Oral Presentation 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019

64-year-old man was a long-term patient at the Endocrinology Clinic for the management of osteoporosis following liver transplantation.  

He underwent liver transplantation in 2004 for hepatocellular carcinoma and hepatitis B related cirrhosis. Of note his post-transplant immunosuppression included high dose prednisolone which was gradually weaned to 5mg in 2005 and stopped by 2009. In 2018, the only anti-rejection treatment he required was mycophenolate mofetil but in previous years immunosuppressive treatment included tacrolimus and azathioprine. He was treated with lamivudine 100mg and adefovir 10mg daily prior to liver transplantation and this continued post transplantation.  

His other medical history included gastrectomy for gastric cancer in 2010, chronic renal impairment and post-transplant diabetes mellitus. His other medications include phosphate 500mg daily, calcium carbonate 600mg twice daily, magnesium aspartate 500mg daily, pantoprazole 40mg daily and gliclazide 80mg daily.  

Post-transplantation DXA  in2006 demonstrated osteoporosis with a T-score of -4.0 at the lumbar spine and -1.9 at the left femur. Between 2006-2012 he was treated with 6 doses of zoledronic acid with improvement and stabilisation in bone density. In 2010 he sustained bilateral rib fractures following heavy lifting. These fractures healed well. From 2012-2014 he did not have any new fractures and bone density remained stable. 

In 2015, he had new atraumatic bilateral rib fractures. At this time, he had mild hypocalcaemia(Corrected Calcium 2.07 mmol/L). DXA bone density was stable at the lumbar spine (T-score -2.6) but there was a greater than 5% decrease at left femur (T-score -2.0).  He was advised to use calcium citrate instead of calcium carbonate to improve absorption.  

From mid-2017 he reported the onset of significant chest, back, hip and foot pain. A technetium-99m mdp bone demonstrated increased uptake in the ribs, pelvis and right lesser femoral trochanter, and sacrum. The results were suggestive of multiple new fractures.

The pain worsened over the following 12 months. He previously enjoyed bush walking but was now having difficulty walking short distances due to pain. Investigations in 2018 revealed hypophosphataemia (plasma Pi 0.48mmol/L) despite oral phosphate supplementation. Bone-specific ALP was also elevated at 63.1ug/L (ref 5.5-24.6). Bone densitometry showed an 8.5% decrease at the lumbar spine and 20% decrease at the left femur compared to the BMD performed 18 months previously.

Urinary studies demonstrated hyperphosphaturia, aminoaciduria and glycosuria. Fractional excretion of phosphate was  elevated at 0.55 (ref 0.1-0.2) and calculated maximum tubular reabsorption of phosphate was reduced at 0.22mmol/L .

Renal tubular dysfunction and osteomalacia secondary to adefovir were suspected. The need for ongoing antiviral treatment, lack of availability of alternative antivirals and viral resistance meant that adefovir could not be stopped. Oral phosphate replacement was increased, and calcitriol was commenced. Consideration was given to possible treatment with teriparatide once the plasma calcium and phosphate levels had stabilised. 

In late 2018 the patient was able to access the antiviral Tenofovir Alafenamide (TAF), which was used in place of Adefovir and Lamivudine.  

In the months following these changes, the patient noticed marked improvement in bone pain. There was reduced uptake in some areas on bone scan.  Bone turnover markers increased in the months following commencement of calcitriol and change of antiviral therapy with a notable increase in P1NP. (See graphs) Urine phosphate excretion remained elevated. 

Results: 

Literature review

The nucleotide analogue antivirals adefovir and tenofovir disoproxil(TDF) are extensively used for treatment of chronic hepatitis B. These medications are associated with renal and bone toxicity, which require attention. Patients using TDF have been noted to have 1-3% lower bone density compared to those using alternative antiviral treatments in clinical trials(1). 

Renal tubular dysfunction is seen in up to 15% of patients with hepatitis B treated with adefovir or TDF over a 10 year period (2). In another study, urine biochemistry assessment showed that 17% of people with HIV treated TDF had tubular dysfunction(3). Fanconi’s Syndrome with severe generalised tubular dysfunction (aminoaciduria, glycosuria and phosphate wasting) is rare (4). 

Case reports have described osteomalacia and Fanconi syndrome secondary to adefovir improving within weeks of cessation and treatment with calcium, phosphate and calcitriol (4).  Increase in bone specific ALP in the weeks following cessation of adefovir was noted in these studies. This was also seen in our case. We also demonstrate a marked increase in P1NP reflecting bone formation.

It is important to be aware of osteomalacia as potential complication of these medications. In two case studies, treatment with anti-resorptives including bisphosphonates and denosumab have been shown to worsen osteomalacia and electrolyte disturbances(5,6). In a single case study, use of denosumab after adequate phosphate, calcium replacement and calcitriol supplementation resulted in improvement in bone pain and bone density(7). 

Tenofovir Alafenamide (TAF) is a newer nucleoside analogue closely related to TDF associated with 90% lower systemic levels of drug compared to TDF.  It has been shown to be as efficacious as TDF in treatment of hepatitis B with lower rates of renal and bone toxicity(8). Switching from TDF to TAF in HIV treatment has also been shown to improve renal function and bone density(9). 

There is one previous study demonstrating recovery form Fanconi syndrome and improvement of osteomalacia after switching from adefovir to TAF for treatment of HIV/Hepatitis B coinfection(10). 

Take home message

• Osteomalacia and Fanconi syndrome are potential causes for bone pain, fractures and hypophosphatemia in patients treated with the nucleotide analogues antivirals adefovir and tenofovir
• Initial management includes calcium, phosphate and calcitriol supplementation and cessation of the causative antiviral if possible.
• Tenofovir alafenamide is an alternative to adefovir and tenofovir with low rates of renal and bone toxicity.