Longitudinal osteoporosis therapy: treat-to-target and sequential strategies—a narrative review

Introduction

Osteoporosis is a chronic skeletal disorder in which reduced bone strength translates into excess fracture risk, with major downstream consequences on function, independence, and mortality.^1–3 Contemporary guidance emphasizes that pharmacotherapy should be individualized to baseline fracture probability (including “very-high-risk” phenotypes such as recent fragility fracture or multiple fractures) and that therapy should be planned as a long-term strategy rather than a single drug choice, because available agents reduce fracture risk, but do not “cure” the disease (i.e., fracture risk re-accumulates when effective therapy is stopped or when a less potent agent is substituted). Professional guidelines from patient advocacy groups (e.g., Bone Health and Osteoporosis Foundation [BHOF]) and professional societies (e.g., American Association of Clinical Endocrinologists [AACE], Endocrine Society, American Society for Bone Mineral Research [ASBMR]) increasingly converge on patient risk stratification, early use of potent agents for very-high-risk patients, and explicit sequencing decisions (i.e., anabolic-first approaches followed by antiresorptive “consolidation”).^4–7

A related conceptual shift has been the rise of “treat-to-target (TTT)” or “goal-directed” osteoporosis care, as an attempt to define measurable short- and intermediate-term targets (e.g., fracture-free intervals and/or bone mineral density [BMD] thresholds) and to adjust therapy intensity and sequence until a target is reached.^8–11 While targets and operational fracture risk definitions can be debated, the underlying logic is clinically pragmatic: patients near “imminent risk” may require rapid, larger-magnitude fracture risk reduction; patients who remain above target after an initial phase may require therapy escalation or switching; and de-escalation/tapering should be linked to achieved fracture risk reduction rather than time alone. ¹¹ The 2024 ASBMR/BHOF task force explicitly frames osteoporosis care as a sequence of decisions designed to achieve a patient-specific goal and to sustain BMD gains over time. ¹¹

Sequential and combination osteoporosis regimens sit at the center of this approach. Evidence from pivotal trials shows that anabolic therapy followed by an antiresorptive can produce substantial and, importantly, durable fracture risk reduction as illustrated by romosozumab followed by antiresorptive therapy in large phase III fracture endpoint trials, and by abaloparatide followed by alendronate in extension clinical trial data.^12–16 Combination therapy has also been examined as a strategy for rapid skeletal rebuilding in select settings; for example, denosumab plus higher-dose teriparatide produced larger short-term BMD increases than standard-dose strategies in a randomized phase IV trial. ¹⁷ However, sequencing is not merely an efficacy choice—it is a safety and continuity of care issue. Denosumab discontinuation, in particular, can precipitate rebound high bone turnover, rapid BMD loss, and increased risk of multiple vertebral fractures, making structured transition (“follow-on”) therapy essential.^18–20

