{"product_id":"zoledronic-acid-and-bone-health-in-multiple-myeloma-who-benefits-from-continuing-treatment-beyond-two-years","title":"Zoledronic Acid and Bone Health in Multiple Myeloma: Who Benefits From Continuing Treatment Beyond Two Years?","description":"\u003cp\u003eThis follow-up analysis of the Magnolia trial found that continuing zoledronic acid beyond 2 years reduced the risk of progressive bone disease by 60%. Zoledronic acid is a bone-protective drug given intravenously. The patients in the trial had multiple myeloma and had achieved at least a very good partial response. Among patients who stopped treatment, rising levels of bone resorption markers were linked to a higher short-term risk of new or worsening bone lesions. These markers include CTX at or above 0.30 μg\/L and TRAcP at or above 4 U\/L. The authors conclude that stopping zoledronic acid simply because a patient has achieved a very good partial response may not be justified. The authors also conclude that bone turnover markers may help identify who could benefit from restarting treatment.\u003c\/p\u003e\n\n\u003ch1\u003eZoledronic Acid and Bone Health in Multiple Myeloma: Who Benefits From Continuing Treatment Beyond Two Years?\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why Bone Protection Matters in Multiple Myeloma\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#question\"\u003eWhat Question Did This Study Ask?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#methods\"\u003eHow Was the Study Conducted?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#substudy1\"\u003eKey Findings Part 1: Zoledronic Acid in Patients With Very Good Partial Response\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#substudy2\"\u003eKey Findings Part 2: Bone Turnover Markers and Bone Disease Risk\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#longitudinal\"\u003eKey Findings Part 3: How Bone Markers Changed Over Time\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#implications\"\u003eClinical Implications: What This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations: What the Study Could Not Prove\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations and Practical Advice\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eThe number needed to treat was 7.5, meaning about one case of progressive bone disease was prevented for every 7.5 patients who continued zoledronic acid beyond two years.\u003c\/li\u003e\n\u003cli\u003eIn patients who stopped zoledronic acid, CTX at or above 0.30 μg\/L was linked to a 28.6% risk of progressive bone disease within six months, versus 6.1% below that level; TRAcP at or above 4 U\/L was linked to 15.2% versus 6.1%.\u003c\/li\u003e\n\u003cli\u003eZoledronic acid can cause medication-related osteonecrosis of the jaw in 2.6% to 4% of myeloma patients treated with bisphosphonates, and may also impair kidney function and cause low blood calcium.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why Bone Protection Matters in Multiple Myeloma\u003c\/h2\u003e\n\n\u003cp\u003eBone destruction is one of the most common complications of multiple myeloma (MM), a cancer of plasma cells in the bone marrow. Bone damage causes significant illness and disability. It frequently leads to permanent disability, including in patients of working age.\u003c\/p\u003e\n\n\u003cp\u003eEarly treatment with monthly zoledronic acid (ZOL) reduces the risk of developing progressive bone disease (PBD) in multiple myeloma. Zoledronic acid is a bisphosphonate — a drug that slows bone breakdown. Because of this benefit, zoledronic acid is an important supportive therapy, and guidelines recommend starting it for all patients with active myeloma.\u003c\/p\u003e\n\n\u003cp\u003eHowever, the best duration of zoledronic acid treatment is not clearly established. Current guidelines recommend at least 12 months and up to 48 months of treatment.\u003c\/p\u003e\n\n\u003cp\u003eIn the original Magnolia study, patients with newly diagnosed multiple myeloma were randomly assigned after 2 years of zoledronic acid treatment. These patients were assigned either to stop the drug or to continue it for a total of 4 years. The researchers observed significantly lower rates of progressive bone disease in the group that continued treatment. However, that analysis did not examine results by response category — that is, whether patients who had achieved a deep response to myeloma treatment fared differently from those who had not.\u003c\/p\u003e\n\n\u003cp\u003eBisphosphonates such as zoledronic acid are not without side effects. Medication-related osteonecrosis of the jaw (MRONJ) — death of jawbone tissue — occurs in 2.6% to 4% of myeloma patients treated with bisphosphonates. Risk factors for MRONJ include longer treatment duration, higher bisphosphonate potency, poor dental health before starting therapy, and dental extractions performed after treatment begins.