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Single Dose Zoledronic Acid Effective for Paget’s Prevention

GLASGOW, Scotland – A single infusion of zoledronic acid (Aclasta) prevents bone turnover in people at risk of Paget’s disease in an analysis of data from the Zoledronate in the Prevention of Paget’s disease (ZiPP) study. 

The study results were presented as a poster at the Society for Endocrinology annual meeting 2023 (SfE BES 2023) by Jonathan Tang, PhD, a researcher in metabolic bone disease at the University of East Anglia, Norwich. The poster was awarded the 2023 BES prize for the bone and calcium category. 

Participants all had a relative with Paget’s disease, were around 50 years old, and had the sequestosome1 (SQSTM1) mutation that has a high penetrance for the disease, placing carriers at high risk of developing the disease in future years. As such, they were suitable for inclusion in the study that investigated prevention of disease onset.

The study found that the effect of a single dose of 5 mg zoledronate compared with placebo was highly significant for bone turnover markers – C-telopeptide of type I collagen (CTX) and procollagen type I N-propeptide (PINP) (P < .0001) – and significant for bone specific alkaline phosphatase (BSALP) (P = .0005).

“Zoledronic acid is very effective in regressing existing lesions and reduces the formation of new lesions when given prophylactically. This particular analysis shows the biochemical markers of bone resorption and formation are reduced,” Tang told Medscape UK. “It definitely proves there’s a role in giving zoledronic acid as a prophylaxis in these particular people [with the SQSTM1 mutation]." 

Bone Turnover Markers Followed for 7 Years

“People are usually diagnosed with Paget’s disease very late, once they have bone deformities, pain, fracture, and bone loss, and usually over the age of 55 years,” Tan said. “Because we know that this particular gene [SQSTM1] mutation is so highly penetrative, we can screen the relatives of patients with Paget’s and give them zoledronic acid to see if we can prevent the disease developing later on,” he added, explaining the study rationale. 

The multi-centre, double-blind, placebo-controlled, randomised trial was based on the hypothesis that prophylactic zoledronic acid would prevent the development of bone lesions and/or elevated turnover in these patients, which are typical in carriers of the mutation.

Participants were equally split between single intravenous dose of 5 mg zoledronic acid (n=111) and placebo (n=111). Measurements of bone markers were taken from serum samples. These included CTX for bone resorption, PINP for bone formation, and BSALP for osteoblast activity, measured every year for 5 years and then after 2 years of follow up at study end. Urine bone resorption (uNTX) and radionucleotide bone scans were performed at the start and end of the study (7 years).

“The two arms were very well-matched, with very similar numbers of females in each at around 60, and aged at around 50 years, which is the exact age we’re aiming for to prevent disease,” Tang said. 

Bone Resorption and Formation ‘Put Into Sleep Mode’

In participants who received zoledronic acid, CTX and PINP showed respective decreases in serum concentrations of average -44.8% and -29.2% across all time points. The greatest reductions were seen at 12 months from baseline (CTX -57.6%, PINP -46.7%). These levels remained below baseline concentrations for up to 7 years of follow up (CTX -15.2%, PINP -20%).

“So right from the get-go, these markers dropped at 12 months with bone resorption reduced,” said Tang. “There is some placebo effect happening but, of note, the levels stay reduced after a single dose for up to 7 years. And when we adjust for various confounders, we still see the effect.” 

Asked whether less bone formation was a bad thing, Tang said, “Because the bone breakdown has reduced, so this was reflected in the bone formation too. It’s almost like the cycle of bone resorption and formation has been brought down to a sleep mode.”

Serum BSALP showed a -20.9% decrease at 12 months and then returned to baseline concentration at 36 months, while uNTX showed a -36% decrease at study end. 

Bone scans revealed that the zoledronic acid treatment effect was associated with lower risks of developing new bone lesions (zero new lesions in the zoledronic acid arm versus two in the placebo arm). They also demonstrated that existing lesions did not worsen with zoledronic acid (zero lesions worsening in the zoledronic acid arm versus two in the placebo arm). However, these results did not reach statistical significance due to small numbers. 

Finally, the numbers of patients with a poor outcome at the end of the study were zero in the zoledronic acid arm compared with eight in the placebo arm (P = .003). 

No difference was seen in adverse effects between groups. 

“This is the first step to understand if zoledronic acid helps with prevention. But going forward, we need to determine how often these relatives may need further preventative doses, for example every 2 or 3 years,” remarked Tang. “But these data do suggest that if someone has a relative with Paget’s disease, then they should get tested for the gene mutation.”

Stephanie Kaiser, MD, from Dalahousie University, Halifax, Canada, who was not involved in the study, commented: “This speaks to the importance of using zoledronic acid, which is a very potent anti-resorptive agent for both treating and also preventing Paget’s disease, as we see here in the study, which looks at the relatives of patients with Paget’s disease who have the sequestosome 1 mutation.”

Adrian Heald, MD, endocrinologist at Salford Royal Hospital, Salford, remarked that Paget’s disease is disabling and can cause significant health challenges for people in the older age group and, as such, anything that stops Paget’s disease happening is a good thing. “In Manchester, we recently looked at the frailty index of people with Paget’s disease and particular problems for those who have disease in the hip girdle or the femur, affecting mobility and frailty,” said Heald, who was not involved in the study. “Reducing bone turnover markers that could be suggestive of future development of disease is an interesting option to explore further in a larger study.” 

Tang, Kaiser, and Heald have declared no conflicts of interest.