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SEATTLE — Among bariatric surgery patients treated with denosumab to counter bone loss, follow-up treatment with zoledronic acid prevented the rebound effect on markers of bone turnover that is typically seen with cessation of denosumab, according to results from a new extension study.

Bone turnover markers can increase significantly after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG): Longitudinal studies have shown increases in C-terminal telopeptide of type I collagen (CTX) two to three times higher than baseline, and these changes can last up to 10 years, compared to weight-matched controls, according to Elaine Yu, MD, who presented the results of the extension study at the American Society for Bone and Mineral Research (ASBMR) 2025 Annual Meeting.

"[Zoledronic acid] administered after denosumab cessation in bariatric surgery patients prevented the expected rebound increase in bone absorption, and in contrast to what has been previously reported about early or perioperative use of bisphosphonates, late postoperative treatment with zoledronic acid effectively lowered postoperative bone marker elevations in the placebo to [zoledronic acid] group down to preoperative levels," said Yu, who is director of the Bone Density Center at Massachusetts General Hospital, Boston. 

The results are exciting, but the small sample size means that more data are needed, according to Flavia Kiweewa Matovu, MBChB, PhD, who co-moderated the session. "It [would need to] be studied in a larger trial with a longer follow-up before the findings can be included in guidelines," said Matovu, who is a senior research scientist at Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda. 

The findings underscore the need to address bone loss in the population, said Richard Eastell, MD, who was asked to comment. "There's not only some bone loss [after surgery], but it lasts for many years, and we know it's associated with more fractures, so we have to take it seriously," said Eastell, who is a professor of bone metabolism at the University of Sheffield, Sheffield, England.

Milder osteoporosis therapies have failed to deliver a substantial benefit, leading the researchers to turn to denosumab, but the drug can lead to rebound bone loss and fractures once it's discontinued, Eastell said. 

However, the length of treatment may be critical, he added. "What we've learned is that if you only give a year or a short course of denosumab, you don't get much of an overshoot, whereas if you give it for 4 years or more, you get a huge overshoot. Maybe the reason why there was no overshoot in their study was that it was quite a short course of 18 months. It probably points to what we should be doing, which is maybe giving denosumab for 18 months, and then changing over to [zoledronic acid]," he said. 

During the Q&A session following Yu's presentation, he noted that flu-like acute-phase reaction symptoms occurred in more than two thirds of patients in the trial — higher than the typical one third or so of patients who have such symptoms. "What I was asking was, why on earth is it such a high proportion? [Yu answered] that maybe it's because the people are young. We do need to think about how we deal with this because it can be quite debilitating," Eastell said.

Building on Prior Efforts to Stop Post-Bariatric Surgery Bone Loss

Two randomized controlled trials have sought to address bone loss following bariatric surgery, one with risedronate and another with zoledronic acid. "But surprisingly, neither of these treatments was able to fully suppress CTX rise after bariatric surgery, with a 40% increase in CTX in the risedronate-treated, sleeve gastrectomy patients, and 85% CTX increase in zoledronic acid-treated gastric bypass and sleeve gastrectomy patients," Yu said.

She noted that both treatments prevented bone loss in the spine, but there was incomplete preservation of femoral bone density following bariatric surgery with both drugs, although they were better than no treatment. 

First Results From Denosumab Trial

In the initial 18-month, two-site, pilot trial of 36 patients, men aged 50 years or older and postmenopausal women (mean age, 57 years; 67% female) who underwent RYGB or SG were randomly assigned 2:1 to receive denosumab or placebo injections every 6 months, starting at 1 month after surgery. Throughout the study, patients consumed calcium 1500 mg/day via supplementation and their diet and vitamin D 3000 IU/day, with individualized adjustments based on their diet and labs.

The initial results from the pilot trial, which were presented at the ASBMR 2024 Annual Meeting, showed that denosumab preserved total hip bone mineral density (+0.6% vs -6.4%; P < .01) and spine bone mineral density (+4.3% vs -4.1%; P < .01) on dual-energy X-ray absorptiometry (DXA) scans out to 19 months. At 19 months, the denosumab group had little change in CTX (-4%), while the placebo group had a large increase (+81%; P = .014). There also was a decline at 19 months in procollagen type 1 intact N-terminal propeptide (P1NP) in the denosumab group and an increase in the placebo group (-38% vs +41%; P < .001).

Extension Study Results

In the current extension study, Yu and her colleagues examined whether treatment with zoledronic acid would maintain these gains. Over the extension period, all participants received IV zoledronic acid 5 mg at 19 months. The final visit was conducted at 24 months. 

After initiation of zoledronic acid, results at 24 months showed that CTX remained stable in the group who received denosumab and declined in the placebo group (0% vs -53%; P = .005). P1NP increased in the denosumab group and decreased in the placebo group (+44% vs -51%; P < .001). 

Between 0 and 24 months, the denosumab group had improved bone mineral density changes in the spine (+4.2% vs -3.9%; P = .002), total hip (+0.3% vs -5.2%; P = .002), and femoral neck (+1.9% vs -4.4%; P = .015). 

There were no incidents of hypocalcemia or fracture in either group.

The study was funded by Amgen. Matovu had no financial disclosures. Eastell has consulted for Samsung, Curatech, and Sandoz. Yu owns stock in OPKO. 

Jim Kling is a writer based in Bellingham, Washington.