From Risk to Treatment: Clinical Updates in Osteoporosis Management

Osteoporosis is a chronic skeletal condition characterized by reduced bone mass and structural deterioration, resulting in elevated fragility fracture risk. It affects an estimated 200 million people worldwide, with approximately one in two postmenopausal women and one in four men over 50 expected to sustain an osteoporotic fracture in their lifetime; yet fewer than 30% of eligible patients receive appropriate therapy following a fracture event [1]. Hip fracture alone carries a one‐year mortality of approximately 20% [2]. Two landmark guidelines published in 2024 from the National Osteoporosis Guideline Group (NOGG, UK) and the Royal Australian College of General Practitioners (RACGP, Australia) provide a contemporaneous synthesis of evidence‐based recommendations for fracture prevention and osteoporosis management [3, 4].

This editorial synthesizes clinically actionable updates from these guidelines and recent trial evidence, focusing on fracture risk stratification and its international application. This includes the expanding role of osteoanabolic therapies, safe pharmacological sequencing including denosumab cessation. This was developed from an invited presentation at the 2nd Royal College of Physicians Global Medicine Conference, June 2026. A structured narrative review was conducted drawing on NOGG 2024 [3], RACGP 2024 [4], the International Osteoporosis Foundation/European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (IOF/ESCEO) European guidance [5], the American College of Rheumatology (ACR) Guideline for Glucocorticoid‐Induced Osteoporosis [6], and Asia Pacific Consortium on Osteoporosis (APCO) framework statements [7], supplemented by a targeted MEDLINE and Embase search (2019–2025).

The NOGG 2024 guideline recommends a risk‐stratified approach using Fracture Risk Assessment Tool (FRAX) to calculate the 10‐year probability of major osteoporotic fracture (MOF: spine, hip, forearm, humerus) and/or hip fracture, stratifying individuals into low, moderate, high, or very high‐risk groups (Table 1). Very high risk is now formally defined as MOF > 30% or hip fracture probability > 4.5%, the threshold triggering consideration of anabolic‐first therapy. IOF/ESCEO and APCO similarly endorse FRAX‐based stratification, with country‐calibrated models available across the Asia‐Pacific region. Patients with rheumatoid arthritis carry approximately double the population fracture risk through systemic inflammation, glucocorticoid exposure, and Receptor Activator of Nuclear factor Kappa‐B Ligand (RANK‐RANKL)‐mediated bone loss [8]. Patients with systemic lupus erythematosus face similarly elevated fracture risk, with meta‐analytic data reporting a near‐doubling of osteoporosis prevalence (OR 2.03) and all‐site fracture risk (RR 1.97) compared to age‐ and sex‐matched controls [9]. For glucocorticoid‐induced osteoporosis (GIOP), any patient receiving prednisolone ≥ 7.5 mg/day for ≥ 3 months should receive bone‐protective therapy regardless of T‐score, with FRAX corrected by multiplying hip risk by 1.20 and MOF by 1.15 [3] consistent with NOGG 2024 and the 2022 ACR GIOP guidelines.

TABLE 1.

FRAX calculator and risk stratification.

FRAX input variables	Risk stratification (NOGG 2024)
Age (40–90 years) Sex Weight and height (BMI calculated) Previous fragility fracture Parent hip fracture (family history) Current smoking Corticosteroids use ≥ 3 months Rheumatoid arthritis Secondary osteoporosis Alcohol (3 or more units/day) Femoral neck BMD (T‐score)—Optional

Note: FRAX risk stratification thresholds and clinical decision pathways for osteoporosis management: Input variables, 10‐year fracture probability categories (NOGG 2024), and corresponding treatment actions. FRAX calculator accessible at fraxplus.org (free, country‐specific models available).

Treatment selection should be guided by fracture risk, comorbidities, renal function, and patient preference (Table 2). Oral bisphosphonates or annual intravenous zoledronate are first line for high‐risk patients (MOF > 20%), consistent across NOGG 2024, RACGP 2024, and IOF/ESCEO guidance. For very high‐risk patients, all three bodies advocate anabolic‐first therapy such as romosozumab or teriparatide before antiresorptive consolidation. NOGG 2024 additionally repositions hormone replacement therapy (HRT) as a first‐line option for younger postmenopausal women (≤ 60 years) at high fracture risk with low cardiovascular risk, supported by updated Women's Health Initiative (WHI) analyses demonstrating a more favorable benefit–risk profile in women commencing HRT before the age of 60 [10]. Denosumab is second‐line, or first‐line in chronic kidney disease (CKD) stages G4–G5D. It must never be stopped without a bridging antiresorptive as rebound vertebral fractures occur in up to 7%–20% of patients and IV zoledronate 5 mg given 6 months after the last injection is preferred. Fracture Liaison Service (FLS) referral following any fragility fracture reduces subsequent fracture risk by up to 40% [11].

