VANCOUVER, Canada — With treatment with a bisphosphonate following sequential use of teriparatide (Forteo) and denosumab (Prolia) for premenopausal women with idiopathic osteoporosis, bone mineral density (BMD) was maintained over the first year following denosumab cessation, according to results from a small, nonrandomized extension of a phase 2 study.
Bisphosphonates are recommended for patients after they have completed a course of denosumab because cessation of the bone resorption blocker is known to increase bone turnover markers, decrease BMD, and raise the risk of vertebral fractures. Although there is evidence to support this treatment sequence for postmenopausal women, there was no evidence regarding premenopausal women with idiopathic osteoporosis, said Adi Cohen, MD, who presented the results of the study at the American Society for Bone and Mineral Research (ASBMR) 2023 Annual Meeting.
In the extension study, neither length of treatment with denosumab nor transition to menopause affected BMD results. Weekly doses of alendronate (ALN) better suppressed C-terminal telopeptide (CTX) than did zoledronic acid (ZOL) and led to better maintenance of BMD than did a single dose of ZOL. The researchers suggested that single-dose ZOL may not prevent bone loss for an entire year.
It is too early to call the results practice changing, said Cohen, professor of medicine and endocrinology at Columbia University Irving Medical Center (CUIMC), but she noted, “It’s important just to provide information about how sequences of osteoporosis medications might be used in a rare but certainly understudied group of premenopausal women with osteoporosis who need treatment, and these data hopefully will help make some treatment decisions.”
In the early 2000s, researchers initially believed that premenopausal women with low BMD had experienced some kind of temporary event and that they would likely improve on their own over time. “I think we now recognize that whatever it is that causes this is an ongoing issue and that this is a problem they’re going to have to deal with for the rest of their lives. This is something that they have to stay on top of,” said co-author Elizabeth Shane, MD, who is a professor of medicine at CUIMC.
However, there are no practice guidelines for the management of osteoporosis in premenopausal women, according to Shane. She noted that there is controversy as to whether to treat women with low bone density who do not have a history of fractures. “I think that there’s pretty much agreement that anybody who has a lot of fractures has an early-onset form of osteoporosis. The controversy is what to do about the person who just has a low bone density and hasn’t yet fractured and what is the utility of trying to treat them at that point and perhaps prevent a fracture. I don’t think we have enough data to address that,” Shane said.
Still, the research has provided some clarity in her own practice. “I think if somebody would come to my office who had very low bone density, I would probably treat them. If they have fractures, I would definitely treat them. I think that our work has provided a framework for people to approach that,” she said.
The study was an extension of a sequential treatment approach that began with 2 years of teriparatide (20 µg daily) followed by an extension study of 2–3 years of treatment with denosumab (60 mg every 6 months). Seven months after the last dose of denosumab, patients underwent 1 year of treatment with ALN (70 mg weekly; n = 18) or a single dose of ZOL (5 mg IV; n = 6), according to patient choice.
The original phase 2 study started with 41 women. At 24 months, teriparatide treatment led to BMD increases of 13% in the lumbar spine (LS), 5% in the total hip (TH), and 5% in the femoral neck (FN). There was a 2% decline in BMD in the forearm (distal radius [DR]). A group of 32 of the women participated in an extension study and took denosumab for 12 months. Of those patients, 29 continued to take it for another 12 months. At 12 months, BMD increased 5% in the LS, 3% in the TH, 3% in the FN, and 1% in the DR (P < .05 for all). At 24 months, BMD rose by 22%, 10%, and 10% at the first three of those locations. BMD in the DR remained stable compared with the baseline after taking teriparatide.
The bisphosphonate phase of the extension study included 24 women (mean age, 43 years). The mean body mass index of the patients was 23.0 kg/m2. The patients had experienced a mean of 3.0 fractures in adulthood, and 38% of patients had a history of vertebral fracture.
Over 12 months of follow-up, the researchers found no statistically significant difference in BMD in the LS, TH, or FN, compared with bisphosphonate extension baseline. There was also no statistically significant change in serum CTX. There was evidence that among patients with higher rates of bone turnover, there were higher rates of LS and FN bone loss during bisphosphonate treatment.
Among patients taking ZOL, at 12 months there was a statistically significant rise in CTX levels, but not among patients taking ALN. There were no new vertebral fractures among any participants during the bisphosphonate extension period.
The results represent critical data for an understudied population, according to Yumie Rhee, MD, PhD, who was comoderator of the session in which the study was presented. “They are showing that by using a bisphosphonate, [patients] have this just slight decrease, but within error, so it’s maintaining the BMD, at least. I think it’s very important. It will be fascinating to see next year’s follow-up,” said Rhee, a professor of endocrinology at Yonsei University College of Medicine in Seoul, South Korea. “The problem with premenopausal osteoporosis is that we don’t have good evidence. Even though this study is very small, we’re just following that data, all of us.”
Comoderator Maria Zanchetta, MD, a professor of osteology at the Institute of Diagnostics and Metabolic Research, Universidad del Salvador, Buenos Aires, Argentina, agreed. “We know what to do when we stop denosumab in postmenopausal women. We didn’t have any work about what to do when we stopped in premenopausal women. You can think that probably it’s going to be the same, but this is the first time you have the evidence that if you give bisphosphonate, you will maintain BMD.”
Limitations to the study include its small size and the lack of a placebo-treated control group. In addition, the bisphosphonate extension was not randomized.
The studies were funded by the US Food and Drug Administration and Amgen. Cohen and Shane received research funding from Amgen. Rhee and Zanchetta have disclosed no relevant financial relationships.
American Society of Bone and Mineral Research (ASBMR) 2023 Annual Meeting: Abstract 1010. Presented October 13, 2023.
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