\u003c\/p\u003e\n\n\u003cp\u003eZoledronic acid may also impair kidney function and cause hypocalcaemia (low blood calcium). When kidney function is impaired, denosumab is often used instead. However, denosumab carries a similar risk of hypocalcaemia and MRONJ.\u003c\/p\u003e\n\n\u003cp\u003eBecause of these potential toxicities, zoledronic acid ideally should be reserved for patients most likely to benefit. Identifying those patients remains challenging. Previous International Myeloma Working Group (IMWG) guidelines suggested that patients who have received at least 1 year of zoledronic acid may have less need for continued bone-protective therapy. This applies to patients who have also achieved very good partial response (VGPR) or better. Those recommendations were based on subanalyses of the Myeloma IX study, on the deeper responses achieved with newer myeloma therapies, and on studies exploring longer dosing intervals for zoledronic acid.\u003c\/p\u003e\n\n\u003cp\u003eHowever, newer guidelines from the European Hematology Association (EHA) and the European Myeloma Network (EMN) recommend at least 12 and up to 48 months of treatment for patients achieving at least VGPR.\u003c\/p\u003e\n\n\u003cp\u003eSome studies have reported very low rates of skeletal complications even in patients not receiving bone-protective therapy. This finding is consistent with the idea that a lower disease burden lowers the risk of progressive bone disease.\u003c\/p\u003e\n\n\u003cp\u003eBone turnover markers are small molecules released into the bloodstream during bone resorption (breakdown) and bone formation. Their levels reflect how active bone formation and bone breakdown are. There may be threshold levels of these markers below or above which bone-protective therapy can safely be withheld — or, conversely, levels that indicate the need to restart treatment.\u003c\/p\u003e\n\n\u003cp\u003eBone formation activity can be assessed by measuring bone-specific alkaline phosphatase (BAP) and procollagen type I N-terminal propeptide (P1NP). Bone resorption can be evaluated using C-terminal cross-linked telopeptide of type I collagen (CTX) and tartrate-resistant acid phosphatase isoform 5b (TRAcP). CTX is a marker of type I collagen degradation and increases with bone resorption. TRAcP is released during bone breakdown and reflects osteoclastic activity (the activity of bone-destroying cells).\u003c\/p\u003e\n\n\u003cp\u003eCombining anabolic (bone-building) and catabolic (bone-breaking) markers may improve predictive accuracy. For example, a prior study demonstrated the prognostic value of the CTX\/BAP ratio.\u003c\/p\u003e\n\n\u003ch2 id=\"question\"\u003eWhat Question Did This Study Ask?\u003c\/h2\u003e\n\n\u003cp\u003eThe researchers wanted to determine whether specific subgroups of patients with multiple myeloma could safely omit zoledronic acid treatment. They based this question on treatment response or on measurements of bone turnover markers.\u003c\/p\u003e\n\n\u003cp\u003eSpecifically, they examined two questions. First, do patients achieving a VGPR or better continue to benefit from zoledronic acid beyond 2 years of therapy? Second, can bone turnover markers identify patients at increased risk of progressive bone disease, independent of disease response status?\u003c\/p\u003e\n\n\u003ch2 id=\"methods\"\u003eHow Was the Study Conducted?\u003c\/h2\u003e\n\n\u003cp\u003eThis study used data from the Magnolia trial (EudraCT number 2014-002494-12). The principal outcomes of the trial have been reported previously.\u003c\/p\u003e\n\n\u003cp\u003eThe Magnolia trial enrolled 193 patients with newly diagnosed, treatment-requiring multiple myeloma. All patients received monthly zoledronic acid for 2 years. After that, participants were randomly assigned either to continue monthly zoledronic acid for an additional 2 years or to enter a 2-year observation phase with no further zoledronic acid.\u003c\/p\u003e\n\n\u003cp\u003eThe present study examined two overlapping subpopulations from the Magnolia trial:\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003eParticipants who at randomization had achieved VGPR or better according to the IMWG Uniform Response Criteria with their most recent treatment regimen (n = 150).\u003c\/li\u003e\n  \u003cli\u003eAll patients randomized to observation after 2 years of initial zoledronic acid therapy (n = 94).\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eAll participants were monitored for progressive bone disease at monthly clinic visits. Myeloma bone imaging was performed every 6 months or when clinically indicated. Progressive bone disease was defined as any of the following:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eA 25% or greater increase in existing osteolytic lesions (areas of bone destroyed by the cancer)\u003c\/li\u003e\n  \u003cli\u003eThe appearance of new osteolytic lesions at least 10 mm in diameter\u003c\/li\u003e\n  \u003cli\u003eNew fractures\u003c\/li\u003e\n  \u003cli\u003eNew lesions requiring radiotherapy or surgery\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eProgressive disease (PD) — progression of the myeloma itself — was monitored monthly using serum M-protein, free light kappa and free lambda chains, ionized calcium and kidney markers. MRONJ was assessed by oral examination every 3 months. Suspected cases were referred to oral surgeons for confirmation and management.