In the JournalsPerspective

Zoledronic acid increased sclerostin, spurred new bone formation

It has been established in previous studies that zoledronic acid improves bone density and reduces risk for fracture. However, new data suggests it may also significantly encourage new bone formation by targeting a specific biomarker.

“The key to effectively treating osteoporosis lies in increasing bone mass,” researcher Antonino Catalano, MD, PhD, of the University of Messina in Italy, said in a press release. “Zoledronic acid halts bone loss, but it also signals the body to stop forming new bone mass. The drug may need to be combined with other treatments to add bone mass.”

Catalano and colleagues randomly assigned 40 women (with postmenopausal osteoporosis; mean age, 62.6 years) to 5-mg zoledronic acid or placebo. The researchers measured serum levels of sclerostin, a circulating inhibitor of the Wnt signaling pathway produced by osteocytes which acts as a negative regulator of bone formation, according to the literature.

They also measured bone-specific alkaline phosphatase (BSAP) and serum C-telopeptide of type 1 collagen (CTX) at baseline and 2, 7, 30 and 360 days after zoledronic acid or placebo administration.

According to data, sclerostin serum levels increased by day 2, reached a peak at day 7 (threefold baseline; P<.001) and decreased at day 30. The levels returned to those near baseline after 360 days in the zoledronic acid group, the researchers wrote.

Data also indicate CTX and BSAP decreased. Researchers observed a negative correlation between the percentage changes of sclerostin and variation of BSAP and CTX at each follow-up in the zoledronic acid group (P<.05), they added. However, no changes were seen in the placebo group, they wrote.

“The data points to an opportunity to increase bone mass by combining zoledronic acid with a drug that suppresses the resulting sclerostin's effect,” Catalano said. “An innovative combination therapy using zoledronic acid and selective antibodies to block the sclerostin could simultaneously stop bone loss and encourage new bone formation. This is an important avenue for researchers to explore as they develop new osteoporosis treatments.”

Catalano and colleagues wrote that zoledronic acid increased sclerostin serum levels, suggesting that combination therapies may be needed to halt bone loss and promote growth in this patient population. They conclude that further studies testing the hypothesis of additional benefits to bone mass resulting from combined therapy with bisphosphonates are warranted.

Disclosure: The researchers report no relevant financial disclosures.

It has been established in previous studies that zoledronic acid improves bone density and reduces risk for fracture. However, new data suggests it may also significantly encourage new bone formation by targeting a specific biomarker.

“The key to effectively treating osteoporosis lies in increasing bone mass,” researcher Antonino Catalano, MD, PhD, of the University of Messina in Italy, said in a press release. “Zoledronic acid halts bone loss, but it also signals the body to stop forming new bone mass. The drug may need to be combined with other treatments to add bone mass.”

Catalano and colleagues randomly assigned 40 women (with postmenopausal osteoporosis; mean age, 62.6 years) to 5-mg zoledronic acid or placebo. The researchers measured serum levels of sclerostin, a circulating inhibitor of the Wnt signaling pathway produced by osteocytes which acts as a negative regulator of bone formation, according to the literature.

They also measured bone-specific alkaline phosphatase (BSAP) and serum C-telopeptide of type 1 collagen (CTX) at baseline and 2, 7, 30 and 360 days after zoledronic acid or placebo administration.

According to data, sclerostin serum levels increased by day 2, reached a peak at day 7 (threefold baseline; P<.001) and decreased at day 30. The levels returned to those near baseline after 360 days in the zoledronic acid group, the researchers wrote.

Data also indicate CTX and BSAP decreased. Researchers observed a negative correlation between the percentage changes of sclerostin and variation of BSAP and CTX at each follow-up in the zoledronic acid group (P<.05), they added. However, no changes were seen in the placebo group, they wrote.

“The data points to an opportunity to increase bone mass by combining zoledronic acid with a drug that suppresses the resulting sclerostin's effect,” Catalano said. “An innovative combination therapy using zoledronic acid and selective antibodies to block the sclerostin could simultaneously stop bone loss and encourage new bone formation. This is an important avenue for researchers to explore as they develop new osteoporosis treatments.”

Catalano and colleagues wrote that zoledronic acid increased sclerostin serum levels, suggesting that combination therapies may be needed to halt bone loss and promote growth in this patient population. They conclude that further studies testing the hypothesis of additional benefits to bone mass resulting from combined therapy with bisphosphonates are warranted.

Disclosure: The researchers report no relevant financial disclosures.

    Perspective
    Clifford J. Rosen, MD

    Clifford Rosen

    This was an interesting, although not a novel study. It was not totally surprising that there is an acute elevation in sclerostin in response to zoledronic acid as it likely that the osteocyte has to suppress bone turnover relatively rapidly in response to specific signals; the bone turnover markers are very consistent with those findings (i.e. reduction due to acute elevation in sclerostin).

    The real question is whether after 1 year, does the sclerostin decrease such that remodeling begins again? That's the big question that was not answered by this study.

    • Clifford Rosen, MD
    • Director of clinical and translational research at Maine Medical Center
      Senior scientist at Maine Medical Center Research Institute
      Adjunct staff scientist at The Jackson Laboratory Professor of medicine at Tufts University

    Disclosures: Rosen reports no relevant financial disclosures.

    Perspective

    Nelson B. Watts

    Produced and acting in the bone microenvironment, sclerostin is an inhibitor of osteoblast differentiation and function. The relevance of circulating sclerostin levels is unknown. Zoledronic acid is considered an antiresorptive agent, but all current agents classified as “antiresorptive” actually reduce bone remodeling – decreasing resorption more than formation. Zoledronic acid has a main effect on osteoclasts, inhibiting their resorptive function. It’s possible that there is a local effect on sclerostin, reflected in increased serum levels, that mediates the reduction in bone formation that is seen with zoledronic acid. The clinical relevance of this finding is not known at this time.

    • Nelson B. Watts, MD
    • Professor of medicine at University of Cincinnati College of Medicine
      Director of the University of Cincinnati Bone Health and Osteoporosis Center

    Disclosures: Watts reports stock options/holdings, royalties, company ownership, patent ownership, and an official role with OsteoDynamics. He also has received honoraria for lectures from Amgen, Lilly, Novartis, and Warner Chilcott; consulting fees from Abbott, Amgen, Bristol-Myers Squibb, Imagepace, Johnson & Johnson, Lilly, Medpace, Merck, Nitto Denko, Noven, Novo Nordisk, Pfizer/Wyeth, and Quark; with research support from Merck and NPS.