Postmenopausal women experience ongoing loss of bone mass, with resulting increases in the risk of fracture. This review describes the nature of postmenopausal bone loss, the definition of osteoporosis, and the current status of fracture risk estimation, which is pivotal in osteoporosis management. Important lifestyle measures include taking a balanced diet to maintain a healthy weight throughout life, safe physical activity, not smoking, and moderating alcohol intake. Severe vitamin D deficiency accelerates bone loss so should be avoided. Falls prevention becomes increasingly important with age, since falls cause most fractures. Pharmaceuticals to increase bone mass and prevent fractures either act by inhibiting bone resorption or by stimulating bone formation. Bisphosphonates are the most widely used antiresorptives, often taken as weekly oral doses. The intravenous bisphosphonate, zoledronate, has a long duration of action with effects on bone turnover, density, and fractures over a decade after a single dose. It is increasingly used in both prevention and treatment of osteoporosis. Denosumab is effective in preventing fractures but has a rapid offset of effect after its cessation. Some anabolic agents act via the PTH1 receptor, producing substantial increases in spine bone density but are not yet proven to prevent hip fractures. Romosozumab is a monoclonal antibody directed at sclerostin. It has both anabolic and antiresorptive effects and shows broad antifracture efficacy. Anabolics are used for 1 to 2 years in those with high fracture risk, before transition to long-term antiresorptive therapy. Treatment sequence options are discussed but more research is needed to establish which provide optimal fracture reduction.

Bisphosphonates (BPs) have been used effectively to treat excessive bone loss for over 50 years. Recent clinical evidence suggests extra-skeletal benefits but how this occurs remains unknown. Here we use a panel of human, murine and cellular assessments to chart BP-induced ageing-related changes both systemically and at local organ sites. In vivo spatial transcriptomics in aged mice treated with zoledronate showed a shift in cellular composition towards that of young animals specifically in heart, liver and intestine, with upregulation of genes governing detoxification, mitochondrial stability, energy metabolism, and antioxidation. A 5000-plex randomized trial based human proteomic analysis showed significant alterations in ~400 proteins after zoledronate treatment, with downregulation of proteins linked to genomic instability, proteostasis loss, mitochondrial dysfunction, stem cell exhaustion, and SASPs. Fluorescent labeling and tracing confirmed uptake of bisphosphonates by non-skeletal cells. In addition, low doses of several common, clinically utilized BPs stimulated growth and protected against DNA damage-induced senescence in multiple human cell types, with strongest effects in cardiomyocytes. Finally, proteome-wide target deconvolution with AlphaFold identified previously unrecognized binding partners, including PHB2 and ASAH1, and downstream upregulation of MEF2A was validated to be a key mediator of zoledronate triggered benefits in cardiomyocytes. Collectively, these results identify potential geroprotective mechanisms for BP action in multiple non-skeletal tissues.

The anti-fracture efficacy of most osteoporosis drugs is assessed in trials of up to 3 yr duration. However, treatment of osteoporosis is required long-term, so it is important to know whether effectiveness of treatment changes over time. To date, this information has only been available from open extensions of the treatment groups from clinical trials. Such data are subject to selective loss of frailer patients from the cohort, and no placebo comparator group is available to permit reliable measurement of anti-fracture efficacy. The 6-yr Auckland zoledronate RCT administered zoledronate or placebo every 18 mo to 2000 osteopenic women aged >65 yr. It is longer than most osteoporosis trials, and only 3.6% of participants withdrew or were lost to follow-up. Therefore, anti-fracture efficacy can be validly compared between the first and second halves of this study. There were 178 non-vertebral fractures in the placebo group and 108 in the zoledronate group (excluding fractures of the hands, feet, and face). Fracture rates per 1000 women-years in the placebo group were 28 (95% CI 23, 35) and 32 (26, 40) in years 1-3 and years 4-6, respectively. In the zoledronate group, fracture rates were 23 (18, 30) and 13 (9, 18) per 1000 women-years in the first and second halves of the study. The rate ratios for non-vertebral fractures were 0.83 (0.60, 1.14) in years 1-3, and 0.40 (0.27, 0.58) in years 4-6 (between-period comparison, p < .05). Rate ratios for total fragility fractures, which include vertebral fractures also, showed a similar pattern: years 1-3, 0.76 (0.56, 1.02) and years 4-6, 0.39 (0.29, 0.53). These findings suggest that the efficacy for non-vertebral fracture prevention of anti-resorptive drugs has been underestimated because of the short-term evaluation of their effects. Further, it indicates that longer term treatment with these drugs may yield greater benefit to patients.

