Suppression Of Bone Turnover Markers Research Articles

239 Predictors of raised bone turnover markers after transitioning to Zoledronic acid from denosumab

Abstract Background Denosumab is a commonly used to treat osteoporosis though if stopped there is a rebound increase in bone turnover and vertebral fracture risk. Treatment with Zoledronic Acid (ZA) after denosumab discontinuation is recommended to reduce this risk, though in some patients a second ZA infusion may be required six months later to maintain adequate suppression of Bone Turnover Markers (BTM). We aimed to assess the proportion of patients with a sub-therapeutically suppressed BTM after a single dose of ZA post denosumab cessation and explore for predictors of this. Methods We identified patients at our bone health clinic who received ZA 6 to 9 months after the last and final denosumab injection. BTM measured was cross linked C-Telopeptide type I collagen (CTX). Sub-therapeutic BTM response was defined as a CTX >0.300 ng/ml. Logistic regression was used to explore for prectiors of CTX >0.300 including age, body mass index (BMI), denosumab duration and lumbar spine bone mineral density (BMD). Results There were 88 patients, 93% female with a mean age of 67 years. Median duration of denosumab therapy was 5.0 years and 44% had osteoporosis prior to transitioning to ZA. Mean CTX after ZA (median 127 days post ZA) was 0.252. However, 45% had a CTX >0.300 and in these patients the median value was 0.412. Older age (p = 0.045), longer denosumab duration (p = 0.010) and lower BMD at the spine (p = 0.008) were associated with a CTX >0.30. Conclusion A large proportion (45%) had subtherapeutic BTM suppression 3 to 6 months after receiving ZA post stopping denosumab and this was predicted by older age, lower spine BMD and longer denosumab duration. Guidelines suggest a second ZA infusion at 6 months in such patients. If transitioning to ZA, findings highlight the importance of optimising BMD first, especially in older adults with longer denosumab therapy.

RF30 | PSAT172 Effects of 12 Months of Alendronate Therapy Subsequent to 12 Months of Denosumab Administration in Women With Anorexia Nervosa

Abstract Low bone mineral density (BMD) and increased fracture risk are common complications of anorexia nervosa. We assessed whether 12 months of alendronate subsequent to 12 months of denosumab would 1) maintain the increases in BMD observed with denosumab and 2) result in higher BMD than alendronate for 12 months alone in 30 ambulatory women with anorexia nervosa and areal BMD (aBMD) Z- or T-score <-1.0. Participants were randomized in a 2: 1 ratio to 12 months of denosumab (60mg subcutaneously q6 months) followed by 12 months of open-label alendronate (70mg orally qweek)("denosumab-to-alendronate" n=20) or 12 months of subcutaneous placebo followed by 12 months of open-label alendronate (70mg orally qweek)("placebo-to-alendronate" n=10). The prespecified primary outcome was PA lumbar spine aBMD by DXA. Secondary outcome measures included tibial and radial volumetric BMD (vBMD) and microarchitecture by high-resolution peripheral quantitative CT (HR-pQCT), and markers of bone turnover. Twelve-month results were reported in abstract form; 24-month results have not been published. At baseline, mean age [29±8 y (mean±SD)], BMI (18.6±1.9 kg/m2), and aBMD (PA lumbar spine Z-score -1.6±1.1) were similar between groups. From 12 to 24 months in the denosumab-to-alendronate group, favorable changes in spine aBMD, radial vBMD, and radial and tibial microarchitecture from 12 months of denosumab were maintained after 12 months of alendronate. However, there was a rebound increase in markers of bone turnover (p<0.003), and PA and lateral lumbar spine aBMD decreased in 6 and 9 participants, respectively. Both a greater suppression of bone turnover markers and a greater increase in aBMD from baseline to 12 months were predictors of partial reversal of BMD gains from 12 to 24 months in the denosumab-to-alendronate group. Over 24 months, PA lumbar spine aBMD (3.9±4.3%), femoral neck aBMD (3.1±5.5%), tibial vBMD and failure load increased within the denosumab-to-alendronate group, and PA lumbar spine aBMD (5.8±5.3%) increased within the placebo-to-alendronate group (p<0.05). In a 24-month between-group comparison, there was no difference in change in aBMD at any site; however, the denosumab-to-alendronate group demonstrated favorable changes in tibial vBMD and trabecular microarchitecture compared to the placebo-to-alendronate group (p<0.05). In conclusion, this pilot study suggests that 12 months of alendronate maintains BMD gains achieved with 12 months of denosumab administration in some, but not all, women with anorexia nervosa. A more robust response to denosumab may be a risk factor for partial reversal of denosumab-related BMD gains despite alendronate. Therefore, a more effective antiresorptive agent may be necessary to maintain gains in BMD achieved with denosumab therapy in some women with anorexia nervosa. Moreover, sequential therapy of denosumab followed by alendronate over 24 months results in greater improvements in tibial vBMD and microarchitecture than 12 months of alendronate, although increases in aBMD were similar between groups. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 12:30 p.m. - 12:35 p.m.

