A Case Report of Oral Bisphosphonate Treatment for Osteoporosis Leading to Atypical Femoral Fracture and Pathologic Mandibular Fracture

Background

Osteoporosis is a critical health hazard, with over 200 million people affected worldwide [1]. The first-line treatment for osteoporosis is pharmacotherapy with bisphosphonates, in addition to other anti-resorptive drugs (ARD) such as denosumab and romosozumab [1,2]. Bisphosphonates are divided into 2 groups: nitrogen-containing (alendronate, risedronate, ibandronate, pamidronate and zoledronic acid) and non-nitrogen-containing (ethidronate, clodronate and tiludronate) [2]. The exact anti-resorptive mechanism of bisphosphonates is still unclear, but may be due to their attachment to hydroxyapatite binding sites, mainly in areas of active resorption, and also by reducing osteoclastic activity [1,2].

It is well established that bisphosphonates stop bone loss and preserve bone density in patients with postmenopausal osteoporosis, but there are other non-modifiable risk factors for the development of the disease like age, race, and genetic predisposition [3,4]. Current recommendations for treatment of postmenopausal osteoporosis with bisphosphonates include initial therapy with oral drugs for younger women with low to moderate fracture risk, and with intravenous agents in older women and those at highest fracture risk [4]. Patients should be carefully monitored and re-evaluated for further need after 3–5 years of therapy, and when the risk of fractures remains high, it should be continued for a maximum of 10 years [1]. The most common adverse effects of bisphosphonates are non-severe and include gastrointestinal adverse effects, infusion reaction, and transient hypocalcemia [5]. Patients present more rarely with bone pain, arthralgia, myalgia, ocular problems, and renal adverse effects [1,2].

Nevertheless, the long-term use of bisphosphonates can produce serious consequences. One of them is medication-related osteonecrosis of the jaw (MRONJ), which can occur in patients taking bisphosphonates to treat osteoporosis, with an incidence of approximately 1: 10 000 to 1: 100 000 [2]. MRONJ is characterized by exposed bone in the maxillofacial region that persists for more than 8 weeks, without a history of radiation therapy, or obvious metastatic disease to the jaws [6]. Considering the anti-resorptive effect of bisphosphonates, jawbones may be more susceptible to osteonecrosis because of higher remodeling rates when compared to other bones, further complicated by inflammation and bacterial biofilm in the surrounding tissues [7]. Risk factors for MRONJ include long-term medication use, pre-existing dental disease, dental implants, tooth extraction, and poorly fitting dentures [2,5]. The most advanced form of MRONJ is stage 3, which can be debilitating when associated with a pathologic mandibular fracture (PMF) [6,8]. Fracture-related problems can be chronic and include pain, swelling, halitosis, purulent drainage, neurosensory deficit, and masticatory dysfunction, which reduce patients’ quality of life [8].

Another rare complication from long-term use of bisphosphonates is the development of atypical femoral fractures (AFF). They usually occur spontaneously or after minimal trauma, and are mostly seen after long-term treatment with bisphosphonates [5]. AFF can be diaphyseal or subtrochanteric, breaking the external cortical bone horizontally but in an oblique direction, and may not be preceded by pain in the thigh [9]. Their reported incidence in patients taking bisphosphonates range from 1.8: 100 000 cases per year in patients treated for less than 2 years, up to 113: 100 000 cases per year when treatment is extended to 8–9 years [10].

Furthermore, osteomyelitis is one of the most difficult infections to cure and is caused by hematogenous spread in 22.97% of cases [11]. A small number of cases of actinomycotic osteomyelitis in the legs of healthy patients resulting from hematogenous spread have been reported [12]. Furthermore, Actinomyces sp. is the bacteria most commonly involved in the pathogenesis of MRONJ, and opportunistic infections may be an important risk factor for PMF [13].

MRONJ-related PMF treatment options range from conservative therapies, with the use of teriparatide [14,15], mouth rinses, and oral antibiotics [16], to surgical treatment. These include relatively simple surgical approaches combined with intermaxillary fixation [13], as well as more extensive and aggressive surgeries such as resection and musculocutaneous free-flap mandibular reconstructions [8], using internal or external fixations [17].

Although rarely reported, distant complications of MRONJ and the concomitant occurrence of AFF should be considered in the clinical evaluation of patients using ARD. Here, we report a case of MRONJ-related PMF and AFF with osteomyelitis secondary to bisphosphonate treatment for osteoporosis.

Case Report

A 63-year-old white woman presented with AFF on her left leg as a result of a fall. Her previous medical history indicated she had osteoporosis and was being treated with 70 mg of alendronate weekly for 2 years. A diaphyseal fracture of the left femur was evident upon radiographic examination, along with diffuse thickening of both cortices, breaking the external cortex horizontally but in an oblique direction through the internal cortex (Figure 1). The fracture was treated with internal fixation by the orthopedic surgeon (Figure 2), but evolved with postoperative infection and osteomyelitis. Upon hospital re-admission to treat the infection, she was medicated with ceftriaxone, and a maxillofacial evaluation was requested to investigate an intraoral suppuration as a possible cause of the femoral osteomyelitis.

