1 Introduction

Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI) used as an effective treatment for chronic hepatitis B virus (HBV) or human immunodeficiency virus (HIV) infections.¹ The long-term use of tenofovir has been associated with dysfunction of the proximal convoluted tubule of nephrons leading to Fanconi syndrome,² which is associated with increased urinary excretion of phosphate and hypophosphatemia. Electrolyte disturbances due to impaired renal tubular reabsorption in Fanconi syndrome can eventually result in defects in bone mineralization.³ This may result in osteomalacia or decreased mineralization of bone, due to inadequate levels of available phosphate and calcium, leading to fragility fractures.⁴ Few case studies have reported the occurrence of pathological fractures, including hip fractures, associated with antiretroviral therapy-induced Fanconi syndrome.^5,6 However, to our knowledge there have been no studies reporting the presence of bilateral atraumatic neck of femur fractures from tenofovir-induced Fanconi syndrome. Here, we report a case of bilateral pathological neck of femur fractures in a patient with Fanconi syndrome secondary to the use of Tenofovir for chronic hepatitis B infection.

2 Case history

A 67-year-old Chinese man, who was premorbidly community-ambulant, presented with bilateral thigh pain (worse on the left) for four months duration associated with gradual difficulty in walking. He had no history of any recent falls or trauma. He reported having similar episodes of bilateral thigh pain about 10 years ago, which resolved spontaneously after 2–3 weeks each time. He did not have any family history of bone disorders or childhood history of trauma.

Significantly past medical history in this patient included chronic hepatitis B infection previously treated with adefovir for 12 years, before being switched to tenofovir for the last 3 years. He also had hypertension, and a mitral valve replacement for which he was initially anticoagulated and subsequently maintained on aspirin. He had no known renal disease or impairment. He also denied intake of alcohol, any exogenous glucocorticoids, or other medications.

On physical examination, there was severe pain elicited upon range or motion of his left hip (lesser on his right) and he had an antalgic gait bilaterally with the left side being more affected. There was no weakness or numbness of bilateral lower limbs, no loss of perianal sensation and straight leg raise test was negative. He was clinically euthyroid and there was no features of Cushing's syndrome or hypogonadism.

Initial laboratory investigations revealed Haemoglobin of 10.4g/dL, severe hypophosphatemia <0.4mmol/L, severe hypocalcemia with adjusted calcium of 1.94mmol/L and elevated Alkaline phosphatase (ALP) of 205U/L. Urine studies revealed high fractional urinary excretion of phosphate of 50% and high urine protein to creatinine ratio of 138mg/mmol. Parathyroid hormone (PTH), thyroid panel and 25-hydroxycholecalciferol levels within normal range. Additionally, bone mineral density (BMD) scan of the lumbar spine revealed a T-score of −2.6. An endocrinologist was consulted, and based on the low BMD T-score, together with severe hypocalcemia, hypophosphatemia, elevated ALP and high fractional urinary excretion of phosphate, a diagnosis of osteomalacia secondary to tenofovir-induced Fanconi syndrome was made.

Pelvic radiographs were performed and varus remodeling deformities of bilateral neck of femur were seen (Fig. 1). This was compared to a pelvic radiograph taken 7 years prior to his presentation which showed an absence of the varus remodeling and normal femoral neck anatomy (Fig. 2). Multiplanar multisequence Magnetic Resonance Imaging (MRI) of both hips were performed which showed bilateral neck of femur (NOF) fractures with avascular necrosis as evidenced by hypointense bands on both femoral heads delineating the ischemic segment beneath the articular surface (Fig. 3).⁷ The fracture on the right side appeared subacute while that on the left side appeared acute, with more marrow edema in the left proximal femur. Background osteoarthritic changes were present in both hips with the left being more advanced than the right.

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Fig. 1 Pelvic radiograph Anterior-Posterior view demonstrating bilateral NOF fracture.

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Fig. 2 Pelvic radiograph Anterior-Posterior view demonstrating absence of NOF fracture 7 years prior to presentation.

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Fig. 3 MRI imaging of the (a) coronal view of pelvis, and axial views of (b) right hip and (c) left hip, demonstrating avascular necrosis of both femoral heads.

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In consultation with an endocrinologist, tenofovir was replaced with entecavir, and the patient was started phosphate replacements. Once serum phosphate levels were replete, bilateral simultaneous total hip replacement was planned. A direct anterior approach was utilised as the patient could be kept supine for both operations without the need to redrape or reposition the patient intraoperatively. However, only the left hip was replaced (Fig. 4) due to significant blood loss of about 1200mL intraoperatively, coupled with the fact that the patient had hemolytic anemia due to his previous valve replacement. Total hip replacement surgery for the right hip was planned to be staged at a later date.

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Fig. 4 Pelvic radiograph Anterior-Posterior view after left total hip arthroplasty.