This review is particularly relevant to clinicians who routinely manage osteoporosis at the intersection of inflammatory rheumatic disease, glucocorticoid exposure, frailty, multimorbidity, and complex medication transitions. In that setting, the harder clinical question is rarely which drug to start; it is how to sequence, transition, and ultimately stop therapy across years of changing risk—yet practical guidance for those choices remains scattered across clinical specialty statements and individual trials. Our intent is to synthesize the evidence base for sequential osteoporosis pharmacotherapy, illustrate a TTT framework for choosing and transitioning therapies, and highlight practical safety considerations, including rebound phenomena, rare adverse events, and monitoring that inform real-world decision-making.^{4–7,10,18–20} We searched PubMed/MEDLINE and Google Scholar from January 2001 through January 2026 using combinations of: osteoporosis (postmenopausal and glucocorticoid-induced), TTT, goal-directed, sequential, and combination therapy, individual antiresorptive and anabolic agents, discontinuation, rebound, drug holiday, atypical femoral fracture (AFF), medication-related osteonecrosis of the jaw (MRONJ), BMD, trabecular bone score (TBS), FRAX, adherence, persistence, and cost-effectiveness. Current society and agency guidance was retrieved directly from BHOF, AACE/Americal College of Endocrinology (ACE), the Endocrine Society, the 2024 ASBMR/BHOF Task Force, American College of Physicians (ACP), International Society for Clinical Densitometry (ISCD), European Calcified Tissue Society (ECTS), European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO)/International Osteoporosis Foundatin (IOF), the U.S. Department of Veterans Affairs Pharmacy Benefits Management Services, the Asia-Pacific consensus, and the U.S. Food and Drug Administration.^{4–7,10,11,20–31} Source selection prioritized English-language human studies and emphasized pivotal randomized fracture- or BMD-endpoint trials and their extensions, FRAME, ARCH, ACTIVE/ACTIVExtend, FREEDOM, HORIZON-PFT, VERO, STRUCTURE, DATA-Switch, and DATA-HD,^{12–17,32–36} alongside systematic reviews and network meta-analyses, major observational and registry studies, and cost-effectiveness analyses.^16,37–48 Older landmark papers were identified retrospectively through the reference lists of newer reviews, guidelines, and trials, and were retained where they remained foundational to current practice.^44,49,50 Five additional references—one scoping review on sequential versus step-therapy approaches in orthopedic populations, two recent studies of romosozumab added to ongoing denosumab, two landmark studies of bisphosphonate and anabolic combinations—were identified during peer review and incorporated to address reviewer and editor recommendations.^51–55 Conference abstracts without peer-reviewed full text, preclinical-only sources without translational relevance, duplicate dataset reports, and clearly superseded sources were excluded. As a narrative review, prospective protocol registration, Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) procedures, and structured risk-of-bias scoring were not applied.

Pathophysiology and pharmacological classes: Why sequence?

Osteoporosis reflects an uncoupling of bone remodeling in which bone resorption outpaces bone formation, leading to microarchitectural deterioration and reduced bone strength. ⁵⁶ Clinically relevant heterogeneity exists across skeletal compartments: trabecular-rich sites (e.g., spine) remodel more rapidly and often show earlier density changes, while cortical-rich sites (e.g., hip/long bones) contribute substantially to overall skeletal strength and are very important for hip fracture outcomes. Patients may also differ by turnover phenotype (high vs. low), which influences both the speed of skeletal loss and the expected magnitude and tempo of drug response, making mechanism- and risk-aligned therapeutic planning essential.^4–6

Major osteoporosis drug classes map onto this biology with distinct onset/offset characteristics. Bisphosphonates (e.g., alendronate, risedronate, zoledronic acid) bind to mineralized bone and suppress osteoclast-mediated bone resorption; their skeletal retention supports durable antiresorptive effects that can persist after discontinuation, enabling “drug holidays” in selected lower-risk patients.^4–6

Denosumab, a monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL), produces potent antiresorptive activity but is rapidly reversible; interruption or cessation without follow-on antiresorptive therapy can precipitate rebound high turnover, rapid BMD loss, and vertebral fractures, making planned transitions a core safety principle.^18–20 Anabolics, including teriparatide (PTH analog), abaloparatide (PTH receptor agonist), and dual agents, such as romosozumab, a sclerostin inhibitor that increases bone formation and decreases bone resorption, can achieve faster and larger BMD gains, particularly when used early in high-risk patients.^57,58

Risk stratification operationalizes these mechanistic differences. “Very-high-risk” phenotypes (e.g., recent major fragility fracture, multiple fractures, very low BMD, or persistently high fracture risk on therapy) are increasingly directed toward osteoanabolic-first strategies followed by antiresorptive consolidation to maintain gains, whereas lower-risk patients may begin with antiresorptive monotherapy.^4–6,58 In both groups of patients, periodic fracture risk reassessment is recommended.

