Single Zoledronic Acid Infusion Slows Early Bone Loss in Individuals Starting HIV Treatment

A 5-mg infusion of zoledronic acid slowed bone resorption (loss) and stabilized bone mineral density (BMD) in a 48-week placebo-controlled study of people starting a regimen containing tenofovir disoproxil fumarate (TDF, Viread). Emory University researchers propose that accelerated bone loss in the first 48 weeks of antiretroviral therapy (ART) may offer an appropriate window for prophylaxis with antiresorptive agents like zoledronic acid.

Ample research documents declining BMD in the first months of ART, and the impact of TDF on bone health is well appreciated. But the authors of this study note that the less toxic tenofovir alafenamide (TAF) is also linked to early bone loss. On the basis of their earlier research, these investigators blamed early BMD decrements on "a surge in bone resorption" in the first 24 weeks of ART. They conducted this phase 2 double-blind placebo-controlled trial to see if zoledronic acid could prevent these early changes.

The researchers recruited antiretroviral-naive adults 30 to 50 years old who were planning to start ART. No one had osteoporosis or a history of bone disease. Everyone began a regimen containing TDF/emtricitabine (Truvada) plus atazanavir /ritonavir. The investigators randomized them to a single intravenous infusion of zoledronic acid (5 mg per 100 mL) or placebo administered on the first day of ART. C-terminal telopeptide of collagen (CTx) and osteocalcin (bone resorption and formation markers, respectively) and BMD were measured at weeks 0, 12, 24 and 48.

The 34 people in the zoledronic acid arm and the 29 in the placebo arm averaged about 40 years in age and 79% were men. The intervention arm included marginally lower proportions of blacks (79% versus 90%) and current smokers (56% versus 79%). The groups were similar in baseline lumbar spine BMD and levels of calcium and vitamin D.

CTx levels were similar at baseline in the zoledronic acid and placebo arms but became significantly lower relative to placebo in the zoledronic acid arm, indicating lower bone loss, at weeks 12, 24 and 48 (P < .001 at all points). Compared with the placebo group, the zoledronic acid group had 73% lower bone resorption at week 12, 65% lower resorption at week 24 and 57% lower resorption at week 48. Bone formation, as indicated by osteocalcin levels, did not change from baseline to week 48 in the zoledronic acid arm.

BMD did not change significantly through 48 weeks among people who received zoledronic acid. But because of declining BMD in the placebo arm, at study week 12 the zoledronic acid group had 8% greater lumbar spine BMD than the placebo group (P = .003) and 11% greater spine BMD at weeks 24 and 48. Between-group differences proved similar at the hip and femoral neck.

At 48 weeks, viral suppression rates were high and statistically similar in the two study arms (97% in the zoledronic acid arm and 84% in the placebo arm). CD4 gains were similar with zoledronic acid and placebo (mean 270 and 311 cells/mm3, P = .38). The investigators attributed no serious adverse events to zoledronic acid. Rates of moderate or severe diarrhea, weight loss, rash, insomnia and myalgia were similar in the two study arms. Incidence of any grade 3 or 4 lab abnormality through 48 weeks did not differ between arms.

The Emory team concludes that "the heightened bone resorption following ART initiation was completely blunted by [zoledronic acid], resulting in durable BMD preservation at fracture-prone sites that lasted through 48 weeks." They add that the lower bone resorption and higher BMD with zoledronic acid relative to placebo "are the largest reported effect sizes for any prophylactic intervention directed at ameliorating ART-induced bone loss." They call for phase 3 trials to confirm their findings.