TABLE 2.

Pharmacological treatment of osteoporosis using a risk‐stratified approach.

Antiresorptives	Osteoanabolics	When to use which agent
Bisphosphonates (1st line high risk) Alendronate 70 mg weekly PO Risedronate 35 mg weekly PO Zoledronate 5 mg IV annual → Use IV if poor oral tolerance AEs: esophageal irritation (oral), acute‐phase reaction/flu‐like symptoms (IV zoledronate), osteonecrosis of the jaw (ONJ, rare), atypical femoral fracture (prolonged use > 5 years). Denosumab (2nd line/renal impairment) 60 mg SC every 6 months CKD G4–G5D: preferred over bisphosphonates ⚠ NEVER stop without bridging treatment AEs: hypocalcaemia, rebound vertebral fractures on cessation without bridging HRT (NOGG 2024) Younger < 60 years of age Postmenopausal women, high risk, low CV risk—Dual benefit: symptoms + bone AEs: thromboembolic and breast cancer risk (long‐term).	Teriparatide (PTH 1–34) 20 μg SC daily × 24 months ↑ BMD rapidly; vertebral/non‐vertebral fracture ↓ Always follow with antiresorptive AEs: nausea, dizziness, transient hypercalcaemia, contraindicated in prior skeletal radiation, Paget's disease, hypercalcaemia Abaloparatide (PTHrP analogue) 80 μg SC daily × 18 months Similar efficacy to teriparatide Now included in NOGG 2024 AEs: nausea, dizziness, transient hypercalcaemia, contraindicated in prior skeletal radiation, Paget's disease, hypercalcaemia Romosozumab (sclerostin inhibitor) 210 mg SC monthly × 12 months Dual: ↑ formation + ↓ resorption ↓ Vertebral fracture 73% at 12 m (FRAME) ⚠ Avoid if recent MI or stroke AEs: cardiovascular events (contraindicated if recent MI/stroke within 1 year), ONJ (rare).	High risk (FRAX > 20% MOF): → Start bisphosphonate (oral or IV) Very high risk (FRAX > 30% MOF or recent fragility fracture): → Anabolic‐first strategy Romosozumab or Teriparatide Then transition to antiresorptive Renal impairment (CKD stages G4–G5D): → Denosumab preferred → Cautiously consider bisphosphonates for high‐risk patients (KDIGO 2017) Younger postmenopausal women (< 60 years, symptomatic): → Consider HRT first‐line (NOGG 2024)

Note: Risk‐stratified pharmacological treatment of osteoporosis: antiresorptive and osteoanabolic agents, indications, doses, duration, and major adverse effects. Includes guidance for special populations (very high risk, renal impairment, younger postmenopausal women) aligned with KDIGO 2027, NOGG 2024, and RACGP 2024 recommendations. The background color scheme is to highlight three different sections, the first two being modes of actions with antiresorptive in grey and osteoanabolics in pink. The third in blue is for practical use of agents in osteoporosis.

Patients with CKD stages G4–G5D carry substantially elevated fracture risk through CKD‐related mineral and bone disorder yet remain largely excluded from osteoporosis trials [12]. Dual‐energy X‐ray absorptiometry (DXA) is supported by Kidney Disease: Improving Global Outcomes (KDIGO) 2017 as part of integrated CKD fracture risk assessment. Bisphosphonates carry theoretical risks including renal accumulation and potential adynamic bone disease. Denosumab is generally preferred but requires monitoring for hypocalcemia and rebound secondary hyperparathyroidism on cessation. The 2021 European consensus on osteoporosis in CKD stages G4–G5D provides current guidance for this population.