At that time, she reported previous dental treatment for oral rehabilitation with 5 mandibular implants (Figure 3), of which 3 had failed after 1 year of insertion, with mandibular infection and exposed bone. Also, she stated that the bisphosphonate therapy was not discontinued during dental treatment, and that she did not have previous radiation therapy to the maxillofacial region. Clinical examination revealed chin hyperemia and intraoral suppuration, in addition to alveolar bone exposure in the anterior mandible. A computed tomography scan showed a left parasymphyseal fracture (Figures 4, 5) and mandibular osteolysis extending from the anterior alveolar crest to the mandibular base (Figure 6). Therefore, the diagnosis of PMF resulting from MRONJ stage 3 was established.

The mandibular fracture was treated by stable internal fixation with a reconstruction plate extraorally (Figure 7) combined with debridement and sequestrectomy intraorally. Clindamycin was added in the postoperative prescription, but after 1 week, she had to undergo reoperation due to persistent mandibular suppuration. The 2 remaining mandibular implants were then removed and a new debridement with osteoplasty was performed intraorally. Postoperative recovery was uneventful, treatment with clindamycin was continued for another 5 days, and the mandibular infection was controlled after the second surgery. Three weeks later, she was discharged from the hospital, instructed to discontinue the use of alendronate, and referred for 30 sessions of hyperbaric oxygen therapy (HBOT) as an adjuvant treatment for MRONJ.

At the 3-year follow-up, the mandibular fracture was completely healed without signs of intraoral infection or bone exposure. Subsequently, she had a spinal infection, which was treated with ciprofloxacin by an infectious disease specialist. In total, 6 surgical debridements were performed on her spine without arthrodesis, in addition to several femur-lengthening surgeries with bone grafts and a hip prosthesis. Final imaging exams of the mandibular fracture after healing could not be obtained until this time because she is currently confined to bed due to a hip infection.

Discussion

This case report presents the rare concomitant occurrence of AFF and MRONJ, both occurring as possible adverse effects of short-term bisphosphonate therapy for postmenopausal osteoporosis. This situation calls attention to the interaction required among healthcare providers for the correct diagnosis and adequate management of these serious complications of anti-resorptive therapy.

The reported femoral fracture occurred after a fall associated with minimal trauma, and displayed the classical radiographic image of an AFF in the diaphyseal region with transverse orientation, and global thickening of both cortices [9,10,18]. This cortical sign, along with focal femoral cortical thickening also known as “flaring” or “beaking,” are often associated with AFF and can result from long-term bisphosphonate use [10,19]. Although these findings are usually absent during short-term ARD therapy, the present case showed diffuse thickening of the femoral cortices after 2 years of osteoporosis treatment with alendro-nate. Thickened cortices could lead to increased brittleness of the femur, making it more prone to fracture. Nevertheless, other risk factors such as genetic, ethnic, environmental, and anatomic aspects should be considered in AFF pathogenesis rather than cortical thickening alone, since it may not be evident in all patients, even after long-term ARD treatment [19,20]. Indeed, a prospective clinical study by Chen et al [19] showed that femoral cortical thickness of long-term bisphosphonate users was not different from either osteoporotic or healthy controls, further confirming AFF as a rare and idiosyncratic condition.

AFF appear to be more common in patients who have been exposed to anti-resorptive therapy for more than 3 years, and the risk of these fractures decreases with cessation of ARD use [10]. Likewise, MRONJ is usually associated with long-term treatment with ARD [6]. Although the concomitant occurrence of MRONJ and AFF is well documented in cancer patients treated with high doses of parenteral bisphosphonates, it is very rare in patients with osteoporosis receiving these drugs orally and in the usual doses [3,9]. Furthermore, a systematic review verified the prevalence of MRONJ in approximately 30% of patients treated with parenteral bisphosphonates who had AFF [21]. Thus, it seems relevant to investigate the oral condition of patients requiring surgical treatment of AFF to anticipate further MRONJ-related complications.

Pathologic fractures are more likely to appear in the mandible than in the maxilla because of its morphology and, when compared to the mandible, a maxillary pathological fracture rarely reaches large dimensions [6,17,22]. There are limited data on the incidence of MRONJ-related PMF, with previous studies reporting incidence rated of 2.9–4.31% of MRONJ cases [13,17]. The possible predisposing factors for MRONJ-related PMF may include medical comorbidities, systemic factors, additive toxic effects of other medications such as corticosteroids and chemotherapeutic agents, genetic factors, and specific pathogens [6]. In the present case, the patient had a medical comorbidity – osteomyelitis of the femur – which was possibly related to the hematogenous spread of infection from the mandible.

To prevent PMF, it is necessary to know the causative factors and appropriate treatment protocols for MRONJ. Traumatic extractions and implant placement surgeries without the necessary preventive measures in susceptible patients should be avoided, as they present high risk for MRONJ-related PMF [13]. Other precautions include informing patients about the severity of the disease and the importance of regular follow-up, as well as removing the necrotic bone and strengthening the weakened mandible with reconstruction plates as an early surgical intervention [23]. Our patient developed MRONJ after 2-year treatment for osteoporosis with alendronate, the medication was not discontinued prior to the placement of 5 mandibular implants, and she did not receive adequate treatment for MRONJ despite the previous failure of 3 implants.