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eSubstudy 1.\u003c\/strong\u003e Patients were classified according to their IMWG response status at the latest treatment before randomization (year 2). Only patients who had achieved VGPR or better were included. Hazard ratios (HRs) for progressive bone disease, MRONJ, overall survival (OS) and progression-free survival (PFS) were estimated using Cox regression to account for variable follow-up times. Time to event was defined as the interval from randomization to the relevant outcome, or censored at the end of study. To avoid bias, patients in the treatment group were censored at the time of progressive bone disease. Patients in the observation group were withdrawn from the study upon progressive bone disease.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eSubstudy 2.\u003c\/strong\u003e Fasting blood samples were obtained at baseline, 6 months, 12 months, at randomization (after 24 months) and monthly thereafter up to 48 months. Samples were stored at −80°C until analysis. Samples collected at baseline, 6 months, 12 months, at randomization and every third month thereafter were analysed. In patients with progressive disease or progressive bone disease, markers were measured monthly for up to 3 months before the end-point.\u003c\/p\u003e\n\n\u003cp\u003eThe bone turnover markers investigated were CTX, P1NP, TRAcP and BAP.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eLaboratory analyses.\u003c\/strong\u003e All bone turnover biomarker measurements were carried out at the Department of Biochemistry and Immunology, Lillebaelt Hospital, accredited by the Danish Accreditation Fund according to the ISO 15189 standard. For standard serum samples, the blood was allowed to clot at room temperature for 30 minutes before centrifugation at 3000 g for 10 minutes. For plasma samples, centrifugation at 3000 g occurred within 2 hours. Samples were aliquoted and stored at −80°C until analysis. Technicians were not aware of treatment allocation.\u003c\/p\u003e\n\n\u003cp\u003eMeasurement of fasting plasma P1NP and CTX was performed by validated routine methods (Cobas e602 analyzer, Roche Diagnostics, Denmark). The lower limit of quantification (LOQ) for P1NP and CTX was 10 and 0.05 μg\/L, respectively. The interassay coefficients of variation (CV) — a measure of test reproducibility — on two levels for both methods were 10% or lower.\u003c\/p\u003e\n\n\u003cp\u003eLevels of TRAcP and BAP were analysed in serum using commercially available Electrochemiluminescence Immunoassay (ECLIA) assays, according to the manufacturer's instructions (ImmunoDiagnostic Systems Holdings PLC, East Boldon, UK). The limit of quantification for Trap5b and BAP was 0.9 U\/L and 0.1 μg\/L, respectively. The interassay CVs on three levels for both methods were 10% or lower.\u003c\/p\u003e\n\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki. It was approved by the Regional Committees on Health Research Ethics for Southern Denmark (EPN S-20140138) and for Norway (EPN REK 2015\/626). All patients included gave written consent to participation.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eStatistical analysis.\u003c\/strong\u003e For each post-zoledronic acid bone marker measurement (from month 25 onwards), the proportion of progressive bone disease events within 6 months of sampling was calculated. For bone resorption markers (CTX and TRAcP), thresholds were determined to assess associations between elevated levels and subsequent progressive bone disease risk using the chi-squared test. A similar approach was applied to bone formation markers (P1NP and BAP) and to ratios of bone formation to bone resorption markers. The researchers evaluated whether lower ratios were associated with increased progressive bone disease risk. Measurements with less than 6 months of follow-up were excluded.\u003c\/p\u003e\n\n\u003cp\u003eTo assess longitudinal changes in bone marker levels during and after zoledronic acid therapy, mean values were calculated for months 0 (baseline), 6, 25 (after 2 years of treatment) and every 3 months thereafter. Because not all participants completed the full study duration, comparisons were performed using unpaired t-tests between baseline and months 25 and 46.\u003c\/p\u003e\n\n\u003cp\u003eAll statistical analyses were performed using GraphPad Prism 10.2.1 (Dotmatics, USA) and StataBE 18 (StataCorp LLC, Texas, USA). Categorical variables were compared using chi-squared or Fisher's exact test. Continuous variables were compared using unpaired t-tests. Time-to-event outcomes, including progressive bone disease, MRONJ, progression-free survival and overall survival, were analysed using the Cox proportional hazards model. Hazard ratios with 95% confidence intervals (CIs) were reported. The proportional hazards assumption was verified by inspection of log–log survival plots and found to be satisfied. Kaplan–Meier survival curves were generated for visual comparison of time-to-event outcomes.