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MedPageToday.com
Published: Apr 18, 2013 | Updated: Apr 19, 2013
By Charles Bankhead , Staff Writer, MedPage Today
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Action Points

• Note that this randomized trial demonstrated that treatment with zoledronic acid (Brand names: Reclast, Zometa/bisphosphonate) increased sclerostin, which may inhibit healthy bone turn-over.
• Be aware that no clinical outcomes (such as fracture) were studied in this trial.

A drug used to preserve bone mineral density (BMD) might also have an undesirable effect that blocks bone formation, Italian investigators reported.

Postmenopausal women who received zoledronic acid (Reclast) for osteoporosis had increased levels of sclerostin for at least a month after administration of the drug (P<0.001 on day seven versus baseline). Sclerostin levels had an inverse association with two key markers of bone formation — serum C-telopeptide of type 1 collagen (CTX) and bone-specific alkaline phosphatase (BSAP).

A year after the single intravenous infusion of zoledronic acid, sclerostin levels had returned to near baseline values, but negative correlations persisted to the end of the study, as reported online in the Journal of Clinical Endocrinology and Metabolism.

“Overall, our data extend the findings of previous studies on regulation of sclerostin levels by antiosteoporotic agents,” Antonino Catalano, MD, of the University of Messina, and co-authors concluded. “Parathyroid hormone (PTH) has been reported to reduce sclerostin secretion and this may account for some of the anabolic effects of PTH on bone formation.”

“The hypothesis that by increasing sclerostin levels bisphosphonates could impair the anabolic effect of intermittent PTH treatment of postmenopausal osteoporosis is quite intriguing,” they added.

The results also have implications for osteoporosis treatment strategies, the researchers noted.

“Since inhibition of sclerostin, via anti-sclerostin monoclonal antibodies, may promote an anabolic action on bone, further studies testing the hypothesis of additional benefits to bone mass resulting from combined therapy with bisphosphonates are needed,” according to Catalano and colleagues.

Regulation of bone homeostasis by Wnt signaling promotes bone formation. Activation of the signaling pathway is associated with differentiation of osteoblast precursors, reduced apoptosis of mature osteoblasts, and contributes to differentiated osteoblasts’ ability to inhibit osteoclast formation.

Sclerostin inhibits Wnt signaling and is found almost exclusively in osteocytes, which account for 95% of bone cells, the authors noted in their introduction. In preclinical models, overexpression of the sclerostin-producing gene is associated with reduced bone mass and strength tied to decreased osteoblast activity and bone formation.

Serum sclerostin is increased in postmenopausal versus premenopausal women, reinforcing a possible link to age-related impairment in bone formation, the authors continued. Bisphosphonates, a drug class that includes zoledronic acid, preserve bone health primarily by means of inhibition of bone resorption, but secondarily, by affecting formation.

“The coupled decrease in bone formation observed in vivo is a major limiting factor of the long-term benefits on bone mass ensured by bisphosphonates,” said Catalano and colleagues.

To examine more closely the coupled bone effects of zoledronic acid, investigators studied correlations between changes in serum sclerostin and changes in bone-turnover markers in postmenopausal women who received the bisphosphonate for osteoporosis.

The study involved 40 postmenopausal women (age range 54 to 72) who had a BMD T-score of -2.5 standard deviations (SD) or more at the lumbar spine or femoral neck, with or without evidence of vertebral fracture, or a T-score of -1.0 to -2.5 SD with evidence of at least one mild vertebral fracture. The women had no history of treatment for postmenopausal osteoporosis.

The patients were randomized to a 5-mg IV infusion of zoledronic acid or a saline placebo. Investigators obtained fasting blood samples at baseline and then 2, 7, 30, and 360 days after treatment.

Baseline levels of sclerostin, CTX, and BSAP were similar between the treatment groups. Sclerostin levels had positive associations with patient age and with years since menopause (P=0.0003, P=0.01, respectively).

In the zoledronic acid group, sclerostin levels had increased by day two and peaked at day seven (P<0.001 versus baseline), then gradually returned to near baseline levels by day 360. CTX levels were significantly lower by day two (P<0.01) and BSAP by day seven (P<0.01).

Levels of sclerostin, CTX, and BSAP did not vary significantly at any point in time in the placebo group.

Investigators observed a significant inverse correlation between sclerostin levels and those of the bone-turnover markers on day two (P=0.02 for CTX and BSAP), and the negative relationship persisted to day 360 (P=0.05).

Studies of sclerostin levels in women treated with other bisphosphonates have yielded mixed results, the authors noted in their discussion of the findings. Levels of the gene product increased in women treated with neridronate or resedronate but did not change significantly alendronate or risedronate treatment.

The mechanisms by which bisphosphonates modulate sclerostin levels remain undetermined, they added.