Zoledronate prevented fractures in four large trials in cohorts that varied from low to high risk of fracture. Cost-effectiveness analyses are important tools used in funding and regulatory decisions about pharmaceutical agents, and zoledronate generally has appeared to be cost-effective. We used a simple approach to compare zoledronate costs with the savings from fractures prevented to complement previous cost-effectiveness analyses. 18-month costs of major osteoporotic fractures were obtained from published data from 7 US sites in the ICUROS study, costs of zoledronate medication from Medicare, and infusion costs estimated empirically. We applied these costs to data on major osteoporotic fracture from the four trials. We repeated these analyses using 12-month costs from 11 international ICUROS sites. In the trials with high-risk and intermediate-high risk cohorts, the cost-savings from major osteoporotic fractures prevented were approximately US $500,000/1000 patients/3y. In the low-intermediate-risk trial, they were $660,000/1000/6y, and in the low-risk trial, $240,000/1000/10y. When the international fracture cost data were used, these savings approximately doubled. In all four trials, the total costs of zoledronate were substantially less than the savings from fractures prevented, with annual savings ranging from $11-$88/patient/year in low-risk to high-risk patients. The cost-neutral zoledronate cost (maximum infusion cost plus medication cost) ranged from $160-$175 using the US fracture cost data, and was about $350 using international cost data. In summary, in four trials with cohorts at various risk of fracture ranging from low to high risk, zoledronate produced substantial nett savings because the costs of fractures prevented out-weighed total zoledronate costs.

CONTEXT:We recently reported that zoledronate (zol) given once at baseline or twice (every 5 years) reduced fracture risk over 10 years. OBJECTIVE:We assessed whether the effects of zol differ over time or across important baseline variables, and how they relate to changes in bone mineral density (BMD) over time. METHODS:A 10-year, prospective, randomized, double-blind, placebo-controlled trial, was conducted at a clinical research center from 2012 to 2023. Participants included 1054 postmenopausal women, aged 50 to 60 years, with BMD T-score at the lumbar spine, femoral neck, or total hip between 0 and -2.5. Intervention included either 5-yearly 5-mg zol (zol-zol), 5-mg zol infusion at baseline and placebo at 5 years (zol-placebo), or 5-yearly placebo (placebo-placebo). Main outcome measures included morphometric vertebral fractures, major osteoporotic, and any fractures. RESULTS:Morphometric vertebral fractures were not reduced in the years 0 to 5 following zol but were reduced in years 5 to 10 by 58% (95% CI, 21%-77%) (zol-zol) and 57% (21%-77%) (zol-placebo). For any fracture and major osteoporotic fracture, similar temporal patterns were observed. There were no interactions between treatment effect and baseline variables (including age, body mass index, BMD, falls or fracture history, and estimated fracture risk) or between treatment effect and changes in BMD with zol. CONCLUSION:Fracture reductions with single-dose or 5-yearly zol appear greater during years 5 to 10 than years 0 to 5. The risk reductions are broadly consistent across this cohort and independent of baseline or change in BMD. This suggests that routine BMD monitoring may not be necessary for low-risk women considering the option of less frequent zol for long-term fracture risk reduction.

Over the last decade, goal-directed management of osteoporosis has been developed as a concept. In 2024, a working group of the American Society for Bone and Mineral Research (ASBMR) determined that this concept should include specific bone mineral density (BMD) targets during treatment, to ensure optimal fracture risk reduction. Two observations were key to this recommendation: that higher on-treatment BMDs are associated with lower fracture risks in several studies, and that, in a meta-regression of individual clinical trials, agents producing larger increases in BMD also produced greater reduction in fracture risk. However, the inferences drawn from these studies might be unsound. First, on-treatment BMD is the sum of baseline BMD and its change on therapy. In trials in which these variables have both been considered, it was found that the influence of on-treatment BMD is substantially a reflection of the effect of baseline BMD on fracture risk rather than an effect of on-treatment BMD change. Second, the meta-regression findings are heavily dependent on the inclusion of less effective treatments in the analysis. Among more effective antiresorptives, no such relationship is seen. For example, although denosumab has greater effects on BMD than zoledronate, these agents have similar anti-fracture efficacy in trials. Therefore, a key conclusion of the treat-to-BMD-target framework-that denosumab is needed for many patients to reach their BMD targets-has no clinical trial support, suggesting the framework is flawed. Thus, use of BMD treatment targets in osteoporosis management is not supported by available evidence, so the frequent BMD measurements required by the treat-to-target framework will increase costs without demonstrable benefit.