Progression of Rebound-Associated Vertebral Fractures Following Denosumab Discontinuation Despite Reinstitution of Treatment: Suppressing Increased Bone Turnover May Not Be Enough

Rebound-associated vertebral fractures (RAVFs) could occur in a minority of the patients who discontinue denosumab. In such patients, denosumab is often reinstituted to rapidly suppress bone turnover and avert the risk of additional fractures. Herein we report the cases of 2 patients who sustained RAVFs, and in whom resuming denosumab treatment did not avert the occurrence of new RAVFs a few months later, despite the suppression of bone turnover markers. It seems that denosumab reinstitution cannot completely eliminate the risk of new RAVFs and that the rebound of bone turnover may not be the sole mechanism to explain this phenomenon.

Preserved postprandial suppression of bone turnover markers, despite increased fasting levels, in postmenopausal women.

Menopause leads to an increased bone turnover associated with a high risk of fractures. Bone turnover is inhibited by meal intake, to some extent mediated by gut hormones, and interventions based on these endocrine changes may have potential in future prevention of osteoporosis. To investigate whether postmenopausal women exhibit postprandial suppression of bone turnover markers to the same extent as premenopausal women, despite higher fasting levels. Furthermore, to assess whether menopausal differences in bone turnover markers are related to postmenopausal changes in plasma gut hormone levels. A cross-sectional study of 21 premenopausal, 9 perimenopausal, and 24 postmenopausal women between 45 and 60years of age. Serum/plasma levels of bone turnover markers and gut hormones were investigated during a 120min oral glucose tolerance test. Bone turnover markers included N-terminal propeptide of type-I procollagen (PINP, bone formation marker) and carboxyterminal collagen I crosslinks (CTX-I, bone resorption marker). Gut hormone secretion was evaluated from responses of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP). Fasting levels of s-CTX-I were increased in peri- and postmenopausal women compared to premenopausal women (p=0.001). Despite higher fasting levels, the relative postprandial s-CTX-I suppression was comparable across menopausal status (p=0.14). Fasting levels of s-PINP were also increased in postmenopausal women compared to premenopausal women (p<0.001) with comparable and modest s-PINP suppression over menopause (p=0.13). Postprandial plasma GLP-1 (p=0.006) and GLP-2 (p=0.01) were significantly increased in postmenopausal women compared to premenopausal women while GIP responses were slightly increased in the perimenopausal group (p=0.02) but comparable between pre- and postmenopausal women. None of the postprandial gut hormone increases predicted postprandial bone turnover suppression in these women. Glucose-induced suppression of bone turnover markers is preserved in postmenopausal women, despite significantly higher fasting values, indicating that CTX-I lowering treatments based on these postprandial mechanisms might be a feasible strategy to prevent postmenopausal osteoporosis.

Consumption of nutrients and insulin resistance suppress markers of bone turnover in subjects with abdominal obesity.

