The development of hypophosphataemic osteomalacia with myopathy in two patients with HIV infection receiving tenofovir therapy

Abstract

We report two cases in which osteomalacia developed in patients on tenofovir-containing highly active antiretroviral therapy (HAART) in the context of Fanconi syndrome with hypophosphataemia. Bone pain was the presenting feature and myopathy followed in one case. Disability was reversed with withdrawal of the drug and with mineral supplementation. The cases highlight the importance of considering the diagnosis of osteomalacia in patients treated with tenofovir. A possible association with incipient acute renal failure, particularly during nonsteroidal anti-inflammatory drug (NSAID) use, needs further investigation.Keywords: HIV infections, hypophosphataemia, myopathy, osteomalacia, tenofovir Received: 28 September 2004, accepted 18 February 2005 Introduction Reduced bone mineral density has become increasingly important within the HIV-infected cohort as longevity has increased. It has been documented in a number of studies [1,2] and is possibly linked to the use of highly active antiretroviral therapy (HAART) [3], although, in studying this effect, it is difficult to separate the relative contributions made by length of time since diagnosis and HAART use, the two being interdependent.Osteomalacia, however, has been documented in only a few cases [4] and the myopathy of osteomalacia not at all. Tenofovir causes recognized Fanconi syndrome and hypophosphataemia [5,6], although osteomalacia has rarely been linked to such treatment [7]. Osteomalacia has also occasionally been linked to cidofovir and adefovir, other nucleotide analogues [7]. In animal studies using high-dose tenofovir, osteomalacia was a frequent adverse event [8]. In other settings, however, Fanconi syndrome is known to cause osteomalacia and myopathy, which is reversible if the underlying cause can be corrected [9]. Such instances have included Fanconi syndrome secondary to monoclonal gammopathy [10] and ifosfamide treatment [11]. Hypophosphataemia caused by malabsorption syndrome [12], parathyroid hormone-related protein-producing tumours or other tumours (so called oncogenic osteomalacia) [13][14][15] also produces a reversible osteomalacia, mediated via the phosphaturic hormones fibroblastic growth factor 23 (FGF 23) and matrix extracellular phosphoglycoprotein (MEPE), themselves controlled by the membrane metalloprotease PHEX [16]. In such cases the hypophosphataemia can lead to pathological fractures and tetany [15]. Fractures or Looser's zones can be misdiagnosed as disseminated malignancy, leading to diagnostic delay and disability [17]. Case 1A 47-year-old homosexual man was diagnosed with AIDS in 1989. His past medical history had included Kaposi sarcoma (treated in 1999) and hepatitis B infection (now surface antigen negative), but no abnormality of blood pressure, of renal function, or of phosphate metabolism and no history of a concomitant potentially nephrotoxic agent. He had been on antiretroviral therapy since 1991, with a triple class resistant virus.In February 2002, as a result of virological failure on his previous salvage regime...

Tenofovir-associated bone density loss

“…42,61,[64][65][66][67][68][69][70][71][72] The failure of renal proximal tubular cells to reabsorb filtered bicarbonate from the urine would result in urinary bicarbonate wasting and subsequent acidemia and a more general dysfunction of the proximal tubular cells -called Fanconi's syndrome. Commonly observed conditions in Fanconi syndrome include aminoaciduria, glycosuria, tubular proteinuria, and uricosuria.…”

Osteoarticular complications related to HIV infection and highly active antiretroviral therapy

“…Regarding reverse transcriptase inhibitors, recent reports have linked tenofovir to the occurrence of osteomalacia and the Fanconi syndrome [12]. Other factors can also contribute to accelerate bone loss, such as nutritional deficiency, low serum calcium levels, immobilization, hypogonadism, hyperthyroidism, hyperparathyroidism, renal failure, use of opioids or heroin, use of corticosteroids, postmenopausal period, and alcohol intake higher than 16 g/ day [1,8].…”

Patrón gammagráfico “superscan” en la osteomalacia hipofosfatémica asociada a Tenofovir en un paciente con infección por VIH

“…También se han publicado casos con adefovir, un análogo de nucleótido inhibidor de la transcriptasa inversa utilizado para el tratamiento de la Hepatitis B [10,11]. Otras causas que se deberían considerar en el diagnóstico diferencial de la OMH asociada a TDF son los tumores productores de proteína relacionada con la parathormona (PTHrP) (denominada "osteomalacia oncogénica"), la OMH idiopática del adulto, la OMH hereditaria y los síndromes de malabsorción [9]. En nuestro caso no hubo evidencia de recidiva del tumor neuroendocrino, lo que aleja el origen tumoral.…”

“…Los patrones gammagráficos más frecuentemente en los casos publicados en la literatura son aquellos con captaciones compatibles con fracturas por insuficiencia o pseudofracturas [2,3,9]. Sin embargo, en 3 de ellos se encontró un aumento generalizado de la incorporación del trazador en todo el esqueleto con ausencia o muy débil visualización de las siluetas renales, patrón conocido como "superscan" [4,5,6,19].…”