Osteoporosis Update: Personalized Risk Assessment and Treatment

What we know

Osteoporosis is low bone mass causing increased fracture risk. A dual-energy X-ray absorptiometry (DXA) T-score ≤ −2.5 defines osteoporosis, but most fragility fractures occur in patients with higher T-scores (osteopenia range). ¹ Trabecular bone scoring (TBS) evaluates bone microarchitecture to predict fracture risk independently and enhance risk assessment in osteoporosis. ² The software analyzes lumbar spine DXA images to measure variations in gray shades, translating them into microarchitecture metrics.^3,4 A TBS above 1.31 indicates normal microarchitecture, 1.31–1.23 suggests partial degradation, and below 1.23 reflects degraded microarchitecture.^5,6 Due to increased TBS use, the International Society of Clinical Densitometry (ISCD) convened a task force to review evidence and provide clinical guidance for its application in diagnosing and managing low bone mineral density (BMD).

Recommendations

The Task Force guidance answers multiple questions centered around when and how TBS should be performed, how TBS should be reported, and how TBS should be used clinically. The main findings are as follows:

TBS can be beneficial to enhance fracture risk prediction and aid in treatment decisions in patients who are age 40 and over, particularly those who are on the borderline of requiring pharmacologic intervention.

There are studies that show the mean TBS is higher or lower in certain ethnicities than compared with the white population. This is suspected to be related to changes in soft tissue thickness (STT). Using TBS software that accounts for STT rather than body mass index (BMI) may lead to a more accurate TBS score and improved fracture risk assessment. The Task Force also cautions that TBS should be performed only within BMI ranges recommended by the manufacturer, but can be used regardless of sex, race/ethnicity, and prior or current osteoporosis treatment.

There is no current consensus on whether vertebral levels with artifacts, vascular calcification, hardware, degenerative changes, structural abnormalities, prior laminectomy, or lytic lesions should be excluded from TBS analysis. It was recommended not to report TBS in cases of extreme structural or pathological artifacts, though TBS appears to be generally unaffected by spinal degenerative changes, vertebral fractures, or ankylosing spondylitis.

Currently, it is not recommended to alter osteoporosis treatment based on a change in TBS over time. Given that TBS is more responsive to osteoanabolic therapies, it could potentially be useful for patient monitoring in the future, only if research can establish that a TBS increase correlates with antifracture effects.

What this changes

TBS can be a valuable tool to supplement the BMD T-score to better assess fracture risk, especially when the decision to initiate treatment is unclear. It can also be useful for initial decisions regarding the choice of treatment. Currently, it is not recommended to use TBS to monitor patient response to therapy; treatment decisions about therapy effectiveness should still be based on DXA BMD changes, fracture events, and additional risk factors.

What we know

With the approval of new osteoanabolic agents, abaloparatide and romosozumab, options for the treatment of osteoporosis have expanded over the past several years. Multiple well-designed double-blind randomized controlled trials have shown that treatment with osteoanabolic agents results in greater improvements in bone density and reduction in new fractures than bisphosphonates or denosumab.^7–10 Furthermore, sequential treatment with an osteoanabolic agent first, followed by an antiresorptive agent, has been shown to result in greater improvements to BMD, as opposed to other treatment sequences, which may even be associated with a transient loss of BMD.^11,12 Updated treatment guidelines are needed to optimize osteoporosis management by tailoring therapies to a patient’s risk level. Goal-directed treatment involves risk stratification to select the best initial and sequential therapies, aiming to reduce fracture risk.

Position statement

The position statement of the American Society for Bone and Mineral Research (ASBMR) and Bone Health and Osteoporosis Foundation (BHOF) categorizes patients into various treatment algorithms based on (1) patient risk for fracture, (2) selecting the appropriate treatment for treatment goals, and (3) understanding if the treatment goals have been achieved. Patients at imminent risk of fracture are defined as those with recent fractures within the past 2 years (largely independent of baseline T-score), and multiple prior fractures, even if not recent; the treatment goal for these patients is rapid and maximal fracture risk reduction. For patients not at imminent risk, baseline T-scores, fracture history and other risk factors guide target selection. Initial T-scores of < −2.5 should aim for improvement to at least > −2.5 or more, if possible. For patients with baseline T-score > −2.5 for whom treatment is indicated (based on fracture history or other risks), the target T-score is less clear. Additional recommendations include consistent monitoring with BMD and bone-turnover markers, reassessing fracture risk at defined intervals, adjusting therapy when goals are not met, and setting treatment trajectories whereas incorporating shared decision-making in treatment choices. Monitoring for treatment response can be assessed through not only T-score improvements, but also monitoring of biochemical turnover markers. Higher improvements in BMD and T-score are associated with lower risk for fracture.