Abdominal obesity and type 2 diabetes are associated with insulin resistance and low bone turnover along with an increased fracture risk. The mode of action is poorly understood. The bone resorption marker, C-terminal telopeptide type 1 collagen (CTX), and to a lesser extent, the bone formation marker, Procollagen type 1 N-terminal propeptide (P1NP) appear to be inhibited by food consumption. The link between food consumption, insulin resistance and bone turnover remains to be clarified. Primarily we aimed to compare the postprandial CTX, P1NP and PTH responses by two frequently applied methods in assessing metabolic health; oral glucose tolerance test (OGTT) and mixed meal tolerance test. Secondly, we explored the effect of insulin resistance on bone marker responses. We enrolled 64 subjects with abdominal obesity. Following 10h of fasting, subjects initially underwent a standard OGTT (300kcal) and approximately one week later a mixed meal tolerance test (1130kcal). Circulating CTX, P1NP and PTH were assessed on both days at time=0, after 30min and after 90min for comparison of the two interventions. We analyzed glucose and insulin levels for the assessment of insulin resistance. Additionally, we measured plasma calcium levels along with the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide 2 (GLP-2) in an attempt to identify possible mediators of the postprandial bone response. CTX, P1NP and PTH were suppressed by OGTT and the mixed meal; the latter induced a more pronounced suppression after 90min. Calcium levels were similar between OGTT and meal. GIP and GLP-2 levels increased after both interventions, although only the meal induced a sustained increase after 90min. Fasting P1NP was inversely associated with insulin resistance. The meal-induced suppression of P1NP (but not CTX or PTH) was inversely associated with level of insulin resistance. The acute postprandial suppression of bone turnover markers is extended after ingestion of a mixed meal compared to an OGTT. The response appears to be independent of gender and prompted by a reduction in PTH. The study additionally indicates a possible link between the development of insulin resistance and low bone turnover - which may be of key essence in the development of the fragile bone structure and increased fracture risk demonstrated in subjects with abdominal obesity and T2D.

Effect of Intravenous Glucose Tolerance Test on Bone Turnover Markers in Adults with Normal Glucose Tolerance.

BackgroundIt is well known that enteral nutrients result in acute suppression of bone turnover markers (BTMs), and incretin hormones are believed to play a significant role in this physiological skeletal response. However, there is limited research exploring the impact of parenteral nutrients on BTMs. Our aim was to assess the influence of intravenous glucose on BTMs in adults with normal glucose tolerance (NGT).Material/MethodsWe conducted 1-h intravenous glucose tolerance test (IVGTT) in 24 subjects with NGT. Blood samples were collected before and 5, 10, 15, 20, 30, 60 min after administration of glucose, then serum levels of bone formation marker procollagen type I N-terminal propeptide (P1NP) and resorption marker C-terminal cross-linking telopeptides of collagen type I (CTX) were measured.ResultsDuring IVGTT, the fasting CTX level fell gradually and reached a nadir of 80.4% of the basal value at 60 min. Conversely, the fasting P1NP level decreased mildly and reached a nadir of 90.6% of the basal value at 15 min, then gradually increased and reached 96.6% at 60 min. The CTX-to-P1NP ratio increased slightly and reached a peak of 104.3% of the basal value at 10 min, then fell gradually and reached a nadir of 83% at 60 min.ConclusionsOur study indicates that intravenous glucose results in an acute suppression of BTMs in the absence of incretin hormones. The mechanism responsible for this needs further investigation.

Switching of oral bisphosphonates to denosumab in chronic glucocorticoid users: A 12-month randomized controlled trial

ObjectivesTo evaluate the effect of switching from oral bisphosphonates to denosumab on bone mineral density (BMD) in long-term glucocorticoid users. MethodsAdult patients who were receiving long-term prednisolone (≥2.5mg/day for ≥1year) and oral bisphosphonates (≥2years) were recruited. Participants were randomized to either continue oral bisphosphonates or switch to denosumab (60mg subcutaneously every 6months) for 12months. Serial BMD (lumbar spine, hip) and bone turnover markers (serum osteocalcin, P1NP, β-CTX) were measured. Results42 women were recruited (age 54.7±12.9years; 21 shifted to denosumab and 21 continued on bisphosphonates). The duration of prednisolone therapy was 101±66.3months and the daily dose was 4.4±2.1mg. Baseline demographic data, osteoporosis risk factors, and BMD at various sites were similar between the two groups of patients. At month 12, BMD of the spine and hip increased by +3.4±0.9% (p=0.002) and +1.4±0.6% (p=0.03), respectively, in the denosumab group; whereas the corresponding change was +1.5±0.4% (p=0.001) and +0.80±0.5% (p=0.12) in the bisphosphonate group. The spinal BMD at month 12 was significantly higher in the denosumab than bisphosphonate group after adjustment for baseline BMD and β-CTX values, and other confounding factors (p=0.01). Bone turnover markers (β-CTX and P1NP) were more strongly suppressed by denosumab than the bisphosphonates. Minor infections were more common in denosumab-treated patients while other adverse events occurred at similar frequencies between the two groups. ConclusionsIn patients receiving long-term glucocorticoids, switching from oral bisphosphonates to denosumab resulted in greater gain of the spinal BMD and suppression of bone turnover markers after 12months of therapy. The results have to be confirmed by a larger clinical trial with fracture as endpoint.

