Antiretroviral Therapy and Adverse Skeletal Effects

To the Editor: We read with interest the article by Davidge Pitts and Kearns¹ entitled “Update on Medications With Adverse Skeletal Effects.” In our opinion, antiretroviral compounds should also be added to the list of “bad-to-the-bone” drugs.

During the past 10 years, the average life expectancy of adults with human immunodeficiency virus (HIV) infection has increased because of effective antiretroviral therapy (ART), and the care of HIV-infected individuals has shifted from management of opportunistic infections to prevention and treatment of the metabolic complications of ART, including osteoporosis.

In particular, the synergy between HIV and/or ART-related bone damage with age-associated bone loss could lead to a serious health threat. Several clinical studies have shown that during ART, bone loss is an early event and occurs rapidly, especially within 6 months of initiation. The Strategies for Management of Antiretroviral Therapy (SMART) study has shown that institution of an ART may be followed by a 6% decrease in bone mineral density (BMD) during the first 2 years regardless of the drug combination. Furthermore, continuous ART is associated with reduced BMD and increased fracture risk compared with intermittent, CD4 cell count–guided ART.² Therefore, osteopenia/osteoporosis, occasionally osteomalacia, and an increased risk of fracture are reported as major adverse effects of ART, especially in a regimen including the nucleotide reverse-transcriptase inhibitor tenofovir³ and protease inhibitors.

The mechanism by which antiretroviral drugs act on the bone is multifactorial and not completely clear but is mediated in part by a direct effect on osteoblasts and osteoclasts, increased catabolism of vitamin D, and mitochondrial damage. Interestingly, the mitochondrial damage can also cause proximal renal tubulopathy. Indeed, 1.6% to 22% of tenofovir-treated patients experience phosphate wasting and 1-hydroxylation defects of vitamin D due to proximal renal tubulopathy, leading to osteomalacia with multiple fractures, bone pain, and proximal muscle weakness.

According to the European AIDS Clinical Society guidelines, in HIV-positive patients, especially those treated with ART, dual energy x-ray absorptiometry should be performed; if BMD is abnormal, secondary causes of osteoporosis should be ruled out (eg, hypovitaminosis D, hyperparathyroidism, hyperthyroidism, malabsorption, hypogonadism/amenorrhea, autoimmune diseases, diabetes mellitus, chronic liver diseases), and lateral lumbar and thoracic spine radiography should be performed. If hypophosphatemia is present, a diagnosis of renal Fanconi syndrome should be considered.

Currently, ART-induced bone loss can be managed with a reduction of risk factors for osteoporosis, including ensuring vitamin D supplementation (800-2000 IU of vitamin D₃ daily⁴ or up to 2000 IU in patients treated with efavirenz⁵) to maintain a plasma 25-hydroxyvitamin D concentration greater than 30 ng/mL (75 nmol/L). Other interventions include supplemental dietary calcium (1-1.2 g/d), weight-bearing exercise, and (sometimes) bisphosphonates (oral alendronate, 70 mg once weekly, or zoledronate, 5 mg intravenously once yearly). Furthermore, substituting another drug for tenofovir should be considered for patients presenting with hypophosphatemia, renal Fanconi syndrome, progressive decline of glomerular filtration rate, or fragility fractures.⁴