Natural fatty acids are inhibitory to osteoclastogenesis, but only mildly so, as reported earlier by our and other groups. To improve the potency, we have synthesized two categories of analogues based on the backbone of saturated palmitic acid by inserting an ether or a triazole group in the carbon chain. The most effective compound proved to be with a triazole moiety farthest away from the acid unit. Following this strategy, we now have developed even more potent molecules, methylated triazole and tetrazole analogues. Tetrazole analogue displays about 10-fold higher inhibitory activity over the natural counterpart as tested in the osteoclastogenesis assay using mouse bone marrow cell cultures. Importantly, this inhibition is not due to cytotoxicity as both the methylated triazole and tetrazole molecules slightly increase the viability of bone marrow cells. It was found that the inhibition of osteoclastogenesis by the tetrazole analogue in mouse bone marrow cultures is associated with the decreased expression of the key osteoclastogenic or osteoclastic marker genes: Dcstamp, Nfatc1, Tnfa, Trap and Ctsk. The best analogue-tetrazole was then tested in vivo in a mouse calvarial local injection model after being solubilized by (2-hydroxypropyl)-β-cyclodextrin (β-CD). The results show that the tetrazole at the daily dose of 40 μg/injection (along with 264 μg β-CD) significantly reduce TRAP surface, and significantly increased mineralizing surface/bone surface, mineral apposition rate and bone formation rate. This study provides a novel effective agent for inhibiting osteoclastogenesis and positively regulating bone homeostasis.

Multiple health problems are associated with either over- or under-exposure to ultraviolet (UV) radiation. Using an agent-based microsimulation model, we examined the joint health and economic effects of conditions arising from over-exposure to sunlight (i.e., melanoma, keratinocyte skin carcinoma (KC) and cataract) and under-exposure to sunlight via vitamin D deficiency (i.e., fragility fractures and multiple sclerosis). We developed an agent-based model to estimate and compare incident cases, disease-specific deaths, healthcare costs and losses in quality-adjusted life years (QALYs) attributable to over- or under-exposure to UV radiation. Simulations were performed over a 20-year period for populations in 14 locations across Australia and New Zealand. Conditions caused by over-exposure to UV radiation were predicted to result in 6.0 and 1.2 million new cases compared with 0.12 and 0.08 million cases from under-exposure in Australia and New Zealand, respectively. However, the number of deaths due to under-exposure (Australia: 58,503; New Zealand: 20,104) were higher than those arising from over-exposure (Australia: 49,320; New Zealand: 7136), but this was dependent on the definition of vitamin D deficiency used. The expected healthcare costs from over-exposure to UV radiation were AU$12.4 billion in Australia and NZ$5.2 billion in New Zealand, three-fold higher than costs for conditions attributable to under-exposure in both countries. Despite the enormous burden of skin cancers, highlighting the importance of sun protection, avoidable deaths and healthcare costs of fragility fractures due to a lack of UV radiation requires a reduction in vitamin D deficiency in Australians and New Zealanders.

Bisphosphonates (BPs) have been the major class of medicines used to treat disorders of excessive bone loss for over five decades. Recently it has been recognized that BPs may also have additional significant beneficial extra-skeletal effects. These include a reduction of all-cause mortality and of conditions commonly linked to ageing, such as cancer and cardiovascular disease. Here we show that bisphosphonates co-localize with lysosomal and endosomal organelles in non-skeletal cells and stimulate cell growth at low doses. In vivo spatial transcriptomic analysis revealed differentially expressed senescence markers in multiple organs of aged BP-treated mice, and a shift in cellular composition toward those of young counterparts. Similarly, a 5000-plex plasma proteome analysis from osteopenic patients before and after BP-treatment showed significant alterations in ~400 proteins including GTPase regulators and markers of senescence, autophagy, apoptosis, and inflammatory responses. Furthermore, treatment with BPs protected against the onset of senescence in vitro. Proteome-wide target deconvolution using 2D thermal profiling revealed novel BP-binding targets (PHB2, ASAH1), and combined with RNA- and ATAC-seq of BP-treated cells and patient data, suggests downstream regulation of the MEF2A transcription factor within the heart. Collectively, these results indicate how BPs may beneficially modify the human plasma proteome, and directly impact multiple non-skeletal cell types through previously unidentified proteins, thereby influencing a range of pathways related to senescence and ageing.