Zoledronate for prevention of bone erosion in tophaceous gout: a randomised, double-blind, placebo-controlled trial

ObjectivesThe osteoclast has been implicated in development of bone erosion in gout. The aim of this study was to determine whether zoledronate, a potent antiosteoclast drug, influences bone erosion in...

Failure to Suppress Markers of Bone Turnover on First-Line Hormone Therapy for Metastatic Prostate Cancer Is Associated With Shorter Time to Skeletal-Related Event

BackgroundElevated markers of bone turnover are prognostic for shorter survival in castration-resistant prostate cancer. We aimed to determine the prognostic value of bone turnover markers in metastatic hormone-sensitive prostate cancer. Patients and MethodsMarkers of bone turnover (urine deoxypyridinoline [DPD] and N-telopeptide, serum bone alkaline phosphatase (AP), and osteocalcin [OC]) from baseline and after 6 months of study were assessed in men enrolled in a prospective metastatic prostate cancer trial with androgen deprivation therapy (ADT) with or without risedronate (ClinicalTrials.gov, NCT00216060). ResultsSerum samples were collected from 63 patients with bone involvement and a median follow-up of 39.7 months. A multivariate model using Cox regression—which included prostate-specific antigen (PSA) nadir, bisphosphonate treatment, and extent of metastases—showed that suppression of bone turnover markers after 6 months of therapy compared with baseline was significantly associated with longer skeletal-related event (SRE)-free survival. ADT without bisphosphonate therapy was also associated with a decline in markers of bone turnover, presumably resulting from direct anticancer activity. Elevated baseline bone turnover markers were not prognostic. ConclusionFailure to suppress bone turnover while receiving ADT, even when otherwise responding to therapy, may identify patients with hormone-sensitive metastatic prostate cancer who are destined for a shorter time to SREs and progression.

Denosumab and changes in bone turnover markers during androgen deprivation therapy for prostate cancer

Androgen deprivation therapy (ADT) for prostate cancer increases fracture risk, decreases bone mineral density, and increases bone turnover markers (BTMs) including serum type 1 C-telopeptide (sCTX), tartrate-resistant alkaline phosphatase 5b (TRAP-5b), and procollagen-1 N-terminal telopeptide (P1NP). In a prespecified exploratory analysis of a phase 3, multicenter, double-blind study, we evaluated the effects of denosumab (60 mg subcutaneously every 6 months for 3 years) versus placebo (1468 patients, 734 in each group) on BTM values. BTMs were measured at baseline, month 1, and predose at months 6, 12, 24, and 36 in the overall population. BTMs at month 1 are also reported for subgroups based on age (< 70 years versus ≥ 70 years), prior duration of ADT (≤ 6 months versus > 6 months), and baseline BTM (≤ median versus > median BTM values). Treatment with denosumab provided a rapid and sustained decrease of BTM values compared with placebo. The median change in sCTX levels at month 1 was -90% in the denosumab group and -3% in the placebo group (p < 0.0001). The median change in TRAP-5b levels at month 1 was -55% in the denosumab group and -3% in the placebo group (p < 0.0001). The maximal median change in P1NP was -64% in the denosumab group and -11% in the placebo group, (p < 0.0001). Significantly greater decreases in BTM for denosumab were also seen in subgroup analyses based on age, prior ADT treatment, and baseline BTM values. Suppression of bone turnover markers was consistent with marked increases in bone mineral density reported previously.

A randomized, double-blind, placebo-controlled, single-dose study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of denosumab administered subcutaneously to postmenopausal Japanese women

Denosumab is a fully human monoclonal antibody that has high affinity for RANK ligand (RANKL). RANKL is the essential mediator of osteoclast formation, function and survival. The safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of denosumab in healthy postmenopausal Japanese women were assessed. This was a randomized, double-blind, dose-escalation study in which 40 subjects received denosumab at doses of 0.03, 0.1, 0.3, 1.0 or 3.0mg/kg, or placebo administered subcutaneously. Blood and urine samples for determination of serum denosumab, CTX-I, NTX-I/Cr, bone specific alkaline phosphatase (bone ALP) and intact parathyroid hormone (iPTH) were collected. The PK and PD time profiles were compared to those obtained in separate studies conducted in the US. No serious adverse events occurred and all subjects completed this study. Denosumab demonstrated nonlinear PK and dose- and concentration-dependent dispositions. The maximum mean decrease from baseline ranged from 65% to 95% for CTX-I concentrations and from 50% to 85% for NTX-I/Cr. Additionally, the changes were dose-dependent. The suppression of bone turnover markers was rapid (within 2 days after dosing) and duration of suppression was dose-dependent. No marked differences in the PK and PD profiles between Japanese and non-Japanese subjects were noted. The observed results indicate that denosumab may have therapeutic potential for conditions resulting from increased bone turnover, such as osteoporosis in Japanese.