\u003c\/p\u003e\n\n\u003ch2 id=\"substudy1\"\u003eKey Findings Part 1: Zoledronic Acid in Patients With Very Good Partial Response\u003c\/h2\u003e\n\n\u003cp\u003eOf the 193 participants randomized in the Magnolia trial, 150 (78%) had achieved at least a VGPR at their latest treatment following the initial 2 years of zoledronic acid therapy. Of these 150 patients, 77 were randomized to continue zoledronic acid treatment and 73 to observation. Baseline characteristics were comparable between the two groups.\u003c\/p\u003e\n\n\u003cp\u003eThe baseline characteristics of these 150 patients were as follows:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAge:\u003c\/strong\u003e mean 65.4 years (range 42–83) in the zoledronic acid group and 65.9 years (range 43–82) in the observation group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMale gender:\u003c\/strong\u003e 47 patients (61.0%) in the zoledronic acid group and 48 patients (65.8%) in the observation group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMyeloma type — IgG:\u003c\/strong\u003e 44 patients (57.1%) in the zoledronic acid group and 42 patients (57.5%) in the observation group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMyeloma type — IgA:\u003c\/strong\u003e 16 patients (20.8%) in the zoledronic acid group and 15 patients (20.5%) in the observation group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMyeloma type — light chain:\u003c\/strong\u003e 17 patients (22.1%) in the zoledronic acid group and 16 patients (21.9%) in the observation group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eInternational Staging System (ISS) stage I at diagnosis:\u003c\/strong\u003e 38 patients (49.4%) in the zoledronic acid group and 36 patients (49.3%) in the observation group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eISS stage II:\u003c\/strong\u003e 27 patients (35.1%) in the zoledronic acid group and 27 patients (34.2%) in the observation group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eISS stage III:\u003c\/strong\u003e 10 patients (12.9%) in the zoledronic acid group and 10 patients (13.7%) in the observation group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLytic bone disease at diagnosis:\u003c\/strong\u003e 54 patients (70.1%) in the zoledronic acid group and 55 patients (68.5%) in the observation group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAutologous transplant:\u003c\/strong\u003e 49 patients (63.6%) in the zoledronic acid group and 51 patients (69.8%) in the observation group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eTreated with a proteasome inhibitor:\u003c\/strong\u003e 72 patients (93.5%) in the zoledronic acid group and 68 patients (93.2%) in the observation group\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eResponse assessment at randomization showed that in the zoledronic acid group, 17 patients (17.2%) had achieved strict complete response (sCR), 19 patients (19.2%) had achieved complete response (CR), and 41 patients (41.4%) had achieved VGPR. In the observation group, 14 patients (14.9%) had achieved sCR, 19 patients (20.2%) had achieved CR, and 40 patients (42.6%) had achieved VGPR.\u003c\/p\u003e\n\n\u003cp\u003eDuring follow-up, progressive bone disease occurred in 17 of the 73 patients in the observation group and in 7 of the 77 patients in the continued zoledronic acid group. The causes of progressive bone disease are shown in detail below:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eProgressive bone disease (total):\u003c\/strong\u003e 7 patients (9.1%) in the zoledronic acid group versus 17 patients (23.3%) in the observation group (p \u0026lt; 0.05)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMultiple new or growing lesions:\u003c\/strong\u003e 4 patients (5.2%) in the zoledronic acid group versus 14 patients (19.2%) in the observation group (p \u0026lt; 0.01)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eSingle new or growing lesion:\u003c\/strong\u003e 2 patients (2.6%) in the zoledronic acid group versus 2 patients (2.7%) in the observation group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eNon-vertebral spontaneous fracture:\u003c\/strong\u003e 1 patient (1.3%) in the zoledronic acid group versus 2 patients (2.7%) in the observation group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eVertebral collapse:\u003c\/strong\u003e 0 patients (0.0%) in the zoledronic acid group versus 2 patients (2.7%) in the observation group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eHypercalcaemia:\u003c\/strong\u003e 0 patients (0.0%) in both groups\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eMost cases of progressive bone disease were multiple new or growing osteolytic lesions.