Osteoporosis treatment requires a “long-game strategy” that involves advance planning and sometimes challenging decision-making about sequential therapy, Gina Woods, MD, osteoporosis clinic director at University of California San Diego Health, said at the 2026 Rheumatology Winter Clinical Symposium.

Osteoporosis is “unique among chronic diseases because the sequence in which we use available therapies influences their efficacy,” said Woods, also clinical professor of medicine and chief of the Division of Endocrinology at UC San Diego. “Most of the treatments are time-limited, there are some rare but serious side effects, and for some treatments, there’s a high cost that comes with a high administrative burden.”

Still, she emphasized at the meeting and in an email interview afterward, available treatments are highly effective even though they remain underutilized. Osteoporosis treatment rates have been declining over the past 20 years, leaving the majority of postmenopausal women with osteoporosis untreated. And “despite the availability of effective therapies, fracture rates are stable or increasing,” Woods told Medscape Medical News.

At the meeting, Woods discussed three case examples of sequential treatment decision-making: patients with high fracture risk following 5 years of oral bisphosphonates; those with high fracture risk following PTH-analog treatment; and those with denosumab failure.

But first, she called attention to a 2024 “goal-directed osteoporosis treatment” position statement from the American Society for Bone and Mineral Research and the Bone Health and Osteoporosis Foundation.

The position statement establishes that the primary goal of osteoporosis treatment is to rapidly reduce fracture risk in patients at high or very high risk, Woods said, and it emphasizes that initial treatment selection should be based on a patient’s fracture risk and the likelihood of achieving a minimum bone mineral density (BMD) treatment target of a T-score > -2.5. (The FDA announced in December 2025 that change in BMD may be used as a surrogate endpoint in osteoporosis clinical trials, she noted.)

For patients at very high fracture risk, such as those with very low T-scores (eg, < -2.8 at the total hip or < -3.0 at the lumbar spine), recent fracture within the past 2 years, or other major risk factors, initial therapy with an osteoanabolic agent is appropriate, the statement says. Recent fractures, Woods emphasized, are a marker of what the statement coins “imminent fracture risk.”

When assessing BMD response to therapy, the total hip is the preferred site for monitoring change as it most consistently predicts both vertebral and nonvertebral fracture risk and is less subject to artifact compared with the lumbar spine. “But if on the baseline DEXA, the total hip is > -2.5 but the lumbar spine is < -2.5, then our treatment target is to get the spine better than -2.5,” she said in the interview.

In addition to the 2024 position statement, Woods also highlighted a review published in JAMA in 2025 for its helpful algorithms. In this paper, she noted at the meeting, “very high fracture risk” includes patients with a T-score ≤ -2.5 in the setting of multiple or recent vertebral fractures or a hip fracture. Consideration of up-front anabolic therapy is recommended to achieve greater and more rapid fracture risk reduction.

And for patients at “high fracture risk,” the authors suggest an oral or intravenous bisphosphonate, with denosumab (continued indefinitely without interruption) as an alternative for those with contraindications or intolerance to bisphosphonates.

Here are Woods’ case examples of sequential therapy required for long-term treatment of osteoporosis, with her discussion of research that can inform clinical decisions.

High Fracture Risk After Oral Bisphosphonate Therapy

An individual has been on oral bisphosphonate therapy for 5 years and is still at high risk for fracture. What should come next? A different antiresorptive therapy, like zoledronate or denosumab? Or an anabolic therapy, like a PTH1R agonist or romosozumab?

A 2016 study offers some insight into the first option. Investigators randomized 643 postmenopausal women treated with oral bisphosphonates for at least 2 years (a mean of 6 years) to either denosumab or zoledronic acid.

At 12 months, both groups achieved significant gains in BMD at the lumbar spine and total hip, “but the denosumab group achieved more robust gains,” Woods said. “And at the femoral neck and one third radius, only the denosumab group achieved a significant gain in bone density.”

Research looking at the transition to anabolics includes the 2017 international STRUCTURE study that randomized more than 400 patients who had taken an oral bisphosphonate for at least 3 years to receive either romosozumab or teriparatide. At 12 months, the romosozumab group achieved significant gains in BMD at all sites. Patients receiving teriparatide had decreased BMD at the hip at 6 and 12 months, some decline at the femoral neck, and “an increase in at the lumbar spine but not as robust as in the romosozumab group.”

Why did romosozumab outperform teriparatide? “We think it’s because romosozumab was able to act on quiescent sites of bone modeling — sites not affected by prior bisphosphonate use — whereas teriparatide relies on bone remodeling surfaces, which are suppressed after oral bisphosphonate use,” Woods said.