There is no consensus regarding the treatment of advanced cases of stage 3 MRONJ in the elderly population, and there are no clear guidelines for treatment of maxillofacial fractures in patients on active anti-resorptive therapy [14,24]. Removal of necrotic bone and internal fixation of fractures with load-bearing osteosynthesis plates provide better functional and esthetic results than resection only. However, external fixation can also be used in patients with a high risk of infection and wound dehiscence, with consecutive exposure of osteosynthesis material or bone [17]. Although surgical treatment of MRONJ-related PMF is the most frequently described [17,23,24], conservative management with administration of teriparatide as an adjuvant treatment has been reported to be successful [14,15]. HBOT has also been considered an effective adjuvant therapy for MRONJ cases, especially when combined with surgical treatment and antibiotics [25]. The present case of PMF was diagnosed due to interaction among the surgical teams and was successfully treated with surgical debridement and open reduction with stable internal fixation, even though a surgical re-approach was required to control the infection. In addition, the patient underwent 30 sessions of HBOT after hospital discharge as an adjuvant treatment for MRONJ.

It is crucial to highlight the short-term (2 years) anti-resorptive therapy with alendronate for the treatment of osteoporosis in this case, as in similar cases the concomitant occurrence of MRONJ and AFF was reported with long-term use of ARD. Sánchez and Blanco [9] reported a case of an 87-year-old patient who had a subtrochanteric fracture of the left femur after a fall, and was later diagnosed with MRONJ. She had been under bisphosphonate therapy for postmenopausal osteoporosis for a total of 10 years – 7 years with alendronate and another 3 years with zoledronic acid. She had stopped bisphosphonate treatment 1 year before she developed AFF, and 3 years later she developed MRONJ in her mandible after a tooth extraction and denture use. The AFF was surgically treated with internal fixation (plate and nails) and she recovered uneventfully, while her MRONJ improved after surgical debridement with local and systemic antibiotics. Another case of concomitant MRONJ and bilateral AFF in an 81-year-old woman was reported by Payumo et al [26] after intermittent and unsupervised treatment for postmenopausal osteoporosis with ARD. The duration of disease was 14 years, she used alendronate for a total of 6 years, denosumab was used for 3 years, and she used ibandronate for another 5 months before she underwent a tooth extraction and was diagnosed with MRONJ in her mandible. She also had bilateral AFF at different times prior to development of MRONJ. Both of them were caused by falling and were treated surgically with internal fixation (intramedullary nailing). MRONJ was managed with intravenous antibiotics and surgical debridement with necrotic bone removal.

Moreover, the concomitant occurrence of MRONJ-related PMF and AFF with the use of oral bisphosphonates is extremely rare. To the best of our knowledge, this is the second report of such a combination of adverse effects regarding ARD therapy. Pispati et al [3] reported the first case of concomitant MRONJ-related PMF and AFF in a 60-year-old woman with postmenopausal osteoporosis, who used alendronate for a total of 8 years. She was first diagnosed with MRONJ, treated with surgical debridement and sequestrectomy, and alendronate use was suspended. Shortly thereafter, she fell and had an AFF on her right leg that was managed surgically with internal fixation (proximal femoral nailing). Because the femoral fracture had delayed healing, she was started on teriparatide injections. MRONJ relapsed 10 months after the first surgery and another sequestrectomy was carried out, but 3 months later she had a PMF. It was treated surgically with internal fixation, and the patient had complete healing of both mandibular and femoral fractures. Although the adverse effects were common, we must emphasize that both MRONJ-related PMF and AFF occurred after only 2 years of oral bisphosphonate therapy, in contrast to 8 years of use in the aforementioned report [3]. In addition, the etiologies of MRONJ-related PMF seem to be different, since in our case it developed after implant placement surgery and MRONJ treatment was not attempted prior to the PMF diagnosis. The main MRONJ treatments were nonetheless similar, with stable internal fixation, while the adjuvant therapies differed from the teriparatide injections compared to the HBOT regimen herein reported. Furthermore, the rare complications related to anti-resorptive therapy presented in this case evolved differently. The PMF had a good evolution with no signs of MRONJ recurrence, while the AFF evolved into pseudarthrosis, requiring several surgical procedures after hospital discharge, and is still being treated by the orthopedic surgeon.

Our report is limited in that it is a case report of an extremely rare disease. Thus, further clinical studies are needed to define any evidence-based concepts.

Conclusions

Severe complications associated with ARD therapy such as MRONJ-related PMF and AFF pose a risk for potentially debilitated patients. This report raises awareness of both MRONJ and AFF as possible adverse effects of short-term bisphosphonate therapy for postmenopausal osteoporosis, and highlights the importance of dental and orthopedic follow-ups. It is crucial to emphasize the need for early diagnosis and treatment to prevent MRONJ progression to PMF. We recommend further studies on the concomitant occurrence of MRONJ and AFF, as well as future research seeking treatment strategies and guidelines for maxillofacial fractures in patients under active ARD therapy.