Treat-to-Target in osteoporosis

Treat-to-target (TTT), also called goal-directed therapy, reframes osteoporosis management from “choose a drug and treat for a fixed period of time” to a strategy in which clinicians (1) define an explicit, patient-specific BMD target that represents a lower fracture risk compared to baseline, (2) select the initial therapy most likely to reach that target within a reasonable period of time, and (3) reassess and adjust treatment intensity until the target is achieved and then maintained.^9–11,59 The conceptual roots mirror chronic disease paradigms such as hypertension and diabetes, where therapy is titrated toward measurable targets rather than continued indefinitely without explicit endpoints.^10,59

In osteoporosis, this shift emerged because traditional approaches can paradoxically lead to overtreatment in patients at low risk of fracture or undertreatment of patients who remain at high fracture risk due to the lack of consensus on what constitutes therapeutic “success” and when therapy should be intensified, switched, or de-escalated.^10,59

A recurring obstacle is that bone strength cannot be directly measured in routine practice; therefore, TTT depends on validated surrogates that track with fracture risk. ⁸ Among the potential surrogates, fracture occurrence, model-based fracture risk thresholds, and BMD, the most used has been BMD, supported by evidence that larger treatment-related BMD gains correlate with larger fracture risk reductions across agents and trials.^8,9,60

Early position statements and reviews proposed several potential “treatment targets,” including: (a) freedom from incident fracture over a defined interval, (b) fracture probability below a treatment threshold (FRAX-like concepts), and (c) achieving a BMD T-score threshold (most commonly a hip-based T-score above the diagnostic/treatment threshold).^9–11 Of these, “no fracture” is clinically intuitive but statistically problematic because fractures are stochastic, vertebral fractures may be silent, and follow-up intervals may be too short to confidently interpret a “fracture-free” status in a high-risk patient.^8,10 Risk calculators are useful for untreated patients, but TTT highlights a major evidence gap: we lack robust, widely validated tools that accurately quantify residual fracture risk while on therapy, especially incorporating imminent risk after recent fracture and the differential effects of drug classes.^8,10

Sequential therapy for management of osteoporosis

Evidence base for sequential therapy

Sequential therapy has become central to contemporary osteoporosis care because drug effects are not interchangeable over time: drugs differ in onset of action, durability of effect after discontinuation, and the way they “set up” the skeleton for the next phase of therapy. Thus, osteoporosis is often managed as a multi-year (and, frequently, multi-agent) trajectory, where the clinical goal is not only to reduce fractures during an initial treatment window but also to preserve gains and avoid unintended risks of bone loss during treatment transitions, particularly in patients at high or imminent fracture risk.^{37,38,65–67} The BHOF Clinician’s Guide, AACE/ACE and Endocrine Society guidelines, the ASBMR/BHOF goal-directed treatment statement, and regional consensus documents (e.g., Veterans Administration, Asia-Pacific) all recommend planning sequences based on baseline fracture risk, prioritizing anabolic-first strategies with antiresorptive consolidation in very-high-risk patients and structured “exit” strategies after denosumab.^{4,7,11,26,31,65–67} Pivotal fracture-endpoint trials and clinical trial extension studies underpin these recommendations, including romosozumab to alendronate and romosozumab to denosumab sequences, abaloparatide to alendronate, long-term denosumab and zoledronic acid programs, and teriparatide versus risedronate in severe osteoporosis. These studies collectively show that osteoanabolic induction followed by potent antiresorptive therapy yields durable BMD and fracture benefits.^{12–16,32–34,49,68,69} Network meta-analyses and systematic reviews comparing alternative sequences and combinations generally corroborate the “anabolic-first then consolidate” strategy for very-high-risk patients, while emphasizing ongoing uncertainties around head-to-head fracture data, optimal denosumab exit regimens, and long-term safety of dual therapy (Figure 1).^37–41,66

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Figure 1.

Practical decision framework for sequential osteoporosis pharmacotherapy. Original figure synthesizing guidance from BHOF, AACE, the Endocrine Society, the ASBMR/BHOF goal-directed treatment task force, the VA Pharmacy Benefits Management program, and the Asia-Pacific consensus.^{4–6,10–14,16,26–28,31,34,50,69–72}

Antiresorptive to Anabolics

In real-world care, escalation from an antiresorptive to an anabolic is common: many patients start with oral bisphosphonates because of cost, access, or payer step-therapy requirements and are later “upgraded” because they fracture on therapy, remain at very high risk, or develop rare but serious complications such as AFF or MRONJ. A key clinical nuance is that prior antiresorptive exposure may attenuate the subsequent anabolic response, particularly at the hip, so expectations and drug selection matter.^50,67