To assess the efficacy of calcium supplements in preventing fractures, and to review their adverse effects, particularly on the cardiovascular system. There is now a large body of trial evidence demonstrating that calcium supplements do not prevent fractures in community-dwelling adults. They commonly produce gastrointestinal side-effects, sometimes serious, and increase the risk of renal calculi. Meta-analyses of adverse events from clinical trials suggest that the risk of MI is increased by 10–20

BACKGROUND Zoledronate prevents fractures in older women when administered every 12 to 18 months, but its effects on bone density and bone turnover persist beyond 5 years. Whether infrequent zoledronate administration would prevent vertebral fractures in early postmenopausal women is unknown. METHODS We conducted a 10-year, prospective, double-blind, randomized, placebo-controlled trial involving early postmenopausal women (50 to 60 years of age) with bone mineral density T scores lower than 0 and higher than -2.5 (scores of -1 or higher typically indicate normal bone mineral density) at the lumbar spine, femoral neck, or hip. Participants were randomly assigned to receive an infusion of zoledronate at a dose of 5 mg at baseline and at 5 years (zoledronate-zoledronate group), zoledronate at a dose of 5 mg at baseline and placebo at 5 years (zoledronate-placebo group), or placebo at both baseline and 5 years (placebo-placebo group). Spinal radiographs were obtained at baseline, 5 years, and 10 years. The primary end point was morphometric vertebral fracture, which was assessed semiquantitatively and defined as at least a 20% change in vertebral height from that seen on the baseline radiograph. Secondary end points were fragility fracture, any fracture, and major osteoporotic fracture. RESULTS Of 1054 women with a mean age of 56.0 years at baseline, 1003 (95.2%) completed 10 years of follow-up. A new morphometric fracture occurred in 22 women (6.3%) in the zoledronate-zoledronate group, in 23 women (6.6%) in the zoledronate-placebo group, and in 39 women (11.1%) in the placebo-placebo group (relative risk, zoledronate-zoledronate vs. placebo-placebo, 0.56 [95% confidence interval {CI}, 0.34 to 0.92; P=0.04]; and zoledronate-placebo vs. placebo-placebo, 0.59 [95% CI, 0.36 to 0.97; P=0.08]). The relative risk of fragility fracture, any fracture, and major osteoporotic fracture was 0.72 (95% CI, 0.55 to 0.93), 0.70 (95% CI, 0.56 to 0.88), and 0.60 (95% CI, 0.42 to 0.86), respectively, when zoledronate-zoledronate was compared with placebo-placebo and 0.79 (95% CI, 0.61 to 1.02), 0.77 (95% CI, 0.62 to 0.97), and 0.71 (95% CI, 0.51 to 0.99), respectively, when zoledronate-placebo was compared with placebo-placebo. CONCLUSIONS Ten years after trial initiation, zoledronate administered at baseline and 5 years was effective in preventing morphometric vertebral fracture in early postmenopausal women.

Osteoporosis in men is an underdiagnosed and undertreated condition that leads to significant morbidity and mortality, particularly in the aging population. This consensus report provides tailored guidelines for diagnosing, preventing, and treating male osteoporosis in the Asia–Pacific region by integrating global best practices with regional adaptations. To establish evidence-based, region-specific guidelines for the management of male osteoporosis in the Asia–Pacific region, addressing demographic and lifestyle factors. Expert feedback was gathered through premeeting reviews, consensus conferences, and collaborative discussions. A life-course approach was employed to align international best practices with Asia–Pacific-specific needs, emphasizing continuous monitoring and intervention from middle age onward. The 12 consensus strategies systematically approach male osteoporosis management, addressing screening, diagnosis, treatment, and long-term follow-up. Recommendations include the assessment of fracture risk for men aged 50 years and above, use of dual-energy X-ray absorptiometry (DXA) testing for men aged 70 years and above, lifestyle modifications, and pharmacological interventions such as bisphosphonates, denosumab, and anabolic agents for high-risk patients. Secondary causes of osteoporosis were highlighted, along with the establishment of fracture liaison services (FLSs) to improve long-term care. A life-course approach was proposed to optimize bone health throughout men’s lives. This consensus provides a comprehensive framework tailored to the Asia–Pacific region for diagnosing, preventing, and managing osteoporosis in men. By addressing region-specific challenges and promoting evidence-based interventions, the latest guidelines incorporating the consensus may depict the conceptual direction in reducing fracture risk and improving long-term bone health outcomes for osteoporosis in men.