Overall, the lower the initial starting T-score, the more potent the agents required to reach target T-scores. Osteoanabolic-first treatment strategies generally achieve faster and greater BMD improvements compared with antiresorptive-first approaches. The sequence of romosozumab to denosumab had the highest likelihood of achieving target T-scores, followed by romosozumab or abaloparatide to alendronate, lastly followed by denosumab alone over alendronate alone.^11–14 For those patients who reach treatment goals, transition to maintenance therapy with either continued denosumab or bisphosphonates can be considered. Unlike denosumab, which requires continuous use for maintenance, consideration can be made for bisphosphonate holidays depending on treatment response in order to minimize rare side effects such as osteonecrosis of the jaw and atypical femur fractures. For those who do not reach treatment goals or who fracture while on treatment, switching to or changing osteoanabolic therapy, extending osteoanabolic therapy duration, or even addition of osteoanabolic therapy on top of antiresorptive agents could be considered. It should be noted, however, that the extended duration of osteoanabolic therapy is not approved by the food and drug agency (FDA).

What this changes

The 2024 ASBMR/BHOF position statement recommends approaching osteoporosis management with a structured, goal-directed model that sets clear, personalized targets for BMD improvement, fracture-risk reduction, or bone-turnover biomarker improvements from the time of initial treatment. It emphasizes selecting therapies based on initial patient risk, and recommends a treatment regimen with initiation of osteoanabolic medication for very high-risk patients at imminent risk of fracture, as well as a methodical sequencing of medications. The panel does note that pauses in treatment for patients should only be started in those whose last treatment is a bisphosphonate and who have achieved target treatment goals.

What we know

Romosozumab, a monoclonal antibody that inhibits sclerostin, has dual antiresorptive and anabolic effects. Approved in 2019 for treating osteoporosis in women at high fracture risk, it improves BMD more than alendronate or teriparatide. ¹³ However, phase 3 trials led to an FDA boxed warning about potential risks of myocardial infarction, stroke, and cardiovascular death, advising against use in patients with recent cardiovascular events. ¹⁴ A trial which compared patients receiving 12 months of placebo versus monthly romosozumab, both followed by subcutaneous denosumab for one year, showed no significant difference in rates of major adverse cardiovascular events (MACE) in the two groups. ¹⁵ In contrast, a separate trial comparing 12 months of romosozumab followed by weekly oral alendronate (70 mg) versus alendronate only showed an increased risk of MACE in the romosozumab group. ¹⁶ Due to concerns surrounding the FDA boxed warning, more data evaluating MACE risk with romosozumab is needed.

Study results

This observational retrospective cohort study utilized medical record data to investigate the difference in MACE risk with various osteoanabolic agents during 1 year of follow-up using propensity-score matching (PSM) in a large multicenter database. Data queried included patients 40 years and older with a diagnosis of osteoporosis who were prescribed either romosozumab or a parathyroid hormone (PTH) analog, such as teriparatide or abaloparatide. PSM was performed on various baseline characteristics including race, ethnicity, BMI, social determinants of health, medications, as well as diagnoses that confer increased cardiovascular risk such as hypertension, hyperlipidemia, diabetes, and established cardiac and cerebrovascular disease. Following PSM, each group contained 5610 matched patients. Overall composite risk for MACE (including myocardial ischemic events, cardiovascular events and death) was significantly lower in the romosozumab group as compared with the PTH-analog group (hazard ratio [HR] 0.73; 95% confidence interval [CI]: 0.58–0.92; p = 0.003). Results were similar in a reanalysis of only female patients (N = 5292 per group; HR 0.79; 95% CI 0.63–0.98).

What this changes

Given the FDA boxed warning, these results provide reassurance regarding the risk of cardiovascular or cerebrovascular events with romosozumab. One potential reason for the discrepancy in the risk of MACE between the prior two trials is differences in participants’ baseline cardiac risk in the studies. By using PSM, this observational study was able to compare the incidence of these adverse events while controlling for other confounding variables. This study should bolster the confidence of clinicians prescribing romosozumab for osteoporotic patients at high risk of fracture, particularly in those with low cardiovascular risk. More research is needed to evaluate the use of romosozumab in high cardiovascular risk populations.