\u003c\/p\u003e\n\n\u003cp\u003eCox regression analysis demonstrated a significantly lower risk of progressive bone disease in the continued treatment group. The hazard ratio was 0.40 (95% CI 0.16–0.92; p = 0.031). In plain language, this means patients who continued zoledronic acid had a 60% lower risk of progressive bone disease compared with those who stopped. The result was statistically significant, meaning there is about a 3% probability that this finding was due to chance alone.\u003c\/p\u003e\n\n\u003cp\u003eThe number needed to treat (NNT) to prevent one case of progressive bone disease was 7.5. This means that for every 7.5 patients treated with continued zoledronic acid, one case of progressive bone disease was prevented. This NNT is similar to that previously reported for the overall study population, regardless of remission depth.\u003c\/p\u003e\n\n\u003cp\u003eNo significant differences were observed between groups in the risk of progressive disease, overall survival or MRONJ.\u003c\/p\u003e\n\n\u003cp\u003eA subgroup analysis was conducted among patients who had achieved a complete response (CR) before randomization (n = 69). In this subgroup, patients continuing zoledronic acid had a lower hazard ratio for progressive bone disease (HR 0.47; 95% CI 0.12–1.83). However, this difference was not statistically significant (p = 0.278). The lack of statistical significance likely reflects limited statistical power in this smaller group of patients. No significant differences were observed for progressive disease, overall survival or MRONJ in this subgroup.\u003c\/p\u003e\n\n\u003cp\u003eAmong patients with no prior bone disease at diagnosis who achieved VGPR at the latest treatment before randomization (n = 24), three patients experienced progressive bone disease during the study.\u003c\/p\u003e\n\n\u003ch2 id=\"substudy2\"\u003eKey Findings Part 2: Bone Turnover Markers and Bone Disease Risk\u003c\/h2\u003e\n\n\u003cp\u003eFor the bone marker study, a total of 94 patients were randomized to observation without further zoledronic acid treatment. These patients were included in the bone marker substudy. Across these participants, 682 fasting blood samples were analysed for CTX (μg\/L), P1NP (μg\/L), BAP (μg\/L) and TRAcP (U\/L). The haemolytic index was also assessed, and eight samples were excluded because elevated indices could affect assay results.\u003c\/p\u003e\n\n\u003cp\u003eThe 94 patients provided a total of 470 samples from patients who had at least 6 months of follow-up. These samples were included in analyses of progressive bone disease risk within 6 months of measurement. Of these, two samples of CTX, one BAP, two P1NP and one TRAcP were unsuccessful.\u003c\/p\u003e\n\n\u003cp\u003eHigh levels of bone resorption markers were associated with an increased risk of progressive bone disease within 6 months. The specific findings were:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eSamples with CTX at or above 0.30 μg\/L had a 28.6% risk of progressive bone disease within 6 months, compared with less than 5% for CTX below 0.10 μg\/L.\u003c\/li\u003e\n  \u003cli\u003eWhen comparing samples with CTX at or above 0.30 μg\/L versus below 0.30 μg\/L, a significantly higher rate of progressive bone disease was observed (28.6% versus 6.1%; p \u0026lt; 0.001).\u003c\/li\u003e\n  \u003cli\u003eTRAcP showed a similar but less pronounced pattern. Samples at or above 4 U\/L versus below 4 U\/L were associated with a 15.2% versus 6.1% 6-month risk of progressive bone disease, respectively (p = 0.026).\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eAlthough elevated resorption markers were associated with progressive bone disease, this finding applied to only a minority of samples. Specifically, elevated CTX was found in 14 of 468 samples, and elevated TRAcP was found in 46 of 469 samples.\u003c\/p\u003e\n\n\u003cp\u003eBone formation markers (BAP and P1NP) were not predictive of progressive bone disease risk. Combining formation and resorption markers as ratios did not improve predictive value. A significant relation between markedly elevated resorption markers and changes in the level of M-spike or light chains was not found.\u003c\/p\u003e\n\n\u003cp\u003eImportantly, progressive bone disease was seen even at very low levels of bone markers. No threshold low level of bone resorption marker values was identified that could ensure no risk of progressive bone disease.\u003c\/p\u003e\n\n\u003ch2 id=\"longitudinal\"\u003eKey Findings Part 3: How Bone Markers Changed Over Time\u003c\/h2\u003e\n\n\u003cp\u003eAll four bone markers declined after initiation of zoledronic acid therapy. They then gradually increased after discontinuation of treatment. The markers did not return to baseline levels during the study period.