Abstract
Summary
Tenofovir-induced osteomalacia secondary to proximal renal tubular dysfunction is not an uncommon complication known to occur. A 46-year-old woman was referred for the evaluation of osteoporosis which was diagnosed elsewhere. She had polyarthralgia, bony pains and proximal muscle weakness of 1 year duration. She was diagnosed to have HIV infection and was on antiretroviral therapy that consisted of tenofovir, lamivudine and efavirenz for the past 12 years. She had attained menopause 5 years back. On examination, she had bone tenderness, proximal myopathy and painful restriction of movement of her lower limbs. Investigations showed features of renal tubular acidosis, hypophosphatemia and raised alkaline phosphatase that were suggestive of osteomalacia. X-ray of the pelvis showed diffuse osteopenia and an MRI of the pelvis done showed multiple insufficiency fractures involving the head of femur on both sides. Following this, her tenofovir-based regimen was changed to abacavir, efavirenz and lamivudine with addition of neutral phosphate supplements and calcitriol. On follow-up after 6 months, she had significant improvement in her symptoms as well as in the bone mineral density at the lumbar spine (33.2%), femoral neck (27.6%), trabecular bone score (13.2%) and reduction in the buckling ratio at the narrow neck (6.3%), inter-trochanteric region (34%) and femoral shaft (28.8%). Tenofovir-induced osteomalacia is encountered in individuals on prolonged treatment with tenofovir. Treatment consists of changing to a non-tenofovir-based regimen, as well as supplementation of phosphate and calcitriol. Treatment results in remarkable improvement in symptoms and most densitometric indices.
Learning points
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Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI) and is a major drug in the treatment of retroviral and hepatitis B infections.
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Tenofovir-related hypophosphatemic osteomalacia is related to proximal tubulopathy and is not an uncommon occurrence.
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Treatment mandates changing to a non-tenofovir-based regimen with supplementation of neutral phosphate and calcitriol.
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Treatment results in a significant improvement in bone mineral density, trabecular bone score and hip geometric parameters.
Background
Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI) and is a major drug in the treatment of retroviral and hepatitis B infections. There are two preparations of tenofovir, namely, tenofovir disoproxil fumarate (TDF) and tenofovir alfafenamide. The major side effects of tenofovir treatment include nausea, abdominal discomfort, deterioration of bone health, renal tubular dysfunction, lipid abnormalities and hepatic steatosis (1). It is excreted through glomerular filtration and tubular secretion and hence, damage to the proximal tubules may occur resulting in Fanconi syndrome and subsequent osteomalacia. Tenofovir-induced osteomalacia secondary to proximal renal tubular dysfunction is an uncommon complication and here we report a case of tenofovir-induced osteomalacia, presenting with multiple insufficiency fratcures associated with antiretroviral therapy (2).
Case presentation
A 46 years old woman (postmenopausal for 5 years) referred to us for the evaluation of osteoporosis diagnosed elsewhere. She had history of polyarthralgia involving the hip, knees and bilateral shoulder joints of 1 year duration. The pain was not associated with joint swelling or morning stiffness; it worsened with activity and was relieved by rest. Subsequently, she developed severe mid back pain which was aggravated by sitting and turning in bed since the preceding 6 months and caused her to remain bed-ridden for 3 months prior to presentation. There was history suggestive of proximal muscle weakness. There was no history of paraesthesia or renal stones. She was diagnosed to have human immunodeficiency virus (HIV) infection and was on antiretroviral therapy (ART) that consisted of tenofovir (300 mg), lamivudine (300 mg) and efavirenz (600 mg) for the last 12 years. She had attained menopause 5 years ago. On examination, she had severe spinal and hip tenderness with painful restriction of movements in the lower limbs.
