patients using bisphosphonates (BPs) for long periods (1). Patients with malignant skeletal metastases potentially are at greater risk for AFFs, especially considering the high dose and the duration of treatment with BPs (2, 3).

Teriparatide may be one effective treatment for AFFs (4), but teriparatide is contraindicated in patients with malignant skeletal metastases. There is no consensus on whether to continue or cease BPs during treatment of AFFs. For the prevention of new pathological fractures and reduced cancer pain, the continuation of BPs is desirable. At the same time, this approach may delay fracture healing (5–7).

This case report illustrates the effectiveness of low-intensity pulsed ultrasounds (LIPUS) as an alternative to PTH analogs for zoledronate (ZOL)-associated atypical femoral shaft fractures without cessation of ZOL therapy.

Case report

A 50-year-old woman had received a diagnosis of breast cancer and had undergone mastectomy at the age of 31. During follow-up she was found to have systemic bone metastases on her vertebrae, limbs, pelvis and extremities, and ZOL infusions (4 mg weekly) were initiated. Four years and eight months later while traveling abroad, she fell down on a poolside floor from a standing position and was transferred to a local hospital. Plain radiographs showed a left femoral shaft transverse fracture with a medial spike and a thickened lateral cortex (Figure 1a, b).

Figure 1.

Plain radiographs in anterior-posterior (AP) (a) and lateral (b) views show a left femoral shaft transverse fracture with a thickened lateral cortex and a medial spike. Plain radiographs in anterior-posterior (AP) (c) and lateral (d) views just after intramedullary nail fixation. Radionuclide bone scintigraphy (e) done one year before the fracture shows an increased uptake in a spot consistent with the fracture site (black arrows). Coronal T1-weighted (f) and STIR (g) MR images after the fracture show no osteolytic or osteoblastic lesion that would indicate a metastatic bone tumor.

One month prior to the fracture, she had mild pain in her left thigh. The fracture was fixed with an intramedullary nail (Figure 1c, d), and four days later she returned to Japan and was admitted to our hospital where her breast cancer and malignant skeletal metastases were followed up.

Although radionuclide bone scintigraphy one year before the fracture showed an increased uptake in a spot consistent with the fracture site (Figure 1e), plain radiographs and MR images (Figure 1f, g) after the fracture showed no osteolytic or osteoblastic lesion that would indicate a metastatic bone tumor at this site. Blood examination at admission was within the normal range (Table 1), although the bone matrix markers homocysteine (10.5 nmol/ml, normal range 3.7–13.5) and pentosidine (0.0324 μg/ml, normal range 0.00915–0.0431) were in the upper range of normal.

Table 1.

Laboratory data at the time of admission.

Hb	13.1 g/dl
GOT	30 U/l
GPT	19 U/l
ALP	40 U/l
BUN	20 mg/dl
Creatinine	0.64 mg/dl
Na	137 mEq/l
K	4.8 mEq/l
Calcium	9.1 mg/dl
Phosphorus	2.8 mg/dl
BAP	17.1 μg/l
P1NP	47.5 μg/l
TRACP-5b	491 mU/dl
Pentosidine	0.0324 μg/ml
Homocysteine	10.5 nmol/ml

Hb, hemoglobin; GOT, glutamic oxaloacetic transaminase; GPT, glutamic pyruvic transaminase; ALP, alkaline phosphatase; BUN, blood urea nitrogen; Na, sodium; K, potassium; BAP, bone-specific alkaline phosphatase; P1NP, procollagen type 1 N-terminal propeptide; TRACP-5b, tartrate-resistant acid phosphatase 5b.

The patient was diagnosed with an atypical femoral shaft fracture and LIPUS was applied for 10 months beginning 14 days after surgery. ZOL infusions were continued for the prevention of new pathological fractures and cancer pain. After three years of follow-up bone union was observed, but remodeling of the fracture callus to a more normal cortical shell was not yet accomplished (Figure 2). Although there was cortical thickening in the contralateral left femoral shaft, MR images showed no evidence of an insufficiency fracture and she had no prodromal symptoms in her left leg.

Figure 2.

Plain radiographs in anterior-posterior (AP) views immediately after surgery (a), and 2 months (b), 5 months (c), 16 months (d), and 3 years (e) after surgery show progression of fracture healing without apparent remodeling of the fracture callus to a more normal cortical shell.