What we know

Bone loss accelerates during menopause, but the loss starts even before menopause. ¹⁷ Although fracture risk increases as BMD declines, most fractures occur in women without osteoporosis. Zoledronate is a potent IV bisphosphonate with sustained antiresorptive effects. A single 5-mg dose showed persistent protective effects on BMD and suppression of bone turnover for more than 5 years.^18,19

Study results

This 10-year, prospective, double-blinded randomized controlled trial (RCT) evaluated whether infrequent zoledronate infusions, administered at 5-year intervals, could prevent fracture, and maintain BMD in postmenopausal women. A total of 1054 women aged 50–60 with a T-score between 0 and −2.5 were enrolled and assigned to 5-mg zoledronate at baseline and year 5 (zoledronate–zoledronate), zoledronate at baseline only (zoledronate–placebo), or placebo at both time points (placebo–placebo). Overall, 95.2% of participants completed the 10-year follow-up.

For the primary endpoint, morphometric vertebral fractures occurred in 11.1% of women in the placebo group, compared with 6.3% in the zoledronate–zoledronate group (relative risk [RR] 0.56; 95% CI 0.34–0.92) and 6.6% in the zoledronate–placebo group (RR 0.59; 95% CI 0.36–0.97). These findings show a significant reduction in vertebral fractures with either one or two infusions of zoledronate. For the secondary endpoints, the risks of any fracture, fragility fracture, and major osteoporotic fracture, were also lower in both zoledronate groups than in the placebo group, with relative risks 0.74 (95% CI 0.61–0.89), 0.75 (95% CI 0.60–0.94), and 0.65 (95% CI 0.49–0.87), respectively.

Zoledronate maintained BMD for over 10 years. At year 10, BMD was 7.4–8.8% higher in women who received two infusions and 5.0–6.3% higher in women who received a single infusion, compared with placebo. Bone-turnover markers decreased by 30–40% after baseline zoledronate infusion and remained below baseline even in the single-dose group at year 10. No cases of osteonecrosis of the jaw or atypical femoral fracture were reported.

What this changes

This trial demonstrates meaningful fracture prevention in early postmenopausal women with only one or two zoledronate infusions over 10 years. The degree of fracture reduction was comparable with results previously seen in higher-risk groups treated at much shorter intervals. These findings support a preventive strategy for early postmenopausal women who do not qualify for osteoporosis therapy but wish to preserve bone mass and lower future fracture risk. Infrequent zoledronate infusions might provide a low-burden and durable option in this population.

What we know

The 1-year mortality rate of osteoporotic hip fractures in women is high, reaching 20–25%.^20,21 Although intravenous zoledronate effectively reduces fracture risk and mortality, it is underutilized, with only 8–10% of patients treated within a year of fracture.^22,23 To address this, the Massachusetts General Hospital Fracture Liaison Service developed a multidisciplinary collaboration model involving endocrinology, orthopedic surgery, geriatrics, and rheumatology. Within this model, initiating zoledronate during hospitalization was shown to be safe and increased treatment rates from 8–11% to 70%. ²⁴ While earlier guidance recommended delaying treatment for 2 weeks postfracture, studies found early administration does not impair bone healing or increase refracture risk. ²⁵

Study results

This study used real-world data to emulate a 2-arm RCT and evaluated 652 patients who received inpatient zoledronate (IP-ZA) compared with 1962 matched untreated controls. The mean age was 81 years, and 71% were female. Over 24 months of follow-up, all-cause mortality was significantly lower in the IP-ZA group (12.3%) compared with the untreated group (20.7%), with a HR of 0.62; 95% CI, 0.49–0.78, p < 0.001. Nearly 90% of treated patients received only a single dose of ZA, and this subgroup showed a similar mortality rate at 13.3% (HR 0.70). New vertebral compression fractures confirmed by radiology reports were less frequent in the IP-ZA group than in the control (2.0% versus 5.4%, HR 0.4). Rates of nonvertebral fracture and contralateral hip fractures were comparable between groups. IP-ZA was not associated with increased nonunion, atypical fractures, or osteonecrosis of the jaw.

What this changes

This study demonstrated that IP-ZA after hip fracture is clinically meaningful, reducing both the treatment gap in antiresorptive therapy and the risks of mortality and subsequent fracture. The finding that a single inpatient dose offers sustained benefit for up to 2 years is particularly important for women who are homebound, less mobile, or those who may miss postoperative visits. For clinicians caring for postmenopausal women, these results support IP-ZA after hip fracture as a safe, effective, and impactful strategy to close the longstanding osteoporosis care gap.