The Australian and New Zealand Bone and Mineral Society (ANZBMS) is a leading bone research society in the Asia-Pacific region and has been recognised for outstanding contributions to clinical and biomedical musculoskeletal research. To showcase the research being undertaken by ANZBMS members, a joint initiative between ANZBMS and the journal Bone via a special issue was developed to further enhance international collaboration. This editorial serves as an introduction to this initiative, where three past ANZBMS presidents have shared their clinical and fundamental highlights from the 2024 ANZBMS annual scientific meeting in Adelaide, held in conjunction with the Endocrine Society of Australia and the Society for Reproductive Biology. Highlights include the importance of ethnicity when considering fracture risk, influence of paternal age on bone health in their offspring, novel combinations of bone active medications, bone biology and cancer, effect of glucocorticoids on the formation of neurogenic heterotopic ossification, parathyroid hormone signalling in hematopoietic and osteogenic lineages in the bone microenvironment and the regulation of osteoclast formation. Through a highly regarded platform such as Bone, and in line with the wider aims of the ANZBMS, this collaboration provides an update on the work being conducted by members of the society.

Osteopenia was originally a qualitative term denoting bone that appeared to be less dense on radiographs. Since 1994, it has also had the quantitative meaning of a bone mineral density (BMD) T-score between -1·0 and -2·5. More than 60% of White women older than 64 years are osteopenic. Although fracture risk is often lower in osteopenic women than in those with osteoporosis, their greater number means that most fractures occur in osteopenic individuals. Fracture risk varies widely in the osteopenic range, depending on factors including BMD, age, fracture history, and nationality and ethnicity. Therefore, the diagnosis of osteopenia is not an indication for either intervention or reassurance, but BMD is a risk factor that should be incorporated into a quantitative fracture risk calculation. Evidence from trials shows that oral and intravenous bisphosphonates cost-effectively reduce fractures in older osteopenic women. Major osteoporotic fracture risks of 10-15% could be acceptable indications for treatment with generic bisphosphonates in patients older than 65 years motivated to receive treatment. This Review assesses the evidence relating to the management of older adults with osteopenic bone densities.

ObjectivesThis study aimed to present the Asia-Pacific consensus on long-term and sequential therapy for osteoporosis, offering evidence-based recommendations for the effective management of this chronic condition. The primary focus is on achieving optimal fracture prevention through a comprehensive, individualized approach.MethodsA panel of experts convened to develop consensus statements by synthesizing the current literature and leveraging clinical expertise. The review encompassed long-term anti-osteoporosis medication goals, first-line treatments for individuals at very high fracture risk, and the strategic integration of anabolic and antiresorptive agents in sequential therapy approaches.ResultsThe panelists reached a consensus on 12 statements. Key recommendations included advocating for anabolic agents as the first-line treatment for individuals at very high fracture risk and transitioning to antiresorptive agents following the completion of anabolic therapy. Anabolic therapy remains an option for individuals experiencing new fractures or persistent high fracture risk despite antiresorptive treatment. In cases of inadequate response, the consensus recommended considering a switch to more potent medications. The consensus also addressed the management of medication-related complications, proposing alternatives instead of discontinuation of treatment.ConclusionsThis consensus provides a comprehensive, cost-effective strategy for fracture prevention with an emphasis on shared decision-making and the incorporation of country-specific case management systems, such as fracture liaison services. It serves as a valuable guide for healthcare professionals in the Asia-Pacific region, contributing to the ongoing evolution of osteoporosis management.