Discussion

This case meets all the major diagnostic criteria for a BP-associated AFF as defined by the American Society for Bone and Mineral Research (ASBMR) (1). But we cannot rule out a pathological fracture from a metastatis to bone because a biopsy from a fracture site was not available. There are some reports on the femoral fractures caused by minor trauma in patients with multiple myeloma or metastatic bone tumor from breast cancer using bisphosphonate for long periods (3, 8–10). Among some of these reports, the fractures were diagnosed as AFFs with the absence of biopsies only by the fracture patterns characteristic of AFFs (8, 9). In the same way, we diagnosed this patient as BP-associated AFF based on the clinical course and the imaging findings very typical of AFF.

A biochemical and morphometric analysis using a dog model showed that administration of incadronate for three years caused increases in degree of mineralization, collagen maturity, and non-enzymatic cross-links (pentosidine) in bone collagen (11). In another dog study (12), long term treatment with BPs caused the accumulation of microdamage and brittleness of bone by suppressing bone remodeling. These results suggest that long-term suppression of bone remodeling by BPs can impair the material properties and the stiffness of bone.

Several reports indicate an association between AFF and delayed fracture healing. Indeed, delayed fracture healing is one of the minor features for AFF defined by the ASBMR Task Force (1). Solomon et al. reported that long-term BP use doubled the risk of non-union after a humeral fracture (13). Weil et al. reported that 7 cases (46%) out of 15 operated cases for a BP-associated AFF required revision surgery (14).

Li et al. examined morphologically how BPs affect the fracture healing process (5–7). They infused rats with incadronate, created a femoral shaft fracture, and fixed the fracture with an intramedullary nail. They compared the fracture healing process between groups that had continued incadronate treatment and groups that had ceased treatment. In the group that had ceased treatment, a soft callus was re-modeled to a hard cortex-like callus within 16 weeks. On the contrary, in the group that had continued on incadronate, the bridging callus increased in size, but remodeling from woven bone to lamellar bone was delayed and most of the bridging callus morphologically resembled cancellous bone. These results suggest that continuing BPs after fracture delays normal fracture healing.

Whether BPs should be continued or stopped in a patient with malignant skeletal metastases is an important issue to be resolved. But there is no consensus on whether BP treatment should continue or stop. In this case ZOL was continued because the patient was young, and the risks of new pathological fracture and cancer pain would interfere greatly with her activities of daily life (ADL). This benefit for this patient should take priority over the risk of delayed fracture healing. Denosumab, another antiresorptive drug that is also used for the skeletal lesions in various cancers, won’t be an ideal alternative to ZOL. Recent reports on denosumab-related AFFs (15–17) discourage us from choosing denosumab because it won’t necessarily lower the risk of AFF.

Despite the reported effectiveness of teriparatide for treatment of BP-related AFFs (4), teriparatide was not available in the case reported here because the patient had systemic malignant skeletal metastases. Other than teriparatide, LIPUS can be utilized as a means to promote fracture healing. There are evidences from multiple randomized control trials for fresh fractures (18, 19) suggesting that LIPUS shorten the time for fracture healing when applied soon after operation. In Japan LIPUS is a medical service covered by health insurance. And from basic studies, LIPUS enhances the function of osteoblasts, induces maturation of enzymatic cross-links without inducing non-enzymatic ones, and promotes calcification of the bone (20, 21). It seems appropriate to apply LIPUS to bone that is likely to have material properties impaired by long-term BP use. Although, to our knowledge, there is no reported adverse effect of applying LIPUS for malignant skeletal metastases, this patient should be observed closely.

Bone union was achieved in this case. But it is not clear whether LIPUS was responsible for the fracture healing because there was no negative control. More research is needed to understand to what extent LIPUS promotes fracture healing. But if LIPUS made it unnecessary to discontinue ZOL treatment, this could contribute greatly to patients’ ADL.

Conclusion

A case of atypical femoral shaft fracture was evaluated in a patient with breast cancer and systemic malignant skeletal metastases who had used ZOL for approximately 5 years. Bone union was achieved by 3 years following the fracture, without cessation of ZOL therapy, by applying LIPUS as an alternative to PTH analogs, although the remodeling process had not removed the fracture callus. For BP-associated AFF, LIPUS is an effective treatment for promoting fracture healing and may avoid the necessity to discontinue BP therapy.