Abstract
The prevalence of Paget’s disease of bone (PDB) reaches 1–2% of all adults aged ≥55 years old. However, reports describing PDB among HIV positive patients are extremely rare. We report here the case of a HIV positive person receiving tenofovir disoproxil fumarate (DF)-based antiretroviral therapy and who had persistently elevated alkaline phosphatase (AP) revealing PDB. It is well established that tenofovir-DF use is associated with reversible increases in serum AP levels. Clinicians should bear in mind that persistently elevated AP in a person receiving tenofovir DF-based cART could be related to PDB, in particular in person older than 50 years with no other notable biological abnormalities related to kidney tubular dysfunction.
Paget’s disease of bone (PDB) is a non-inflammatory, metabolic, skeletal disorder that mainly affects the pelvis, spine, femur and tibia. 1 PDB increases bone turnover, and remodelling alters the bone’s quality, leading to bone thickening and deformity. 2 The physiopathology of this disease is not entirely clear. Mutations in the gene-producing sequestosome 1, and/or in the gene that encodes the receptor activator of nuclear factor kB, both involved in osteoclast formation and activity, increase susceptibility to the development of PDB.1–3 The potential role of viral infections has been suggested, since pagetic osteoclasts containing paramyxoviral-like nuclear inclusions have been described in animal models that cross-react with antibodies to measles virus, respiratory syncytial virus and canine distemper virus. 2 The prevalence of PDB reaches 1–2% among adults ≥55 years old and is highest in people of British descent.1,2 Prevalence has decreased drastically in Europe since 1978, but the reason for this steep decline remains unknown.1,2,4 Nowadays, PDB is the second most common metabolic disorder after osteoporosis. 1 However, reports describing PDB among people with HIV (PWH) are exceedingly rare. 3 We report here the case of a PWH with persistently elevated alkaline phosphatase (AP) revealing PDB.
Case presentation
A 67-year-old man who has sex with men was diagnosed as HIV-positive in 2010, CDC stage A3. The nadir CD4 T cell count was 54/mm3 and the HIV viral load was 200,000 copies/ml. Combined antiretroviral therapy (cART) with emtricitabine/tenofovir disoproxil fumarate (DF) and ritonavir/darunavir was initiated, and rapidly led to an undetectable HIV viral load. At initiation of cART, the AP level was normal (76 IU/L). Six months later, the AP level reached 230 IU/L (reference <105 IU/L), with a normal level of gamma-glutamyl transpeptidase (GGT). No abnormalities were observed in terms of phosphorus or calcium levels, or 25-OH vitamin D level. In July 2018, tenofovir DF was discontinued due to the elevated AP level (300 IU/L) and cART was switched to lamivudine and ritonavir/darunavir but no decrease in AP level ensued.
In January 2019, the patient reported lumbar pain. The CD4 T cell count was 475/mm3 and the HIV viral load was undetectable. The AP level was 276 IU/L whereas calcium, phosphorus, parathyroid hormone and creatinine levels were normal. No proteinuria was detected.
The abdomino-pelvic computed tomography (CT) scan performed because of lumbar pain revealed typical radiological features in favour of PDB. Bone scintigraphy showed that PDB focused on the L3 vertebrae, sacrum and right hemi-pelvic-bone. The patient refused to be treated with zoledronic acid. Three years after the PDB diagnosis, the AP level had increased to 323 IU/L.
Discussion
Serum AP bone isoenzyme is a surrogate of osteoclast activity and increased levels indicate stimulated bone metabolism. 5 Elevated bone-specific AP can be caused by a number of pathologies affecting the bone, such as recent fracture, Paget’s disease, osteomalacia, hyperparathyroidism and metastatic bone disease. 5 In antiretroviral treated PWH, tenofovir-DF use is associated with reversible increases in serum AP levels. 5 Indeed, tenofovir-DF use can damage the proximal kidney tubules by accumulation that hinders phosphate and calcium reabsorption. Hyperphosphaturia secondary to tubular dysfunction could lead to progressive bone loss and to a lesser extent, to hypophosphatemic osteomalacia. 6 Overall, tenofovir DF-based cART leads to a larger reduction in bone mineral density than cART not based on tenofovir-DF. 6
Our patient presented a progressive increase of AP 6 months after initiation of tenofovir DF-based cART. Persistently elevated AP was observed over the course of 8 years of tenofovir-DF use, with no other biological anomalies related to renal dysfunction. In addition, the AP level continued to increase despite discontinuation of tenofovir-DF and normal 25-OH Vitamin D levels. The patient developed PDB symptoms 6 months after interruption of tenofovir-DF, and around 9 years after observation of an isolated elevation of serum AP. Therefore, in view of the lumbar pain and isolated persistently elevated AP, the PDB diagnosis was proposed and confirmed by radiological imaging. PDB is usually asymptomatic; most cases are diagnosed incidentally on radiography or as an isolated elevation of serum AP, which is the most clinically useful indicator of PDB disease activity. 1 Symptomatic patients present with bone pain, fractures, arthritis and features of compression neuropathy. 1 To the best of our knowledge, only one other case of PDB has been described in a PWH with a positive family history. 3
Clinicians should bear in mind that persistently elevated AP in PWH receiving tenofovir DF -based cART could be related to PDB, in particular in people older than 50 years with no other notable biological abnormalities related to kidney tubular dysfunction.
Footnotes
Acknowledgements
We thank Fiona Ecarnot, PhD (EA3920, University Hospital Besancon, France) for editing the manuscript.
Author Contributions
AA and FBS wrote the first manuscript draft. All authors were involved in the care of the patient. All authors participated in the writing of the final manuscript and all authors approved final manuscript
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