Biochemical markers of bone turnover. New aspect. Biochemical markers of bone turnover in long term treatment with bisphosphonate

Bisphosphonates (BPs) are now widely used for the prevention of osteoporotic fracture. The elevation of bone turnover markers (BTM) is an independent risk factor for the bone fracture, and their significant decrease with BPs treatment is considered to reflect BPs' efficacy to "adjust" bone turnover. A large-scale study so far showed that BPs continuously suppress both BTM levels and the incidence of fracture as long as 7 to 10 years, though possible deterioration of bone strength with long-term severe suppression of BTM has been pointed out.

Recent developments in the management of postmenopausal osteoporosis with bisphosphonates: enhanced efficacy by enhanced compliance

Bisphosphonates are the current mainstay of treatment for postmenopausal osteoporosis. Although daily oral dosing is effective, it is associated with poor compliance, partly because of the pre and postdose fasting and posture requirements. This negatively impacts treatment outcomes, leading to a reduced clinical benefit. Improved, yet still suboptimal adherence has been noticed with less frequent bisphosphonate dosing e.g. once-weekly and once-monthly oral regimens. The recently approved quarterly intravenous (i.v.) injection regimen of ibandronate and yearly i.v. infusion of zoledronic acid are attractive options in the management of postmenopausal osteoporosis. These regimens may assure quarterly and year long compliance.

Monitoring Osteoporosis Therapy: Bone Mineral Density, Bone Turnover Markers, or Both?

Monitoring the efficacy associated with antiresorptive therapy is an intuitive yet integral part of successful osteoporosis management. Although response rates to bisphosphonates in clinical trials—as judged by changes in bone mineral density (BMD)—are generally high, a small percentage of compliant patients do not respond. Accordingly, monitoring may help identify noncompliant patients and allow for other, possibly more successful, therapeutic interventions. Dual energy x-ray absorptiometry is the accepted method of assessing BMD to determine the need for treatment and to monitor its effects. Change in BMD is considered a valid intermediate end point for efficacy of fracture risk reduction. However, clinical trials have shown that the reduction in fracture risk associated with antiresorptive therapy may occur before changes in BMD become apparent. Vertebral fracture benefit is observed even among women who maintain rather than gain BMD during antiresorptive therapy. Clinical trials show that suppression of bone turnover markers after as little as 3 months of therapy is strongly associated with reductions in risk for fracture. Although formal guidelines for monitoring bone turnover markers do not yet exist, there are data to suggest that changes in these markers are valid intermediate endpoints for efficacy of fracture risk reduction that may provide valuable additional data on therapeutic success, particularly early in treatment and before changes in BMD become apparent.

Improving Compliance and Persistence with Bisphosphonate Therapy for Osteoporosis

The successful treatment of patients at increased risk for fracture requires proper diagnosis and the development of a treatment plan that permits the patient to take medications in accordance with dosing guidelines and on the correct schedule. Data indicate that patients with osteoporosis who have good long-term medication compliance experience substantially lower risk of fracture. Persistence with therapy also correlates with better bone mineral density and improved suppression of bone turnover markers. Although bisphosphonates are the most potent currently approved antiresorptive agents, they have special dosing issues that can have a negative impact on long-term persistence. The inconvenience and complexity of some dosing requirements; the potential for adverse effects, especially when dosing recommendations are not followed; and very low absorption rates—even under ideal conditions—all contribute to poor outcomes. Extension of the dosing interval from a once-daily to a once-weekly regimen is associated with comparable efficacy, theoretically may improve gastrointestinal safety, and is associated with substantial improvement in persistence with therapy. However, compliance with weekly regimens remains suboptimal. Monthly dosing of ibandronate, a bisphosphonate, was recently approved by the US Food and Drug Administration (FDA). Although extending the dosing interval may improve compliance and persistence with bisphosphonate therapy, it is important to recognize that missed doses or improper dosing may have greater consequences with extended dosing intervals. This article highlights the importance of educating patients about their diagnosis and long-term treatment plan, including the importance of persistence with therapy and compliance with dosing recommendations.