\u003c\/p\u003e\n\n\u003cp\u003eBone marker levels were measured at multiple myeloma diagnosis (visit 0). Bone marker levels were also measured after 6 months of treatment with zoledronic acid (visit 6). Bone marker levels were measured after 2 years of zoledronic acid treatment (visit 25). Bone marker levels were measured every 3 months after stopping treatment (visits 28 to 46).\u003c\/p\u003e\n\n\u003cp\u003eNo significant differences in bone marker levels were observed between three groups of patients. The first group subsequently developed progressive disease without progressive bone disease. The second group developed progressive bone disease. The third group remained without disease progression at study end. This finding applied to both individual markers and ratios of bone formation to bone resorption markers.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eClinical Implications: What This Means for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThe 2021 IMWG guidelines and the 2025 EHA\/EMN guidelines differ in their recommendations regarding zoledronic acid treatment. The IMWG recommends monthly treatment for at least 12 months. After that, patients achieving at least VGPR may consider reducing treatment frequency to every 3 months, extending intervals to every 6 to 12 months according to osteoporosis guidelines, or discontinuing treatment. This recommendation is based on a subgroup analysis from the Myeloma IX trial.\u003c\/p\u003e\n\n\u003cp\u003eIn contrast, the EHA\/EMN guidelines, which incorporate data from the Magnolia study, recommend treatment for at least 12 months and up to 48 months. These guidelines acknowledge that the optimal duration for patients achieving VGPR or CR remains uncertain.\u003c\/p\u003e\n\n\u003cp\u003eIn this study, patients achieved at least VGPR after 2 years of monthly zoledronic acid treatment. For these patients, the risk of progressive bone disease remained significantly higher in those randomized to observation compared with those continuing zoledronic acid. The magnitude of benefit was similar to that observed in the overall Magnolia study population, which included patients across all response categories.\u003c\/p\u003e\n\n\u003cp\u003eHowever, this was a secondary analysis not planned in advance, so the risk of a type 1 error (a false-positive result) must be noted. Overall, these findings indicate that discontinuing zoledronic acid based on achievement of VGPR or better may not be justified. On the contrary, this study suggests continued treatment for up to 48 months.\u003c\/p\u003e\n\n\u003cp\u003eIt remains possible that patients attaining even deeper responses, such as complete response, or patients with VGPR and without bone disease at diagnosis, have less benefit from continued zoledronic acid. Of the 14 patients with progressive bone disease who had achieved VGPR, three patients (21%) had no prior bone disease. This suggests that even patients without prior bone disease are at risk of progressive bone disease even when in VGPR. To clarify the magnitude of benefit of zoledronic acid in patients with complete response or VGPR without bone disease, a larger study is needed.\u003c\/p\u003e\n\n\u003cp\u003eWhile MRONJ was not significantly different between groups, cases were found only in the zoledronic acid treatment group. This suggests there may still be an increased risk that this study did not have the statistical power to identify.\u003c\/p\u003e\n\n\u003cp\u003eIn this study, most patients were treated with proteasome inhibitors, and 63.6% in the zoledronic acid group and 69.8% in the observation group received autologous hematopoietic stem cell transplant. It is possible that with new induction regimens achieving high complete response rates or high minimal residual disease (MRD) negativity rates, zoledronic acid treatments may become less relevant over time. As such, new studies similar to this one might continuously be considered as treatments improve, to avoid overtreatment based on older data.\u003c\/p\u003e\n\n\u003cp\u003eHigher levels of bone resorption markers, CTX and TRAcP, were associated with an increased short-term risk of progressive bone disease. However, no threshold low level of bone resorption marker values was identified to ensure no risk of progressive bone disease. Moreover, markedly elevated values were observed in only a minority of samples.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations: What the Study Could Not Prove\u003c\/h2\u003e\n\n\u003cp\u003eThis study has several important limitations that patients and clinicians should consider.\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eSecondary analysis:\u003c\/strong\u003e The analysis of patients achieving VGPR or better was not planned in advance. This means there is a risk of a type 1 error — a false-positive result — and the findings should be interpreted with caution.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLimited statistical power in subgroups:\u003c\/strong\u003e The subgroup analysis of patients achieving complete response included only 69 patients. The difference in progressive bone disease risk in this subgroup was not statistically significant, likely because the group was too small to detect a difference.