On further evaluation, she had hypophosphatemia and mild hypokalemia with a normal anion gap metabolic acidosis and a urine spot pH of 6.42, suggesting a diagnosis of renal tubular acidosis. There was glucosuria and urine evaluation for amino acids was not available. The presence of hypouricemia and absence of nephrocalcinosis were indicative of a proximal tubular pathology. Her TmP/GFR (tubular maximum for phosphate reabsorption corrected for glomerular filtration rate) was 1.2 and this was indicative of a renal phosphate leak. She had elevated alkaline phosphatase, subnormal 25-hydroxy vitamin D levels and normal parathormone (PTH). Her investigations are shown in Table 1. Her x-ray showed diffuse osteopenia (Fig. 1) and an MRI pelvis showed multiple insufficiency fractures which included bilateral sub-capital neck of femur fractures, right intertrochanteric femur fracture and bilateral subchondral fractures of head of femur (Fig. 2). Her BMD showed her T-score to be −3.4 at the neck of femur and −3.5 at the lumbar spine (Fig. 3 and 4). In addition, other densitometric indices were also altered (Figs. 5 and 6). With the above findings, a diagnosis of tenofovir-induced osteomalacia secondary to proximal tubular acidosis as a consequence of antiretroviral therapy was diagnosed.
X-ray of pelvis showing diffuse osteopenia.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-22-0259
MRI of pelvis showed multiple insufficiency fractures.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-22-0259
Lumbar spine BMD at presentation and on follow-up.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-22-0259
Hip BMD at presentation and follow-up.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-22-0259
Trabecular bone score (TBS) at presentation and on follow-up.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-22-0259
Hip geometry at presentation and on follow-up.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-22-0259
Biochemical investigations at presentation and follow-up.
| Investigations | Reference range | At presentation | First follow-up (1 month) | Second follow-up (6 months) |
|---|---|---|---|---|
| Sodium, mmol/L | 135–144 | 136 | 135 | 137 |
| Potassium, mmol/L | 3.5–5.0 | 3.2 | 3.8 | 3.8 |
| Chloride, mmol/L | 96–06 | 111 | – | 107 |
| Calcium, mg/dL | 8.3–10.4 | 9.2 | 9.1 | 9.5 |
| Phosphate, mg/dL | 2.5–4.5 | 2.1 | 3.6 | 3.0 |
| Albumin, g/dL | 3.5–5.0 | 4.4 | 4.2 | 4.5 |
| 24-h urine calcium, mg/24 h | <300 | 131 | – | – |
| TmP/GFR | 1.2 | – | 2.6 | |
| Alkaline phosphatase, U/L | 40–125 | 577 | 1041 | 578 |
| 25 OH vitamin D, ng/mL | 30–75 | 17.6 | – | 34.4 |
| PTH, pg/mL | 8–74 | 65.4 | – | 73 |
| Creatinine, mg/dL | 0.5–1.2 | 0.8 | 0.9 | 0.9 |
| Magnesium, mg/dL | 1.5–2.6 | 2.1 | – | 2.1 |
| Serum pH | 7.35–7.44 | 7.29 | – | – |
| Urine pH | 6.42 | – | – | |
| Serum bicarbonate, mmol/L | 24–28 | 17 | 19 | 21 |
| Uric acid, mg/dL | 2.4–5.7 | 2.3 | – | 3.0 |
Treatment
In consultation with the infectious diseases specialist, her ART regimen was changed to abacavir (600 mg), lamivudine (300 mg) and efavirenz (300 mg). She was initiated on neutral phosphate (250 mg thrice daily) supplements as well as calcitriol (0.25 mcg daily) and oral potassium chloride 15 mL thrice daily.
Outcome and follow-up
At first follow-up at the end of 1 month, she reported about 75% improvement in her symptoms. At the second follow-up after 6 months, however, she was able to walk independently with no bony pains. The alkaline phosphatase did not show a significant decline probably due to difficulty in procuring medications during the COVID-19 lockdown in the country and doubtful compliance to medication during this time. A DXA scan repeated this time showed the T-scores at the femoral neck and lumbar spine to be −2.2 and −1.4, respectively. There was 33.2% improvement in the lumbar spine BMD, 27.6% improvement in BMD at the femoral neck and definite reduction in the bucking ratio – 6.3% at the narrow neck, 34% at the intertrochanteric region and 28.8% at the femoral shaft. The trabecular bone score increased from 1.201 to 1.359, indicating a definite improvement (13.2%) in the bone microarchitecture (Fig. 5).
Discussion
Tenofovir-induced osteomalacia is a known complication reported following its prolonged use especially after antiretroviral therapy. Hypophosphatemia in TDF-treated individuals is usually secondary to proximal tubulopathy and its prevalence among tenofovir-treated patients can be as high as 31% (3).