Antiresorptive to antiresorptive (“lateral”) switches

Denosumab to bisphosphonate (exit strategy) is a unique “lateral” switch that is often mandatory rather than elective, because delayed/stopped denosumab can trigger rebound high bone turnover, rapid BMD loss, and vertebral fractures. Endocrine Society guidance explicitly cautions that denosumab should not be stopped or delayed without subsequent antiresorptive therapy. ⁷⁰ In a randomized follow-on study, after 1 year of denosumab with transition to alendronate, most participants maintained or continued to increase BMD, but a meaningful minority lost BMD at the spine/hip sites highlighting heterogeneity of bisphosphonate “capture” after denosumab. ⁷⁹ For longer prior denosumab exposure, a randomized clinical trial found zoledronic acid did not fully prevent lumbar spine BMD loss in the first year after denosumab discontinuation, although hip sites were better preserved; longer denosumab duration was associated with worse lumbar spine outcomes. ⁷¹ These findings reinforce that “denosumab to bisphosphonate” is not a single-step recipe: timing, prior duration, and (in some algorithms) bone turnover marker-guided repeat dosing matter (Table 1).

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Table 1.

Clinical scenarios that warrant switching osteoporosis pharmacotherapy.

Scenario	Typical trigger/definition	Usual direction of switch	Key rationale/notes
Inadequate response on current antiresorptive	Recurrent fragility fractures on therapy or significant BMD loss exceeding LSC a at the monitored site despite good adherence and evaluation for secondary causes	Oral bisphosphonate or denosumab to more potent agent, often an anabolic (e.g., romosozumab, teriparatide/abaloparatide), with later antiresorptive consolidation	Treat-to-target framework: if target is not reached, or fractures occur when BMD is “far from target,” therapy intensity should be escalated rather than continuing a suboptimal regimen. Romosozumab is often favored after long-term bisphosphonate when hip BMD improvement is the priority.
AFF on long-term antiresorptive	Radiographically confirmed AFF in a patient on prolonged bisphosphonate or denosumab therapy	Hold/stop antiresorptive; consider switch to anabolic (most often teriparatide) once stabilized	AFF usually mandates interruption of the inciting antiresorptive and imaging of the contralateral femur. Anabolic therapy can be considered to support fracture healing and ongoing skeletal protection in patients who remain at very high fracture risk.
MRONJ	Established MRONJ in a patient treated with potent antiresorptives	Hold/stop antiresorptive; consider short course teriparatide in selected high-risk patients	MRONJ typically prompts switching away from the causative agent. A randomized trial supports adjunctive teriparatide to promote MRONJ healing, while longer-term osteoporosis management must be individualized around dental and fracture risk.
Denosumab discontinuation/missed injections (“exit strategy”)	Planned discontinuation of denosumab or repeated delays beyond the 6-month dosing interval	Transition from denosumab to bisphosphonate (oral alendronate or IV zoledronic acid), often timed around the next due denosumab dose	Denosumab cannot be simply stopped: rebound high bone turnover, rapid BMD loss, and multiple vertebral fractures make a follow-on antiresorptive mandatory rather than elective. Exit regimens (often zoledronic acid or alendronate) aim to blunt rebound, sometimes with repeated dosing and/or bone turnover marker-guided monitoring.
Planned transition after time-limited anabolic phase	Completion of the approved course of teriparatide, abaloparatide, or romosozumab in a patient who remains at elevated fracture risk	Transition from anabolic to antiresorptive (typically oral bisphosphonate, IV zoledronic acid, or denosumab)	Anabolic therapy is a phase, not an endpoint. Without antiresorptive consolidation, BMD gains and fracture-risk reduction are partially lost over time. Planned “build then lock-in” sequences (e.g., romosozumab to alendronate/denosumab; abaloparatide to alendronate) are now standard in high-risk pathways.

a

LSC is the minimum BMD change that exceeds DXA measurement error, typically calculated as 2.77 × the site-specific precision error; BMD changes larger than the LSC (≈5% at the total hip and ≈8%–10% at the spine in many centers) are considered “significant.”^28,70,71

AFF, atypical femoral fracture; BMD, bone mineral density; LSC, least significant change; MRONJ, Medication-related osteonecrosis of the jaw.

