Tenofovir-induced pathological neck of femur fractures in Human immunodeficiency virus-positive patients: A report of two cases with review of literature

INTRODUCTION

The advent of antiretroviral therapy (ART) has transformed human immunodeficiency virus (HIV) from a fatal disease to a manageable chronic condition. Among the most commonly used ART combinations is the tenofovir, lamivudine, and dolutegravir (TLD) regimen, recommended by the World Health Organization and widely implemented in India through the National AIDS Control Organization (NACO).^[1]

Tenofovir disoproxil fumarate (TDF) is eliminated by renal excretion and can accumulate in the proximal tubular cells of the kidneys, leading to mitochondrial toxicity. This results in Fanconi syndrome, a proximal renal tubular defect characterized by glycosuria, phosphaturia, aminoaciduria, and bicarbonate loss; hypophosphatemia, which impairs bone mineralization, leading to osteomalacia; and reduced bone mineral density (BMD), which increases fracture risk, particularly in weight-bearing bones such as the femoral neck.^[2]

Several studies have documented a 2–6% reduction in BMD within the 1^st year of initiating TDF. The risk is higher in patients with longer exposure, low body mass index (BMI), coexisting nutritional deficiencies, or preexisting renal disease.^[3,4]

Here, we present two cases of HIV-positive patients on long-term TLD who developed atraumatic neck of femur fractures secondary to tenofovir-induced renal dysfunction and hypophosphatemic osteomalacia.

CASE REPORT

Case 1

A 35-year-old female, diagnosed with HIV 10 years ago, had been on TLD for the past 8 years. She presented with bilateral groin pain and inability to bear weight on the left side. There was no history of trauma, fever, or steroid use. On physical examination, the patient had a restricted and painful range of motion in the left hip. She was ambulatory with difficulty and required assistance. No local swelling or redness was observed. Distal pulses were palpable, and peripheral sensations were intact. Blood investigations and radiological workup were done, which showed a linear sclerotic line in the left femoral neck, suggesting an old, united fracture, with mild marrow edema involving bilateral femoral necks [Table 1 and Figure 1]. Urinalysis revealed proteinuria and glucosuria, and a dual-energy X-ray absorptiometry (DEXA) scan yielded a T-score of −1.5 at the lumbar spine, indicating osteopenia. These findings were consistent with Fanconi syndrome induced by prolonged tenofovir use.

Table 1: Lab results of both patients.

Test	Normal level	Case 1	Case 2
Serum creatinine (in mg/dL)	0.67–1.17	1.41	1.60
Serum phosphate (in mg/dL)	2.5–4.5	1.6	1.3
Serum calcium (in mg/dL)	8.6–10.2	8.8	9.2
Serum vitamin D (in ng/dL)	>30	22.8	20.6

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Figure 1:

(a) 35-year-old HIV positive female who presented with bilateral groin pain. Plain radiograph of pelvis with bilateral hip joints showing left femoral neck fracture (depicted by black arrow). (b) Axial, and (c) Coronal sections of MRI show a linear sclerotic line in the left femoral neck, suggesting an old, united fracture (depicted by red arrow), with mild marrow edema involving bilateral femoral necks.

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The patient was managed conservatively due to incomplete fracture, stable alignment, and signs of union on the recent magnetic resonance imaging. Treatment included immobilization and activity modification, with oral phosphate and Vitamin D supplementation, along with a switch from TLD to a Zidovudine + Lamivudine + Dolutegravir (AZT+3TC+DTG) regimen. At 3-month follow-up, the patient reported significant pain relief and improved mobility. Repeat laboratory tests revealed normalization of the phosphate level and improved renal function. At 4-month follow-up, the patient was walking full-weight-bearing [Figure 2].

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Figure 2:

Radiograph taken at 4-month follow-up shows no displacement at the fracture site (depicted by black arrow).

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Case 2

A 60-year-old male, HIV-positive for 12 years and on TLD for 6 years, presented to the outpatient department with a 2-month history of progressively worsening bilateral hip pain, initially aggravated by activity and later persistent at rest. He had no history of trauma or falls. There was external rotation and shortening of the right lower limb with tenderness in the groin. The left hip was tender but with preserved range of motion. Blood and radiological investigations were done, which showed bilateral neck of femur fractures (Garden stage 3 on the right side and stage 2 on the left side) with minimal joint effusion [Table 1 and Figure 3]. Urinalysis revealed proteinuria and glucosuria, and a DEXA scan yielded a T-score of -2.3 at the lumbar spine. Fanconi syndrome due to long-term tenofovir exposure was again suspected.

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Figure 3:

(a) 60-year-old HIV positive male who presented with bilateral groin pain. Plain radiograph of pelvis with bilateral hip joints showing bilateral femoral neck fracture (depicted by black arrow). (b) Axial, and (c) Coronal sections of MRI show bilateral neck of femur fractures (Garden stage 3 on the right side and stage 2 on the left side, as depicted by red arrows) with bilateral minimal joint effusion.