Tenofovir is a prodrug that achieves high plasma concentration and is actively excreted through glomerular filtration and proximal tubular secretion. It is taken up into the proximal cells through the organic anion transporter in the basolateral membrane and is actively secreted into the tubular lumen through the multidrug resistant protein 4 (2). Tubular dysfunction secondary to mitochondrial damage results from high intracellular concentration of TDF. Mild to moderate tubular damage can present with varying degrees of bicarbonaturia and severe phosphaturia with metabolic acidosis. Fanconi-like syndrome with aminoaciduria, glucosuria and severe osteomalacia may occur with severe tubular damage.
Increased beta 2 microglobulin to creatinine ratio and retinol-binding protein to creatinine ratio is a marker of tubular dysfunction (4). In addition to the dyselectrolemia, there can be calcitriol deficiency which might contribute to deterioration in bone health. Besides renal tubular dysfunction, TDF has direct effect on bone and it causes altered cell signaling with defective amino acid and energy metabolism in osteoclast cells. Tenofovir has been associated with increase in the number of vitamin D receptors. This causes greater binding between vitamin D and its receptors, resulting in a decrease in the biologically active form of the vitamin D, leading to secondary hyperparathyroidism (2, 4). From a meta-analysis published in 2020, it was found that, after the initiation of TDF, there was an initial decline in bone mineral density which was followed by a stabilization phase. Progressive bone loss and osteomalacia with increased bone turn over markers and fragility fractures are documented among patients with renal tubular dysfunction. Bone biopsy is reported to show increased osteoid formation characteristic of osteomalacia (2, 5).
The risk factors for tenofovir-induced osteomalacia include duration of therapy, advanced HIV disease with low CD4 counts, genetic polymorphism in ABCC4 transporter protein-coding gene, advanced age, diabetes mellitus, co-existing hepatitis C infection, renal dysfunction with decreased creatinine clearance, concomitant use of non-steroidal anti-inflammatory drugs, decreased BMI and concomitant use of protease booster therapy such as lopinavir and ritonavir (6). Ritonavir compete with tenofovir for proximal tubular excretory protein for tubular secretion and hence results in raised plasma concentration of TDF (6). From a review conducted in 2006 among patients with tenofovir-induced osteomalacia, 83% had concomitant use of protease inhibitor (7). TDF drug level of more than 160 ng/mL was associated with higher occurrence of proximal tubulopathy (8). Clinical presentation of tenofovir-induced osteomalacia includes, bone pain predominantly involves the lower limbs, proximal myopathy and insufficiency fractures (9).
Tenofovir-induced osteomalacia may be prevented by active monitoring of bone mineral density, fasting phosphate levels, avoidance of nephrotoxic drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) and by the supplementation of vitamin D. Renal-adjusted dose is recommended when creatinine clearance is less than 50 mL/L/min and drug should be avoided when the creatinine clearance is less than 10 mL/L/min. Switching to tenofovir alafenamide or non-TDF regime may help in the prevention of progressive tubular damage and reverse the osteomalacia (10). Frequent monitoring and active surveillance for the occurrence of this complication along with the use of non-TDF regimes have significant effect on bone health recovery (11).
Our patient’s ART was changed to non-TDF regime, and on subsequent follow-up after 3 months, she had showed significant improvement in BMD. The repeat x-ray of the pelvis done showed improvement. There was significant increment in the bone mineral density and trabecular bone score following treatment. The indices of the hip structural analysis also showed significant improvement, with marked reduction in the buckling ratio upon treatment indicating a reduction in the propensity to proximal femoral fracture. While it is known that bone mineral density shows significant improvement upon treatment of osteomalacia, reports on improvement in the trabecular bone score and parameters of hip geometry are hitherto not available in literature. To the best of our knowledge, this is the first report on the improvement in trabecular bone score and parameters of hip geometry following treatment of tenofovir-induced osteomalacia.
The occurrence of muscle aches, bony pains and proximal muscle weakness in individuals on tenofovir should promptly be evaluated. Active surveillance, vitamin D supplementation and cautious use of the drug in chronic kidney disease could prevent the occurrence of this complication.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work did not receive any specific grant from any funding agency
Patient consent
Written informed consent for publication of her clinical details and clinical images was obtained from the patient.
Author contribution statement
All authors took care of the patient during the patient’s hospitalization and all authors contributed to the editing of the manuscript.
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