A multicenter case-control study published in 2025 compared BMD outcomes after switching to either of these anabolics or to denosumab and found that, while each group saw gains over 12 months, romosozumab outperformed teriparatide and denosumab. At the lumbar spine, all three groups had significant gains, but romosozumab came out on top. At the total hip, significant gains were seen with romosozumab and denosumab, and in the femoral neck, only with romosozumab.

The bottom line? “In the absence of a prospective randomized trial comparing all of these agents to one another, I’d rank romosozumab at the top, with significant gains at both spine and hip,” Woods said.

“Denosumab achieves moderate gains at spine and hip, [as does] zoledronate, though not quite as strong as denosumab,” she said. “Teriparatide achieves moderate spine gains but there [may be] transient hip loss.”

High Fracture Risk Following a PTH1R Agonist

A patient who initially presented as treatment naive and at very high risk has completed a 2-year course of treatment with teriparatide or abaloparatide. “We know we can’t simply stop treatment — they’d lose the gains they achieved,” Woods said. “Do we transition them to an antiresorptive like a bisphosphonate, denosumab, or raloxifene? Or is there any role for sequential anabolic treatment?”

An anabolic-to-antiresorptive sequence is well established as highly effective with continued gains in bone density over time, Woods said. In 2018, the ACTIVExtend trial reported continual gains in BMD at the spine and total hip during 24 months of alendronate following 18 months of abaloparatide. And data published in 2015 from the DATA-Switch study showed brisk increases in spine and hip BMD over 4 years in patients switching from teriparatide to denosumab. (Conversely, patients receiving the opposite sequence in the DATA-Switch study experienced a loss in hip BMD.)

A transition to raloxifene was also examined in an older European study (EUROFORS) that reported further increases in hip BMD and maintenance of spine BMD 1 year after switching from teriparatide, making raloxifene “an alternate option,” Woods said.

Data on continuing a bone-forming agent are limited. A retrospective cohort study reported in 2024 looked at 69 patients transitioning from teriparatide to romosozumab and 25 patients receiving the opposite sequence. Patients in the teriparatide to romosozumab group achieved continued gains in the spine and total hip and femoral neck over 12 months, whereas patients transitioning from romosozumab to teriparatide had loss of BMD in the total hip and femoral neck and no further gains in the spine.

“This makes sense given that romosozumab is a dual-acting agent with both antiresorptive and anabolic properties. Toward the end of treatment with romosozumab, it’s acting more as an antiresorptive agent,” Woods said.

The 2024 study “suggests that romosozumab may be an option following teriparatide, but more robust data are needed,” she said.

Denosumab Failure

“This is a tough one, and one that I’ve experienced. Typically, this is a patient of advanced age, frail, and with very high fracture risk and very low BMD who’s been on long-term denosumab,” Woods said. “The patient is coming in every 6 months for their injection, but they keep falling and breaking bones.”

Transitioning to a bisphosphonate “would be expected to mitigate bone loss, but we wouldn’t expect to see any further gains, so that doesn’t seem like a good option,” she said. Neither does transitioning to a PTH1R agonist; the DATA-Switch study documented loss of hip BMD in patients who transitioned from denosumab to teriparatide.

There is concern about transitioning to romosozumab because this agent “does not seem to be able to suppress the rebound increase in bone resorption,” she said. But there are signs that potential strategies include combination or overlapping therapy with denosumab and an anabolic agent (PTH analog or romosozumab).

In a small cohort study published in 2025, direct transition from denosumab to romosozumab — with the first romosozumab dose given 6 months after the last dose of denosumab — was associated with a rapid rise in C-telopeptide (CTX, a marker of bone turnover) and with major fractures in the first 3 months in two of 10 women.

In contrast, overlapping denosumab and romosozumab for 3 months — with the first dose of romosozumab given 3 months after the last denosumab dose — “appeared to delay and blunt the rebound in bone turnover,” Woods said at the meeting.

In another recent, small observational study, researchers added romosozumab to ongoing denosumab in women who were failing denosumab monotherapy. They documented significant gains in spine BMD over 6 months. “There was no significant change at the hip, but importantly, no loss either,” she said.

Also notable is the inclusion of a combination treatment group in the DATA-Switch study on denosumab and teriparatide transitions — and the finding that “the combination group achieved better increases in bone density at the lumbar spine, femoral neck, and total hip compared to either option alone,” Woods said at the meeting.

“Based on these limited data, in patients who are failing denosumab monotherapy, potential strategies may include short-term overlap of romosozumab with denosumab or combination approaches — for example denosumab plus romosozumab or teriparatide,” Woods said in the interview. “However, the evidence is sparse, and more research is clearly needed to guide best practice.”

Woods disclosed that she has consulted for Bayer, Alexion, Solaria Bio, and Roon.