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The right-sided fracture was managed surgically with uncemented bipolar hemiarthroplasty, given the patient’s age, moderately active lifestyle, and quality of bone [Figure 4], while the left-sided fracture was treated conservatively due to stable alignment and the possibility of union as seen in the previous case. Bedside physiotherapy was started immediately postoperatively in the form of quadriceps and hamstring strengthening, knee bending, ankle pumps, and bedside sitting, and the patient was started on full weight-bearing walking on the right limb and non-weight-bearing on the left limb with walker support. ART was switched to AZT + 3TC + DTG, and supportive therapy with oral phosphate, Vitamin D, and calcium was initiated. At the 3-month follow-up, the patient was walking partial weight-bearing on the left limb with minimal pain, and the radiograph showed a well-seated prosthesis on the right side and no significant fracture displacement on the left side [Figure 5]. The left side was still managed conservatively, given the possibility of union in the previous case, but the patient was counseled regarding the need for appropriate surgical management in case of fracture displacement at any point in time. Biochemical markers showed partial recovery in renal and bone parameters.

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Figure 4:

Immediate post-operative plain radiograph shows a well-seated prosthesis on the right side (depicted by black arrow).

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Figure 5:

3-month follow-up radiograph shows a well-seated prosthesis on the right side (depicted by black arrow) and no significant fracture displacement on the left side (depicted by red arrow).

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DISCUSSION

The above cases reinforce that pathological fractures may occur silently and present with vague symptoms, and hence, renal and bone health should be routinely monitored in patients on TDF-based ART, especially after 3–5 years. The management approach involves discontinuation of tenofovir, switching to AZT or abacavir (ABC)-based regimens, and supplementation with phosphate, calcium, and Vitamin D. Displaced or complete fractures must be managed surgically, while a trial of conservative management can be given for early, incomplete fractures.

Moorthy and Tan described a 67-year-old male on tenofovir who presented with bilateral atraumatic femoral neck fractures due to Fanconi syndrome.^[5] After correcting phosphate levels and discontinuing TDF, the patient underwent successful staged total hip replacements. Chaganty and James reported a 35-year-old HIV-positive male on ART who developed sequential femoral neck stress fractures.^[6] In a low-resource setting, osteopenia was diagnosed using Singh’s Index (a radiological method used to assess the degree of osteoporosis based on the trabecular pattern of the proximal femur seen on a standard anteroposterior pelvic radiograph), and ART-related bone loss was identified as the likely cause. Tompkins et al. observed subcapital fractures in HIV-positive patients with radiographic osteonecrosis in Malawi, highlighting ART and HIV as contributory factors and favoring total hip arthroplasty over internal fixation due to poor healing capacity in necrotic bone^[7] [Table 2].

These findings collectively highlight the multifactorial interplay between HIV infection, ART (particularly Tenofovir), renal tubular dysfunction, and impaired bone remodeling. Furthermore, all these studies stress the importance of early diagnosis through clinical suspicion and basic biochemical workup.

While TDF-based regimens remain associated with adverse effects, they continue to be used as the preferred first-line therapy in many national HIV programs, including NACO in India. This is largely due to their potent antiviral efficacy, favorable resistance profile, availability in once-daily fixed-dose combinations, and cost-effectiveness. Alternatives such as ABC or tenofovir alafenamide may offer improved safety in terms of renal and bone health, but are limited by issues such as cost, availability, and the need for HLA-B5701 testing (for ABC).^[8]

In addition to monitoring and ART modification, prophylactic nutritional support may play a key role in preventing TDF-associated skeletal complications. Supplementation with oral phosphate, Vitamin D, and calcium, either from dietary sources (such as dairy, leafy greens, fish, and fortified foods) or pharmaceutical formulations, may help mitigate early metabolic imbalances.^[9] While routine supplementation for all patients on TDF is not universally recommended, targeted prophylaxis in high-risk individuals (e.g., those with low BMI, renal dysfunction, or poor nutrition) is a low-cost, low-risk intervention that could reduce long-term morbidity. However, the efficacy and optimal regimen of such prophylaxis remain areas for future study.

CONCLUSION

These cases illustrate the potentially serious skeletal complications of long-term TDF use in HIV-positive individuals. Atraumatic femoral neck fractures, though rare, may be the first sign of underlying renal tubular dysfunction and osteomalacia. Clinicians must maintain vigilance in identifying individuals at risk and intervene early to prevent catastrophic outcomes. Routine monitoring for renal function and BMD, along with timely ART modification and nutritional correction, can significantly reduce morbidity and improve quality of life in this population. Despite its known toxicities, TDF remains a first-line agent due to its efficacy, affordability, and accessibility, particularly in resource-constrained settings. In light of these case studies, our report provides additional evidence to the growing concern about skeletal complications associated with tenofovir. It underscores the necessity of proactive screening and management protocols within HIV treatment programs, especially in resource-limited environments. Long-term follow-up studies are required to evaluate the efficacy of conservative management in these cases.