To the Bone: Experts Discuss Developments in Osteoporosis Care

SAN DIEGO—Ending treatment with denosumab, a RANKL-binding agent, is tricky and may result in losses of bone mineral density (BMD) gained by patients during treatment. The best strategy to optimize patient outcomes is still unclear. In a session on osteoporosis during ACR Convergence 2023, experts addressed efforts to find an optimal approach to ending treatment with denosumab, as well as the value of bone turnover markers and the need for a better way to assess vitamin D levels.

Denosumab

Dr. Langdahl

Bente Langdahl, MD, PhD, clinical professor at Aarhus University, Denmark, noted that good reasons to use denosumab exist, such as better results for BMD than with bisphosophonates and a lower of fracture risk. However, studies have shown that when denosumab is discontinued, a startling drop in BMD is typically seen in patients—but it’s not necessarily a drop to baseline levels. Also, the longer a patient is on denosumab, the worse this drop tends to be.¹

“We need to do something about it,” Dr. Langdahl said.

In one study, zolendronate was started either six or nine months after the last denosumab dose in patients who’d been treated with denosumab for a median of 4.6 years. The goal was to determine whether treatment after remodeling had begun and, therefore, later treatment may be better. Although patients had the same amount of BMD loss, with early treatment the loss happened at a slower pace. Because fast bone loss is associated with fracture risk, early treatment is still considered best, Dr. Langdahl said.²

Another study, which included 13 post-menopausal women, examined a gradual decrease in denosumab. The researchers found that BMD appeared to be satisfactory during the de-escalation. But after denosumab discontinuation, BMD loss was significant at the spine, but not at the hip. Over time, levels of C-telopeptide of type I collagen (CTX), the marker of bone resorption, increased.³

“I don’t know if this [approach] is the solution,” Dr. Langdahl said. “There would need to be longer follow-up.” But it could be an interim solution. “Maybe then you wouldn’t need to use as much bisphosphonates as we now need in most of our patients,” she added.

Dr. Langdahl emphasized—and it’s reflected in European guidelines—the need to aim for a higher target during denosumab treatment is the ultimate goal, with the expectation that BMD will be lost after treatment ends.⁴

Dr. Eastell

Bone Turnover Markers

Richard Eastell, MD, professor of bone metabolism at the University of Sheffield, U.K., said that bone turnover markers offer crucial information that has important implications for osteoporosis treatment. However, these markers are not used often.

BMD changes take about 18 months before providing a solid read on treatment efficacy—a rather a long time, he said. Bone turnover markers, such as CTX and Procollagen 1 Intact N-Terminal Propeptide (P1NP), give a faster indication of a patient’s response.

“They respond early and to a larger extent than, for example, bone density when we give anti-resorptive treatments,” he said. “This [fact] makes them an ideal marker because we can make the measurement before we have any problems with adherence.”

In the PINP and Osteoporosis in Sheffield Evaluation (POSE) study, researchers assessed a group of patients who had their P1NP monitored and another that didn’t.⁵ A significantly higher number of patients with P1NP monitoring had a change in osteoporosis management, as well as a significantly greater improvement in BMD after five years, than patients without P1NP monitoring. An incremental cost-effective ratio analysis found P1NP monitoring to be cost-effective.

A retrospective claims database analysis found that only 6,075 of 457,829 patients with osteoporosis had bone markers measured and that marker testing was associated with a lower risk of fractures.⁶

“The use of bone turnover markers does seem to be helping decision making,” said Dr. Eastell, “but the uptake has been low.”  

In a discussion at the end of Dr. Eastell’s presentation, one attendee said she had been using these markers, but insurance coverage became problematic. Thus, she stopped using them. He noted that in the U.K., the tests cost about $15.

“We don’t have the problem that you have. It’s partly because the bone markers are so much less expensive,” Dr. Eastell said. “The issue about insurance is an important issue in relation to the American practice.”

Vitamin D

Ms. Weaver

Connie Weaver, professor of exercise and nutritional sciences at San Diego State University, said recent research has shown that the 25-hydroxy vitamin D (25[OH]D) test is not the ideal measure for monitoring vitamin D levels.

Free vitamin D accounts for just 1% of a person’s vitamin D levels, she said. Researchers have found the 10–15% is bound to albumin, and about 85% is bound to the vitamin D binding protein and is likely inert.⁷

“Yet we’re using as a status measure, the total amount of vitamin D,” she said.

A better indicator, she noted, may be the vitamin D metabolite ratio—the ratio of 24,25 dihydroxyvitamin D to 25(OH)D3. It has been found to reflect vitamin D sufficiency independent of vitamin D binding protein.

Ms. Weaver also said that supplementation with vitamin D needs to be re-evaluated. In the Vitamin D and OmegA-3 Trial (VITAL) study of more than 25,000 older Americans (mean age=78 years) over an average of 5.3 years, researchers found that supplementation with vitamin D had no distinguishable difference in fracture advantage.⁸

“That’s the longest, biggest study we have,” Ms. Weaver said.

Thomas Collins is a freelance medical writer based in Florida.

References

1. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011 Apr;96(4):972–980.
2. Solling AS, Harslof T, Langdahl B, et al. Treatment with zoledronate subsequent to denosumab in osteoporosis: A randomized trial. J Bone Miner Res. 2020 Oct;35(10):1858–1870.
3. Laroche M, Couture G, Degboé Y, et al. Discontinuation of denosumab: Gradual decrease in doses preserves half of the bone mineral density gain at the lumbar spine. JBMR Plus. 2023 May 18;7(7):e10731.
4. Tsourdi E, Zillikens MC, Meier C, et al. Fracture risk and management of discontinuation of denosumab therapy: A systematic review and position statement by ECTS. J Clin Endocrinol Metab. 2020 Oct 26:dgaa756.
5. Mattia L, Davis S, Mark-Wagstaff C, et al. Utility of PINP to monitor osteoporosis treatment in primary care, the POSE study (PINP and osteoporosis in sheffield evaluation). Bone. 2022 May:158:116347.
6. Lane NE, Saag K, O’Neill TJ, et al. Real-world bone turnover marker use: Impact on treatment decisions and fracture. Osteoporos Int. 2021 May;32(5):831–840.
7. LeBoff MS, Chou SH, Ratliff KA, et al. Supplemental vitamin D and incident fractures in midlife and older adults. N Engl J Med. 2022 Jul 28;387(4):299–309.
8. Ginsberg C, Katz R, de Boer IH, et al. The 24,25 to 25-hydroxyvitamin D ratio and fracture risk in older adults: The cardiovascular health study. Bone. 2018 Feb:107:124–130.