Patient Persistence on Osteoporosis Medications

Clinical trial efficacy assumes near-perfect medication-taking, while real-world effectiveness depends on whether patients start therapy, take it correctly, and stay on therapy. In claims-based and registry studies, oral bisphosphonate adherence and persistence are consistently suboptimal, driven by dosing complexity (fasting, upright posture), gastrointestinal intolerance, polypharmacy, and risk-benefit concerns. A foundational systematic review of administrative database studies confirmed poor persistence/adherence with bisphosphonates in routine practice. ⁸¹ Another review focused specifically on oral bisphosphonates emphasized that nonadherence has tangible downstream effects—less suppression of bone turnover, smaller BMD gains, and diminished anti-fracture benefit. ⁸² In the largest contemporary systematic review of real-world oral bisphosphonate use (89 observational studies, 15 countries), mean 1-year persistence ranged roughly ~18%–75% and 2-year persistence ~13%–72%, with medication possession ratios commonly falling well below the “good adherence” threshold (e.g., ⩾80%). ⁸³ Put simply, many patients discontinue long before the biologic potential of therapy is realized, so population fracture prevention underperforms relative to RCT expectations.^45,84

Route and dosing frequency matter, but do not “solve” the adherence problem. Parenteral options (twice-yearly denosumab; yearly zoledronic acid) generally show better persistence than weekly/monthly oral agents, consistent with the idea that less frequent, clinic-anchored dosing improves implementation. ⁴⁶ For example, Karlsson et al. ⁴⁷ reported denosumab persistence of 83% at 12 months and 62% at 24 months, compared with pooled oral bisphosphonate persistence estimates of 45% and 30% at those same time points. Similarly, a Swedish real-world cohort found ~81% long-term adherence (>3 years) and 77% persistence with zoledronic acid, with discontinuations often related to adverse events and older age (and noting the context that the drug was cost-free in that setting). ⁴⁸ However, even with injectables, persistence declines over time in many systems, and “missed dose windows” (particularly for denosumab) can convert a highly effective regimen into a high-risk discontinuation pattern.^46,85

These adherence realities are not just process metrics—they track with fracture outcomes. Reviews of real-world studies show that lower adherence/persistence is associated with higher fracture rates and higher downstream healthcare utilization/costs.^45,46 Large observational analyses in older women similarly demonstrate that low or moderate adherence to osteoporosis medications is associated with a higher risk of subsequent fracture versus high adherence. ⁸⁶ This is the core “efficacy versus effectiveness” problem: a potent drug taken inconsistently behaves like a weaker strategy.

In summary, a TTT/goal-directed framework may improve persistence because it transforms osteoporosis into a monitored, shared-goal chronic condition: (1) define a target (e.g., TH T-score threshold or fracture-free interval), (2) set expectations for when reassessment will occur, and (3) escalate/de-escalate based on whether the target is reached.^8,11 In practice, adherence tends to improve when the regimen is simple, the follow-up cadence is explicit, and the route matches patient preferences and constraints (e.g., swallowing difficulties, cognitive burden, transportation, medication copays). This is also where sequential therapy design intersects with adherence: an “anabolic-first then consolidation” plan may be biologically rational, but it must be operationally feasible.

Conclusion

Longitudinal osteoporosis management increasingly requires risk-stratified planning rather than isolated drug selection. TTT frameworks help clinicians match initial potency to fracture risk, define pragmatic goals, most often anchored at the TH, and reassess whether current therapy remains sufficient as risk evolves. For very-high-risk patients, anabolic-first sequencing followed by antiresorptive consolidation offers the most efficient route to meaningful skeletal gains. For patients receiving denosumab, deliberate transition planning is essential to avoid rebound bone loss and vertebral fractures. Real-world medication adherence, persistence, safety, and access considerations often determine whether theoretically optimal sequences are feasible in clinical practice. To close the remaining evidence gaps, particularly around cumulative risk across decade-long, multi-agent pathways, pragmatic longitudinal data from patient registries and real-world practice will be essential, alongside individualized, goal-directed clinical judgment.