Oral and Intravenous Ibandronate in the Management of Postmenopausal Osteoporosis: A Comprehensive Review

Convenient strategies are needed for postmenopausal osteoporosis management. Current oral bisphosphonates are effective and generally well tolerated, but are hampered by strict dosing requirements. Less frequent dosing schedules are expected to improve adherence to therapy and hence outcomes. Ibandronate is a potent, nitrogen-containing bisphosphonate in ongoing clinical development exploring its potential to be administered less frequently than at weekly intervals. Uniquely, ibandronate can be administered either orally or as an intravenous (i.v.) injection, with a between-dose interval of >2 months. In postmenopausal women, oral ibandronate, when administered either daily or intermittently, has demonstrated robust antifracture efficacy at the spine (62% [p=0.0001] and 50% [p=0.0006] risk reduction versus placebo), accompanied by significant increases in bone mineral density (BMD) at the spine and hip, and suppression of bone turnover markers. Studies of intermittent i.v. ibandronate injections in postmenopausal women have shown dose-related BMD gains and bone turnover marker suppression comparable to those obtained after a similar duration of treatment with the proven effective oral ibandronate regimen. Furthermore, in a trial conducted in patients with corticosteroid-induced osteoporosis, intermittent i.v. ibandronate injections reduced vertebral fracture risk by 62% versus an active control (p=0.043). In all these trials, the oral and i.v. ibandronate regimens were well tolerated. Ongoing, large multinational clinical trials are investigating two intermittent ibandronate regimens: once-monthly oral and intermittent i.v. injections. These simple ibandronate regimens are expected to provide the optimal combination of efficacy, tolerability and patient convenience, leading to improved treatment adherence and thus, enhanced outcomes in postmenopausal osteoporosis.

Potential Role of Pancreatic and Enteric Hormones in Regulating Bone Turnover

Potential Role of Pancreatic and Enteric Hormones in Regulating Bone Turnover

Suppression of bone turnover markers by zoledronic acid and correlation with clinical outcome

532 The bone resorption marker N-telopeptide (Ntx) provides valuable prognostic information in patients with bone metastases. Across all tumor types an elevated baseline Ntx increases the relative risk of skeletal-related events (SREs), disease progression and death (Brown, et al., ASCO 2003). In this study, urinary N-telopeptide was measured at baseline and at month 3 in 290 patients with breast cancer and multiple myeloma treated with monthly 4 mg of zoledronic acid. At baseline, 120 patients had a urinary Ntx value of 0–64 nmol/mmol creatinine (upper limit of normal for premenopausal women) and 170 had an elevated baseline Ntx (greater than 64 nmol/mmol creatinine). At month 3 of zoledronic acid treatment, only 2/120 (1.7%) patients who started with normal Ntx developed an elevated value. At month 3, 137/170 (80.6%) of patients who began treatment with elevated Ntx had a normal Ntx, 26/170 (15.3%) had persistent elevation of Ntx, and 7/170 (4.1%) patients died. A persistently elevated Ntx (greater than 64 nmol/mmol creatinine) was a significant predictor of subsequently developing a first SRE (RR = 1.71; p = 0.035) and SRE-free survival (RR = 1.65; p = 0.039). It did not predict time to progression of cancer in the skeleton (RR = 1.26; p = 0.417) or survival (RR = 1.33, p = 0.316). In summary, in breast cancer and multiple myeloma patients, normalization of an elevated baseline urinary Ntx at month 3 of treatment with zoledronic acid is a significant predictor of favorable outcome as measured by SREs and time to first SRE. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis Novartis Novartis Novartis

Skeletal and nonskeletal effects of raloxifene

Raloxifene, a selective estrogen receptor modulator, is approved for the prevention and treatment of postmenopausal osteoporosis. Prevention studies with raloxifene have demonstrated preservation of bone density and suppression of bone turnover markers in young postmenopausal women. The Multiple Outcomes of Raloxifene Evaluation study was the pivotal treatment trial for raloxifene. It demonstrated significant reduction in the risk for vertebral fractures after 1 and 3 years. Significant reduction of nonvertebral fractures with raloxifene has not yet been demonstrated. In addition to the effects of raloxifene on bone, potentially beneficial effects on the cardiovascular system, breast, and uterus have been described. Most of these nonskeletal effects have been reported as secondary endpoints from large osteoporosis trials with raloxifene. Prospective, randomized, double-blind studies of raloxifene with breast cancer prevention and cardiovascular protection as primary endpoints are now underway.