Osteoanabolic agents are now recommended as initial therapy for very high‐risk patients across NOGG 2024, RACGP 2024, and IOF/ESCEO guidance. Teriparatide (20 μg SC daily for 24 months) and abaloparatide (80 μg SC daily for 18 months) are PTH receptor agonists that preferentially stimulate bone formation [13, 14]. Both agents reduce vertebral and non‐vertebral fracture, and abaloparatide's sequential alendronate strategy demonstrated sustained efficacy in the ACTIVExtend trial [15]. Romosozumab (210 mg SC monthly for 12 months) inhibits sclerostin with dual anabolic and antiresorptive effects, reducing vertebral fractures by 73% at 12 months in FRAME [16, 17] and outperforming alendronate alone in ARCH. It should be avoided in patients with recent myocardial infarction or stroke. All osteoanabolics must be followed by antiresorptive consolidation (zoledronate or denosumab 2–3 years, or oral bisphosphonates 3–5 years) and a single lifetime course applies. A bisphosphonate drug pause may be considered in stable, low‐risk patients. Denosumab should not be discontinued without bridging antiresorptive therapy [7]. Bone turnover markers (BTMs) should be monitored at 3–6 months with rising procollagen type 1 N‐terminal propeptide (P1NP) confirming anabolic activity and falling C‐terminal telopeptide (CTX) confirms antiresorptive response [18].

The importance of the recent guidelines is that it provides a clear stratified framework enabling clinicians to match treatment intensity to fracture risk systematically. There are differences from previous guidelines that impact clinical practice. The formal definition of very high risk directly triggering anabolic‐first prescribing is a landmark shift for the patients most likely to sustain a second, potentially disabling fracture within 12 months. The persistent treatment gap with fewer than 30% treated after fracture [1], represents the central challenge these guidelines must help address. Three changes represent meaningful changes. First, anabolic‐first therapy for very high‐risk patients reverses the bisphosphonate‐first convention dominant since the 1990s, now supported by ARCH trial head‐to‐head data [16]. Second, HRT's repositioning reflects a reassessment of benefit–risk balance following updated Women's Health Initiative (WHI) analyses [10]. Third, the denosumab cessation warning addresses a pharmacovigilance signal that emerged largely after the previous NOGG iteration and is now formalized as a contraindication to abrupt discontinuation.

Current controversies include romosozumab's non‐significant major adverse cardiovascular event (MACE) imbalance in ARCH (2.5% vs. 1.9% with alendronate; p = 0.07) [16]. This is substantially contextualized by the absence of any cardiovascular signal in the larger FRAME trial [17] and post hoc analyses suggesting the difference reflects an unusually low alendronate MACE rate rather than a romosozumab harm [19]. Current guidance appropriately excludes patients with recent MI or stroke, but individual shared decision‐making is essential where fracture prevention benefit is substantial. The single lifetime osteoanabolic course restriction derives from regulatory precedent rather than re‐treatment trial data. The optimal vitamin D supplementation threshold, particularly in the Middle East and Asia‐Pacific where deficiency rates of 70%–90% are documented, is an area that requires harmonization with guideline recommendations for supplementation to deficient individuals.

While these newer recommendations are welcome, there remain existing gaps in evidence. The near‐complete exclusion of patients with advanced CKD from major trials leaves clinicians without adequate evidence for this high‐risk population. Fracture risk in inflammatory rheumatic diseases where FRAX may substantially underestimate burden due to active disease and biological therapies is under‐studied. Primary osteoporosis in children and young adults represents a further under‐recognized population, with emerging data highlighting the diagnostic challenges and treatment outcomes in this group [20]. Long‐term sequential osteoanabolic strategies and the concept of imminent fracture risk (disproportionately elevated for 12–24 months after an index fracture) both lack dedicated trial data. Opportunistic CT‐based screening with automated identification of low BMD and vertebral fractures from scans performed for other indications could substantially expand fracture prevention reach. Future directions include AI tools to perform this analysis at scale as these are in development. Scaling FLS programmes across the Asia‐Pacific region, where the fracture burden is growing rapidly with demographic aging, is an urgent implementation priority. Novel therapeutic targets under investigation include anti‐activin receptor type IIA/IIB agents such as bimagrumab, which have shown dual musculoskeletal benefits in early studies through inhibition of activin‐mediated signaling, with potential applications in osteosarcopenia. Cathepsin K inhibitors demonstrated substantial fracture reduction efficacy in Phase III trials but have not progressed to regulatory approval due to an increased risk of cerebrovascular events and remain a mechanistic proof‐of‐concept rather than an active clinical pipeline.

The 2024 osteoporosis guideline updates represent a substantive reconfiguration of clinical practice in a decade. Their core messages which are: stratify risk with FRAX, deploy anabolic therapy first in very high‐risk patients, and never discontinue denosumab without a bridging antiresorptive are actionable in clinical settings. Closing the persistent gap between guideline recommendations and practice remains the greatest opportunity to reduce the global burden of preventable fragility fractures.

Author Contributions

Karam Alchi: writing – original draft, review and editing. Antoni Chan: conceptualization, writing – original draft, review and editing, critical revision.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing is not applicable to this article as no new data were generated.