BackgroundWe previously identified that zoledronate administered at 18-month intervals reduced fragility fractures by a third in a 6-year trial of women older than 65 years with osteopenia. This extension aims to identify the persistence of these effects.MethodsOf the 2000 ambulant, community dwelling, postmenopausal women older than 65 years recruited in Auckland, New Zealand, with T-scores at the total hip or femoral neck in the range –1·0 to –2·5, we invited participants who received four doses of intravenous zoledronate, completed follow-up to year 6 of the core trial, did not have metabolic bone disease (other than osteoporosis), and were not using bone-active drugs into this 4-year observational study extension, during which further treatment was at the discretion of their own doctors. Participants were asked to notify study staff of any new fractures and were telephoned at 7·5 years and 9·0 years to update their health status. Participants were then invited to an onsite visit at 10·0 years. Fractures and other health events were documented at each contact and analysed in all women who entered the extension, and bone mineral density (BMD; analysed in participants without notable use of bone-active medications who attended an onsite visit at 10 years) and turnover markers (measured from fasting morning blood in a random subset of 50 participants) were measured at year 10.FindingsOf the 1000 women randomly assigned to receive zoledronate in the core trial, 796 participants were eligible for the extension, of whom 762 (96%) entered the extension between Sept 24, 2015, and Dec 13, 2017. Mean follow-up duration was 4·24 years (SD 0·57, range 0·61–6·55; final follow-up on May 25, 2022). 727 (91%) of participants were assessed at 10 years. 25 women died during the extension, six withdrew for medical reasons, and four were lost to follow-up. 92 women suffered 114 non-vertebral fractures during the extension. Non-vertebral fracture rates increased from a nadir of 15 fractures per 1000 woman-years (95% CI 10–21) in the last 2 years of the core trial to 24 fractures (17–33) in years 6–8 and 42 fractures (32–53) in years 8–10, similar to that in the placebo group in the last 2 years of the core trial. Total hip BMD (relative risk per 0·1 g/cm2 0·73, 95% CI 0·57–0·93; p=0·011) and a previous history of non-vertebral fracture (1·74, 1·12–2·69; p=0·013) at year 6 predicted incident fractures but change in total hip BMD did not. Total hip BMD decreased from 4·2% above study baseline to 0·8% above baseline (p<0·0001) during the extension. Turnover markers were not useful for predicting BMD loss in individuals. Osteonecrosis of the jaw or atypical femoral fractures did not occur in any participants.InterpretationThe reduced fracture rates following zoledronate in the core trial were substantially maintained for 1·5–3·5 years after the last zoledronate infusion, but not thereafter.FundingHealth Research Council of New Zealand.

Exposure to ultraviolet (UV) radiation from the sun has both harms and benefits for human health. The best-known benefit of sun exposure is the generation of vitamin D within the skin and the best-known harm is malignant skin cancer. Australia and New Zealand have very high ambient UV radiation, resulting in high rates of skin cancer incidence and mortality, yet there is an appreciable prevalence of vitamin D deficiency (defined as blood 25-hydroxyvitamin D (25(OH)D) <50 nmol/L) in both populations. The purpose of this study was to create a microsimulation model to replicate population 25(OH)D concentrations of people living in Australia and New Zealand, thus enabling the effect of different population-wide interventions to be estimated. We used large population datasets containing data on sun behaviours and socio-demographic variables, and environmental data on UV radiation, ozone, and solar zenith angle. Latitude, weather and time of day were accounted for. We simulated the conversion of daily UV radiation to a standard vitamin D dose (SDD) (100 J/m2 vitamin D-weighted UV) and monthly accumulation of SDD to 25(OH)D concentration. The model was calibrated to match the seasonal prevalence of vitamin D deficiency. This report describes the SunExposure (SUNEX) microsimulation model, its development, data inputs and calibration against population prevalence of vitamin D deficiency.

Bisphosphonates are widely used for the prevention and treatment of osteoporosis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are also widely used among the older population group at high risk of fractures. NSAIDs have been shown to impact on bone turnover, and a recent reanalysis of a clinical trial of clodronate found that NSAID use at baseline abrogated any effect of clodronate on either bone density (BMD) or fracture risk. To determine whether NSAIDs influence the efficacy of other bisphosphonates, we have reanalyzed our 6-year randomized controlled trial of zoledronate in 2000 osteopenic postmenopausal women. NSAID use was reported at baseline in 38% of the cohort and anytime use was reported by 65%. The evolution of the zoledronate effects on BMD were almost identical whether or not women were using NSAIDs at baseline and were significant in both subgroups at all BMD sites ( p  < 0.0001). The significant reduction in the risk of fracture in those allocated to zoledronate ( p  < 0.0001) showed no interaction with baseline use of NSAIDs ( p  = 0.33) nor with NSAID use at any time during the study ( p  = 0.28). The odds of fracture were significantly reduced in both NSAID users and nonusers. We conclude that the present analysis provides no support for the suggestion that NSAIDs interfere with the efficacy of potent bisphosphonates in terms of their effects on bone density or fracture. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).