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eSmall number of patients without prior bone disease:\u003c\/strong\u003e Only 24 patients had no prior bone disease at diagnosis and achieved VGPR. Three of these patients experienced progressive bone disease. A larger study is needed to clarify the benefit of zoledronic acid in this group.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eBone marker thresholds apply to few patients:\u003c\/strong\u003e Elevated CTX was found in only 14 of 468 samples, and elevated TRAcP in 46 of 469 samples. This means the marker thresholds identified apply to only a minority of patients.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eNo safe low threshold identified:\u003c\/strong\u003e The study could not identify a low level of bone resorption markers that guaranteed no risk of progressive bone disease. Progressive bone disease was seen even at very low marker levels.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMRONJ power:\u003c\/strong\u003e While MRONJ was not significantly different between groups, cases occurred only in the zoledronic acid group. The study may not have had enough patients to detect a real difference in MRONJ risk.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eTreatment era:\u003c\/strong\u003e Most patients were treated with proteasome inhibitors and many received autologous transplant. Results may differ with newer treatment regimens that achieve higher response rates.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations and Practical Advice\u003c\/h2\u003e\n\n\u003cp\u003eBased on this study, the following points are relevant for patients with multiple myeloma and their care teams:\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eDo not assume that achieving VGPR means zoledronic acid can be stopped.\u003c\/strong\u003e This study found that patients who continued zoledronic acid beyond 2 years had a 60% lower risk of progressive bone disease compared with those who stopped. This was true even when the patients had achieved VGPR or better.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eDiscuss the optimal duration of zoledronic acid treatment with your doctor.\u003c\/strong\u003e Guidelines differ. The IMWG suggests that patients achieving VGPR may reduce or stop treatment after 12 months, while the EHA\/EMN guidelines recommend treatment for at least 12 and up to 48 months.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eBe aware of the side effects of zoledronic acid.\u003c\/strong\u003e These include medication-related osteonecrosis of the jaw (MRONJ), which occurs in 2.6% to 4% of patients treated with bisphosphonates, as well as kidney problems and low blood calcium. Good dental health before and during treatment is important.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAsk about bone turnover marker testing.\u003c\/strong\u003e If you have stopped zoledronic acid, elevated levels of CTX (at or above 0.30 μg\/L) may indicate a higher short-term risk of progressive bone disease. Elevated levels of TRAcP (at or above 4 U\/L) may also indicate a higher short-term risk of progressive bone disease. These markers may help your doctor decide whether to restart treatment.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eUnderstand that bone markers are not a perfect guide.\u003c\/strong\u003e This study could not identify a low marker level that guaranteed no risk of progressive bone disease. Progressive bone disease occurred even at very low marker levels.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eContinue regular monitoring.\u003c\/strong\u003e All patients in this study were monitored for progressive bone disease at monthly clinic visits, with bone imaging every 6 months or when clinically indicated. Regular monitoring remains essential.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThe authors conclude that continuation of zoledronic acid beyond 2 years seems to reduce the risk of skeletal progression in patients achieving VGPR or better. Elevated CTX or TRAcP levels may help identify patients who could benefit from re-initiating zoledronic acid.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eI have multiple myeloma and achieved a very good partial response. Can I stop zoledronic acid after two years?\u003c\/h3\u003e\n\u003cp\u003eIn a follow-up analysis of the Magnolia trial, patients with multiple myeloma who had achieved at least a very good partial response and continued zoledronic acid beyond two years had a 60% lower risk of progressive bone disease than those who stopped. The authors conclude that stopping zoledronic acid simply because a very good partial response has been achieved may not be justified.\u003c\/p\u003e\n\u003ch3\u003eWhat does a 60% lower risk of progressive bone disease actually mean for me?