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His postoperative recovery was uneventful, and he was subsequently discharged to a community hospital for further rehabilitation. At 1-month post-operation review, he was ambulating without the use of walking aid. He had returned to his previous social activity and reported that his bilateral thigh pain has resolved. In view of the resolution of his right hip symptoms and the treatment of his Fanconi syndrome addressing the underlying metabolic bone disorder, the decision for contralateral hip replacement was shelved with a view to offer hip replacement should symptoms recur in future.

3 Discussion

The incidence of Fanconi syndrome is about 1.09/1000 Person-Year of tenofovir exposure.⁸ Tenofovir is a nucleotide analogue reverse transcriptase inhibitor (NRTI) which selectively inhibits the reverse transcriptase enzyme needed for Hepatitis B viral replication.² However, long-term use of tenofovir has been associated with dysfunction of the proximal convoluted tubule of the nephron leading to Fanconi syndrome, which can lead to osteomalacia.⁹ Fanconi syndrome results from the dysfunction of the proximal convoluted tubule of the nephron in reabsorbing molecules such as phosphate, uric acid, bicarbonate and amino acids from the tubular fluid back into the blood (Fig. 5).¹⁰ As a result, these molecules are passed excreted in the urine resulting in severe hypophosphatemia and osteomalacia due to inadequate mineralization of bone.⁴

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Fig. 5 Simplified diagram showing the pathophysiology of tenofovir-induced Fanconi syndrome.

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While current evidence shows an association between tenofovir and bone metabolism abnormalities, the exact mechanism remains unclear. Tenofovir has been associated with BMD loss, possibly by altering gene expression in osteoclasts and osteoblasts, leading to disruption of bone resorption and formation, resulting in bone loss.¹¹ To prevent the adverse effect of long-term tenofovir use in hepatitis B infection, physicians need to closely monitor renal function via serum creatinine and phosphate, urine glucose and urine protein levels at least once yearly according to the American Association for the Study of Liver.¹² Previous reports have suggested tenofovir treatment duration of four months to five years before patients present with Fanconi syndrome.^13,14 This is corroborated by our present case study, where the patient presented with Fanconi syndrome and fragility fractures after tenofovir use of three years duration.

Based on our patient's history and previous radiographs of the pelvis, we believe that he most likely he had repeated episodes of bilateral NOF stress fractures over the last few years that resulted in the varus remodeling deformity of the subcapital region of femoral neck (Fig. 1). Optimal management of fragility fractures secondary to tenofovir-induced Fanconi syndrome would be to switch to another effective antiretroviral drug such as entecavir and repletion of any deranged electrolytes (phosphate) as in the case of our patient. Similarly, another case report by Rebolledo et al.¹⁴ demonstrated that cessation of tenofovir treatment resulted in rapid alleviation of clinical symptoms of bone pain and gradual improvement in electrolyte derangements associated with Fanconi syndrome.

As such it is important for orthopaedic surgeons to be aware of the potential adverse drug complications in patients being treated for chronic Hepatitis B infection, which can lead to osteomalacia and predispose to fragility fractures. Tenofovir-associated Fanconi syndrome is confirmed by laboratory investigation and is reversible upon cessation of the drug.¹⁴ Clinical symptoms of Fanconi syndrome include polyuria, weight loss, muscle weakness, and bone pain with osteomalacia.¹⁵ A high index of suspicion is needed when managing such patients, so as to avoid delay in diagnosis and instituting treatment.

Treatment of the fracture depends on several factors such as the location, completeness and severity of the fracture, age and comorbidities of the patient. In suitable patients and fracture patterns, surgeons can consider non-surgical option of treating the underlying Fanconi syndrome together with protected weight bearing for certain fractures. The existing body of literature on Fanconi syndrome and associated fractures is not enough to make a clear decision if fractures associated with Fanconi syndrome could be treated conservatively or not. This case report could help contribute to the currently scarce literature on Fanconi syndrome and its associated fractures and allow us to understand this condition better.

4 Conclusion

This case highlights the importance of close monitoring of serum creatinine and phosphate in patients who are on long-term tenofovir treatment as well as to identify clinical signs of osteomalacia secondary to Fanconi syndrome. Early identification will allow doctors to discontinue tenofovir before adverse effects such as nephrotoxicity, osteomalacia or fragility fractures occur. Treatment of NOF fractures in patients with Fanconi syndrome should be a total hip replacement after discontinuing tenofovir and subsequent correction of any electrolyte abnormalities.

Funding/sponsorship

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Informed consent (patient/guardian), mandatory only for case reports/clinical images

Informed consent from relevant parties obtained.

Institutional ethical committee approval (for all human studies)

Ethical board approval was not required for this case report study as per local institutional review board guidelines.

Authors contribution statement

All authors were involved in Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Supervision; Visualization; Writing – original draft; Writing – review & editing.