\u003c\/h3\u003e\n\u003cp\u003eIt means that in the Magnolia trial, patients who continued zoledronic acid beyond two years were about 60% less likely to develop progressive bone disease compared with those who stopped. The number needed to treat was 7.5, meaning about one case of progressive bone disease was prevented for every 7.5 patients treated with continued zoledronic acid.\u003c\/p\u003e\n\u003ch3\u003eWhat are the risks of continuing zoledronic acid beyond two years?\u003c\/h3\u003e\n\u003cp\u003eZoledronic acid can cause medication-related osteonecrosis of the jaw (MRONJ), which occurs in 2.6% to 4% of myeloma patients treated with bisphosphonates. Risk factors include longer treatment duration, poor dental health before starting therapy, and dental extractions after treatment begins. It may also impair kidney function and cause low blood calcium. In the Magnolia follow-up, MRONJ cases occurred only in the zoledronic acid group, but the difference was not statistically significant.\u003c\/p\u003e\n\u003ch3\u003eWhat are CTX and TRAcP, and what do my levels mean?\u003c\/h3\u003e\n\u003cp\u003eCTX and TRAcP are bone turnover markers released into the bloodstream during bone breakdown. In patients who stopped zoledronic acid, CTX at or above 0.30 μg\/L was linked to a 28.6% risk of progressive bone disease within six months, compared with 6.1% below that level. TRAcP at or above 4 U\/L was linked to a 15.2% versus 6.1% risk. These markers may help identify who could benefit from restarting treatment.\u003c\/p\u003e\n\u003ch3\u003eHow long do guidelines recommend taking zoledronic acid?\u003c\/h3\u003e\n\u003cp\u003eGuidelines differ. The International Myeloma Working Group suggests that patients achieving at least a very good partial response may reduce or stop treatment after 12 months. The European Hematology Association and European Myeloma Network recommend treatment for at least 12 months and up to 48 months. The Magnolia follow-up suggests continued treatment for up to 48 months may reduce the risk of progressive bone disease.\u003c\/p\u003e\n\u003ch3\u003eWhat monitoring will I need if I stop or continue zoledronic acid?\u003c\/h3\u003e\n\u003cp\u003eIn the Magnolia trial, all patients were monitored for progressive bone disease at monthly clinic visits, with bone imaging every six months or when clinically indicated. MRONJ was assessed by oral examination every three months. Regular monitoring remains essential whether you continue or stop zoledronic acid, so that any bone changes or side effects are detected early.\u003c\/p\u003e\n\u003ch3\u003eI have multiple myeloma and achieved a very good partial response after two years of zoledronic acid — should I get a second opinion before stopping treatment?\u003c\/h3\u003e\n\u003cp\u003eGuidelines disagree on this exact decision. The IMWG suggests patients achieving VGPR may reduce or stop zoledronic acid after 12 months, while the EHA\/EMN guidelines recommend at least 12 and up to 48 months. Continuing beyond 2 years was associated with a 60% lower risk of progressive bone disease, and stopping based on VGPR alone may not be justified. A second opinion can help weigh this against MRONJ, kidney and calcium risks, and whether bone turnover markers such as CTX or TRAcP should guide restarting. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Bone progression in multiple myeloma: Benefit of zoledronic acid for patients achieving at least Very Good Partial Response and prognostic value of bone turnover markers.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Gundesen MT, Vangsted AJ, Helleberg C, Haukås E, Silkjær T, Madsen JS, Asmussen JT, Teodorescu EM, Jensen BA, Slørdahl TS, Nielsen AA, Olsen DA, Søe K, Nahi H, Waage A, Abildgaard N, Schjesvold F, Lund T.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e British Journal of Haematology, 2026; volume 209, pages 1076–1084. DOI: 10.1111\/bjh.70612.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eCorrespondence:\u003c\/strong\u003e Michael Tveden Gundesen, Department of Hematology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c\/strong\u003e Kræftens Bekæmpelse (Danish Cancer Society); Nordic Cancer Union; Nordic Myeloma Study Group.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c\/strong\u003e Magnolia trial, EudraCT number 2014-002494-12.\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace discussion with your healthcare team. Always consult your doctor about your individual treatment plan.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47797554577564,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/0599\/5449\/5644\/files\/ddn-medical-article-zoledronic-acid-and-bone-health-in-multiple-myeloma-who-benefits-from-continuing-treatment-beyond-two-years-hero.png?v=1791955259","url":"https:\/\/diagnosticdetectives.com\/fi\/products\/zoledronic-acid-and-bone-health-in-multiple-myeloma-who-benefits-from-continuing-treatment-beyond-two-years","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}